Frank Rauch

Abstract: The impact of intravenous bisphosphonate treatment to treat painful vertebral fractures in boys with DMD has not been documented. In this retrospective observational study of seven boys, 2 years of intravenous bisphosphonate therapy was associated with back pain improvement and stabilization or increases in the height ratios of fractured vertebrae. INTRODUCTION: Boys with Duchenne muscular dystrophy (DMD) are at risk for vertebral fractures. We studied the impact of intravenous bisphosphonate therapy for the treatment of painful vertebral fractures in DMD. METHODS: This was a retrospective observational study in seven boys with DMD (median 11.6 years, range 8.5 to 14.3) treated with intravenous pamidronate (9 mg/kg/year) or zoledronic acid (0.1 mg/kg/year) for painful vertebral fractures. RESULTS: At baseline, 27 vertebral fractures were evident in the seven boys. After 2 years of bisphosphonate therapy, 17 of the fractures had an increase in the most severely affected vertebral height ratio, 10 vertebrae stabilized, and none showed a decrease in height ratio. Back pain resolved completely (N = 3) or improved (N = 4). The median change in lumbar spine volumetric bone mineral density Z-score was 0.5 standard deviations (interquartile range, -0.3 to 1.7). Two boys had three incident vertebral fractures in previously normal vertebral bodies that developed over the observation period. There was a decline in the trabecular bone formation rate on trans-iliac bone biopsy but no evidence of osteomalacia. First-dose side effects included fever and malaise (N = 4), hypocalcemia (N = 2), and vomiting (N = 1); there were no side effects with subsequent infusions. CONCLUSIONS: Intravenous bisphosphonate therapy was associated with improvements in back pain and stabilization to improvement in vertebral height ratios of previously fractured vertebral bodies. At the same time, such therapy does not appear to completely prevent the development of new vertebral fractures in this context.

Abstract: Background: A decrease in muscle mass, low motor performance, and normal lumbar spine bone mineral density (BMD) have been reported in children with Prader-Willi syndrome (PWS). However, these data are limited by the fact that PWS children (who have short stature) were compared to age-matched healthy or obese individuals of normal height. Objective: The goal of the present study was to compare bone and muscle characteristics in PWS children to sex- and age- or height-matched healthy subjects. Materials and Methods: The study population included 17 PWS children (ages 6.2 to 17.5 yr; nine girls) who were not treated with GH. The axial skeleton was analyzed at the lumbar spine using dual-energy x-ray absorptiometry, and the appendicular skeleton (radius and tibia) was evaluated using peripheral quantitative computed tomography. Muscle parameters (mass, size, and functional parameters) were measured by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and jumping mechanography, respectively. Results: Compared to height-matched controls, PWS patients had normal axial and appendicular BMD, as well as normal muscle size. Compared to age- or height-matched controls of normal weight, PWS patients had lower maximal muscle force and power relative to body mass during jumping. PWS patients had similar absolute maximal muscle force but lower absolute maximal power compared to age- or height-matched controls. Relationships between bone mass and muscle size and force were similar in PWS patients and in healthy subjects. Conclusion: Relative to their height, PWS patients not treated with GH had normal axial and appendicular BMD, muscle size, and muscle-bone relationships.

Abstract: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). INTRODUCTION: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. METHODS: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. RESULTS: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. CONCLUSIONS: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.

Abstract: To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk.

Abstract: The pubertal growth spurt is a time of rapid changes in bone length, mass and structure, followed by the cessation of longitudinal growth. The two best studied anatomical areas in this respect are the metaphyses and the diaphyses of peripheral long bones. A model is presented here in which the speed of longitudinal growth and the resulting age gradient in metaphyseal bone are key factors in explaining the high incidence of distal radius fractures during puberty. As growth in length accelerates, the age of the bone structural elements at a given distance to the growth plate decreases, leaving less time for cortical thickening through trabecular coalescence. This leads to a discrepancy between stagnant metaphyseal bone strength and increasing mechanical requirements in the case of accidents. In comparison to the metaphysis, diaphyseal bone develops more in line with the increasing mechanical requirements, presumably because the bone formation rates needed for diaphyseal growth in width are only a fraction of the apposition rates in the metaphysis. It remains largely unexplored how local and systemic signals are integrated to achieve site-specific changes in bone structure.

Abstract: Osteogenesis imperfecta type VI (OI type VI) is a rare autosomal recessive disorder caused by mutations in the SERPINF1 gene that encodes pigment epithelium-derived factor (PEDF). Cystinosis is an autosomal recessive lysosomal transport disorder caused by mutations in the CTNS gene. Both SERPINF1 and CTNS are located on chromosome 17p13.3. We describe an individual presenting with both OI type VI and cystinosis. The patient was diagnosed with cystinosis at the age of 11 months and OI type VI on bone biopsy at the age of 8 years. He has sustained over 30 fractures during his lifetime, and at the age of 19 years entered end-stage renal disease and subsequent renal transplant. An Affymetrix 6.0 array was used to look for areas of loss of heterozygosity on chromosome 17. Sequencing of the SERPINF1 and CTNS genes was performed, followed by quantitative PCR and Western blot of PEDF to characterize the identified mutation. A 6.58 Mb region of homozygosity was identified on the Affymetrix 6.0 array, encompassing both the SERPINF1 and CTNS genes. Sequencing of the genes identified homozygosity for a known pathogenic CTNS mutation and for a novel in-frame duplication in SERPINF1. Skin fibroblasts produced a markedly reduced amount of SERPINF1 transcript and PEDF protein. This patient has the concurrent phenotype of two rare recessive diseases, cystinosis and OI type VI. We identified for the first time an in-frame duplication in SERPINF1 that is responsible for the OI type VI phenotype in this patient. © 2012 Wiley Periodicals, Inc.

Abstract: Background: Several studies suggest that 24,25-dihydroxyvitamin D [24,25(OH)(2)D] may have an effect on bone mass and metabolism. Objective: We evaluated the relationship between serum 24,25(OH)(2)D levels and bone density and bone metabolism in children with a primary bone disorder-osteogenesis imperfecta (OI). Materials and Methods: The study included 132 patients (age, 1.1 to 17.9 yr; 67 girls) with OI types I, III, or IV who had not received bisphosphonate treatment at the time of analysis. Results: Serum 24,25(OH)(2)D levels were significantly higher in OI type III than in OI type I or IV. Serum 24,25(OH)(2)D concentrations were positively correlated with serum 25-hydroxyvitamin D (25OHD) levels and negatively correlated with serum PTH levels, and were not correlated with serum 1α,25-dihydroxyvitamin D [1,25(OH)(2)D]. The ratio between serum 24,25(OH)(2)D and 25OHD was negatively correlated with age and was independent of serum 25OHD concentrations. Regression analysis revealed that OI severity (P = 0.04), serum 25OHD levels (P < 0.001), and serum PTH concentrations (P = 0.045), but not age, gender, or serum 1,25(OH)(2)D, were independent predictors of serum 24,25(OH)(2)D levels. No correlation was found between serum 24,25(OH)(2)D levels or the ratio between serum 24,25(OH)(2)D and 25OHD and lumbar spine bone mineral density z-scores or bone marker levels (serum osteocalcin and urinary collagen type I N-telopeptide) after adjusting for OI type, age, and gender. Conclusion: Patients with more severe OI type had higher 24,25(OH)(2)D serum levels and higher serum 24,25(OH)(2)D to 25OHD ratios, suggesting an increased 25OHD-24-hydroxylase activity.

Abstract: Background: The prevalence of vitamin D deficiency and its consequences on bone in pediatric bone fragility disorders is not well characterized. In the present study, we evaluated determinants of vitamin D status in children and adolescents with osteogenesis imperfecta (OI) and assessed the relationship between 25-hydroxyvitamin D (25OH D) serum concentrations and lumbar spine areal bone mineral density (LS-aBMD). Materials and Methods: This retrospective cross-sectional study comprised 315 patients with a diagnosis of OI type I, III, or IV (aged 1.1-17.9 yr; 161 girls) who had not received bisphosphonate treatment at the time of 25OH D analysis. In 282 patients (90%), LS-aBMD measurements were available at the same time. Results: Serum concentrations of 25OH D ranged from 14 to 133 nmol/liter and were less than 50 nmol/liter in 86 patients (27%). Regression analysis revealed that age (P < 0.001), season (P < 0.001), and OI severity (P = 0.048), but not gender, were significant independent predictive factors of 25OH D levels. Serum 25OH D concentrations were negatively correlated with serum PTH levels (P = 0.003) and urinary cross-linked N-telopeptides of type I collagen to creatinine ratios (P = 0.005). Serum 25OH D levels were positively associated (P = 0.02) with LS-aBMD z-scores after accounting for OI severity, age, and gender. Conclusion: Serum 25OH D levels are positively associated with LS-aBMD z-scores in children and adolescents with OI types I, III, and IV.

Abstract: Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2. We identified a dominant missense mutation, c.3235G>A in COL1A1 exon 45 predicting p.G1079S, in a Japanese family with mild OI. As mutations in exon 45 exhibit mild to lethal phenotypes, we tested if disruption of an exonic splicing cis-element determines the clinical phenotype, but detected no such mutations. In the Japanese family, juvenile-onset hyperuricemia cosegregated with OI, but not in the previously reported Italian and Canadian families with c.3235G>A. After confirming lack of a founder haplotype in three families, we analyzed PRPSAP1 and PRPSAP2 as candidate genes for hyperuricemia on chr 17 where COL1A1 is located, but found no mutation. We next resequenced the whole exomes of two siblings in the Japanese family and identified variable numbers of previously reported hyperuricemia-associated SNPs in ABCG2 and SLC22A12. The same SNPs, however, were also detected in normouricemic individuals in three families. We then identified two missense SNVs in ZPBP2 and GPATCH8 on chromosome 17 that cosegregated with hyperuricemia in the Japanese family. ZPBP2 p.T69I was at the non-conserved region and was predicted to be benign by in silico analysis, whereas GPATCH8 p.A979P was at a highly conserved region and was predicted to be deleterious, which made p.A979P a conceivable candidate for juvenile-onset hyperuricemia. GPATCH8 is only 5.8 Mbp distant from COL1A1 and encodes a protein harboring an RNA-processing domain and a zinc finger domain, but the molecular functions have not been elucidated to date.

Abstract: Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by heterozygous mutations in the genes encoding transforming growth factor beta receptor 1 or 2 (TGFBR1 or TGFBR2). Although an association between LDS and osteoporosis has been reported, the skeletal phenotype regarding bone mass is not well characterized. Here we report on two LDS patients with mutations in TGFBR2. Patient 1 was a 24 year old man who had a total of three fractures involving the left radius, the left metacarpal and the right femur. At the age of 14 years, lumbar spine areal bone mineral density z-score was -4.0 and iliac bone histomorphometry showed elevated bone turnover (bone formation rate per bone surface: 91 µm(3) /µm(2) /year; age-matched control values, 37 [10], mean [SD]) and mildly low trabecular bone volume per tissue volume (17.2%; age-matched control values: 25.7 [5.3]). Bone mineralization density distribution (BMDD) in trabecular bone was increased (Ca(Peak) : 22.70 wt% Ca; age-matched control values, 21.66 [0.52]). Patient 2, a 17 year old girl, suffered from diffuse bone pain but had not sustained fractures. At 14 years of age, her lumbar spine areal bone mineral density z-score was -3.4. Iliac bone histomorphometry at that age confirmed low bone mass (bone volume to tissue volume 10.1%, same control values as above) and high bone turnover (bone formation rate per bone surface: 70 µm(3) /µm(2) /year). BMDD in trabecular bone was significantly shifted towards increased mineralization (Ca(Peak) : 22.36 wt% Ca). Thus, it appears that LDS can be associated with low bone mass and high bone turnover but increased matrix mineralization of trabecular bone. © 2011 American Society for Bone and Mineral Research.

Abstract: Glucocorticoids (GCs) are associated with fragility fractures in children with various chronic illnesses. The impact of GCs on bone health in children with nephrotic syndrome (NS) is less well understood. Here we report skeletal findings in a 10-year-old boy with steroid-sensitive NS who presented with back pain due to vertebral fractures 5 years after NS diagnosis. Spine radiographs showed a Genant grade 2 fracture at T7 and a grade 1 fracture at T8. Dual-energy X-ray absorptiometry (DXA) revealed a lumbar spine areal bone mineral density (BMD) Z-score of -0.5 and a total body areal BMD Z-score of -0.4. Quantitative transiliac bone histomorphometry revealed low trabecular bone volume and cortical width but no osteomalacia. Our findings show the potential for significant bone morbidity due to osteoporosis in steroid-sensitive NS treated with intermittent GC therapy and emphasize that vertebral fractures may be an underrecognized complication. Furthermore, our report highlights that vertebral fractures can be associated with normal spine areal BMD in this context, suggesting that DXA-based, anteroposterior areal BMD should not be relied upon exclusively for assessing bone health and disease in children with steroid-sensitive NS.

Abstract: Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization. © 2011 American Society for Bone and Mineral Research.

Abstract: Mutations of proteins involved in posttranslational modification of collagen type I can cause osteogenesis imperfecta (OI) inherited in a recessive pattern. The cartilage-associated protein (CRTAP) is part of a heterotrimeric complex (together with prolyl-3-hydroxylase-1 [P3H1] and cyclophilin B) that 3-hydroxylates the alpha 1 chain of collagen type I at proline residue 986 and plays a collagen chaperon role. CRTAP mutations usually cause severe OI. We report on a patient with OI and a homozygous in-frame deletion in CRTAP and a severe form of OI. The girl was born with markedly deformed long bones. Despite intravenous bisphosphonate treatment, she developed multiple vertebral compression fractures and severe scoliosis and at 4 years of age was able to sit only with support. Although CRTAP transcript levels were normal in the patient's fibroblasts, protein levels of both CRTAP and P3H1 were severely reduced. The degree of 3-hydroxylation at proline residue 986 was also decreased. This report characterizes a patient with a CRTAP small in-frame deletion. We are unaware of prior reports of this finding. We suggest that this deletion affects crucial amino acids that are important for the interaction and/or stabilization of CRTAP and P3H1. © 2011 Wiley Periodicals, Inc.

Abstract: The effect of low vitamin D levels in children with bone fragility disorders has not been examined in detail. In this study, we evaluated the relationship between vitamin D status and parameters of skeletal mineralization, mass, and metabolism in a group of pediatric osteogenesis imperfecta (OI) patients. This retrospective study consisted of 71 patients with a diagnosis of OI type I, III, or IV (ages 1.4 to 17.5 years; 36 girls) who had not received bisphosphonate treatment before iliac bone biopsy. Serum 25-hydroxyvitamin D [25(OH)D] levels ranged from 13 to 103 nmol/L and were less than 50 nmol/L in 37 patients (52%). None of the OI patients had radiologic signs of rickets or fulfilled the histomorphometric criteria for the diagnosis of osteomalacia (ie, elevated results for both osteoid thickness and mineralization lag time). Serum 25(OH)D levels were negatively correlated with age and serum parathyroid hormone levels but were not correlated with any parameter of bone mineralization (ie, osteoid thickness, mineralization lag time, or bone-formation rate per bone surface) or bone mass (ie, lumbar spine areal bone mineral density, iliac bone volume per tissue volume, or iliac cortical width). We found no evidence that serum 25(OH)D levels in the range from 13 to 103 nmol/L were associated with measures of bone mineralization, metabolism, or mass in children with OI. © 2011 American Society for Bone and Mineral Research.

Abstract: Objective Pseudohypoparathyroidism (PHP) is a heterogeneous disorder characterized by hypocalcemia and hyperphosphatemia resulting from selective renal resistance to parathyroid hormone (PTH). One autosomal dominant form of PHP type 1b (PHP-Ib) is most frequently caused by a maternally inherited 3-kb deletion within STX16, the gene encoding syntaxin 16. To date, increased bone mineral density (BMD) has been described only in PHP type 1a, and there is a lack of detailed information on bone histomorphometry in PHP-Ib. The objective of this report was to present trans-iliac static and dynamic histomorphometry in two brothers with the 3-kb deletion in the STX16 region and elevated BMD. Design Observational study of two brothers (age 18.0 and 22.7 years) with the 3-kb STX16 deletion and increased BMD. Results The brothers had elevated PTH (146 pg/ml (15.6 pmol/l) and 102 pg/ml (10.9 pmol/l); normal: 10-64 pg/ml (1.1-6.8 pmol/l)) and striking osteosclerosis (lumbar spine areal BMD Z-scores: +5.4 and +4.9). Bone histomorphometry showed marked elevations in cortical width for both brothers (241 and 209% of the mean result expected for age), with elevations in the bone formation rate on the endocortical (119 and 260% of the healthy mean) and trabecular (220 and 190% of mean) surfaces. Conclusion Our findings suggest that PTH in this PHP-Ib genotype can increase cortical thickness due to its anabolic effect on endocortical bone, and underscore the heterogeneity in the skeletal phenotype among patients with PHP-Ib.

Abstract: Purpose To examine the functional outcomes of children with osteogenesis imperfecta (OI) following initial Fassier–Duval (FD) rodding to the femur at 1 year, and to determine which factors are associated with change in gross motor function, ambulation, and functional performance. Methods Approval from our Institutional Review Board was obtained. A retrospective chart review identified 60 children (28 males, 32 females) with OI who underwent initial FD femoral rodding (101 rods) and who were receiving bisphosphonates. The mean age of the children was 3 years, 11 months at the initial femoral FD rodding. Two had type I OI, 30 type III, 27 type IV, and one type VI. The maximum length of follow-up was 4 years. Telescoping FD rods were used for the femurs, with surgeries performed one leg at a time, with a 1-week interval. The active range of motion (AROM) of the hips and knees in flexion was measured 4–5 weeks post-initial rodding. Outcomes on the Gillette Functional Assessment Questionnaire (FAQ) Ambulation Scale, the Gross Motor Function Measure (GMFM), and the Pediatric Evaluation of Disability Inventory (PEDI) were compared pre-operatively and at 1 year post-surgery using t -tests and multivariate linear regression. Results Pre-operatively, the mean FAQ score was 2.0, and this increased to 5.8 at 1 year post-surgery. Statistically significant improvements ( P ≤ 0.05) were found on the FAQ, crawling, standing, walking and running, and total domains of the GMFM, and PEDI mobility and self-care from baseline to 1 year. The results from the multivariate linear regression indicate that older age ( P = 0.0045) and higher weight ( P = 0.0164) are significantly associated with lower scores in the self-care domain of the PEDI, and that OI type III compared to type IV is significantly associated ( P = 0.0457) with greater improvement on the crawling domain of the GMFM. Higher weight was also associated ( P = 0.0289) with lower scores in the standing domain of the GMFM, as well as with the total GMFM score ( P = 0.0398). Conclusions Our findings indicate that initial FD femoral rodding resulted in benefits in ambulation, gross motor function, self-care, and mobility for children with OI beyond physiological expectations due to developmental growth. FD rodding is a procedure which can improve the overall mobility in children with OI with significant femoral deformities.

Abstract: Cranial base abnormalities are an important complication of osteogenesis imperfecta (OI), a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. To elucidate which clinical characteristics are associated with the occurrence of cranial base abnormalities in OI, we compared cephalometric results of 187 OI patients (median age 12.0 years, range 3.4 to 47 years; 96 female) with those of 191 healthy subjects and related findings to clinical descriptors of the disease. Overall, 41 patients (22%) had at least one unambiguously abnormal skull base measure. Multivariate logistic regression analysis in patients with OI types I, III, and IV (n = 169) revealed that height Z-score [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.43-0.66, p < .001]-but not age, gender, scleral hue, lumbar spine areal bone mineral density, or a history of bisphosphonate treatment-was a significant independent determinant of skull base abnormalities. Among patients with a height Z-score below -3, 48% had a skull base abnormality regardless of whether they had received bisphosphonate treatment in the first year of life or not. Genotype-phenotype correlations were evaluated in patients with detectable mutations in COL1A1 or COL1A2, the genes coding for collagen type I (n = 140). Skull base abnormalities were present in 6% of patients with haploinsufficiency (frameshift or nonsense) mutations, in 43% of patients with helical glycine substitutions caused by COL1A1 mutations, in 32% of patients with helical glycine substitutions owing to COL1A2 mutations, and in 17% of patients with splice-site mutations affecting either COL1A1 or COL1A2. However, multivariate logistic regression analysis showed that height Z-score but not the type of collagen type I mutation was independently associated with the prevalence of skull base abnormalities. In conclusion, this study shows that clinical severity of OI, as expressed by the height Z-score, was the strongest predictor of skull base abnormalities. We did not find evidence for the hypothesis that bisphosphonate treatment protects against skull base abnormalities. © 2011 American Society for Bone and Mineral Research.

Abstract: The objective of this cross-sectional study was to compare the activities and participation in the domains of mobility, self-care, domestic life and social functioning in young adults according to osteogenesis imperfecta (OI) type. Fifty-four former OI patients were invited to participate and were sent a structured questionnaire. Twenty-four patients (mean age: 25.0 years, SD: 2.6 years) with OI types I (n=7), III (n=7), IV (n =8) and V (n=2) completed the questionnaire. Participants with OI type I reported full independence, and only few respondents with OI types IV and V reported some limitations in mobility and domestic life activities. Young adults with OI type III had significantly lower activity scores in aspects of mobility and domestic life and lower levels of participation in employment, sporting activities and transportation. Participation in leisure and social interactions were not different across OI types. Young adults with more severe types of osteogenesis imperfecta have greater activity limitations and participation restrictions. Our findings indicate the importance of promoting and facilitating involvement in meaningful activities and roles in young adults with moderate to severe forms of OI.

Abstract: Pseudo-vitamin D deficiency rickets (PDDR; OMIM 264700) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to an inability to synthesize 1α,25-dihydroxyvitamin D(3) (calcitriol). The long-term (>1 yr) effects of calcitriol replacement treatment have not been reported.

Abstract: Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited.

Abstract: The goal of the present study was to determine the repeatability of gait parameters measured by a force plate gait analysis system (Leonardo Mechanograph® GW).

Abstract: In this 6-month trial, twenty children with cerebral palsy (age 6.2 to 12.3 years; 6 girls) were randomized to either continue their school physiotherapy program unchanged or to receive 9 minutes of side-alternating whole-body vibration (WBV; Vibraflex Home Edition II((R)), Orthometrix Inc) per school day in addition to their school physiotherapy program. Patients who had received vibration therapy increased the average walking speed in the 10 m walk test by a median of 0.18 ms(-1) (from a baseline of 0.47 ms(-1)), whereas there was no change in the control group (P=0.03 for the group difference in walking speed change). No significant group differences were detected for changes in areal bone mineral density (aBMD) at the lumbar spine, but at the distal femoral diaphysis aBMD increased in controls and decreased in the WBV group (P=0.03 for the group difference in aBMD change). About 1% of the WBV treatment sessions were interrupted because the child complained of fatigue or pain. In conclusion, the WBV protocol used in this study appears to be safe in children with cerebral palsy and may improve mobility function but we did not detect a positive treatment effect on bone.

Abstract: The past 3 years have been exciting for collagen biologists and human geneticists studying the disease known as osteogenesis imperfecta (OI or brittle bone disease). Functional studies on cartilage-associated protein (Crtap) have identified it as an essential component of a heterotrimeric, endoplasmic reticulum resident complex responsible for collagen prolyl 3-hydroxylation and chaperone function. Importantly, human mutations in the CRTAP gene have been associated with recessive forms of OI. Although the function and in vivo biological significance of the 3-hydroxyproline modification are still poorly understood, studies on Crtap have led to the identification of additional genes in which mutations also cause recessive forms of OI. These discoveries have now focused the interest of geneticists on the endoplasmic reticulum that will require the help of biochemists to unravel the molecular dynamics and complexities of collagen folding.

Abstract:

Abstract: Cartilage-associated protein (CRTAP) is an essential cofactor for the proper post-translational chain modification and collagen folding. CRTAP mutations lead mice (Crtap-/- mice) and humans (OI type VII) to a severe/lethal osteochondrodystrophy; patients have fractures at birth, deformities of the lower extremities and impaired growth. The consequences of CRTAP deficiency on intrinsic bone material properties are still unknown. In the present study we evaluated bone quality based on quantitative backscattered electron imaging (qBEI) to assess bone mineralization density distribution (BMDD) in femurs from 12 weeks old Crtap-/- mice and transiliac bone biopsies from 4 children with hypomorphic mutations and having residual CRTAP expression. The analyses revealed in the bone matrix of Crtap-/- animals and OI type VII patients a significant increase in mean (CaMean) and most frequent mineral concentration (CaPeak) compared to wild-type littermates and control children, respectively. The heterogeneity of mineralization (CaWidth) was reduced in Crtap-/- mice but normal in OI type VII patients. The fraction of highly mineralized bone matrix (CaHigh) was remarkably increased in the patients: cancellous bone from 2.1 to 3.7 times and cortical bone from 7.6 to 25.5 times, associated with an increased persistence of primary bone. In conclusion, the BMDD data show that CRTAP deficiency results in a shift towards higher mineral content of the bone matrix similar to classical OI with collagen gene mutations. Our data further suggest altered mineralization kinetics resulting ultimately in an overall elevated tissue mineralization density. Finally, in OI type VII patients the increased portion of primary bone is most likely reflecting a disturbed bone development.

Abstract: Whole-body vibration (WBV) is receiving increasing interest as a therapeutic modality to improve neuromuscular performance or to increase bone mass or density. In order to help improve the quality of reports about WBV treatment studies, the International Society of Musculoskeletal and Neuronal Interactions (ISMNI) invited experts in the field to provide suggestions on how the intervention should be described in such reports. The recommendations are presented here.

Abstract: OBJECTIVE: Vertebral fractures are an under-recognized problem in children with inflammatory disorders. We studied spine health among 134 children (87 girls) with rheumatic conditions (median age 10 years) within 30 days of initiating glucocorticoid therapy. METHODS: Children were categorized as follows: juvenile dermatomyositis (n = 30), juvenile idiopathic arthritis (n = 28), systemic lupus erythematosus and related conditions (n = 26), systemic arthritis (n = 22), systemic vasculitis (n = 16), and other conditions (n = 12). Thoracolumbar spine radiograph and dual x-ray absorptiometry for lumbar spine (L-spine) areal bone mineral density (BMD) were performed within 30 days of glucocorticoid initiation. Genant semiquantitative grading was used for vertebral morphometry. Second metacarpal morphometry was carried out on a hand radiograph. Clinical factors including disease and physical activity, calcium and vitamin D intake, cumulative glucocorticoid dose, underlying diagnosis, L-spine BMD Z score, and back pain were analyzed for association with vertebral fracture. RESULTS: Thirteen vertebral fractures were noted in 9 children (7%). Of these, 6 patients had a single vertebral fracture and 3 had 2-3 fractures. Fractures were clustered in the mid-thoracic region (69%). Three vertebral fractures (23%) were moderate (grade 2); the others were mild (grade 1). For the entire cohort, mean +/- SD L-spine BMD Z score was significantly different from zero (-0.55 +/- 1.2, P < 0.001) despite a mean height Z score that was similar to the healthy average (0.02 +/- 1.0, P = 0.825). Back pain was highly associated with increased odds for fracture (odds ratio 10.6 [95% confidence interval 2.1-53.8], P = 0.004). CONCLUSION: In pediatric rheumatic conditions, vertebral fractures can be present prior to prolonged glucocorticoid exposure.

Abstract: To describe mechanographic tests that can be performed by patients with a range of functional abilities and to assess the reproducibility of test results in healthy adults and children.

Abstract: Although vitamin D deficiency is common at birth, the consequences to growth and bone mass by weaning are unclear. This study was designed to determine whether maternal dietary vitamin D deficiency in pregnancy has a negative impact on the bone mass of full-term neonates and if postnatal supplementation could restore bone mass. Forty guinea pigs were randomized to receive a control (C) or deficient (D) diet (0.03 mug vs. 0.00 mug cholecalciferol/g) during pregnancy. Offspring were randomized at birth to receive 0.25 mug of cholecalciferol supplement (S) or a placebo (P) orally per day for 28 d. Measurements at birth and d 28 included whole body and regional bone mass and serum osteocalcin and deoxypyridinoline, plus biomechanical testing and peripheral quantitative computed tomography of excised tibias and femurs. Main and interactive effects were tested using mixed model ANOVA and post hoc Bonferronirsquos tests. At birth and d 28, offspring of the D sows had lower serum vitamin D and osteocalcin concentration, lower body weight, length, whole body and total tibia bone mineral content, and lower biomechanical integrity of tibia compared with those of the C sows, regardless of supplementation. Although postnatal vitamin D supplementation improved vitamin D status at d 28 in D offspring, values remained significantly lower than C groups. This study suggests that efforts should be made to optimize maternal vitamin D status in pregnancy, along with maintenance of vitamin D status in infancy, rather than relying on postnatal supplementation to normalize vitamin D status and bone mass.

Abstract: Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that in the majority of cases is caused by mutations in COL1A1 or COL1A2, the genes that encode the two collagen type I alpha chains, alpha1(I) and alpha2(I). In this study, we examined the relationship between collagen type I mutations and bone densitometric and histomorphometric findings in pediatric OI patients who had not received bisphosphonate treatment. Lumbar spine areal bone mineral density (LS aBMD) was measured in 192 patients (99 girls, 93 boys; age range 3 weeks to 16.9 years) who had either COL1A1 mutations leading to haploinsufficiency (n = 52) or mutations that lead to the substitution of glycine by another amino acid in the triple-helical domain of either the alpha1(I) (n = 58) or the alpha2(I) chain (n = 82). Compared with patients with helical mutations, patients with COL1A1 haploinsufficiency on average were taller and heavier and had higher LS aBMD. After adjustment for age, sex, and height Z-scores, the mean LS aBMD Z-scores were -4.0 for the haploinsufficiency group and -4.7 for both helical mutation groups. In the whole patient population, the average LS aBMD Z-score was higher by 0.6 (95% confidence interval 0.2-1.0) in girls than in boys. Iliac bone histomorphometry (in a subgroup of 96 patients) showed that outer bone size (core width) and trabecular bone volume were similar between genotypic groups, but cortical width was 49% higher in the haploinsufficiency group compared with patients with helical mutations in alpha2(I). Bone turnover parameters were lower in the haploinsufficiency group than in patients with helical mutations. In the group of patients with helical mutations, neither the type of alpha chain affected, nor the type of amino acid substituting for glycine, nor the position of the mutation in the alpha chain had a detectable relationship with LS aBMD or histomorphometric results. Thus patients with haploinsufficiency mutations had a milder skeletal phenotype than patients with mutations affecting glycine residues, but there was no clear genotype-phenotype correlation among patients with helical glycine mutations.

Abstract: Children with inflammatory bowel disease (IBD) manifest low bone mass; the cause remains unclear. We performed transilial bone biopsies in 20 IBD children at diagnosis and found a mild cortical bone deficit and slow bone turnover. It is possible that low mechanical stimulation due to inadequate muscle mass contributes to the bone deficit. INTRODUCTION: Children with newly diagnosed IBD can have low bone mineral density and disturbed bone metabolism, but the tissue level characteristics of the bone involvement in pediatric IBD have not been elucidated. METHODS: In the present study, we evaluated the skeletal status, including static histomorphometry on transiliac bone samples, in 20 patients (age range 8.4 to 17.7 years, 12 boys) with newly diagnosed IBD and compared results to published normative data. RESULTS: Despite normal height (mean Z-score 0.04, SD 1.2), areal bone mineral density at the lumbar spine was moderately low (mean age- and sex-specific Z-score -0.8, SD 1.1). Total body bone mineral content and lean mass were low for age and sex as well (mean Z-scores -1.2, SD 0.9 and -2.0, SD 0.9, respectively). Biochemical bone markers indicated low bone formation and resorption activity. Bone histomorphometry revealed a slightly low cortical width (mean 23%, SD 25%, below the result expected for age) but a normal amount of trabecular bone. The percentage of trabecular bone surface covered by osteoid or osteoclasts was low, suggesting that both bone formation and bone resorption were suppressed. CONCLUSIONS: Our results indicate that young patients manifest a mild cortical bone deficit at the iliac crest and slow trabecular bone turnover even at diagnosis, in the setting of IBD.

Abstract: The presence of a larger than usual number of Wormian bones (accessory skull bones completely surrounded by a suture line) is a well-known radiographic sign of osteogenesis imperfecta (OI), but the phenotypic and genotypic correlates are not well characterized. In the present study we retrospectively analyzed skull radiographs of 195 OI patients (median age 11.8 years, range 0.4-48 years; 100 female). A significant number of Wormian bones (SNWB, defined as the presence of 10 or more Wormian bones) were found in at least one patient in all of the OI types studied (I, III to VII). SNWB were observed in 35% of patients with OI type I, in 96% of patients with OI type III and 78% of patients with OI type IV. SNWB were present in 28% of patients with haploinsufficiency (nonsense and frameshift) mutations in COL1A1, in 96% of patients with helical glycine substitutions in the alpha 1 chain of collagen type I and in 72% of patients with helical glycine substitutions in the alpha 2 chain of collagen type I. Stepwise multivariate logistic regression analysis showed that height z-score, an indicator of disease severity, was inversely related with the prevalence of SNWB. SNWB were visible in 19 of the 26 patients who had skull radiographs in the first year of life, including a 2-week-old newborn. Thus, it appears that SNWB occur more frequently in more severely affected OI patients and seem to develop mostly in utero. (c) 2010 Wiley-Liss, Inc.

Abstract: The relationship between aBMD and osteoarthritis (OA) remains unclear. We compared aBMD, BMC and bone size among children and grandchildren of Hutterites with hip or knee replacement (n=23 each) to children and grandchildren of age- and sex-matched controls (178 children and 267 grandchildren). There were no differences in anthropometric measures or activity levels between case and control probands, but femoral neck (FN) and spine (LS) aBMD and Z-scores were greater in cases than controls (0.89 vs. 0.80 g/cm2; 1.15 vs. 1.03 g/cm2; 1.5 vs. 0.8; 2.4 vs. 1.2: all p<0.05). Hip, FN and LS aBMD (1.05 vs. 0.97, 0.92 vs. 0.84, 1.15 vs. 1.03 g/cm2), BMC (34.1 vs. 32.0, 4.58 vs. 4.27, 69.5 vs. 62.4 g) and Z-scores (1.0 vs. 0.4; 0.9 vs. 0.2; 1.3 vs. 0.2) were greater in daughters of cases than controls (hip BMC p=0.06, others p<0.05); there were no differences between sons. Grandchildren (aged 8-39 years) were categorized as growing (premenarcheal or male<14 years) or not growing (> or =2 years post-menarcheal or males> or =18 years): 33 were not classified. Post-menarcheal, but not premenarcheal, granddaughters of cases had greater hip, FN and LS aBMD Z-scores (0.7 vs. -0.1; 0.6 vs. -0.1; 0.8 vs. -0.3); greater hip and spine aBMD (1.03 vs. 0.95, 1.10 vs. 0.98 g/cm2); greater femoral neck and spine BMC (4.77 vs. 4.21, 66.7 vs. 55.4 g); and greater spine bone area (60.7 vs. 56.6 cm2) compared to granddaughters of controls (all, p<0.05), which remained significant when height, weight, and age were included as covariates. Growing grandsons of cases were taller and heavier than control grandsons, and a greater hip aBMD among grandsons of cases (0.88 vs. 0.76 g/cm2) was the only bone difference that remained significant after taking into account body size differences. Grandsons who were not growing had greater spine bone area (1.19 vs. 1.08 cm2) if their grandparent had OA compared to grandsons whose grandparents did not have OA. We speculate that there is a genetic basis for OA that leads to early differences in growth patterns among boys and greater peak bone mass and aBMD among girls.

Abstract: Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the alpha1 or the alpha2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of alpha1(I) (n=67) or alpha2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in alpha2(I) (n=40), patients with serine substitutions in alpha1(I) (n=42) on average were shorter (median height z-score -6.0 vs -3.4; P=0.005), indicating that alpha1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the alpha2(I) chain but not in the alpha1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients.

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Abstract: Intravenous pamidronate is the most widely used treatment for moderate to severe osteogenesis imperfecta (OI). Currently, there is no medical treatment for patients with mild OI. We conducted a single-center randomized double-blind placebo-controlled trial to examine the efficacy and safety of oral risedronate in the treatment of pediatric patients with mild OI. A total of 26 children and adolescents (age, 6.1-17.7 yr; 11 girls) with OI type I were randomized to either placebo (N = 13) or risedronate (N = 13) for 2 yr. Risedronate doses were 15 mg once per week in patients weighing <40 kg and 30 mg once per week in patients weighing >40 kg. After 2 yr of treatment, risedronate decreased serum levels of the bone resorption marker collagen type I N-telopeptide by 35% compared with a 6% reduction with placebo (p = 0.003). Risedronate increased lumbar spine areal BMD Z-scores by 0.65, whereas patients receiving placebo experienced a decrease of 0.15 (p = 0.002). In contrast, no significant treatment differences in bone mass and density were found at the radial metaphysis and diaphysis, the hip, and the total body. Histomorphometric analysis of transiliac bone biopsies at the end of the study period did not show a significant treatment difference in cortical width, trabecular bone volume, or parameters of bone turnover. Similarly, there was no detectable treatment effect on vertebral morphometry, second metacarpal cortical width, grip force, bone pain, or number of new fractures. Regarding safety, risedronate was generally well tolerated, and the incidence of clinical or laboratory adverse experiences was similar among treatment groups. These results suggest that the skeletal effects of oral risedronate are weaker than those that are commonly observed with intravenous pamidronate treatment but still lead to an increase in lumbar spine areal BMD. Future studies should investigate whether oral risedronate is effective in reducing fracture rates in children and adolescents with mild OI type I.

Abstract: Vertebral compression is a serious complication of childhood acute lymphoblastic leukemia (ALL). The prevalence and pattern of vertebral fractures, as well as their relationship to BMD and other clinical indices, have not been systematically studied. We evaluated spine health in 186 newly diagnosed children (median age, 5.3 yr; 108 boys) with ALL (precursor B cell: N = 167; T cell: N = 19) who were enrolled in a national bone health research program. Patients were assessed within 30 days of diagnosis by lateral thoraco-lumbar spine radiograph, bone age (also used for metacarpal morphometry), and BMD. Vertebral morphometry was carried out by the Genant semiquantitative method. Twenty-nine patients (16%) had a total of 75 grade 1 or higher prevalent vertebral compression fractures (53 thoracic, 71%; 22 lumbar). Grade 1 fractures as the worst grade were present in 14 children (48%), 9 patients (31%) had grade 2 fractures, and 6 children (21%) had grade 3 fractures. The distribution of spine fracture was bimodal, with most occurring in the midthoracic and thoraco-lumbar regions. Children with grade 1 or higher vertebral compression had reduced lumbar spine (LS) areal BMD Z-scores compared with those without (mean +/- SD, -2.1 +/- 1.5 versus -1.1 +/- 1.2; p < 0.001). LS BMD Z-score, second metacarpal percent cortical area Z-score, and back pain were associated with increased odds for fracture. For every 1 SD reduction in LS BMD Z-score, the odds for fracture increased by 80% (95% CI: 10-193%); the presence of back pain had an OR of 4.7 (95% CI: 1.5-14.5). These results show that vertebral compression is an under-recognized complication of newly diagnosed ALL. Whether the fractures will resolve through bone growth during or after leukemia chemotherapy remains to be determined.

Abstract: Cyclical intravenous treatment with pamidronate is widely used to treat osteogenesis imperfecta (OI) types I, III, and IV, which are due to dominant mutations affecting collagen type I alpha chains. There is no information about the effects of pamidronate in children with OI type VII, an autosomal-recessive form of OI caused by a mutation in the cartilage-associated protein gene. In this retrospective single-center study, we compared the effects of pamidronate in four girls with OI type VII (age range 3.9-12.7 years) to those in eight girls with OI types caused by collagen type I mutations who were matched for age and disease severity. During 3 years of pamidronate therapy, lumbar spine areal bone mineral density increased and lumbar vertebral bodies improved in shape in patients with OI type VII. Other outcomes such as fracture rates and mobility scores did not show statistically significant changes in this small study cohort. There were no significant side effects noted during the time of follow-up. Thus, intravenous treatment with pamidronate seems to be safe and of some benefit in patients with OI type VII.

Abstract: Bone mineralization density distribution (BMDD) as assessed by quantitative backscattered electron imaging (qBEI) in iliac crest bone biopsies has become in the last years a powerful diagnostic tool to evaluate the effect of metabolic bone diseases and/or therapeutic interventions on the mineralization status of the bone material. However until now, normative reference data are only available for adults. The aim of the present study is to close this gap and establish normative data from children and compare them with reference BMDD data of adults. qBEI analyses were performed on bone samples from 54 individuals between 1.5 and 23 years without metabolic bone diseases, which were previously used as study population to establish normative histomorphometric standards. In the trabecular compartment, none of the BMDD parameters showed a significant correlation with age. The BMDD was shifted towards lower mineralization density (CaMean -5.6%, p<0.0001; CaPeak -5.6%, p<0.0001; CaLow +39.0% p<0.001; CaHigh -80.7%, p<0.001) and the inter-individual variation was higher compared to the adult population. The cortices appeared to be markedly less mineralized (CaMean -3.1%, p<0.0001) than cancellous bone due to higher amounts of low mineralized secondary bone. However, the cortical BMDD parameters showed a strong correlation (r=0.38 to 0.85, with p<0.001 to<0.0001) with cancellous BMDD parameters. In conclusion, this study provides evidence that BMDD parameters in growing healthy subjects are relatively constant and that these data can be used as normative references in pediatrics osteology. The larger inter-individual variability compared to adults is most likely related to alterations of the bone turnover rate during growth.

Abstract: Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by fractures with minimal trauma. Intracranial hemorrhage has been reported in a small number of OI patients. Here we describe three patients, a boy (aged 15 years) and two girls (aged 17 and 7 years) with OI type III who suffered intracranial hemorrhage and in addition had brachydactyly and nail hypoplasia. In all of these patients, OI was caused by glycine mutations affecting exon 49 of the COL1A2 gene, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen type I alpha 2 chain. These observations suggest that mutations in this region of the collagen type I alpha 2 chain carry a high risk of abnormal limb development and intracranial bleeding.

Abstract: In the context of metabolic bone disorders, obtaining biopsies of iliac bone can be useful for establishing a diagnosis in an individual patient or for investigating pathomechanisms when a series of samples is examined. Although bone specimens are usually decalcified for routine pathology to facilitate sample processing, when investigating metabolic bone disorders it is usually much more informative to analyse undecalcified samples. Biopsy samples can be assessed qualitatively and quantitatively. Quantitative analysis by computerised histomorphometry of undecalcified bone biopsy samples is a key tool for studying bone metabolism and, to a lesser extent, bone mass and structure. Standard histomorphometric analyses focuses on trabecular bone and therefore mainly provides information on trabecular remodelling. Remodelling activity changes markedly with age during development. This has to be taken into account when histomorphometry is used in the paediatric setting. Children and adolescents with severe bone fragility should have a bone biopsy for diagnostic purposes unless the diagnosis is obvious from non-invasive examinations. Quantitative histomorphometric analysis of transiliac bone biopsy samples is especially valuable in clinical studies, as this method provides safety and efficacy data that can not be obtained in any other way.

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Abstract: Whole-body vibration training is a method for muscle strengthening that is increasingly used in a variety of clinical situations. Key descriptors of vibration devices include the frequency, the amplitude, and the direction of the vibration movement. In a typical vibration session, the user stands on the device in a static position or performs dynamic movements. Most authors hypothesize that vibrations stimulate muscle spindles and alpha-motoneurons, which initiate a muscle contraction. An immediate effect of a non-exhausting vibration session is an increase in muscle power. Most studies of the longer term use of vibration treatment in various disorders have pursued three therapeutic aims: increasing muscle strength, improving balance, and increasing bone mass. In a small pilot trial in children we noted improvements in standing function, lumbar spine bone mineral density, tibial bone mass, and calf muscle cross-sectional area.

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Abstract: Intravenous pamidronate is widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Changes in the appearance of osteoclasts have previously been noted in children receiving pamidronate and have been interpreted as signs of toxicity. In this study, we analyzed osteoclast parameters in paired iliac bone specimens before and after 2-4 yr of cyclical intravenous pamidronate therapy in 44 pediatric OI patients (age range: 1.4-17.5 yr; 21 girls). During pamidronate treatment, average osteoclast diameter and the mean number of nuclei present per osteoclast increased by 18% (p = 0.02) and 43% (p < 0.001), respectively. The number of samples containing large osteoclasts (LOcs, diameter > 50 mum) increased from 6 (14%) before treatment to 23 (52%) after pamidronate therapy (p < 0.001 by chi(2) test). Post-treatment samples containing LOcs had a greater core width (p = 0.04) and a higher cancellous bone volume per tissue volume (p < 0.001), because cancellous bone volume had increased more during pamidronate treatment (p < 0.001). Osteoclast number and surface were higher in samples with LOcs, but there was no difference in cancellous bone formation parameters. The presence of LOcs was independent of OI type, type of collagen type I mutation, lumbar spine BMD, and other clinical or biochemical measures. In conclusion, this study did not show any indication that LOcs during pamidronate treatment are indicative of toxicity. It seems more likely that the observed abnormalities in osteoclast morphology are part of the mechanism of action of this drug.

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Abstract: The International Society for Clinical Densitometry (ISCD) convenes a Position Development Conference (PDC) every 2yr to make recommendations for standards in the field of bone densitometry. The recommendations are based on clinically relevant issues in bone densitometry such as quality control, acquisition, analysis, interpretation, and reporting. In 2007, ISCD convened its first Pediatric Position Development Conference to address issues specific to the assessment of skeletal health in children and adolescents. Topics for consideration are developed by the ISCD Board of Directors and its Scientific Advisory Committee. Clinically relevant questions related to each topic area are assigned to task forces for a comprehensive review of the medical literature and subsequent presentation of the reports to an international panel of experts. For this PDC, the Expert Panel included representatives of the American Society for Bone and Mineral Research and International Bone and Mineral Society. The recommendations of the PDC Expert Panel are then reviewed by the ISCD Board of Directors. Recommendations that are approved become Official Positions of the ISCD. The Pediatric PDC was held June 20-21, 2007, in Montreal, Quebec, Canada. Topics considered were restricted to children and adolescents, and included DXA prediction of fracture and definition of osteoporosis; DXA assessment in diseases that may affect the skeleton; DXA interpretation and reporting; and peripheral quantitative computed tomography measurement. This report describes the methodology and results of the 2007 Pediatric PDC, and a summary of all ISCD Official Positions, including the ones recently adopted by this 2007 Pediatric PDC and the 2007 Lansdowne, Virginia, USA Adult PDC.

Abstract: The International Society for Clinical Densitometry periodically holds Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines for the assessment of skeletal health, including nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests. Topics are selected for consideration according to criteria that include clinical relevancy, uncertainty in the application of medical evidence to clinical practice, and the likelihood of the expert panel to reach a consensus agreement. The first Pediatric PDC was June 20 to 21, 2007 in Montreal, Quebec, Canada. Topics included fracture prediction and definition of osteoporosis in children; dual-energy x-ray absorptiometry (DXA) assessment in children with chronic disease that may affect the skeleton; DXA interpretation and reporting in children and adolescents; and the use of peripheral quantitative computed tomography in children and adolescents. This report describes the methodology and presents the results of this recent PDC.

Abstract: The International Society for Clinical Densitometry (ISCD) periodically convenes Position Development Conferences (PDCs) in order to establish standards and guidelines for the assessment of skeletal health. The most recent Adult PDC was held July 20-22, 2007, in Lansdowne, Virginia, USA; the first Pediatric PDC was June 20-21, 2007 in Montreal, Quebec, Canada. PDC topics were selected according to clinical relevancy, perceived need for standardization, and likelihood of achieving agreement. Each topic area was assigned to a task force for a comprehensive review of the scientific literature. The findings of the review and recommendations were presented to adult and pediatric international panels of experts. The panels voted on the appropriateness, necessity, quality of the evidence, strength, and applicability (worldwide or variable according to local requirements) of each recommendation. Those recommendations that were approved by the ISCD Board of Directors become Official Positions. This is a review of the methodology of the PDCs and selected ISCD Official Positions.

Abstract: Hyperplastic callus (HPC) formation is a prominent feature of osteogenesis imperfecta (OI) type V; however, little is known about its long-term outcome. In this case report we describe the occurrence, appearance and course of a femoral HPC in a patient with OI type V during 10 years of follow-up. Radiographs of HPC in this child were compared and contrasted with HPC formation in the femur of his father and paternal grandfather, who also were affected with OI type V. This case report makes it clear that HPC can lead to significant morbidity, not only in the acute phase but also long term as a result of residual alteration in bone architecture.

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Abstract: The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

Abstract: Osteonecrosis of the jaw (ONJ) has been described as a complication of bisphosphonate therapy in adults. In the present study, we did not find a case of ONJ among 278 pediatric patients who had received intravenous pamidronate during childhood or adolescence.

Abstract: The aim of this contribution is to provide reference data for peripheral quantitative computed tomography (Stratec XCT2000(R)) performed at the proximal radius (the so-called '65% site') of young subjects and to discuss the interpretation of such analyses. Data from a previous reference data study on 469 subjects between 6 and 40 years were re-analyzed and smooth curves were fitted. The corresponding equations allow for calculation of age-, height- and sex-specific z-scores of total cross-sectional area, cortical cross-sectional area, bone mineral content, cortical bone mineral density, total bone mineral density, Strength-Strain Index, muscle cross-sectional area and the ratio between bone mineral content and muscle cross-sectional area. These data should facilitate the clinical use of peripheral quantitative computed tomography in young subjects.

Abstract: Osteoporosis in adults has been defined on the basis of densitometric criteria, but at present the term osteoporosis does not have a widely recognized definition in pediatrics. Consequently, the International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference reviewed the literature describing the relationship between bone densitometric studies and fractures in apparently healthy children and adolescents, and prepared Official Positions regarding the definition of osteoporosis in children and adolescents. The ISCD Official Positions with respect to the above issues, as well as the rationale and evidence used to derive these positions, are presented here.

Abstract: INTRODUCTION: When expressed as a percentage of the average result in young adults, bone mineral content lags behind bone length before puberty. Even though this observation has led to speculation about bone fragility in children, such relationships could simply be due to scaling effects when measures with different geometrical dimensions are compared. METHODS: The study population comprised 145 healthy subjects (6-25 years, 94 females). Magnetic resonance imaging and dual-energy X-ray absorptiometry were used to determine femur length, bone mineral content, cortical bone mineral density, cross-sectional bone geometry (bone diameter; cortical thickness; total, cortical and medullary areas; cross-sectional and polar moments of area; bone strength index) and muscle area at the proximal one-third site of the femur. Results were dimensionally scaled by raising two-, three- and four-dimensional variables to the power of 1/2, 1/3 and 1/4, respectively. Sex-differences were also assessed before and after functionally adjusting variables for femur length and weight or muscle size. RESULTS: In prepubertal children, unscaled results expressed as percentages of adult values were lowest for variables with the highest dimensions (e.g., moments of area<bone mineral content<cross-sectional areas<femur length). However, when dimensionally scaled, results in children represented similar percentages of the respective average adult values, even after functional adjustments. Before puberty, there was no sex-difference in adjusted bone or muscle variables. After puberty, males had greater total and cortical bone area, bone diameter, moments of area, bone strength index and muscle area than women, both in absolute terms as well as adjusted for femur length and weight. The largest sex-difference was found for muscle area. When compared relative to muscle size, young adult women attained greater total and cortical bone area than men. CONCLUSIONS: Growth in femoral length, diameter, mass and strength appears well coordinated before puberty. Postpubertal females have narrower femora, less bone strength and muscle size than males. However, when muscle size is taken into account, females have a larger femoral bone cross-section and more cortical bone. These sex-differences likely result from a combination of mechanical and hormonal effects occurring during puberty.

Abstract: Osteogenesis imperfecta type I (OI-I) represents the mildest form of OI. The collagen I mutations underlying the disorder can be classified as quantitative mutations that lead to formation of a decreased amount of normal collagen or qualitative mutations where structurally aberrant collagen chains are generated. However, the phenotypic consequences of a particular mutation are not well understood. Transiliac bone biopsies from 19 young OI-I patients (age range 2.0-14.1 years) and 19 age-matched controls were used to assess bone histomorphometric parameters and bone mineralization density distribution, measured by quantitative backscattered electron imaging. Thirteen of the OI-I patients were affected by quantitative and six patients by qualitative mutations. Compared to age-matched controls, iliac bone samples in the OI group were smaller and had thinner cortices and less trabecular bone. Resorption parameters were similar between groups, whereas surface-based parameters of bone formation were considerably higher in OI patients than in controls with the exception of bone formation rate per osteoblast surface, which was reduced in OI. Backscattered electron imaging revealed a higher mean mineralization density (+7%, P &lt; 0.001) in OI-I patients than in age-matched controls, which was accompanied by a reduced heterogeneity of mineralization (-13%, P &lt; 0.001). However, the increase of mean degree of mineralization in OI did not exceed the average level of normal adult bone. No differences were found between the two mutation types. In summary, the tissue- and material-level abnormalities found in OI-I (low bone mass and increased mineral content of the matrix) seem to be independent of the collagen mutations.

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Abstract: Hyperplastic callus formation was assessed in 23 patients with osteogenesis imperfecta type V. Hyperplastic callus mostly affected long bones in the lower extremities and occurred predominantly during phases of rapid growth. INTRODUCTION: Hyperplastic callus (HPC) formation is one of the most conspicuous features of osteogenesis imperfecta (OI) type V, but the natural history of HPC has not been well characterized. MATERIALS AND METHODS: In this retrospective single-center study, we assessed HPC in 23 OI type V patients (9 females and 14 males). RESULTS: Fifteen patients (65%) had HPC at 48 skeletal sites, 30 of which affected the lower limbs. The number of HPC sites per patient ranged from 0 to 7, with an average of 2.6 for men and 1.1 for women (p = 0.047 for this sex difference; t-test). New HPC formation was observed both after fractures and outside of the context of fractures. Only a minority of lower limb fractures (26%) precipitated HPC formation. After an initial enlargement phase, HPC lesions usually stabilized, but could also resolve completely (n = 2) or progress and lead to bone deformation. The most common complication of HPC was a fracture through the lesion (n = 7). Neither pamidronate nor indomethacin seemed to influence the course of HPC. CONCLUSIONS: HPC is a potentially serious complication of OI type V. Given the rarity of the disorder, treatment studies will require multicenter collaborations.

Abstract: BACKGROUND: Opsismodysplasia is a rare spondylo(epi)chondrodysplasia characteristized by delayed skeletal maturation and a constellation of dysplastic features. Although metaphyseal irregularities/cupping have been noted, neither renal phosphate wasting nor rickets have previously been reported. OBJECTIVE: To evaluate hypophosphatemia and rickets in opsismodysplasia. PATIENTS: Two girls with opsismodysplasia presenting with hypophoshpatemia by 3 years of age. METHODS: Routine biochemistries to assess hypophosphatemia and renal phosphate wasting; radiographs (rachitic changes) and DEXA scan (BMD); FGF23 levels, PHEX and FGF23 gene analyses performed (Patient 1). RESULTS: Both children had hypophosphatemia, decreased TRP, and rickets. Oral phosphorus and calcitriol improved metaphyseal mineralization, yet serum phosphate levels remained relatively low and renal phosphate wasting persisted. PHEX and FGF23 gene analyses were negative, whereas serum FGF23 levels were markedly elevated in Patient 1. CONCLUSION: We now demonstrate an association between opsismodysplasia, hypophosphatemic rickets, and FGF23 elevation. Screening phosphorus levels may thus uncover a potentially treatable component of this disease.

Abstract: BACKGROUND: Children with chronic illnesses are at increased risk for reductions in bone strength and subsequent fractures (osteoporosis), either due to the impact of the underlying condition on skeletal development or due to the osteotoxic effect of medications (e.g., glucocorticoids) used to treat the chronic illness. Bisphosphonates are being administered with increasing frequency to children with secondary osteoporosis; however, the efficacy and harm of these agents remains unclear. OBJECTIVES: To examine the efficacy and harm of bisphosphonate therapy in the treatment and prevention of secondary osteoporosis in children and adolescents. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Issue 4, 2006), MEDLINE, EMBASE, CINAHL and ISI Web of Science (inception-December 2006). Further literature was identified through expert contact, key author searches, scanning reference lists of included studies, and contacting bisphosphonate manufacturers. SELECTION CRITERIA: Randomized, quasi-randomized, controlled clinical trials, cohort, and case controls of bisphosphonate(s) in children 0-18 years of age with at least one low-trauma fracture event or reductions in bone mineral density in the context of secondary osteoporosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed quality. Case series were used for supplemental harms-related data. MAIN RESULTS: Six RCTs, two CCTs, and one prospective cohort (n=281 children) were included and classified into osteoporosis due to: 1) neuromuscular conditions (one RCT) and 2) chronic illness (five RCTs, two CCTs, one cohort). Bisphosphonates examined were oral alendronate, clodronate, and intravenous (IV) pamidronate. Study quality varied. Harms data from 23 case series (n=241 children) were used.Heterogeneity precluded statistically combining the results. Percent change or Z-score change in lumbar spine areal BMD from baseline were consistently reported. Two studies carried out between-group analyses; one showed no significant difference (using oral alendronate in anorexia nervosa) while the other demonstrated a treatment effect on lumbar spine with IV pamidronate in burn patients. Frequently reported harms included the acute phase reaction, followed by gastrointestinal complaints, and bone/muscle pain. AUTHORS' CONCLUSIONS: The results justify further evaluation of bisphosphonates among children with secondary osteoporosis. However, the evidence does not support bisphosphonates as standard therapy. Short-term (3 years or less) bisphosphonate use appears to be well-tolerated. An accepted criterion for osteoporosis in children, a standardized approach to BMD reporting, and examining functional bone health outcomes (e.g., fracture rates) will allow for appropriate comparisons across studies.

Abstract: OBJECTIVES: The purpose of this study was to evaluate the effect of calcium and vitamin D2 supplementation on bone mineral density (BMD) in children with inflammatory bowel disease (IBD). PATIENTS AND METHODS: This was an open-label, prospective study conducted over a 12-month period. Seventy-two patients were divided into 2 groups based on lumbar spine areal BMD (L2-4 aBMD). Patients with an L2-4 aBMD z score of -1 or higher were assigned to the control group (n = 33; mean age, 11.0 +/- 3.5 years; 20 boys). Patients with an L2-4 aBMD of less than -1 (n = 39; mean age 11.8 +/- 2.5 years; 25 boys) were allocated to the intervention group and received 1000 mg of supplemental elemental calcium daily for 12 months (n = 19) or supplemental calcium for 12 months and 50,000 IU of vitamin D2 monthly for 6 months (n = 20). RESULTS: The 2 groups differed in L2-4 aBMD z scores (intervention, -1.9 +/- 0.6; control, -0.2 +/- 0.6; P < 0.001) and volumetric L2-4 BMD (vBMD; intervention, 0.29 +/- 0.04; control, 0.33 +/- 0.06; P < 0.001). After 1 year of therapy, the control and intervention groups had similar changes in height z scores, L2-4 aBMD, L2-4 vBMD (z score change, L2-4 aBMD: control 0.2 +/- 0.6 [n = 21], intervention 0.4 +/- 0.6; P = 0.4 [n = 26]; z score change, L2-4 vBMD: control 0.1 +/- 0.4, intervention 0.2 +/- 0.6; P = 0.74). The changes in these parameters were similar between patients who had received calcium only or calcium plus vitamin D. CONCLUSIONS: These results suggest that, in children with IBD, supplementation of calcium and vitamin D does not accelerate accrual in L2-4 BMD.

Abstract: Although intracortical bone remodeling is a key aspect of bone physiology, very little is known about this process during human bone development. In this study, we examined transiliac bone samples from 56 individuals between 1.5 and 22.9 years of age (31 female; tetracycline labeling present in 42 subjects) who did not have evidence of metabolic bone disease. Parameters of osteonal structure (osteon diameter, wall thickness, diameter of osteonal canals) and dynamic measures of intracortical remodeling were determined separately for the external and internal cortex. We found that measures of osteonal structure were independent of age. However, the percentage of osteons showing metabolic activity was lower in the older study subjects, corresponding to a slowdown in the turnover of cortical bone. Most dynamic parameters of bone metabolism were higher in the internal cortex than in the external cortex. Cortical porosity was negatively associated with age on the external, but not on the internal cortex. The bone forming activity that refills the remodeling cavities seemed to favor the side of the osteonal canal that faced towards the periosteum. In summary, intracortical remodeling activity varies markedly during bone development, and is slightly asymmetric between the two cortices of an iliac bone specimen. Remodeling during development is thus an age-dependent process that varies with location even within the same bone.

Abstract: Nanoindentation was used to compare the intrinsic mechanical properties of bone tissue (iliac crest biopsy) from children with type III and type IV osteogenesis imperfecta (OI). Young's modulus and hardness values were not significantly different between the two clinical severity groups on either cortical or trabecular measurement. In comparing the ratio of modulus over hardness (E/H) between OI type III and IV. The type III bone showed a marginally significant decrease for cortical bone and significant decrease for trabecular bone, which indicated that the OI type III bone was more brittle than OI type IV bone at the tissue level. In addition, nanoindentation measurements of the bone tissue harvested at femur/tibia from the same patients were compared with the results from the iliac crest biopsy. Young's modulus and hardness values were not significantly different between the two anatomic locations in either cortical or trabecular measurements. The ratio of E/H was not significantly different between the two groups. Results indicate that intrinsic modulus, hardness, and indentation deformation pattern (E/H) of OI bone tissues are not significantly different at long bone (midshaft of femur/tibia) and iliac crest. We observed that age (1.9 to 13.2 years) did not influence OI bone tissue intrinsic mechanical properties.

Abstract: BACKGROUND: Upper limb deformity in children with osteogenesis imperfecta may substantially impair function. The aims of this retrospective work were to study the prevalence of radial head malalignment (dislocation or subluxation) in different types of osteogenesis imperfecta and to identify factors linked to it. METHODS: We assessed 489 upper limbs from 254 patients (with a mean age of 9.6 years and including 130 female patients) who had various types of osteogenesis imperfecta. Radiographs representing a single time-point for each patient were assessed for the presence and direction of radial head malalignment and associated abnormalities (dysplasia of the capitellum or of the radial head or neck, calcification of the interosseous membrane, or radioulnar synostosis). Deformations of the humerus, radius, and ulna were assessed with regard to location, direction, and magnitude. The forearm range of motion in pronation and supination and the hand grip force were measured in a subset of patients. RESULTS: We observed radial head dislocation or subluxation in forty-four and thirty-nine upper extremities, respectively. The frequency of radial head malalignment was significantly higher in type-V osteogenesis imperfecta (86%) than in the other types (0% to 29%) (p < 0.001). Dysplasia of the humeral capitellum, radial head, or radial neck was associated with malalignment in all types of osteogenesis imperfecta, with the exception of capitellum dysplasia in type V. Malalignment in type V was associated with calcification of the interosseous membrane, an abnormality that was specific for type V. In the other osteogenesis imperfecta types, malalignment was commonly linked with radial and ulnar deformation and was associated with decreased forearm range of motion in supination and pronation and a lower grip force. CONCLUSIONS: Radial head malalignment is common in osteogenesis imperfecta, especially in type V. Malalignment is associated with bowing characteristics and impaired function of the upper limb. These findings may provide support for surgical correction of radial and ulnar bowing in selected patients with osteogenesis imperfecta. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

Abstract: We report that osteopenia is a prominent and previously unappreciated clinical feature of patients with X-linked hyper-IgM syndrome, an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L). We therefore conducted studies to determine the relationship between CD40L and osteoclastogenesis. Recognizing that activated T cells express surface receptor activator of NF-kappaB ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, we assessed the capacity of wild-type T cells and CD40L(-/-) T cells to induce osteoclastogenesis in vitro. Relative to wild-type T cells, activated CD40L(-/-) T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L(-/-) T cells had normal expression of RANKL, they were deficient in IFN-gamma production. In subsequent studies, we cultured activated CD40L(-/-) T cells in the presence of IFN-gamma, and we found that the osteoclastic capacity of CD40L(-/-) T cells could be greatly diminished. These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome.

Abstract: Cyclical intravenous pamidronate is a widely used symptomatic therapy in moderate to severe osteogenesis imperfecta (OI). The effects of treatment discontinuation on long bone development have not been characterized. In this observational study we used peripheral quantitative computed tomography to assess the radius at the distal metaphysis and at the diaphysis in 23 young OI patients (11 female) who had received pamidronate for at least 3 years. Measurements were performed twice, at the time of treatment discontinuation (when the age of the patients ranged from 5.9 to 21.3 years) and at an average of 1.9 years (range 1.5 to 2.4 years) later. At the time of pamidronate discontinuation, all but one of the patients who were below 15 years of age (n=14) had a positive age- and sex-specific z-score for bone mineral content (BMC) at the metaphysis, resulting in a mean z-score of +2.0 (SD=1.0) for this subgroup. In contrast, patients aged 15 years or older (n=9) had an average metaphyseal BMC z-score of -1.5 (SD=1.5). After pamidronate discontinuation, metaphyseal BMC z-score decreased by an average of 2.4 (SD=2.0) in the whole group. The change in BMC z-score was growth-dependent, as BMC z-scores decreased by about 2 or more in all patients in whom distal radius growth plates were open when pamidronate was discontinued. In contrast, none of the 11 patients with closed distal radius growth plates experienced a decrease in metaphyseal BMC z-score by more than 2. At the diaphysis, the average BMC z-score was low at the time of the last pamidronate infusion [z-score -1.7 (SD=1.4)]. After pamidronate discontinuation, the average diaphyseal BMC z-score decreased by only 0.3 (SD=0.4). In summary, this study shows that the effect of pamidronate discontinuation is much larger at the radial metaphysis than at the diaphysis and is dependent on growth. Metaphyseal bone tissue added by longitudinal growth after treatment discontinuation has a lower density than tissue created during treatment. It is possible that this produces zones of localized bone fragility after pamidronate treatment is stopped in growing children.

Abstract: The mass of growing bones increases through changes in outer dimensions and through the net addition of tissue on inner bone surfaces. In this overview I examine bone accrual as it occurs on trabecular (inner) and periosteal (outer) surfaces. In the axial skeleton, the amount of trabecular bone increases during development, because trabeculae grow thicker as a result of bone remodeling with a positive balance. Remodeling is a process in which osteoblasts and osteoclasts are tightly linked ("coupled") in time and space. In contrast to trabecular thickness, trabecular number and material density change little throughout development. Bone accrual on periosteal surfaces leads to an increase in bone size, which is a crucial determinant of bone strength throughout life. Periosteal osteoblasts deposit new bone on an extended surface area and over an extended period of time without being interrupted by osteoclasts. This type of bone metabolic activity is called modeling, which is much more efficient than remodeling for increasing bone mass. In the past, research has focused on bone remodeling on trabecular surfaces. However, the key to an improved understanding of bone mass and strength development in children will lie with studies on bone modeling on periosteal surfaces.

Abstract: Cyclical intravenous treatment with pamidronate is of clinical benefit in children with moderate to severe osteogenesis imperfecta (OI) types I, III and IV, but there is no information on the effects of this treatment on the newly described OI type VI. Here, we report on the results of 3 years of pamidronate treatment in 10 children and adolescents with OI type VI (age range 0.8 to 14.5 years, three girls). Treatment effects were compared to those of 10 patients with OI types I, III, and IV, who were matched for age and disease severity (based on height and lumbar spine areal bone mineral density). During pamidronate therapy, lumbar spine areal bone mineral density z scores increased and lumbar spine vertebral bodies improved in shape. Iliac bone histomorphometry showed a tendency to higher cortical thickness (+53%, P=0.06) but the mineralization defect, a characteristic feature of OI type VI, did not change during pamidronate treatment. Annualized fracture incidence decreased from 3.1 per year before treatment to 1.4 fractures per year during treatment (P<0.05). Regarding mobility, the Pediatric Evaluation of Disability Inventory gross motor score increased by 42% during pamidronate treatment (P<0.005). Significant improvements were also found for age-related z scores of maximal isometric grip force. In comparison to the OI control group, the fracture incidence was higher and the gross motor scores were lower in OI type VI, both before and after pamidronate treatment (P<0.05 for each parameter). No differences were found between the groups for changes in densitometric measures and cortical thickness during pamidronate treatment. Our results suggest that 3 years of intravenous pamidronate therapy led to improvements in bone mineral mass, gross motor function, muscle force and fracture incidence in patients with OI type VI. However, the gains in mobility scores and reductions in fracture incidence during pamidronate treatment are less than in other OI types.

Abstract: Transiliac cortical bone histomorphometry was performed in 56 metabolic bone disease-free individuals 1.5-22.9 years of age. During the growing years, the two cortices of an iliac bone specimen differ with regard to bone cell activity on their surfaces, probably reflecting a modeling drift. INTRODUCTION: Standard bone histomorphometry in the clinical setting is typically limited to the analysis of cancellous bone. However, during the growth period, important changes occur also in the cortical compartment. MATERIALS AND METHODS: Transiliac bone samples from 56 individuals between 1.5 and 22.9 years of age (25 male; tetracycline labeling present in 42 subjects) and without evidence of metabolic bone disease were analyzed. Each of the three bone surface types (periosteal, intracortical, endocortical) of each cortex was evaluated separately. Results were expressed relative to those obtained in trabecular bone. RESULTS: A significant increase in cortical width with age was detected only for the internal cortex. Porosity of the external cortex was highest in the 7- to 10.9-year age group and decreased thereafter, whereas there was no clear trend with age for the porosity of the internal cortex. Intracortical remodeling activity decreased after 14 years of age. Periosteal bone formation was very active until 13 years of age, but was close to zero in subjects above that age. As to endocortical surfaces, all bone surface-based parameters of bone formation were higher on the internal cortex than on the external cortex, whereas bone resorption parameters were higher on the external cortex. CONCLUSIONS: In growing subjects, the two cortices of an iliac bone specimen differ with regard to bone cell activity on their surfaces. These data raise fundamental questions about the regulation of bone cell activity in children and adolescents.

Abstract: Context: Intravenous pamidronate treatment is beneficial to children and adolescents with osteogenesis imperfecta (OI), but the effects of prolonged therapy are not well characterized. Objective: The objective of this study was to assess the effect of long-term pamidronate treatment on the bone tissue of children and adolescents with OI. Design: This is an observational study on OI patients receiving iv pamidronate for more than 4 yr. Setting: The study was carried out in a pediatric metabolic bone research unit. Patients: Patients were 25 moderately to severely affected OI patients (seven girls) aged 1.4-15.3 yr at baseline. Intervention: Intervention was cyclical iv pamidronate at a dose of 9 mg/kg.yr. Main Outcome Measures: Iliac bone biopsy and lumbar spine bone mineral density measures were obtained at treatment start, after 2.7 +/- 0.5 yr (mean +/- sd), and after 5.5 +/- 0.7 yr of therapy. Results: Average areal bone mineral density increased by 72% in the first half of the observation period, but by only 24% in the second half. Mean cortical width and cancellous bone volume increased by 87 and 38%, respectively, between baseline and the first time point during treatment (P < 0.001 for all changes). Thereafter, cortical width did not change significantly, but there was a trend (P = 0.06) toward higher cancellous bone volume. Average bone formation rate on trabecular surfaces decreased by 70% after pamidronate treatment was initiated and showed a trend (P = 0.08) toward a further decline in the second part of the study interval. Conclusion: The gains that can be achieved with pamidronate treatment appear to be largely realized in the first 2-4 yr.

Abstract: Children with moderate to severe forms of osteogenesis imperfecta (OI) require adequate physiotherapy, rehabilitation and orthopedic surgery. Supportive treatment with bisphosphonates can improve the effects of these nonmedicinal treatment modalities. Benefits of bisphosphonate treatment include decreased pain, lower fracture incidence, and better mobility. Among the various bisphosphonates, intravenous pamidronate has been studied in most detail. However, the optimal treatment regimen and the long-term consequences of pamidronate treatment in children are currently unknown. Given these uncertainties, treatment with bisphosphonates during growth should be reserved for patients who have significant clinical problems, such as vertebral compression fractures or long-bone deformities. Medical therapies other than bisphosphonates play a minor role at present. Gene-based therapy currently remains in the realm of preclinical research.

Abstract: This perspective paper presents a hypothesis that links abnormalities of bone material with densitometric findings in two congenital metabolic bone disorders, osteogenesis imperfecta type I (OI) and X-linked hypophosphatemic rickets (XLH). Analyses of iliac bone samples from OI patients have shown that material bone density is elevated and that the bone material is abnormally stiff in this disorder. Therefore, a given mechanical load on an OI bone will generate a smaller than normal deformation. This in turn should lead osteocytes, the putative mechanosensing cells, to systematically underestimate the prevailing mechanical forces. According to the mechanostat model, bone strength should then be adapted to the underestimated mechanical loads, which means that bone architecture and mass remain below requirements. Available densitometric studies are in accordance with this hypothesis. In XLH, a mild mineralization defect persists despite treatment. This mineralization defect should lead to soft bone material. In analogy to the above model for OI, mechanical loads should be overestimated, resulting in increased densitometric parameters of bone strength. Indeed, lumbar spine areal bone mineral density is usually elevated in such patients.

Abstract: Intravenous treatment with pamidronate is beneficial in children and adolescents with moderate to severe forms of osteogenesis imperfecta (OI) types I, III and IV, but there is little information on the effects of this treatment on the newly described OI type V. Here, we describe the results of 2 years of pamidronate treatment in 11 children and adolescents with OI type V (age at start of therapy 1.8 to 15.0 years; 6 girls). Pamidronate was given in intravenous cycles at a cumulative yearly dose of 9 mg/kg. The first infusion cycle was associated with fever and mild hypocalcemia in most patients, but no other short-term side effects were noted. Two years of pamidronate treatment led to a decrease in the urinary excretion of N-terminal telopeptide of type I collagen to 50% of baseline levels. Both the size and volumetric bone mineral density of lumbar vertebrae increased compared to age- and sex-matched reference data (P < 0.05 in both cases). Histomorphometry of transiliac bone samples showed an average increase of 86% in cortical thickness (N = 7; P = 0.005). No significant changes with treatment were observed in the age-related z scores of isometric maximal grip force and height. Fracture incidence decreased from 1.5 fractures per year before treatment to 0.5 fractures per year during the fist 2 years of treatment. Ambulation status improved in four patients and remained unchanged in the others. In conclusion, the intravenous pamidronate therapy has a similar effect in OI type V as it has in the other OI types.

Abstract: In this study we investigated the expression of bone morphogenetic protein (BMP)-signaling Smads in distraction osteogenesis (DO). Osteotomy of the right tibia was performed in 14 skeletally mature white New Zealand male rabbits. Lengthening was started 1 week later at a rate of 0.5 mm/12 hr and was maintained for 3 weeks. Expression of Smad proteins 1, 4, 5, 6, 7, and 8 and Smad ubiquitin regulatory factors (Smurfs) 1 and 2 was evaluated in the distracted zone using immunohistochemistry. Expression of receptor-regulated Smads (R-Smads) 1, 5, and 8 showed a significant increase during the distraction phase, followed by a gradual decrease during the consolidation phase. Smad 4 showed significant expression during both distraction and the beginning of the consolidation phase. Smad 6 and Smad 7 were highly expressed during the consolidation phase. Staining for both Smurfs 1 and 2 was maximal at the end of the distraction period. Staining for all proteins was most intense in chondrocyte and fibroblast-like cells. Expression pattern of R-Smads correlated with our previously reported expression pattern of BMPs 2, 4, and 7 and their receptors. These results therefore suggest a role for the whole BMP signaling pathway including the Smad proteins in DO.

Abstract: The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.

Abstract: Histomorphometric analysis of iliac bone samples is a key tool for studying bone metabolism and, to a lesser extent, bone mass and structure. Two types of bone metabolic activity can be distinguished: modeling and remodeling. Both processes are performed by the same effector cells, osteoblasts and osteoclasts, but differ in the way these cells are arranged. The main effect of remodeling is to renew bone, whereas modeling can lead to rapid changes in bone shape, size and mass. Standard histomorphometric analysis focuses on trabecular bone and therefore mainly provides information on remodeling. Remodeling activity changes markedly with age during development. This must be taken into account when histomorphometry is used in the pediatric setting. Remodeling disorders encountered in the context of pediatric renal bone disease include mineralization defects, as well as abnormally high remodeling activity due to secondary hyperparathyroidism or suppressed remodeling activity as a consequence of over-treatment. Children and adolescents with severe bone fragility should have a bone biopsy unless the diagnosis is obvious from noninvasive examinations. Histomorphometric analysis of transiliac bone biopsy samples is especially valuable in clinical studies, as this method provides safety and efficacy data that cannot be obtained in any other way.

Abstract: Cyclical intravenous pamidronate therapy increases bone mass in children with osteogenesis imperfecta (OI), but the effect on the intrinsic material properties of bone is unknown at present. Thus, a possible influence of pamidronate treatment on bone quality at the material level might negate the beneficial effects of the gain in bone mass and lead to bone fragility in the long term. In the present study, we used transiliac bone biopsy samples and assessed the intrinsic material properties of the bone tissue at the micron-level by combined backscattered electron imaging and nanoindentation. Paired iliac bone samples from 14 patients (age 3 to 17 years) with severe OI before and after 2.5 +/- 0.5 years (mean +/- SD) of pamidronate treatment as well as age-matched controls were examined. Bone histomorphometry was performed in all samples and confirmed an increase of bone mass in treated patients. Backscattered electron imaging was used to measure the weighted mean calcium content (Ca(Mean)), the most frequent calcium content (Ca(Peak)), the variation in mineralization (Ca(Width)) and the amount of lowly mineralized areas (Ca(Low)) that correspond to sites of primary mineralization. Nanoindentation was performed in a subgroup of 6 patients and 6 controls to determine hardness and elastic modulus. Compared to controls, untreated OI patients had a significantly higher degree of bone matrix mineralization (Ca(Peak) +7%, P < 0.001) and a strong reduction of Ca(Low) (-38%, P < 0.001) despite enhanced bone formation, as well as increased hardness (+21%, P < 0.01) and elastic modulus (+13%, P < 0.01). However, none of these parameters was significantly altered by the subsequent pamidronate treatment. This shows that OI bone is stiffer and more mineralized and that, despite the enhanced bone formation rate in these patients, areas of primary mineralization are hardly visible. We also conclude that pamidronate treatment in children with OI does not have an adverse effect on the intrinsic material properties of bone and, as a consequence, that a long-term administration of the drug might not increase brittleness and fragility of the bone matrix. The antifracture effectiveness of pamidronate treatment in OI, as shown in previous clinical studies, has to be explained by the increase of mainly cortical bone volume.

Abstract: The purpose of this study was to determine the incidence and clinical presentation of coxa vara in 283 patients with osteogenesis imperfecta (OI). The charts and X-rays of 150 girls and 133 boys with OI were reviewed. The patients were classified according to the Sillence classification modified by Glorieux: 94 type I, 90 type IV, 67 type III, 18 type V, 10 type VI, and 4 type VII. The mean age was 9.4 years (range 0.3-23.3). Twenty-nine patients (10.2%) had coxa vara (23 left and 20 right). Fifty-five percent of them were type III, 24% type IV, 13.8% type VI, and 3.4% each of types V and VII. The incidence of coxa vara was 6% in type V, 8% in type IV, 24% in type III, 25% in type VII, and 40% in type VI (P < 0.001 for difference between types I, III, and IV). The mean neck-shaft angle was 99 degrees (range 80-110 degrees), the average head-shaft angle was 104 degrees (range 90-120 degrees), and the mean Hilgenreiner-epiphyseal angle was 68 degrees (range 40-90 degrees). Twenty-five patients (36 hips) had previous femoral rodding before diagnosis and seven hips (all type III) had no history of rodding. Abduction and internal rotation of the hip joints were restricted in all patients with this deformity. All children with coxa vara had a Trendelenburg gait. In conclusion, coxa vara in OI is not rare, especially in severe forms of the disease. Regular clinical and radiologic follow-up is indicated in children with previous femoral rodding and in severely affected children, particularly those with OI type III.

Abstract: OBJECTIVE: To evaluate the functional abilities and the level of ambulation during pamidronate therapy in children with moderate to severe osteogenesis imperfecta. STUDY DESIGN: Functional abilities, ambulation, and grip force were assessed in 59 patients (mean age, 6.1 years; range, 0.5-15.7 years; 30 girls) during 3 years of pamidronate treatment. Functional skills (mobility and self-care) were both assessed by using the Pediatric Evaluation of Disability Inventory. Ambulation level was assessed by using the modified Bleck score. For 48 patients, results after 3 years of pamidronate treatment could be matched to those of patients with similar age and disease severity who had not received pamidronate. RESULTS: Mobility and self-care scores increased during the study period (+43% and +30%, respectively). The average ambulation score changed from 0.8 to 1.9. Maximal isometric grip force increased by 63%. Mobility and ambulation scores and grip force measures were significantly higher than in patients who had not received pamidronate. The difference in self-care scores did not reach significance. CONCLUSION: This study suggests that cyclical pamidronate treatment improves mobility, ambulation level, and muscle force in children with moderate to severe osteogenesis imperfecta.

Abstract: Prolyl hydroxylation is a critical posttranslational modification that affects structure, function, and turnover of target proteins. Prolyl 3-hydroxylation occurs at only one position in the triple-helical domain of fibrillar collagen chains, and its biological significance is unknown. CRTAP shares homology with a family of putative prolyl 3-hydroxylases (P3Hs), but it does not contain their common dioxygenase domain. Loss of Crtap in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/- bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover, mutant collagen shows evidence of overmodification, and collagen fibrils in mutant skin have increased diameter consistent with altered fibrillogenesis. In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms. Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease.

Abstract: Results in small patient series suggest that cyclical intravenous treatment with pamidronate can lead to reshaping of compressed vertebral bodies in children and adolescents with osteogenesis imperfecta (OI), but more detailed analyses are lacking. In this study of patients with moderate to severe OI (age range 0.1 to 16.7 years), we used vertebral morphometry to longitudinally assess changes in lumbar vertebral shape before (n = 17 patients) and during 2 to 4 years of pamidronate treatment (n = 72 patients). Anterior, posterior and midpoint vertebral heights of lumbar vertebrae L1 to L4 were determined on lateral lumbar spine X-rays and were related to vertebral body length in the antero-posterior direction. Before pamidronate treatment, vertebral body height ratios did not change significantly, but the mean concavity index (defined as the ratio between midpoint and posterior vertebral body heights) decreased by 22% (P = 0.002). Pamidronate treatment was associated with an increase in vertebral height ratio at each of the 12 sites that were analyzed. Consequently, patients who had received pamidronate for an average of 3 years had less compressed vertebrae than a historical control group of patients who had the same OI type, age and sex but who had not received pamidronate. Multiple regression analysis revealed that age was negatively and lumbar spine areal bone mineral density z score was positively associated with vertebral shape at baseline. The main determinant of treatment response was the severity of vertebral deformities at baseline. These results suggest that vertebral deformations worsen in patients with moderate to severe OI who do not receive medical treatment and that pamidronate helps to reverse this trend. In moderate to severe forms of OI, pamidronate should be started as early as possible to treat or to prevent vertebral deformations.

Abstract: Distraction osteogenesis (DO) is a surgical technique for generating new bone by applying controlled distraction of two bony segments post osteotomy. A limitation of the technique is the long time required for the new bone to consolidate. We investigated the effect of injecting osteogenic protein 1 (OP-1) at the beginning of distraction in a rabbit model of DO. Regenerate bone was evaluated using radiology, densitometry, micro-computed tomography (microCT) and histomorphometry. Immunohistochemsitry was used to evaluate changes in expression of various ligands, growth factors and receptors following OP-1 treatment. Compared to the control, a two-fold increase in bone volume was apparent for treated groups at 3 weeks post injection. An upregulation of almost all of the 41 genes examined was observed. Results suggested that applying OP-1 early during distraction can accelerate bone formation by the activation of numerous pathways. This study provides further insights on strategies to improve bone regeneration rate in DO.

Abstract: Intramuscular injections with botulinum toxin A (BTX-A) lead to a rapid decrease in muscle mass and force, but the effect of this drug on bone development is unclear. In the present pilot study we evaluated the effect of a one-time injection of BTXA in growing rabbits. Twelve young (weight 1.5 kg) New Zealand rabbits were randomly assigned to receive either BTX-A (total dose 8 units per kg body weight) or sodium chloride 0.9% injections into the left quadriceps and gastrocnemius muscles. Both groups continued to gain weight in a similar manner following the injection. However, when the animals were sacrificed at five weeks after the injection, the group receiving BTX-A had a significant deficit (of 10%) in gastrocnemius muscle mass on the injected side, whereas no significant side-difference was found for the quadriceps. BTX-A injections did not affect the length of the tibia. Nevertheless, bone mineral content of the whole tibia, as measured by dual-energy X-ray absorptiometry, was 7% lower in the BTX-A injected side than on the contralateral side. Peripheral quantitative computed tomography showed that this bone mass deficit was larger in the metaphysis than in the epiphysis or diaphysis. In the diaphysis, the bone mass deficit was due to a reduction in cross-sectional bone dimensions, which equally affected the cross-section of the entire bone, the cortical compartment and the marrow space. BTX-A injections did not have a detectable effect on cortical bone mineral density. The bone mass deficit in the diaphysis thus appeared to be caused by a lack of periosteal bone apposition rather than increased endocortical or intracortical resorption. These preliminary data suggest that intramuscular BTX-A injections can have a deleterious effect on the development of bones that are loaded by the injected muscles.

Abstract: Context: Cyclical iv pamidronate is a widely used symptomatic therapy of osteogenesis imperfecta (OI). What happens after treatment discontinuation is unknown. Objective: The objective of this study was to assess the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. Design: This was an open-label controlled and observational study in patients who had received pamidronate for more than 3 yr. Setting: This study was performed at a pediatric metabolic bone research unit. Patients: In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 yr). Intervention: The intervention was discontinuation of pamidronate treatment for 2 yr. Main Outcome Measures: The main outcome measures were lumbar spine bone mineral content and areal bone mineral density (aBMD), biochemical markers of bone metabolism, fracture incidence, and clinical evaluation. Results: In the controlled study, bone resorption activity was higher after treatment discontinuation. Bone mineral content continued to increase in both groups. aBMD z-scores decreased in the untreated group, but increased in the continuation cohort. Fracture rates and functional status were similar between groups. In the observational study, bone resorption activity increased after treatment discontinuation, but remained significantly lower than in untreated OI patients. Bone mineral content and aBMD continued to increase, whereas aBMD z-scores decreased. Changes were faster in patients who continued growing. Conclusions: Bone metabolism is still suppressed 2 yr after pamidronate discontinuation. Bone mass gains continue after treatment is stopped, but lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent.

Abstract: This analysis of 50 growing patients with osteogenesis imperfecta revealed that 2-4 years of pamidronate treatment lead to abnormalities in the shape of the distal femoral metaphyses. INTRODUCTION: Cyclical intravenous pamidronate therapy is of clinical benefit in children and adolescents with moderate to severe osteogenesis imperfecta (OI) but might interfere with the shaping of long bone metaphyses during growth. MATERIALS AND METHODS: We evaluated the distal femur in 50 growing children with moderate to severe OI (mean age, 6.7 +/- 3.4 years; 26 girls) who had received 2-4 years of pamidronate therapy (annual dose, 9 mg/kg body weight). The mediolateral width of the distal femoral growth plate and of the metaphysis, as well as the ratio between these two measures (called metaphyseal index), were determined on lower limb radiographs. RESULTS: Compared with untreated OI patients who were matched for OI type and age, pamidronate-treated patients had similar growth plate width but wider metaphyses, resulting in a 26% higher metaphyseal index (p < 0.001). Apart from the effect on bone shape, each pamidronate cycle induces a transverse line in metaphyses that are adjacent to active growth plates. Analyses of these transverse lines revealed that they persist for an average time of approximately 4 years, with a range from 2 to 8 years. CONCLUSIONS: Pamidronate interferes with the process of periosteal resorption that is normally responsible for shaping the distal femoral metaphysis. Pamidronate-induced transverse lines disappear with time, supporting the view that these lines represent horizontal trabeculae that undergo remodeling. There is no evidence at present that these treatment induced morphological changes have any clinical implications.

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Abstract: Physiotherapy, rehabilitation, and orthopedic surgery are the mainstay of treatment in moderate to severe forms of osteogenesis imperfecta (OI). Nevertheless, medical treatment with bisphosphonates can bring significant additional improvements. Benefits include decreased pain, lower fracture incidence, and better mobility. Among the various bisphosphonates, intravenous pamidronate has been studied in most detail. It is unclear whether oral bisphosphonates are as effective as intravenous pamidronate. As the effect of bisphosphonates on the skeleton is largest during growth, it appears logical to start medical therapy of OI patients as early as possible. However, the optimal treatment regimen and the long-term consequences of pamidronate treatment in children are currently unknown. Given these uncertainties, treatment with bisphosphonates during growth should be reserved for patients who have significant clinical problems, such as vertebral compression fractures or long bone deformities. Medical therapies other than bisphosphonates, such as growth hormone and parathyroid hormone, play a minor role at present. Gene-based therapy currently remains in the early stages of preclinical research.

Abstract: Application of bone densitometry to clinical use requires the availability of accessible reference data and is helped by an interpretative framework that is based on bone physiology. The aim of this contribution is to provide both reference data and help in the interpretation of results for peripheral quantitative computed tomography (Stratec XCT2000(R)) performed at the distal radius of young subjects. Data from a previous reference data study on 478 subjects between 6 and 40 years were re-analyzed and smooth curves were fitted. The corresponding equations allow for calculation of age- and sex-specific z-scores of bone mineral content, volumetric bone mineral density (vBMD) of the trabecular compartment, vBMD of the entire radial cross-section, total cross-sectional area and cortical thickness. These data should facilitate the clinical use of peripheral quantitative computed tomography in young subjects.

Abstract: Clinical and histomorphometric outcome was compared between children with OI who had received pamidronate since infancy and age-matched patients who had never received pamidronate. Pamidronate was associated with improved vertebral shape and mass, higher cortical width, increased cancellous bone volume, and suppressed bone turnover. INTRODUCTION: Observations in small patient series indicate that infants with severe osteogenesis imperfecta (OI) benefit from treatment with cyclical intravenous pamidronate. However, detailed analyses of outcome are lacking for this age group. MATERIALS AND METHODS: Clinical outcome was evaluated in 29 children with OI types I (n = 3), III (n = 14), or IV (n = 12) who started pamidronate therapy before 2 years of age (age at treatment onset: median, 6 months; range, 2 weeks to 23 months) and who had completed 3 years of treatment (total annual pamidronate dose, 9 mg/kg). They were compared with a historical control group of 29 untreated children with severe OI who were matched for OI type and age at the 3-year treatment time-point. In addition, iliac bone histomorphometry was compared between 24 pamidronate-treated patients and 24 age-matched OI patients who had not received pamidronate. RESULTS: Morphometric evaluation of lumbar vertebrae (L(1)-L(4)) showed that the shape of vertebral bodies was better preserved in pamidronate-treated patients. This was accompanied by significantly higher lumbar spine areal and volumetric BMD (+110 and +96%, respectively) and a larger vertebral bone volume (+26%) on densitometry. Regarding mobility function, the Pediatric Evaluation of Disability Inventory gross motor score was 50% greater in the pamidronate group (p < 0.001). Iliac bone histomorphometry showed 61% higher cortical width and 89% higher cancellous bone volume in pamidronate-treated patients. Bone formation rate per bone surface in the pamidronate group was only 17% that of untreated patients. CONCLUSIONS: In conclusion, this study suggests that cyclical pamidronate treatment started in infancy leads to improved bone strength and better gross motor function but also suppresses bone turnover markedly. It is therefore prudent to reserve pamidronate treatment to infant OI patients who present with a moderate to severe phenotype.

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Abstract: CONTEXT: Alendronate (ALN) is a bisphosphonate compound that can be administered orally and has potential use in pediatric osteoporotic conditions. OBJECTIVE: The objective was to evaluate the pharmacokinetics and single-dose tolerability of ALN in children with osteogenesis imperfecta. DESIGN: ALN was administered iv and orally in a two-period, randomized crossover study, with doses separated by a 2-wk washout and follow-up carried out within 2 wk after the last ALN dose. SETTING: The study was conducted at the pediatric metabolic bone research unit at the Shriners Hospital for Children, Montreal, Canada. PATIENTS: Twenty-four children (aged 4-16 yr; eight girls) with osteogenesis imperfecta type I participated. INTERVENTIONS: All patients received iv ALN at a dose of 125 mug. In addition, patients weighing less than 40 kg received an oral dose of ALN 35 mg, whereas those weighing 40 kg or more received ALN 70 mg orally. MAIN OUTCOME MEASURES: Total urinary excretion and oral bioavailability of ALN, blood and urine safety parameters, and adverse events were the main outcome measures. RESULTS: The total urinary excretion of ALN after the iv dose was similar for both weight groups. The mean oral bioavailability (95% confidence interval) was 0.43% (0.28, 0.64%) for patients weighing less than 40 kg and 0.56% (0.36, 0.87%) for patients weighing 40 kg or more. Eighteen patients reported a total of 44 clinical adverse experiences, none of which were serious. The most common adverse experiences were mild to moderate headache (n = 7), nausea (n = 7), fever (n = 5), and abdominal pain (n = 6). Eighty percent of the adverse experiences (35 of 44) occurred within 48 h of medication administration, 91% (40 of 44) lasted less than 24 h, and 84% (37 of 44) were reported after oral dosing. Laboratory safety monitoring revealed a marginal decrease in absolute lymphocyte count and serum alkaline phosphatase after the study compared with baseline for both weight categories. CONCLUSIONS: The mean oral bioavailability of 35- and 70-mg ALN tablets was less than 0.6%, comparable to adult studies. Adverse experiences from single-dose ALN were minor, and the drug was generally well-tolerated.

Abstract: Treatment with bisphosphonates has brought significant clinical improvements for children and adolescents suffering from moderate to severe forms of osteogenesis imperfecta (OI). Benefits include decreased pain, lower fracture incidence, and better mobility. Among the various bisphosphonates, intravenous pamidronate has been studied in most detail. It is unclear whether oral bisphosphonates are as effective as intravenous pamidronate. As the effect of bisphosphonates on the skeleton is largest during growth, it appears logical to start medical therapy of OI patients as early as possible. Nevertheless, the optimal treatment regimen and the long-term consequences of pamidronate treatment in children are currently unknown. Given these uncertainties, treatment with bisphosphonates should be reserved for patients who have significant clinical problems, such as vertebral compression fractures or long bone deformities. At present, bisphosphonate treatment has little justification in growing patients with mild forms of OI who have few or no clinical symptoms. Such patients should not be treated unless clear clinical benefit can be demonstrated in ongoing placebo-controlled trials.

Abstract: Mechanostat theory postulates that developmental changes in bone strength are secondary to the increasing loads imposed by larger muscle forces. Therefore, the increase in muscle strength should precede the increase in bone strength. We tested this prediction using densitometric surrogate measures of muscle force (lean body mass, LBM) and bone strength (bone mineral content, BMC) in a study on 70 boys and 68 girls who were longitudinally examined during pubertal development. On the level of the total body, the peak in LBM accrual preceded the peak in BMC accretion by an average of 0.51 years in girls and by 0.36 years in boys. In the arms, the maximal increase in LBM was followed by arm peak BMC accrual after an interval of 0.71 years in girls and 0.63 years in boys. In the lower extremities, the maximal increase in LBM was followed by peak BMC accrual after an interval of 0.22 years in girls and 0.48 years in boys. A multiple regression model revealed that total body peak LBM velocity, but not peak height velocity and sex, was independently associated with total body peak BMC velocity (r(2) = 0.50; P < 0.001). Similarly, arm and leg peak LBM velocity, but not peak height velocity and sex, were independently associated with arm and leg peak BMC velocity, respectively (r(2) = 0.61 for arms, r(2) = 0.41 for legs; P < 0.001 in both cases). These results are compatible with the view that bone development is driven by muscle development, although the data do not exclude the hypothesis that the two processes are independently determined by genetic mechanisms.

Abstract: Osteopathia striata with cranial sclerosis (OS-CS) is a rare skeletal dysplasia characterized by linear striations of the long bones, osteosclerosis of the cranium, and extra-skeletal anomalies. We provide a comprehensive description of the skeletal phenotype in a French-Canadian girl with a moderate to severe form of sporadic OS-CS. Multiple medical problems, including anal stenosis and the Pierre-Robin sequence, were evident in the first few years of life. At 14 years, she was fully mobile, with normal intellect and stature. She suffered chronic lower extremity pain in the absence of fractures, as well as severe headaches, unilateral facial paralysis, and bilateral mixed hearing loss. Biochemical indices of bone and mineral metabolism were within normal limits. Bone densitometry showed increased areal bone mineral density in the skull, trunk, and pelvis, but not in the upper and lower extremities. An iliac bone biopsy specimen revealed an increased amount of trabecular bone. Trabeculae were abnormally thick, but there was no evidence of disturbed bone remodeling. In a cranial bone specimen, multiple layers of periosteal bone were found that covered a compact cortical compartment containing tightly packed haversian canals. Bone lamellation was normal in both the iliac and skull samples. Osteoclast differentiation studies showed that peripheral blood osteoclast precursors from this patient formed functional osteoclasts in vitro. Thus, studies of bone metabolism did not explain why bone mass is increased in most skeletal areas of this patient. Cranial histology points to exuberant periosteal bone formation as a potential cause of the cranial sclerosis. Copyright 2004 Wiley-Liss, Inc.

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Abstract: Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH)(2) vitamin D was very low (14 pM; N: 40-140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33-105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

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Abstract: X-linked hypophosphatemia (XLH) is characterized by rickets and osteomalacia and arises from mutations in the Phex and PHEX genes in mice (Hyp) and humans, respectively. The present study was undertaken to examine the effect of gene dose on the skeletal phenotype using a histomorphometric approach. Metrical traits (vertebral length, growth plate thickness, cancellous osteoid volume per bone volume, and cancellous, endocortical, and periosteal osteoid thickness) were compared in caudal vertebrae of mutant female (Hyp/+, Hyp/Hyp) and male (Hyp/Y) mice and their normal female (+/+) and male (+/Y) littermates. Mutant animals had trait values that differed significantly from those of normal animals. However, with the exception of vertebral length and cancellous osteoid thickness, values were not significantly different between the three mutant genotypes. We also examined the effect of gamete-of-origin on histomorphometric parameters in obligate Hyp/+ females derived from male or female transmitting parents. The metrical trait values in both groups of Hyp/+ mice were similar, with the exception of vertebral length and cancellous osteoid volume per bone volume. In summary, we demonstrate that the amount of osteoid per bone volume is similar in the three mutant genotypes and conclude that the extent and magnitude of the mineralization defect is fully dominant and likely not affected by gene dose. The differences in vertebral length in the mutants suggest that rickets and osteomalacia are not the only causes of decreased vertebral growth in Hyp mice and that Phex protein may influence bone growth and mineralization by distinct pathways.

Abstract: This study evaluated factors influencing fracture (n = 197) and osteotomy (n = 200) healing in children with moderate to severe OI. Pamidronate treatment was associated with delayed healing after osteotomy, but not after fracture. The data suggest that both pamidronate and mechanical factors influence bone healing in this cohort. INTRODUCTION: Intravenous pamidronate is widely used to treat children with moderate to severe osteogenesis imperfecta (OI). However, the effect of this treatment on bone healing is not well characterized. We therefore retrospectively analyzed the healing of lower limb fractures and osteotomies in children with moderate to severe OI, both before and after the start of pamidronate treatment. MATERIALS AND METHODS: Bone healing was evaluated on standard radiographs after 197 lower limb fractures (132 femur and 65 tibia) in 82 patients (age at fracture, 0.0-19.9 years) and 200 intramedullary rodding procedures in 79 patients (age at surgery, 1.2-19.8 years). Delayed healing was diagnosed when a fracture or osteotomy line was at least partially visible 12 months after the event. RESULTS: Delayed fracture healing was observed more frequently during than before pamidronate treatment. However, the effect of pamidronate was no longer significant when age differences were taken into account (odds ratio [OR], 1.76; 95% CI, 0.61-5.10). Better mobility status was a strong independent predictor of delayed healing after fractures that occurred during pamidronate treatment. After osteotomies, delayed healing was more frequent when pamidronate had been started before surgery (OR, 7.29; 95% CI, 2.62-20.3), and this effect persisted after adjustment for multiple confounders. During pamidronate treatment, older age (OR per year of age, 1.25; 95% CI, 1.06-1.47) and osteotomy of the tibia (OR, 3.51; 95% CI, 1.57-7.82) were independent predictors of delayed healing. CONCLUSIONS: This study suggests that pamidronate therapy is associated with delayed healing of osteotomy sites after intramedullary rodding procedures. Better mobility status, but not pamidronate treatment, seems to be predictive of delayed healing after fractures.

Abstract: The pregnancies of two women with osteogenesis imperfecta who received intravenous pamidronate before conception are reported. The mothers suffered no ill effects. One baby had transient asymptomatic hypocalcemia and one had bilateral talipes equinovarus. This report documents the pregnancy outcomes of two women with osteogenesis imperfecta (OI), types I and IV, who received intravenous pamidronate as part of an observational trial before conception. Pamidronate was not administered after conception. Other than hyperemesis in one woman, the pregnancies and deliveries were uneventful. Both babies inherited OI from their mothers. The baby with OI type IV also had bilateral talipes equinovarus. Biochemical evaluation of the mothers and babies at 24 h and/or 2 weeks postpartum was normal, apart from one baby with asymptomatic hypocalcemia at 24 h of age that had resolved when next measured on day 11 of life. No biochemistry was available on the second child until 13 days of age. Neither baby had skeletal modeling abnormalities consistent with in utero pamidronate exposure. The lumbar spine (L1-L4) areal BMD and anterior to posterior height ratios of lumbar vertebral bodies of both women remained constant during pregnancy. Both the mothers and babies remain well and free of fracture 14 and 16 months postpartum.

Abstract: In this report, we describe three unrelated children with an apparently novel bone fragility disorder that is associated with an idiopathic mineralization defect. Recurrent lower limb fractures started with weight bearing. The patients had none of the phenotypic, radiological, or histomorphometric features classically associated with known bone fragility disorders such as osteogenesis imperfecta (OI), idiopathic juvenile osteoporosis (IJO), or mild autosomal dominant osteopetrosis. Radiologically, there was increased metaphyseal trabeculation, normal to increased cortical thickness, and no evidence of rickets or osteomalacia. Areal and volumetric bone mineral density (BMD) of the lumbar spine did not show any major alteration. Peripheral quantitative computed tomography of the radius showed elevated cortical thickness and total and trabecular volumetric bone mineral density in one patient. Qualitative histology of iliac bone biopsy specimens showed a paucity of the birefringent pattern of normal lamellar bone. Quantitative histomorphometric analysis demonstrated osteomalacia with a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. There was no biochemical evidence of abnormal calcium or phosphate metabolism. Type I collagen mutation analysis was negative. We conclude that this is a bone fragility disorder of moderate severity that tends to cause fractures in the lower extremities and is associated with the accumulation of osteoid due to an intrinsic mineralization defect. The pathogenetic basis for this disorder remains to be elucidated.

Abstract: This report aims to describe the adverse respiratory events associated with the first pamidronate cycle in four infants with severe osteogenesis imperfecta (OI) who were less than 2 years of age. Fifty-nine infants with severe OI were commenced on cyclical intravenous pamidronate therapy in an observation trial. Routine observations were measured during each infusion cycle. During the first treatment cycle, four infants (7%) with preexisting respiratory compromise developed respiratory distress. The respiratory distress was successfully managed with bronchodilator therapy. Two of the infants required intensive care admission. There was no recurrence of respiratory distress with subsequent pamidronate infusion cycles. In infants with severe OI and preexisting respiratory compromise, the first pamidronate infusion cycle may be associated with an acute deterioration of respiratory function. The etiology is unclear but may involve cytokine release and/or hemodynamic compromise from fluid administration during the first infusion cycle. Close monitoring throughout the first treatment cycle is of paramount importance.

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Abstract: Osteogenesis imperfecta is a genetic disorder of increased bone fragility, low bone mass, and other connective-tissue manifestations. The most frequently used classification outlines four clinical types, which we have expanded to seven distinct types. In most patients the disorder is caused by mutations in one of the two genes encoding collagen type 1, but in some individuals no such mutations are detectable. The most important therapeutic advance is the introduction of bisphosphonate treatment for moderate to severe forms of osteogenesis imperfecta. However, at present, the best treatment regimen and the long-term outcomes of bisphosphonate therapy are unknown. Although this treatment does not constitute a cure, it is an adjunct to physiotherapy, rehabilitation, and orthopaedic care. Gene-based therapy presently remains in the early stages of preclinical research.

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Abstract: OBJECTIVES: Treatment with pamidronate improves the clinical course in children with osteogenesis imperfecta (OI), but theoretically might affect longitudinal growth. In this study we analyzed growth during cyclical intravenous pamidronate treatment in children and adolescents (age.04-15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV. METHODS: The effect of 1 year of pamidronate treatment on height and weight was analyzed in 116 patients (OI-I, N = 29; OI-III, N = 42; OI-IV, N = 45). The results of 4 years of therapy were evaluated in 41 children (OI-I, N = 12; OI-III, N = 14; OI-IV, N = 15). RESULTS: Baseline height was low for age in all OI types. After 1 year of pamidronate therapy, height z scores had increased significantly in OI-III (by 0.3 +/- 0.8, mean +/- standard deviation; P =.04) and did not change in OI-I and OI-IV. Weight z scores increased significantly in OI-I (by 0.2 +/- 0.4, P =.01). After 4 years of pamidronate therapy, mean height z scores increased significantly in OI-IV (by 0.41 +/- 0.71, P =.04), whereas nonsignificant trends to increase were found for OI-I and OI-III. When height was expressed as a percentage of the result expected for untreated patients with the same OI type, long-term pamidronate therapy was associated with a significant height gain in all 3 OI types (P <.001). Eight patients who reached final height after 3.0 +/- 1.0 years of treatment were taller on average than expected for untreated patients (P =.04). CONCLUSIONS: Four years of cyclical intravenous pamidronate treatment led to a significant height gain in moderately to severely affected OI patients.

Abstract: Summary: This article gives an overview of the physiology of biochemical indices of bone metabolism, their origin, the problems of interpreting their activities and the most important clincal applications in childhood and adolescence. Markers of bone formation are osteoblast products which enter the circulation like alkaline phosphatase (bone isoform), osteocalcin and type I procollagen peptides. Both traditional and new markers for bone resorption, detected in urine analyses, are matrix (collagen) degradation products deriving from osteoclast activity. They include urinary hydroxyproline, hydroxylysine glycosides, total or free pyridinoline cross-links and cross-linked N- or C-telopeptides. Many studies have shown that both the old and new markers of bone metabolism are useful tools for basic bone biology research, for defining physiological phenomena in clinical studies, or in drug trials as growth modifying therapies (growth hormone) for following-up individual patients. But for the exact interpretation of bone marker analyses it is absolutely necessary to define the factors which may have an influence on measurement of the markers, such as age, sex, puberty, height velocity, circadian rhythms, diet, liver function, and kidney clearance rates.

Abstract: OBJECTIVE: To examine changes in grip force during pamidronate therapy in children and adolescents with severe osteogenesis imperfecta (OI). METHODS: Maximal isometric grip force of the nondominant hand was prospectively determined in 42 patients (age at the start of the study: 7.3-15.9 years; 18 girls) with severe forms of OI. Patients were treated with intravenous pamidronate infusions given in 4 monthly cycles, each cycle consisting of 3 infusions (1 mg pamidronate/kg body wt) on 3 successive days. RESULTS: At the start of pamidronate therapy, grip force was low compared with age-specific reference data (age z score mean +/- standard deviation: -2.7 +/- 2.1) but was normal for weight (weight z score: -0.1 +/- 1.8). Four months after the first pamidronate infusion cycle, grip force had increased significantly, whether related to age (age z score: -2.0 +/- 1.8) or to weight (weight z score: 0.6 +/- 1.5). At 2 years after the start of therapy, grip force z scores were not significantly different from the 4-month results. CONCLUSIONS: Maximal isometric grip force markedly increases after a single cycle of intravenous pamidronate in children with severe forms of OI, and this gain in grip force is maintained for at least 2 years.

Abstract: Intravenous infusions with the bisphosphonate compound pamidronate decrease bone pain and reportedly can lead to refilling of dysplastic lesions in adults with fibrous dysplasia (FD) of bone. Here we describe the effects of this treatment approach in 18 children and adolescents (age at start of therapy, 6.2-17.5 yr; eight girls) with polyostotic FD, who received pamidronate for 1.2-9.1 yr (median, 3.8 yr). Treatment cycles with pamidronate (1-1.5 mg/kg.d on 3 consecutive days) were given every 4 months. Levels of serum alkaline phosphatase and urinary collagen type I N-telopeptide were elevated at baseline and decreased continuously during the first 3 yr of therapy. There was no radiographic evidence of filling of lytic lesions or thickening of the bone cortex surrounding the lesions in any patient. Histomorphometric results in dysplastic bone tissue of patients receiving pamidronate (n = 7; time of therapy, 1.4-4.8 yr) were similar to those of patients without medical therapy (n = 9). No serious side effects were noted. In conclusion, pamidronate therapy appears to be safe in children and adolescents with polyostotic FD. However, we found no clear evidence that pamidronate has an effect on dysplastic lesions in such patients.

Abstract: Osteogenesis imperfecta is a heritable disorder of bone formation resulting in low bone mass and a propensity to fracture. It exhibits a broad range of clinical severity, ranging from multiple fracturing in utero and perinatal death to normal adult stature and a low fracture incidence. The disorder is currently classified into seven types based on differences in clinical presentation and bone architecture. Mutation in one of the type I collagen genes is commonly associated with osteogenesis imperfecta, but is not a prerequisite for the diagnosis. Indeed, the newer forms of osteogenesis imperfecta (types V, VI and VII) are not associated with type I collagen gene defects. Amongst the type I collagen gene mutations that can occur, missense base substitutions involving glycine codons in the exons encoding the central triple-helix forming domain predominate. Such mutations can occur in all the classical forms of osteogenesis imperfecta (types I-IV), but genotype/phenotype correlations are complex and often unpredictable. Treatment of osteogenesis imperfecta by bisphosphonate therapy can improve bone mass in all types of the disorder, and while not being a cure for the disorder does improve the quality of life of the patient.

Abstract: Cyclical intravenous therapy with pamidronate improves the clinical course in children and adolescents with osteogenesis imperfecta (OI). In this study, we evaluated the effect of this therapy on lumbar spine bone mass (bone mineral content [BMC]), size (bone volume [BV]), and density (volumetric bone mineral density [vBMD]). Results from 56 patients (age, 0.2-15.9 years; 25 girls) on long-term pamidronate treatment were compared with those of 167 patients who had not received pamidronate before densitometry. In all patients who received pamidronate, BMC, BV, and vBMD increased above levels expected for untreated patients (p < 0.001 in each case). After 4 years of treatment, BMC, BV, and vBMD were 154%, 44%, and 65% higher, respectively, in treated than in untreated patients who were matched for age and OI type. A multiple regression model showed that baseline BMC was negatively associated with the increase in BMC. In conclusion, the bone mass increase in pediatric OI patients receiving pamidronate is caused by increases in both bone size and density. Patients with larger deficits in bone mass at baseline have a more marked bone mass gain during therapy.

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Abstract: In this study we tested the effect of locally applied osteogenic protein 1 (OP-1) on distraction osteogenesis in rabbits. Seven days after tibial osteotomy, distraction was started at a rate of 0.25 mm per 12 h for 3 weeks. At the end of the distraction period, OP-1 was injected at the site of osteotomy. Four different dosages were tested (0, 80, 800, or 2000 microg; eight rabbits per dose group). Rabbits were sacrificed 3 weeks later, and histologic, densitometric, and biomechanical parameters were assessed. No significant differences were found between groups for any parameter. To explain why this approach was only modestly successful, the expression of BMP receptor protein in the newly formed tissue was analyzed by immunohistochemistry. Strong expression of BMP receptor IA, IB, and II was found during the early distraction phase, but not during later stages of the process. Thus, it appears that the lack of receptor protein in the target tissue impairs the effect of OP-1 given at the end of the distraction period. Possibly, OP-1 could be more useful when applied early in the distraction phase.

Abstract: Distraction osteogenesis is a form of in vivo tissue engineering in which the gradual separation of cut bone edges results in the generation of new bone. In this study, the temporal and spatial expression of bone morphogenetic proteins (BMPs) 2, 4, and 7 was examined in a rabbit model of mandibular distraction osteogenesis. Fourteen skeletally mature male rabbits were studied. After osteotomy, a distractor was applied to one side of the mandible. After 1 week of latency, distraction was initiated at 0.25 mm every 12 hours for 3 weeks (distraction period), followed by a 3-week consolidation period. Two animals were killed each week after surgery. The generate bone was analyzed for the expression of BMP-2, -4, and -7 by using standard bone histological and immunohistochemical techniques. BMP-2 and -4 were highly expressed in osteoblastic cells during the distraction period and in chondrocytes during the consolidation period. BMP-7 demonstrated relatively minor expression in osteoblastic cells during the distraction period. All BMPs were strongly expressed in vascularized connective tissue during the distraction period. These data indicate that BMPs participate in the translation of mechanical stimuli into a biological response during mandibular distraction osteogenesis.

Abstract: A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often, events at the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost's mechanostat theory. In this model, the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone.

Abstract: Cyclical iv therapy with pamidronate improves the clinical course in children and adolescents with osteogenesis imperfecta (OI). In this study we evaluated the effect of this therapy on bone and mineral metabolism in 165 patients with OI types I, III, and IV (age, 2 wk to 17.9 yr; 86 girls and 79 boys). All patients received iv pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2-4 months. During the 3 d of the first infusion cycle, serum concentrations of ionized calcium dropped by 0.14 +/- 0.008 mmol (mean +/- SE; P < 0.001), and serum PTH levels transiently almost doubled (P < 0.001). At the same time, urinary excretion of the bone resorption marker type I collagen N-telopeptide related to creatinine (uNTX/uCr) decreased by 61-73% (P < 0.001). Two to 4 months later, ionized calcium had returned to pretreatment levels, and uNTX/uCr remained 30-35% lower than at baseline (P < 0.001). During 4 yr of pamidronate therapy (n = 40 patients), ionized calcium levels remained stable, but PTH levels increased by about 30% (P < 0.01). uNTX/uCr, expressed as a percentage of the age- and sex-specific mean value in healthy children, decreased from 132 +/- 13% (mean +/- SE) at baseline to 49 +/- 3% after 4 yr of therapy (P < 0.001). In conclusion, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The consequences of chronically low bone turnover in children with OI are unknown at present.

Abstract: Cyclical pamidronate infusions increase bone mass in children suffering from osteogenesis imperfecta. The histological basis for these effects remains unknown. Therefore, we compared parameters of iliac bone histomorphometry from 45 patients before and after 2.4 +/- 0.6 years of pamidronate treatment (age at the time of the first biopsy, 1.4-17.5 years; 23 girls). Although biopsy size did not change significantly (P = 0.30), cortical width increased by 88%. Cancellous bone volume increased by 46%. This was due to a higher trabecular number, whereas trabecular thickness remained stable. Bone surface-based indicators of cancellous bone remodeling decreased by 26-75%. There was no evidence for a mineralization defect in any of the patients. These results suggest that, in the growing skeleton, pamidronate has a twofold effect. In remodeling, bone resorption and formation are coupled and consequently both processes are inhibited. However, osteoclasts and osteoblasts are active on different surfaces (and are thus uncoupled) during modeling of cortical bone. Therefore resorption is selectively targeted, and continuing bone formation can increase cortical width.

Abstract: Definition: Fibrous dysplasia (FD) of bone is a non-inheritable congenital disorder affecting both genders. It is characterized by expanding fibrous lesions, which contain bone-forming mesenchymal cells. Pathophysiology: FD is caused by a somatic activating mutation of the alpha subunit of the Gs protein (Gsalpha). Bone mesenchymal cells produce a matrix of randomly distributed collagen fibres and islands of woven bone. Osteoclasts are responsible for the spread of the lesions. Clinical Findings: The symptoms are bone pain, fracture, bone deformities and neurological deficits. Spontaneous regression of lesions does not occur. Treatment: Recently, an observational study of treatment with bisphosphonate has yielded promising results. There was a decreased intensity of bone pain, a decrease in biochemical markers of bone turnover and a radiographically apparent 'refilling of osteolytic sites' in about half of the patients. Conclusions: Very little is known about the effects of bisphosphonate treatment in children and adolescents with FD. Most patients report decreased bone pain after the first pamidronate infusion, which, in our view, justifies the use of this drug in severely affected patients. The many unanswered questions regarding this form of treatment can only be addressed when a large number of patients is treated in a standardized fashion, and data on the outcome are collected.

Abstract: Bone densitometric data often are difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. Here, we propose a functional approach to bone densitometry that addresses two questions: Is bone strength normally adapted to the largest physiological loads, that is, muscle force? Is muscle force adequate for body size? To implement this approach, forearm muscle cross-sectional area (CSA) and bone mineral content (BMC) of the radial diaphysis were measured in 349 healthy subjects from 6 to 19 years of age (183 girls), using peripheral quantitative computed tomography (pQCT). Reference data were established for height-dependent muscle CSA and for the variation with age in the BMC/muscle CSA ratio. These reference data were used to evaluate results from three pediatric patient groups: children who had sustained multiple fractures without adequate trauma (n = 11), children with preterminal chronic renal failure (n = 11), and renal transplant recipients (n = 15). In all three groups mean height, muscle CSA, and BMC were low for age, but muscle CSA was normal for height. In the multiple fracture group and in renal transplant recipients the BMC/muscle CSA ratio was decreased (p <. 0.05), suggesting that bone strength was not adapted adequately to muscle force. In contrast, chronic renal failure patients had a normal BMC/muscle CSA ratio, suggesting that their musculoskeletal system was adapted normally to their (decreased) body size. This functional approach to pediatric bone densitometric data should be adaptable to a variety of densitometric techniques.

Abstract: We have previously shown that idiopathic juvenile osteoporosis (IJO) is characterized by a decreased cancellous bone volume and a very low bone formation rate on cancellous surfaces. Whether IJO similarly affects cortical bone is unknown. We therefore compared tetracycline double-labeled transfixing iliac-crest bone biopsies from eight children with typical clinical features of IJO (six girls; age 10-12 years) and from nine children (four girls; age 9-12 years) without metabolic bone disease. No differences in intracortical remodeling activity were detected. Both structural parameters reflecting intracortical remodeling (cortical porosity, active canal diameter, and quiescent canal diameter) and bone surface-based metabolic parameters (osteoid, osteoblast, mineralizing, osteoclast and eroded surfaces, and bone formation rate) were similar in IJO patients and controls (p > 0.2 each, t-test). Although the internal cortex of the biopsy was thinner in IJO patients than in controls (660 +/- 170 microm vs. 980 +/- 320 microm; p = 0.02), there was no difference in the width of the external cortex (p = 0.36). In growing children, both cortices exhibit an external modeling drift. Therefore, the difference in internal cortical width point to a decreased modeling activity on the endocortical surface of the internal cortex. In fact, bone formation rate on this surface was 48% lower in IJO patients than in controls (82 +/- 45 microm(3)/microm(2) per year vs. 159 +/- 162 microm(3)/microm(2) per year). However, this difference did not achieve statistical significance (p = 0.21) due to the high variability of bone formation rate on modeling surfaces. The disturbance of bone remodeling in IJO is limited to cancellous bone, but there may be a modeling defect affecting the internal cortex. Thus, the process causing IJO appears to mainly affect bone surfaces that are in contact with the bone marrow cavity.

Abstract: BACKGROUND: In children and adolescents, markers of bone and collagen metabolism reflect the dynamics of skeletal growth and development. The aim of this study was to assess the relationship of the urinary collagen markers deoxypyridinoline (DPD) and hydroxylysine (Hyl) and its glycosides [galactosyl-Hyl (Gal-Hyl) and glucosyl-Gal-Hyl] with growth. METHODS: Urine samples from 240 apparently healthy children and adolescents (6-19 years; 124 girls) and from 51 prepubertal children with growth hormone (GH) deficiency (3-14 years; 14 girls) were analyzed. Urinary Hyl and its glycosides were quantified by HPLC, and DPD was assessed by chemiluminescence assay. Urinary concentrations of all markers were related to urinary creatinine. RESULTS: Multiple regression analysis revealed that only age and height velocity were independently associated with these markers in healthy children. In GH-deficient patients, the urinary excretion of both analytes after 4 weeks of GH therapy correlated significantly with the height increase during the first treatment year (r = 0.79 for Gal-Hyl; r = 0.70 for DPD; P <0.001 each). In a multivariate linear regression model using Gal-Hyl concentrations at 4 weeks, baseline concentrations of insulin-like growth factor 1 and height velocity after 3 months accounted for 80% of the variability in height gain during the first treatment year. A model using DPD concentrations at 4 weeks, in place of Gal-Hyl concentrations, as well as baseline concentrations of insulin-like growth factor 1 and height velocity after 3 months accounted for 83% of the variability. CONCLUSIONS: These urinary bone and collagen markers give some early indication of growth response, but the prediction of an individual marker is too imprecise to serve as a basis for clinical decisions. Markers of bone and collagen metabolism might be more useful as components of multivariate growth prediction models.

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Abstract: We have identified a novel form of autosomal recessive osteogenesis imperfecta (OI) in a small First Nations community from northern Quebec. Mutation screening of the COL1A1/COL1A2 genes revealed no detectable mutations, and type I collagen protein analyses were also normal. By linkage analysis, we mapped this unique autosomal recessive variant of osteogenesis imperfecta to chromosome 3p22-24.1. Based on the assumption of a founder effect, genome-wide screening was performed on a DNA sample pooled from seven affected individuals. Familial as well as historical recombinations identified within an extended haplotype of 19 markers localized the disease between markers D3S2324 and D3S1561, separated by <5 cM. Based on chromosomal localization to 3p22-24.1, the transforming growth factor-beta receptor 2 gene and the parathyroid hormone/parathyroid hormone-related peptide receptor were tested, but were excluded as being associated with the phenotype. This study excludes type I collagen mutations in the pathogenesis of the disease and assigns this form of OI to a locus other than the ones containing the type I collagen genes.

Abstract: Despite its fundamental importance for physical development, the growth of the muscle system has received relatively little consideration. In this study, we analyzed the relationship between cross-sectional area (CSA) of forearm muscles and maximal isometric grip force with age and pubertal stage. The study population comprised 366 children, adolescents, and young adults from 6 to 23 yr of age (185 female) and 107 adults (88 female) aged 29 to 40 yr. By use of peripheral quantitative computed tomography, muscle CSA was determined at the site of the forearm, whose distance to the ulnar styloid process corresponded to 65% of forearm length. Both muscle CSA and grip force were higher in prepubertal boys than in girls. The gender differences decreased until pubertal stage 3 and reincreased thereafter. In girls at pubertal stage 5, muscle CSA no longer increased with age (P > 0.4), whereas there was still some age-related increase in grip force (P = 0.02). In boys at pubertal stage 5, both muscle CSA and grip force continued to increase significantly with age (P < 0.005 each). Specific grip force (grip force per muscle CSA) adjusted for forearm length increased by almost one-half between 6 and 20 yr of age, with no difference between the genders. In conclusion, forearm muscle growth takes a gender-specific course during puberty, indicating that it is influenced by hormonal changes. However, the increase in specific grip force is similar in both genders and thus appears to be independent of sex hormones.

Abstract: Areal bone mineral density (BMD) is the most widely used densitometric parameter. However, this approach makes it difficult to understand the structural basis of bone diseases, because a large number of bone properties are integrated into a single number. This is exemplified in the present case of a 27-year-old woman with osteogenesis imperfecta type I. Peripheral quantitative computed tomographic analysis at the radial metaphysis and at the radial diaphysis revealed a decreased areal BMD at both sites (z score -3.9 and -3.4, respectively). Yet, the structural basis for this decrease was different for the two locations: At the distal radius areal BMD was decreased because volumetric BMD was very low, whereas bone size was above the mean of the reference range. At the proximal radius areal BMD was decreased, because bone size was very low but volumetric BMD was above average. Bone mineral content of the radial diaphysis was very low for forearm muscle size, a finding which is compatible with Frost's hypothesis that the mechanostat setpoint is increased in osteogenesis imperfecta.

Abstract: Currently bone development is commonly presented as a process leading to the 'accumulation of peak bone mass'. Consequently, the usual approach to a suspected bone disorder in a child is to address the question are this child's bones as heavy as those of a healthy child of the same sex and age? However, from a functional perspective the aim of bone development should not be make bones as heavy as possible but to make them as stable as necessary. A functionally oriented approach should address two different questions: how strong are the bones? are they as strong as they need to be? It is clear that the bone has to be strong enough to withstand the mechanical forces to which it is exposed. CONCLUSION: since the main forces applied to bones are due to muscle action, the strength of a bone should be related to the force of the muscles attached to it.

Abstract: Quantitative data on metaphyseal bone histology during early human development are scarce. In the present study the proximal femoral metaphysis of 35 fetuses and newborns (gestational age 16-35 weeks) was analyzed by histomorphometry. Averaged over the entire metaphyseal area, the relative amount of bone and cartilage was higher in the third compared to the second trimester. Osteoid thickness increased with gestational age, whereas indices of bone resorption decreased. The relative amount of cartilage decreased with increasing distance from the growth plate, whereas the relative amount of bone increased. This was due to trabecular thickening, which occurred at an estimated rate of 3 &mgr;m/day in areas close to the growth plate. Despite this rapid rate of net bone gain, osteoid indices were relatively low, indicating that mineralization occurred very rapidly after bone deposition. These observations suggest that modeling, not remodeling, is the predominant mechanism responsible for the development of femoral metaphyseal cancellous bone in utero.

Abstract: Osteogenesis imperfecta (OI) is a heritable disease of bone with low bone mass and bone fragility. The disease is generally classified into four types based on clinical features and disease severity, although recently fifth and sixth forms have also been reported. Most forms of OI are autosomal dominant. Rarely, autosomal recessive disease has been described. We report the clinical, radiological, and histological features of four children (age 3.9-8.6 years at last follow-up; all girls) and four adults (age 28-33 years; two women) with a novel form of autosomal recessive OI living in an isolated First Nations community in northern Quebec. In keeping with the established numeric classification for OI forms, we have called this form of the disease OI type VII. The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. Rhizomelia is a prominent clinical feature. Histomorphometric analyses of iliac crest bone samples revealed findings similar to OI type I, with decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone. The disease has subsequently been localized to chromosome 3p22-24.1, which is outside the loci for type I collagen genes. The underlying genetic basis for the disease remains to be determined.

Abstract: Fibrous dysplasia (FD) of bone can be complicated by renal phosphate wasting. The effect of hypophosphatemia on normal and dysplastic bone of FD patients has not been well characterized. In this study, we compared serum phosphorus (sPi) levels to histomorphometric findings in 27 iliac bone samples from 23 children and adolescents (aged 4.2-16.4 years) with polyostotic FD. The samples were separated into two groups, based on the presence (n = 10) or absence (n = 17) of a dysplastic lesion within the specimen. Histomorphometric results were compared with those from 18 age-matched control subjects without metabolic bone disease. In dysplastic lesions, trabeculae were clearly thinner and increased in number. Osteoid indices, osteoblast surface per bone surface, and mineralization lag time were elevated in dysplastic areas, but there was no detectable effect of sPi concentrations on these indices. In nondysplastic bone tissue, low sPi levels were associated with mildly increased osteoid thickness and prolonged mineralization lag time. None of the 13 patients in whom hand X-rays were available at the time of biopsy had radiological signs of rickets. In conclusion, low sPi can cause a mild systemic mineralization defect in FD, but the more severe mineralization defect seen in dysplastic lesions is independent of sPi levels. It is debatable whether the mild systemic mineralization defect warrants treatment with oral phosphorus supplementation if signs of rickets are absent.

Abstract: Osteogenesis imperfecta (OI) is a heritable disease of bone in which the hallmark is bone fragility. Usually, the disorder is divided into four groups on clinical grounds. We previously described a group of patients initially classified with OI type IV who had a discrete phenotype including hyperplastic callus formation without evidence of mutations in type I collagen. We called that disease entity OI type V. In this study, we describe another group of 8 patients initially diagnosed with OI type IV who share unique, common characteristics. We propose to name this disorder "OI type VI." Fractures were first documented between 4 and 18 months of age. Patients with OI type VI sustained more frequent fractures than patients with OI type IV. Sclerae were white or faintly blue and dentinogenesis imperfecta was uniformly absent. All patients had vertebral compression fractures. No patients showed radiological signs of rickets. Lumbar spine areal bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Serum alkaline phosphatase levels were elevated compared with age-matched patients with type IV OI (409 +/- 145 U/liter vs. 295 +/- 95 U/liter; p < 0.03 by t-test). Other biochemical parameters of bone and mineral metabolism were within the reference range. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations, and type I collagen protein analyses were normal. Qualitative histology of iliac crest bone biopsy specimens showed an absence of the birefringent pattern of normal lamellar bone under polarized light, often with a "fish-scale" pattern. Quantitative histomorphometry revealed thin cortices, hyperosteoidosis, and a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. We conclude that type VI OI is a moderate to severe form of brittle bone disease with accumulation of osteoid due to a mineralization defect, in the absence of a disturbance of mineral metabolism. The underlying genetic defect remains to be elucidated.

Abstract: OBJECTIVE: To study the relation between muscle force, bone mass, and metabolic control in patients with glycogen storage disease type (GSD 1).Study design: Distal radius bone mass and density were evaluated in 19 patients with GSD 1 (15 GSD 1a, 4 GSD 1b) by means of peripheral quantitative computed tomography. Grip force was quantified with a dynamometer. RESULTS: Height, weight, bone mass, and grip force were significantly decreased in the patients with GSD 1a, mainly as the result of low values in the poorly controlled subgroup. Boys had lower bone mass than girls. Patients with GSD 1b had higher values for bone mineral density in the trabecular compartment. In most of the study participants bone mass appeared to be adequately adapted to the mechanical requirements imposed by muscle contraction. However, 3 patients with GSD 1a had evidence for a low bone mass. CONCLUSIONS: In GSD 1, both reduced muscle strength and a direct disease effect can contribute to low bone mass. The quality of treatment is crucial to prevent disturbances in musculoskeletal development.

Abstract: Skeletal muscle development is one of the key features of childhood and adolescence. Determining maximal isometric grip force (MIGF) using a hand-held Jamar dynamometer is a simple method to quantify one aspect of muscle function. Presently available reference data present MIGF as a function of chronological age. However, muscle force is largely determined by body size, and many children undergoing muscle performance tests in the clinical setting suffer from growth retardation secondary to a chronic disorder. Reference data were established from simple regressions between age or log height and log MIGF in a population of 315 healthy children and adolescents aged 6 to 19 y (157 girls). These data were used to calculate age- or height-dependent SD scores (SDS) for MIGF in three pediatric patient groups. In renal graft recipients (n = 14), the age-dependent MIGF SDS was markedly decreased (-2.5 +/- 1.9; mean +/- SD). However, these patients had short stature (height SDS, -2.5 +/- 1.2), and the height-dependent MIGF SDS was close to normal (-0.4 +/- 1.5). Similarly, in cystic fibrosis patients (n = 13) age-dependent MIGF SDS was -1.6 +/- 1.6, but height-dependent MIGF SDS was -0.5 +/- 1.1. Children with epilepsy who were taking anticonvulsant therapy (n = 34) had normal stature, and consequently age- and height-dependent MIGF SDS were similar (0.4 +/- 1.0 and 0.4 +/- 0.8, respectively). In conclusion, MIGF determination provides information on an important aspect of physical development. Height should be taken into account to avoid misinterpretation.

Abstract: Bone development is usually seen as a process of bone mineral accretion or increase in bone mass, and treatment of bone disorders usually consists of attempts to maximise bone mass accumulation by nutritional means only. However, from a functional perspective, bones should not be as heavy as possible, but rather as stable as necessary. It is therefore important to create conditions that stimulate bones to become more stable.

Abstract: It is well established that puberty affects the geometry of cortical bone differently in females and males. In the present study we investigated whether there are also gender differences in the volumetric bone mineral density of the cortical compartment (BMDcort). BMDcort was determined at the proximal radial diaphysis in 362 healthy children and adolescents (age 6-23 years; 185 females, 177 males) and in 107 adults (age 29-40 years; 88 women, 19 men) using peripheral quantitative computed tomography (pQCT). The densitometric result for BMDcort was similar in prepubertal girls and boys, but was significantly higher in females after pubertal stage 3. pQCT results for BMDcort are influenced by cortical thickness due to the partial volume effect. Therefore, these gender differences were reanalyzed in groups of subjects of the same developmental stage who were matched for cortical thickness. Thus calculated, no gender difference in BMDcort was detected in prepubertal children. However, adolescent females after pubertal stage 3 and adult women had a 3%-4% higher BMDcort than males at the same developmental stage. BMDcort is an integrated measure of both cortical porosity and mean material density of cortical bone. The metabolic activity of cortical bone (intracortical remodeling) increases cortical porosity and decreases the mean material density of cortical bone. Our results therefore suggest that intracortical remodeling is lower in postpubertal females than in males.

Abstract: Fractures of the distal radial metaphysis are very common in otherwise healthy children. The reasons for this high fracture incidence are not entirely clear. To address this problem, we undertook a detailed analysis of distal radius development using peripheral quantitative computed tomography (pQCT) at a site 4% proximal to the radial articular surface. The study population comprised 337 healthy children and adolescents (aged 6-18 years; 171 girls) and 107 adults (aged 29-40 years; 88 women). Total volumetric bone mineral density (vBMD) remained stable at about 70% of the adult value between the ages of 6-7 years and 14-15 years in both genders. Cortical thickness increased little between 6-7 years and 12-13 years in girls and 14-15 years in boys. Strength-Strain Index (SSI; a parameter combining geometry and density) was still at only 20% of the adult value in girls aged 10-11 years and at 21% of the adult level in boys aged 12-13 years. At these ages, factors that contribute to the mechanical challenge to the distal radius in case of a fall (forearm length and body weight) had already reached 49% and 36% of the adult value in girls and boys, respectively. The shaping of the distal radius cortex (metaphyseal inwaisting) was assessed by analyzing the decrease in cross-sectional bone size between adjacent bone slices in a separate population of 44 children (aged 8-19 years; 26 girls). The rates of periosteal resorption and endocortical apposition were estimated to average 8 microm/day and 10 microm/day, respectively, during the growth period. In conclusion, during growth the increase in distal radius strength lags behind the increase in mechanical challenges caused by a fall, because metaphyseal cortical thickness does not increase sufficiently. The endocortical apposition rate is already very high at that site and apparently cannot be further increased to levels that would be necessary to keep bone strength adapted to the mechanical requirements.

Abstract: Bone densitometry has great potential to improve our understanding of bone development. However, densitometric data in children rarely are interpreted in light of the biological processes they reflect. To strengthen the link between bone densitometry and the physiology of bone development, we review the literature on physiological mechanisms and structural changes determining bone mineral density (BMD). BMD (defined as mass of mineral per unit volume) is analyzed in three levels: in bone material (BMD(material)), in a bone's trabecular and cortical tissue compartments (BMD(compartment)), and in the entire bone (BMD(total)). BMD(material) of the femoral midshaft cortex decreases after birth to a nadir in the first year of life and thereafter increases. In iliac trabecular bone, BMD(material) also increases from infancy to adulthood, reflecting the decrease in bone turnover. BMD(material) cannot be determined with current noninvasive techniques because of insufficient spatial resolution. BM(compartment) of the femoral midshaft cortex decreases in the first months after birth followed by a rapid increase during the next 2 years and slower changes thereafter, reflecting changes in both relative bone volume and BMD(material). Trabecular BMD(compartment) increases in vertebral bodies but not at the distal radius. Quantitative computed tomography (QCT) allows for the determination of both trabecular and cortical BMD(compartment), whereas projectional techniques such as dual-energy X-ray absorptiometry (DXA) can be used only to assess cortical BMD(compartment) of long bone diaphyses. BMD(total) of long bones decreases by about 30% in the first months after birth, reflecting a redistribution of bone tissue from the endocortical to the periosteal surface. In children of school age and in adolescents, changes in BMD(total) are site-specific. There is a marked rise in BMD(total) at locations where relative cortical area increases (metacarpal bones, phalanges, and forearm), but little change at the femoral neck and midshaft. BMD(total) can be measured by QCT at any site of the skeleton, regardless of bone shape. DXA allows the estimation of BMD(total) at skeletal sites, which have an approximately circular cross-section. The system presented here may help to interpret densitometric results in growing subjects on a physiological basis.

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Abstract: OBJECTIVE: To identify parameters which predict individual growth response to recombinant human GH (rhGH) therapy and to combine these parameters in a prediction model. DESIGN: Fifty-eight prepubertal patients with GH deficiency (17 females) participated in this prospective multicenter trial with 1 year of follow-up. METHODS: Auxological measurements, parameters of GH status and markers of bone metabolism were measured at baseline and at 1, 3 and 6 months after the start of rhGH treatment. Correlations with height velocity during the first 12 months of treatment (HV+12) were calculated. Prediction models were derived by multiple regression analysis. RESULTS: The model which best predicted HV+12 combined the following parameters: pretreatment bone age retardation as a fraction of chronological age, pretreatment serum levels of IGF-I, urinary levels of deoxypyridinoline (a marker of bone resorption) after 1 month of treatment and height velocity after 3 months of treatment. This model explained 89% of the variation in HV+12 with a standard deviation of the residuals of 0.93 cm/year. Defining successful rhGH therapy as a doubling of pretreatment height velocity, the model had a specificity of 90% and a sensitivity of 100% in predicting therapeutic success. CONCLUSIONS: This model is an accurate and practicable tool to predict growth response in GH-deficient children. It may help to optimize rhGH therapy by individual dose adjustment and contribute to improved overall outcomes.

Abstract: Current investigations of bone development mostly focus on bone mass, but bone strength may be functionally more important than mass. Therefore, we compared the developmental changes in cortical bone mass (BMCcort) and parameters of cortical bone strength [polar moment of inertia, section modulus, and strength strain index (SSI)]. Analyses were performed at the 65% site of the proximal radius using peripheral quantitative computed tomography. The study population comprised 469 healthy subjects, 6-40 yr of age (273 females). Both in prepubertal children (pubertal stage 1) and after puberty (pubertal stage 5 and adults) all studied parameters were significantly higher in males. During puberty (pubertal stages 2-4) the gender-specific differences were generally somewhat smaller. All of the measured parameters increased significantly with age and pubertal stage. However, although the percent increase in BMCcort between the youngest children and adults was similar between the genders, the increases in polar moment of inertia, section modulus, and SSI were higher in males. The ratio between section modulus and BMCcort was consistently higher in males after the age of 11 yr and after pubertal stage 2. Similar results were found for ratios between polar moment of inertia or SSI and BMCcort. These results show that for a given bone mass, males have stronger bones than females after pubertal stage 2. This reflects the fact that in puberty males add bone mostly on the periosteal surface, where the effect on bone strength is highest, whereas females add bone on the endocortical surface, which has a small effect on bone stability. The purpose of the mechanically inefficient endocortical apposition in female puberty might be to create a reservoir of calcium for future pregnancy and lactation.

Abstract: OBJECTIVE: To examine bone development in children and adolescents who have uncomplicated idiopathic epilepsy and had received monotherapy with carbamazepine or valproic acid for at least 1 year. METHODS: Thirty-nine patients from 6 to 19 years of age (18 girls) were studied. Total bone mineral content (BMC) and trabecular volumetric bone mineral density were measured at the distal radius using peripheral quantitative computed tomography. Maximum isometric grip force was determined with a standard dynamometer. Alkaline phosphatase activity and deoxypyridinoline (a marker of bone resorption) were assessed in serum and urine, respectively. RESULTS: Trabecular volumetric bone mineral density was significantly decreased in the entire group (z score mean +/- standard deviation: -0.62 +/- 1.04) and in the subgroup using valproic acid (-0.75 +/- 1.18). In the carbamazepine subgroup, there was a similar but nonsignificant trend (-0.50 +/- 0.90). Total BMC and isometric maximum grip force were normal in the entire study population (0.10 +/- 1.22) and in the 2 subgroups. The relationship between BMC and grip force was similar between patients and healthy participants. Urinary levels of deoxypyridinoline were significantly elevated above normal in the whole study population (1.35 +/- 2.00) and in both the valproic acid and the carbamazepine subgroups. CONCLUSIONS: Bone turnover can be increased, but bone mass is adequate in children and adolescents who have uncomplicated idiopathic epilepsy and who receive monotherapy with carbamazepine or valproic acid.

Abstract: Turner syndrome (TS) is associated with multiple skeletal abnormalities. Fracture incidence appears to be increased, but the reasons for this are not entirely clear. In the present study, we used peripheral quantitative computed tomography to evaluate bone mass, density, geometry, and strength of the radial metaphysis and diaphysis as well as maximum forearm muscle cross-sectional area (CSA) in a group of 21 TS patients. These individuals were 19.5 +/- 2.3 yr of age (mean +/- SD; range, 16.2-25.4 yr) and had completed growth after having received GH therapy; all but one were receiving estrogen supplementation. Despite short stature, cross-sectional bone size was normal compared with age-matched healthy controls. However, bone mineral content was decreased, resulting in a low total volumetric bone mineral density. This was due to decreased cortical thickness at both sites of measurement, whereas trabecular volumetric bone mineral density of the metaphysis was normal. Muscular CSA was normal. The relationship between muscle CSA and external bone size was similar between TS patients and healthy young women. However, TS patients had less bone mineral content and cortical CSA relative to muscle CSA than healthy young women, but similar muscle-bone relationships as healthy prepubertal girls. These findings are compatible with a normal adaptation of external bone size to the mechanical loads imposed by the muscle system and a lack of pubertal effect on the endocortical bone surface, despite estrogen supplementation. Bone strength may not be adequate for the relatively high body weight of TS patients (+0.8 SD score), which could contribute to an increased propensity for fractures.

Abstract: Peripheral quantitative computed tomography (pQCT) has the ability to improve the diagnostic utility of densitometry in children and adolescents, because bone size and volumetric bone mineral density (vBMD) can be measured independently. Nevertheless, detailed reference data are lacking. We therefore performed pQCT (XCT-2000 scanner, Stratec, Inc., Pforzheim, Germany) at the distal radius in 371 healthy children, adolescents, and young adults (185 males and 186 females, ages 6-23 years) and in 107 of their parents (19 men and 88 women, ages 29-40 years). Total vBMD, trabecular, and "cortical + subcortical" vBMD as well as cross-sectional area (CSA) were determined at the "4% site" of the distal radius. This location was defined as the site whose distance to the most distal portion of the growth plate or to the radial articular surface corresponded to 4% of the forearm length. In both genders, total vBMD remained stable between 6 and 15 years of age and then increased by 30% in girls and by 46% in boys. Regarding pubertal development, total vBMD remained almost constant throughout pubertal stages 1-4 and thereafter increased in both genders. Trabecular vBMD did not change with age in girls, whereas in boys an increase with age of about 10% was noted after 15 years of age. Males had higher trabecular vBMD than females. This gender difference increased from 6% in prepubertal children to 23% in adults. The variation with age and pubertal stage in "cortical + subcortical" vBMD-cort was similar to that of total vBMD. CSA roughly doubled between 6 and 15 years of age in both genders. In conclusion, the availability of this reference material will provide a basis for the use of pQCT in the assessment of pediatric bone diseases.

Abstract: It is becoming increasingly accepted that bone size is an important determinant of bone mass. Studies on the development of bone size may therefore promote a better understanding of the basis of diseases which are due to low bone mass. Here, we characterize the temporal changes in cross-sectional bone size, geometry and mass at the radial diaphysis in healthy subjects from 6 to 40 years of age (n = 469; 273 females). Peripheral quantitative computed tomography was used to measure total and cortical cross-sectional area, bone mineral content (BMC) and volumetric bone mineral density (BMD) at the site of the forearm whose distance from the ulnar styloid process corresponded to 65% of forearm length. Over the age range of the study, total cross-sectional area increased by 39 mm2 (50%) in females and by 85 mm2 (116%) in males. Cortical area increased to a similar extent in both sexes. Between 6-7 years and adulthood, BMC increased by 52 mg/mm (111%) in females and by 73 mg/mm (140%) in males and was significantly higher in males after the age of 15 years. Volumetric BMD increased by 246 mg/cm3 (48%) in females but by only 132 mg/cm3 (23%) in males and was significantly higher in women than in men. In summary, these data show that BMC in men is higher than in women, because periosteal modeling continues longer in boys than in girls. Volumetric BMD is higher in women, partly because the size of the marrow cavity does not increase in girls as it does in boys.

Abstract: Peripheral quantitative computed tomography (pQCT) is an important technique to study the interaction between the muscle and bone systems. We have recently established pQCT reference ranges for children, adolescents and young adults using a recent version (XCT 2000) of the Stratec scanners (Stratec Inc., Pforzheim, Germany). However, the previous version of this type of scanner (XCT 900) is still widely used and cross-calibration is needed to use these reference data. Therefore, both distal radii of 19 healthy subjects (age 21 to 59 years; 11 women) were analyzed at the "4% site" using both the XCT 900 and the XCT 2000. Cross-sectional area, total and trabecular bone mineral density (BMD), total bone mineral content (BMC) and polar Strength-Strain Index (SSI) results from the two scanners were compared using linear regression analysis. To achieve scanner calibration we used the intercept and slope of the correlations. The correlation coefficients between the two devices were 0.82 for the cross-sectional area, 0.81 for total BMD, 0.97 for trabecular BMD, 0.99 for total BMC and 0.86 for polar SSI. In conclusion, these data allow for the conversion of XCT 900 results at the distal radius to XCT 2000 values and vice versa.

Abstract: A large number of molecular, cellular, and epidemiologic factors have been implicated in the regulation of bone development. A major unsolved problem is how to integrate these disparate findings into a concept that explains the development of bone as an organ. Often events on the organ level are simply presented as the cumulative effect of all factors that individually are known to influence bone development. In such a cumulative model it must be assumed that each bone cell carries the construction plan of the entire skeletal anatomy in its genes. This scenario is implausible, because it would require an astronomical amount of positional information. We therefore propose a functional model of bone development, which is based on Frost's mechanostat theory. In this model the genome only provides positional information for the basic outline of the skeleton as a cartilaginous template. Thereafter, bone cell action is coordinated by the mechanical requirements of the bone. When mechanical challenges exceed an acceptable level (the mechanostat set point), bone tissue is added at the location where it is mechanically necessary. The main mechanical challenges during growth result from increases in bone length and in muscle force. Hormones, nutrition, and environmental factors exert an effect on bone either directly by modifying the mechanostat system or indirectly by influencing longitudinal bone growth or muscle force. Predictions based on this model are in accordance with observations on prenatal, early postnatal, and pubertal bone development. We propose that future studies on bone development should address topics that can be derived from the mechanostat model.

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Abstract: The Ilizarov method of limb lengthening makes use of the fact that osteogenesis is induced at an osteotomy site when distraction is applied. It is unknown at present how the mechanical forces created by distraction are translated into biological signals. Because bone morphogenetic proteins (BMPs) are potent inducers of osteogenesis in many experimental systems, they are obvious candidates for playing a role in this process. In this study, we investigated the temporal and spatial expression of BMP-2, -4, and -7 proteins during distraction osteogenesis using immunohistochemistry. An osteotomy was performed on the right tibiae of white New Zealand rabbits. After a delay of 7 days, distraction was started at a rate of 0.25 mm/12 h for 3 weeks, followed by a 3 week consolidation phase. Each week after osteotomy one rabbit was killed for immunohistochemical studies. Staining for BMP-2, -4, and -7 was evident before distraction was applied and was mainly localized to mesenchymal cells and osteoblastic cells in the periosteal region. After distraction was started, the typical fibrous interzone developed between the osteotomy fragments, where both intramembranous and endochondral ossification were noted. In this area, cells resembling fibroblasts and chondrocytes, but not mature osteoblasts, showed intense staining for all three BMPs. This high level of expression was maintained during the entire distraction phase and then gradually disappeared during the consolidation phase. These results are compatible with the hypothesis that BMPs play an important role in the signaling pathways that link the mechanical forces created by distraction to biological responses.

Abstract: Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.

Abstract: Normal postnatal bone growth is essential for the health of adults as well as children but has never been studied histologically in human subjects. Accordingly, we analyzed iliac bone histomorphometric data from 58 healthy white subjects, aged 1.5-23 years, 33 females and 25 males, of whom 48 had undergone double tetracycline labeling. The results were compared with similar data from 109 healthy white women, aged 20-76 years, including both young adult reference ranges and regressions on age. There was a significant increase with age in core width, with corresponding increases in both cortical width and cancellous width. In cancellous bone there were increases in bone volume and trabecular thickness, but not trabecular number, wall thickness, interstitial thickness, and inferred erosion depth. Mineral apposition rates declined on the periosteal envelope and on all subdivisions of the endosteal envelope. Because of the concomitant increase in wall thickness, active osteoblast lifespan increased substantially. Bone formation rate was almost eight times higher on the outer than on the inner periosteum, and more than four times higher on the inner than on the outer endocortical surface. On the cancellous surface, bone formation rate and activation frequency declined in accordance with a fifth order polynomial that matched previously published biochemical indices of bone turnover. The analysis suggested the following conclusions: (1) Between 2 and 20 years the ilium grows in width by periosteal apposition (3.8 mm) and endocortical resorption (3.2 mm) on the outer cortex, and net periosteal resorption (0.4 mm) and net endocortical formation (1.0 mm) on the inner cortex. (2) Cortical width increases from 0.52 mm at age 2 years to 1.14 mm by age 20 years. To attain adult values there must be further endocortical apposition of 0.25 mm by age 30 years, at a time when cancellous bone mass is declining. (3) Lateral modeling drift of the outer cortex enlarges the marrow cavity; the new trabeculae filling this space arise from unresorbed cortical bone and represent cortical cancelization; (4) Lateral modeling drift of the inner cortex encroaches on the marrow cavity; some trabeculae are incorporated into the expanding cortex by compaction. (5) The net addition of 37 mum of new bone on each side of a trabecular plate results from a <5% difference between wall thickness and erosion depth and between bone formation and bone resorption rates; these small differences on the same surface are characteristic of bone remodeling. (6) Because the amount of bone added by each cycle of remodeling is so small, the rate of bone remodeling during growth must be high to accomplish the necessary trabecular hypertrophy.

Abstract: Calreticulin is a ubiquitously expressed protein, which has been implicated in a large number of cellular functions, including calcium storage and signaling, protein folding, and cell attachment. To examine the role of calreticulin during in vivo development, mice deficient in calreticulin were generated by targeted inactivation of the calreticulin gene. Calreticulin-deficient mutants die in utero, mostly in late gestation. Half of these embryos had decreased cardiac cell mass, associated with increased apoptosis of cardiac myocytes. In vitro differentiation cultures of calreticulin-deficient embryonic stem cells resulted in fewer embryoid bodies with contractile activity than cultures derived from calreticulin +/- stem cells (P < 0.001). Sixteen percent of the mutants exhibited exencephaly secondary to a defect in neural tube closure. Embryos surviving until Embryonic Day 16.5 had omphalocele. Lack of calreticulin did not influence survival of embryonic fibroblasts under various endoplasmic reticulum stress conditions. However, calreticulin did influence cell migration in a calcium- and substrate-dependent manner. We conclude that calreticulin is not essential during the early stages of embryonic development, but is important for the development of heart and brain and for ventral body wall closure. The observed abnormalities are compatible with a role of calreticulin in the modulation of cellular calcium signaling. Copyright 2000 Academic Press.

Abstract: In this study we tested the effect of locally applied transforming growth factor-beta1 (TGF-beta1) on distraction osteogenesis in rabbits. A total of 61 rabbits were studied. Seven days after tibial osteotomy, distraction was started at a rate of 0.25 mm/12 h for 3 weeks. Starting with distraction, TGF-beta1 was applied in four different dosages (0, 10, 20, and 40 ng/day) at the site of osteotomy through a catheter connected to a subcutaneously implanted miniosmotic pump. Rabbits were killed at the end of the distraction period or 3 weeks later, and histological, densitometric, and biomechanical parameters were assessed. TGF-beta1 treatment had no detectable effect on bone mineral density or histologically determined bone volume in the distraction gap but it increased the amount of fibrous tissue in the callus region. Load to failure in uniaxial tension tended to be lower in TGF-beta1-treated animals. In conclusion, TGF-beta1 treatment during distraction osteogenesis did not have a beneficial effect in this model.

Abstract: Idiopathic juvenile osteoporosis (IJO), a rare cause of osteoporosis in children, is characterized by the occurrence of vertebral and metaphyseal fractures. Little is known about the histopathogenesis of IJO. We analyzed by quantitative histomorphometry iliac crest biopsies from 9 IJO patients (age, 10.0-12.3 years; 7 girls) after tetracycline labeling. Results were compared with identically processed samples from 12 age-matched children without metabolic bone disease and 11 patients with osteogenesis imperfecta type I. Compared with healthy controls, cancellous bone volume (BV) was markedly decreased in IJO patients (mean [SD]: 10.0% [3.1%] vs. 24.4% [3.8%]), because of a 34% reduction in trabecular thickness (Tb.Th) and a 37% lower trabecular number (Tb.N; p < 0.0001 each; unpaired t-test). Bone formation rate (BFR) per bone surface was decreased to 38% of the level in controls (p = 0.0006). This was partly caused by decreased recruitment of remodeling units, as shown by a trend toward lower activation frequency (54% of the control value; p = 0.08). Importantly, osteoblast team performance also was impaired, as evidenced by a decreased wall thickness (W.Th; 70% of the control value; p < 0.0001). Reconstruction of the formative sites revealed that osteoblast team performance was abnormally low even before mineralization started at a given site. No evidence was found for increased bone resorption. Compared with children with osteogenesis imperfecta (OI), IJO patients had a similarly decreased cancellous BV but a much lower bone turnover. These results suggest a pathogenetic model for IJO, in which impaired osteoblast team performance decreases the ability of cancellous bone to adapt to the increasing mechanical needs during growth. This will finally result in load failure at sites where cancellous bone is essential for stability.

Abstract: In this new column of the JMNI, we will give a six-monthly overview about new publications which, to our eyes, are interesting and relevant. Keeping in line with the 'spirit' of ISMNI, we take the freedom to discuss with a more holistic approach and most importantly, we encourage feed-back from the readers.

Abstract: Many insights into normal and pathologic bone development can only be gained by bone histomorphometry. However, the use of this technique in pediatrics has so far been hampered by the lack of reference data. Therefore, we obtained transfixing iliac bone samples from 58 individuals between 1.5 and 22.9 years of age (25 male; tetracycline labeling performed in 48 subjects), who underwent surgery for reasons independent of abnormalities in bone development and metabolism. The results of histomorphometric analyses of cancellous parameters and cortical width are presented as means and standard deviations, as well as medians and ranges in five age groups. In addition, the original data are available from the authors. There were significant age-dependent increases in both cortical width and cancellous bone volume, the latter being due to an increase in trabecular thickness. Osteoid thickness did not vary significantly with age. Bone surface-based indicators of bone formation showed an age-dependent decline, reflecting similar changes in activation frequency. Mineral apposition rate decreased continuously with age. Parameters of bone resorption did not vary significantly between age groups. Paired biopsies from adjacent sites, obtained in eight subjects, were used to examine the reproducibility of histomorphometric parameters in children. The lowest coefficients of variation (<10%) were found for structural measures, as well as mineral apposition rate and wall thickness. The highest variability was found for cellular parameters. The availability of reference material will greatly facilitate the use of histomorphometry in pediatrics.

Abstract: Severe osteogenesis imperfecta (OI) is a hereditary disorder characterized by increased bone fragility and progressive bone deformity. Cyclical pamidronate infusions improve clinical outcome in children older than 3 yr of age with severe OI. Because earlier treatment may have potential to prevent deformities and improve functional prognosis in young children, we studied nine severely affected OI patients under 2 yr of age (2.3-20.7 months at entry) for a period of 12 months. Pamidronate was administered i.v. in cycles of 3 consecutive days. Patients received four to eight cycles during the treatment period, with cumulative doses averaging 12.4 mg/kg. Clinical changes were evaluated regularly during treatment, and radiological changes were assessed after 6-12 months of treatment. The control group consisted of six age-matched, severely affected OI patients, who had not received pamidronate treatment. During treatment bone mineral density (BMD) increased between 86-227%. The deviation from normal, as indicated by the z-score, diminished from -6.5 +/- 2.1 to -3.0 +/- 2.1 (P < 0.001). In the control group the BMD z-score worsened significantly. Vertebral coronal area increased in all treated patients (11.4 +/- 3.4 to 14.9 +/- 1.8 cm2; P < 0.001), but decreased in the untreated group (P < 0.05). In the treated patients, fracture rate was lower than in control patients (2.6 +/- 2.5 vs. 6.3 +/- 1.6 fractures/year; P < 0.01). No adverse side-effects were noted, apart from the well known acute phase reaction during the first infusion cycle. Pamidronate treatment in severely affected OI patients under 3 yr of age is safe, increases BMD, and decreases fracture rate.

Abstract: Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility and low bone mass. Four clinical types are commonly distinguished. Schematically, type I is the mildest phenotype, type II is usually lethal, type III is the most severe form compatible with postnatal survival, and type IV is moderately severe. Although mutations affecting collagen type I are responsible for the disease in most patients, the mechanisms by which the genetic defects cause abnormal bone development have not been well characterized. Therefore, we evaluated quantitative static and dynamic histomorphometric parameters in tetracycline-labeled iliac bone biopsies from 70 children, aged 1.5 to 13.5 years, with OI types I (n = 32), III (n = 11), and IV (n = 27). Results were compared with those of 27 age-matched controls without metabolic bone disease. Biopsy core width, cortical width, and cancellous bone volume were clearly decreased in all OI types. Decreased cancellous bone volume was due to a 41%-57% reduction in trabecular number and a 15%-27% lower trabecular thickness. Regression analyses revealed that trabecular number did not vary with age in either controls or OI patients, indicating that no trabecular loss occurred. The annual increase in trabecular thickness was 5.8 mum in controls and 3.6 mum in type I OI, whereas no trabecular thickening was evident in type III and IV OI. Wall thickness, which reflects the amount of bone formed during a remodeling cycle, was decreased by 14% in a subgroup of 17 type I OI patients, but was not determined in the other OI types. The remodeling balance was less positive in type I OI than in controls, and probably close to zero in types III and IV. Surface-based parameters of bone remodeling were increased in all OI types, indicating increased recruitment of remodeling units. No defect in matrix mineralization was found. In conclusion, there was evidence of defects in all three mechanisms, which normally lead to an increase in bone mass during childhood; that is, modeling of external bone size and shape, production of secondary trabeculae by endochondral ossification, and thickening of secondary trabeculae by remodeling. Thus, OI might be regarded as a disease in which a single genetic defect in the osteoblast interferes with multiple mechanisms that normally ensure adaptation of the skeleton to the increasing mechanical needs during growth.

Abstract: Previous studies have suggested that the timing of puberty might have an impact on the adult skeleton. What composite of bone structure could be affected by the timing of puberty is unknown at present. In this study, we evaluated the relationship between age at menarche and bone cortex geometry at the distal radius. Using peripheral quantitative computed tomography, we determined total area of the radial cross section, cortical bone area, periosteal cortical perimeter, endosteal cortical perimeter, and cortical width in 169 healthy premenopausal women aged 40-45 years. When stratified according to age at menarche (early, <12 years In = 22]; intermediate, 12-14 years [n = 118]; late, >14 years [n = 29]), only endosteal cortical perimeter varied significantly between the groups (p = 0.02, by analysis of variance), the mean value being 10% higher in the late compared to the early menarche group. However, weight and body mass index also exhibited significant variations between groups. After adjustment for weight the differences in endosteal cortical perimeter remained significant (p = 0.03). In multiple regression analysis, endosteal cortical perimeter was the only parameter of cortex geometry, which was independently associated with age at menarche. In a model including height and weight, age at menarche explained about 2% of the variability in endosteal cortical perimeter (p = 0.04). These data suggest that the bone marrow cavity of the distal radius may be slightly larger when puberty occurs later. Whether this marginal effect influences fracture risk in later life appears questionable.

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