Abstract: INTRODUCTION: This study describes clinical and biochemical characteristics of nutritional rickets and risk factors at diagnosis among children living in Denmark. All medical records from patients with rickets referred to or discharged from hospitals in Southern Denmark from 1985 to 2005 were identified by register search. MATERIALS AND METHODS: Patients included were younger than 15 years of age and fulfilled the diagnostic criteria of primary, nutritional rickets. A total of 112 patients with nutritional rickets were included: 29 were of ethnic Danish origin, and 83 were immigrants. RESULTS: Patients diagnosed before the age of 4 (median 1.4) years displayed the classic clinical signs of rickets, whereas patients diagnosed after the age of 4 (median 12.5) years had few clinical signs and unspecific symptoms. Ethnic Danish patients were only diagnosed before age 24 months, and they accounted for 73% of all cases presenting with hypocalcemic seizures, but biochemically, they did not have more severe rickets. Of patients diagnosed before the age of 4 years, 45% were ethnic Danish. In early childhood, insufficient or no vitamin D supplementation was given in 88% of all cases. Among immigrant girls older than 4 years of age, 78% were veiled. DISCUSSION: Nutritional rickets in Denmark is predominantly a disease among immigrants, but ethnic Danish patients comprised nearly half of all patients diagnosed before the age of 4 years, and they presented more frequently with hypocalcemic seizures. The main risk factors were omitted, such as vitamin D prophylaxis among the youngest patients and veiling among older children/teenagers.
Abstract: The chloride-proton antiporter ClC-7 has been speculated to be involved in acidification of the lysosomes and the resorption lacunae in osteoclasts; however, neither direct measurements of chloride transport nor acidification have been performed. Human osteoclasts harboring a dominant negative mutation in ClC-7 (G215R) were isolated, and used these to investigate bone resorption measured by CTX-I, calcium release and pit scoring. The actin cytoskeleton of the osteoclasts was also investigated. ClC-7 enriched membranes from the osteoclasts were isolated, and used to test acidification rates in the presence of a V-ATPase and a chloride channel inhibitor, using a H(+) and Cl(-) driven approach. Finally, acidification rates in ClC-7 enriched membranes from ADOII osteoclasts and their corresponding controls were compared. Resorption by the G215R osteoclasts was reduced by 60% when measured by both CTX-I, calcium release, and pit area when comparing to age and sex matched controls. In addition, the ADOII osteoclasts showed no differences in actin ring formation. Finally, V-ATPase and chloride channel inhibitors completely abrogated the H(+) and Cl(-) driven acidification. Finally, the acid influx was reduced by maximally 50% in the ClC-7 deficient membrane fractions when comparing to controls. These data demonstrate that ClC-7 is essential for bone resorption, via its role in acidification of the lysosomes and resorption lacunae in osteoclasts.
Abstract: OBJECTIVE: To estimate the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets. DESIGN: Population-based retrospective cohort study based on a review of medical records. METHODS: Patients aged 0-14.9 years referred to or discharged from hospitals in southern Denmark from 1985 to 2005 with a diagnosis of rickets were identified by register search, and their medical records were retrieved. Patients fulfilling the diagnostic criteria of primary rickets were included. RESULTS: We identified 112 patients with nutritional rickets of whom 74% were immigrants. From 1995 to 2005, the average incidence of nutritional rickets in children aged 0-14.9 and 0-2.9 years was 2.9 and 5.8 per 100,000 per year respectively. Among immigrant children born in Denmark, the average incidence was 60 (0-14.9 years) per 100,000 per year. Ethnic Danish children were only diagnosed in early childhood and the average incidence in the age group 0-2.9 years declined from 5.0 to 2.0 per 100,000 per year during 1985-1994 to 1995-2005. Sixteen cases of hereditary rickets were diagnosed during the study period giving an average incidence of 4.3 per 100,000 (0-0.9 years) per year. The prevalence of hypophosphatemic rickets and vitamin D-dependent rickets type 1 was 4.8 and 0.4 per 100,000 (0-14.9 years) respectively. CONCLUSIONS: Nutritional rickets is rare in southern Denmark and largely restricted to immigrants, but the incidence among ethnic Danish children was unexpectedly high. Hereditary rickets is the most common cause of rickets in ethnic Danish children, but nutritional rickets is most frequent among all young children.
Abstract: Osteoclasts degrade bone matrix by secretion of hydrochloric acid and proteases. We studied the processes involved in the degradation of the organic matrix of bone in detail and found that lysosomal acidification is involved in this process and that MMPs are capable of degrading the organic matrix in the absence of cathepsin K. INTRODUCTION: Osteoclasts resorb bone by secretion of acid by the vacuolar H+-adenosine triphosphatase (V-ATPase) and the chloride channel ClC-7, followed by degradation of the matrix, mainly collagen type I, by cathepsin K and possibly by matrix metalloproteinases (MMPs). However, the switch from acidification to proteolysis and the exact roles of both the ion transporters and the proteinases still remain to be studied. MATERIALS AND METHODS: We isolated CD14+ monocytes from human peripheral blood from either controls or patients with autosomal dominant osteopetrosis type II (ADOII) caused by defective ClC-7 function and cultured them in the presence of RANKL and macrophage-colony stimulating factor (M-CSF) to generate osteoclasts. We decalcified cortical bovine bone slices and studied the osteoclasts with respect to morphology, markers, and degradation of the decalcified matrix in the presence of various inhibitors of osteoclast acidification and proteolysis, using normal calcified bone as a reference. RESULTS: We found that ADOII osteoclasts not only have reduced resorption of the calcified matrix, but also 40% reduced degradation of the organic phase of bone. We found that both acidification inhibitors and cathepsin K inhibitors reduced degradation of the organic matrix by 40% in normal osteoclasts, but had no effect in the ADOII osteoclasts. Furthermore, we showed that inhibition of MMPs leads to a 70% reduction in the degradation of the organic bone matrix and that MMPs and cathepsin K have additive effects. Finally, we show that osteoclastic MMPs mediate release of the carboxyterminal telopeptide of type I collagen (ICTP) fragment in the absence of cathepsin K activity, and therefore, to some extent, are able to compensate for the loss of cathepsin K activity. CONCLUSIONS: These data clearly show that osteoclastic acidification of the lysosomes plays a hitherto nonrecognized role in degradation of the organic matrix. Furthermore, these data shed light on the complicated interplay between acidification dependent and independent proteolytic processes, mediated by cathepsin K and the MMPs, respectively.
Abstract: Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts. To investigate the effect of the T253I mutation in LRP5 on osteoclasts, we isolated CD14+ monocytes from ADOI patients and assessed their ability to generate osteoclasts when treated with RANKL and M-CSF compared to that of age- and sex-matched control osteoclasts. We found normal osteoclastogenesis, expression of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found attenuated resorptive response to T3 stimulation, despite a normal bone formation response, in alignment with the reduced number of osteoclasts in vivo. These data demonstrate that ADOI osteoclasts are normal with respect to all aspects investigated in vitro. We speculate that the mutations causing ADOI alter the osteoblastic phenotype toward a smaller potential for supporting osteoclastogenesis.
Abstract: Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation.
Abstract: Sex steroids are important physiologic regulators of bone mass, and genes regulating sex steroid production and metabolism are obvious as candidate genes for osteoporosis susceptibility. We present data from a study of 1795 recent postmenopausal women, assigned to either hormone replacement therapy (HRT) or no treatment and followed for 5 years. The association between bone mass measurements and two single nucleotide polymorphisms, a T (A1) to C (A2) transition in the 5'-UTR of the cytochrome P450c17alpha (CYP17) gene and a G (Val) to A (Met) transition in exon 4 of the catechol- O-methyltransferase (COMT) gene, was evaluated. Association with CYP17 genotype was modified by body mass index (BMI). In lean women, individuals homozygous for the CYP17 A2 allele were 1 cm shorter and had lower baseline BMD (bone mineral density), BMC, and CSA (cross sectional area) in the spine and femoral neck than did other women (BMD spine A2A2: 0.975 g/cm2 versus 1.011 g/cm2 in A1A1 + A1A2, P = 0.002). Conversely, an adverse association with A2A2 and bone loss over 5 years seemed present only in overweight women, but differences were small. Response to HRT was not dependent on CYP17 genotype. COMT genotype was not associated with bone mass at baseline, bone loss in untreated women, or response to HRT. In conclusion, the A2 allele of the CYP17 T(27)-C polymorphism is associated with reduced bone mass and bone size in lean perimenopausal women, whereas high BMI protects against this negative association. The COMT G(1947)-A polymorphism is not associated with bone parameters in this study.
Abstract: Autosomal dominant osteopetrosis II (ADOII) is a relatively benign disorder caused by a missense mutation in the ClCN7 gene. In this study, we characterize the osteoclasts from patients with ADOII, caused by a G215R mutation, and investigate the effect on osteoclast function in vitro. Osteoclasts from ADOII patients and healthy age- and sex-matched controls, were used to evaluate osteoclastogenesis, cell fusion, acidification, and resorptive activity. ADOII osteoclasts in vivo have increased number and size. However, in vitro we observed no significant changes in the osteoclast formation rate, the morphology, and the expression of markers, such as cathepsin K and tartrate-resistant acid phosphatase. When mature ADOII osteoclasts were investigated on mineralized bone, they degraded the bone material, however only to 10 to 20% of the level in controls. We show by acridine orange, that the reduced chloride transport leads to reduced acidification. We show that the residual activity is sensitive to inhibitors of cathepsins and chloride channels, confirming that resorption is reduced but present. In conclusion, this is the first functional in vitro study of human ADOII osteoclasts. We show normal osteoclastogenesis in ADOII osteoclasts. However, the residual activity of the ClC-7 channel in ADOII osteoclasts does not allow sufficient acidification and thereby resorption.
Abstract: BACKGROUND: The mechanisms by which postmenopausal hormone replacement therapy (HRT) may influence risk of cardiovascular disease are still unclear. Impaired fibrinolytic function is associated with an enhanced risk of cardiovascular disease and therefore the effect of HRT on fibrinolysis may be of importance. OBJECTIVES: To investigate the prolonged effect of HRT on the fibrinolytic system and to determine whether two common polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) genes modulate this effect. Methods: Healthy postmenopausal women (n = 248) were randomized to HRT (n = 122) or no substitution (n = 126) 5 years prior to investigation. RESULTS: Significantly higher values of t-PA activity and lower values of PAI-1 activity and PAI-1 antigen were found in the HRT group compared with the control group. This effect was independent of smoking and without influence from the two common polymorphisms PAI-1 -675(4G/5G) and t-PA intron8ins311. Furthermore, no difference between opposed estrogen (with norethisterone acetate as the gestagen component) and unopposed estrogen therapy was found. Both an intention-to-treat and a per-protocol analysis were performed and similar results were obtained. CONCLUSIONS: Long-term treatment with HRT in healthy postmenopausal women was found to be associated with a beneficial fibrinolytic profile. This effect was found independent of smoking status, opposed and unopposed estrogen therapy had equal effect, and no influence of the two common polymorphisms PAI-1-675(4G/5G) and t-PA intron8ins311 was found. This effect of HRT on fibrinolytic capacity may be one of the beneficial effects of HRT in relation to cardiovascular diseases.
Abstract: The aim of this study was to study the influence of hormone replacement therapy (HRT) on weight changes, body composition, and bone mass in early postmenopausal women in a partly randomized comprehensive cohort study design. A total of 2016 women ages 45-58 years from 3 months to 2 years past last menstrual bleeding were included. One thousand were randomly assigned to HRT or no HRT in an open trial, whereas the others were allocated according to their preferences. All were followed for 5 years for body weight, bone mass, and body composition measurements. Body weight increased less over the 5 years in women randomized to HRT (1.94 +/- 4.86 kg) than in women randomized to no HRT (2.57 +/- 4.63, p = 0.046). A similar pattern was seen in the group receiving HRT or not by their own choice. The smaller weight gain in women on HRT was almost entirely caused by a lesser gain in fat. The main determinant of the weight gain was a decline in physical fitness. Women opting for HRT had a significantly lower body weight at inclusion than the other participants, but the results in the self-selected part of the study followed the pattern found in the randomized part. The change in fat mass was the strongest predictor of bone changes in untreated women, whereas the change in lean body mass was the strongest predictor when HRT was given. Body weight increases after the menopause. The gain in weight is related to a decrease in working capacity. HRT is associated with a smaller increase in fat mass after menopause. Fat gain protects against bone loss in untreated women but not in HRT-treated women. The data suggest that women's attitudes to HRT are more positive if they have low body weight, but there is no evidence that the conclusions in this study are skewed by selection bias.
Abstract: OBJECTIVE: Retrospective studies have indicated that anti-thyroid drugs (ATD) might possess a radioprotective effect, leading to a higher rate of recurrence of hyperthyroidism after iodine-131 ((131)I) therapy. DESIGN: A randomized clinical trial was performed to clarify whether resumption of methimazole after (131)I influences the final outcome of this treatment. METHODS: We assigned 149 patients with Graves' disease or a toxic nodular goitre to groups either to resume (+ATD) or not to resume (-ATD) methimazole 7 days after (131)I. Before (131)I therapy, all patients were rendered euthyroid by methimazole, which was discontinued 4 days before the (131)I therapy. RESULTS: During the follow-up period of 12 Months, 13 patients developed hypothyroidism, 42 were euthyroid, and 18 had recurrence of hyperthyroidism in the +ATD group; the respective numbers in the -ATD group were 16, 42 and 18 (P=0.88). At 3 weeks after (131)I therapy, the serum free-thyroxine index was slightly decreased (by 5.7%; 95% confidence interval (CI) -15.5 to 5.4%) in the +ATD group, in contrast to an increase of 35.9% (95% CI 18.8 to 55.5%) in the -ATD group (P<0.001 between groups). In the subgroup that remained euthyroid during follow-up, thyroid Volume reduction, assessed by ultrasonography, was smaller in the +ATD group [38.7% (95% CI 33.3 to 44.1%)] than in the -ATD group [48.6% (95% CI: 41.5-55.6%)] (P<0.05). CONCLUSION: No radioprotective effect could be demonstrated, with regard to final thyroid function, for the resumpton of methimazole 7 days after (131)I therapy. Although resumption of methimazole slightly reduced the magnitude of shrinkage of the goitre obtained by (131)I, the prevention of a temporary thyrotoxicosis in the early period after radiation favours this regimen.
Abstract: The osteopetroses are a heterogeneous group of genetic conditions characterized by increased bone density due to impaired bone resorption by osteoclasts. Within the autosomal dominant form of osteopetrosis, the radiological type I (ADOI) is characterized by a generalized osteosclerosis, most pronounced at the cranial vault. The patients are often asymptomatic but some suffer from pain and hearing loss. ADOI is the only type of osteopetrosis not associated with an increased fracture rate. Linkage analysis in two families with ADOI from Danish origin enabled us to assign the disease-causing gene to chromosome 11q12-13. A summated maximum lod score of +6.54 was obtained with marker D11S1889 and key recombinants allowed delineation of a candidate region of 6.6 cM between markers D11S1765 and D11S4113. Previously, genes causing other conditions with abnormal bone density have been identified from this chromosomal region. The TCIRG1 gene was shown to underly autosomal recessive osteopetrosis (ARO), and, recently, mutations in the LRP5 gene were found both in the osteoporosis-pseudoglioma syndrome and the high bone mass trait. Because both genes map within the candidate region for ADOI, it can not be excluded that ADOI is caused by mutations in either the TCIRG1 or the LRP5 gene.
Abstract: The osteopetroses are a heterogeneous group of conditions characterized by a bone-density increase due to impaired bone resorption. As well as the two or more autosomal recessive types, two autosomal dominant forms of osteopetrosis, differentiated by clinical and radiological signs, are described. Autosomal dominant osteopetrosis (ADO) type II, also known as "Albers-Schönberg disease," is characterized by sclerosis, predominantly involving the spine (vertebral end-plate thickening, or Rugger-Jersey spine), the pelvis ("bone-within-bone" structures), and the skull base. An increased fracture rate can be observed in these patients. By linkage analysis, the presence, on chromosome 1p21, of a gene causing ADO type II was previously suggested. However, analysis of further families with ADO type II indicated genetic heterogeneity within ADO type II, with the chromosome 1p21 locus being only a minor locus. We now perform a genomewide linkage scan of a French extended family with ADO type II, which allows us to localize an ADO type II gene on chromosome 16p13.3. Analysis of microsatellite markers in five further families with ADO type II could not exclude this chromosomal region. A summed maximum LOD score of 12.70 was generated with marker D16S3027, at a recombination fraction (straight theta) of 0. On the basis of the key recombinants in the families, a candidate region of 8.4 cM could be delineated, flanked by marker D16S521, on distal side, and marker D16S423, on the proximal side. Surprisingly, one of the families analyzed is the Danish family previously suggested to have linkage to chromosome 1p21. Linkage to chromosome 16p13.3 clearly cannot be excluded in this family, since a maximum LOD score of 4.21 at theta=0 is generated with marker D16S3027. Because at present no other family with ADO type II has proved to have linkage to chromosome 1p21, we consider the most likely localization of the disease-causing gene in this family to be to chromosome 16p13.3. This thus reopens the possibility that ADO type II is genetically homogeneous because of a single gene on chromosome 16p13.3.
Abstract: OBJECTIVES: to predict spinal and femoral bone mineral density (BMD) in perimenopausal women from simple clinical and biochemical variables. METHODS: 2016 women 3-24 months past last menstrual bleeding. Mean age 50.1+/-2.8 years. Age, height, weight, number of full term pregnancies, weekly hours of physical activity, sunbathing habits, use of sun bed, daily intake of calcium and vitamin D, smoking habits, consumption of alcohol, coffee, and tea, history of forearm or femoral neck fractures among the parents, serum osteocalcin (S-OC), serum bone specific isoenzyme of alkaline phosphatase (BSAP), and urine hydroxyproline/creatinine ratio (U-OHP) were used as predictors in three different mathematical models. Lumbar spine (L2-L4) and femoral neck BMD were measured by DEXA. Three mathematical models (multiple regression, logistic regression, and discriminant analysis) were applied. RESULTS: the multiple regression explained 19-21% of the total variation, and the logistic regression and discriminant function had a sensitivity between 53 and 67% with specificity ranging from 67 to 80%. Age, S-OC, serum bone specific alkaline phosphatase, and a maternal history of forearm or femoral neck fractures seemed to be reproducible risk factors for low bone mineral density irrespective of the mathematical model applied. When applied to a separate population, the models performed poorly. CONCLUSIONS: Simple clinical and biochemical variables are not useful to predict spinal and femoral BMD in the individual perimenopausal woman.
Abstract: We conducted this study to assess the prevalence of vitamin D insufficiency in a population of normal perimenopausal women, to examine the influence of sun exposure and vitamin D intake on the concentration of 25-hydroxyvitamin D (25OHD) and to examine the association between parathyroid hormone (PTH) and 25OHD. A total of 2016 healthy women aged 45-58, who had recently undergone a natural menopause, were enrolled over a 2.5-year period in the Danish Osteoporosis Prevention Study. A marked seasonal fluctuation of 25OHD was seen, with an abrupt rise in June and high values until October. The fluctuation could be related to number of hours of sunshine per month with a two months time lag. Dietary vitamin D intake, vitamin supplementation, sunlight exposure, and use of sun-bed were all significantly related to 25OHD concentrations. Sun exposure seemed to contribute the most. The overall prevalence of vitamin D deficiency (defined as serum ) was 7 %. However, in the subgroup avoiding direct sunshine and abstaining from vitamin D supplementation 32.8 % were vitamin D deficient in the winter-spring period. Although mean PTH was increased in the group with low serum 25OHD, PTH was not a sensitive marker of hypovitaminosis D in the individual, as only 16 % of those with vitamin D deficiency had PTH levels above normal range. Thus, we have shown, that healthy middle-aged Danish women are prone to vitamin D insufficiency in the winter-spring period, if they avoid sun exposure in the summer period and abstain from vitamin D supplementation.
Abstract: In a prospective, controlled, comprehensive cohort trial of 2,016 healthy early postmenopausal women aged 45-58 years we studied fracture prevention through the use of oestrogen. There were two main study arms: a randomised arm (randomised to HRT [n = 502] or not [n = 504]) and a non-randomised arm (on HRT [n = 221] or not [n = 789] by own choice). After five years, an intention-to-treat analysis (n = 2,016) showed a reduction in the overall fracture risk (RR = 0.73, 95% CI: 0.50-1.05) and in the forearm fracture risk (RR = 0.45, 95% CI: 0.22-0.90) with oestrogen. Restriction of the analysis to women who had adhered to their initial allocation of either oestrogen (n = 395) or no oestrogen (n = 977) showed a significant reduction in both the overall fracture risk (RR = 0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR = 0.24, 95% CI: 0.09-0.69). We conclude that it is possible to reduce the number of forearm fractures in early postmenopausal women by the use of oestrogen as primary prevention.
Abstract: Albers-Schönberg disease, or autosomal dominant osteopetrosis, type II (ADO II), is the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption. Following the assignment of the gene causing ADO II to chromosome 16p13.3, we now report seven different mutations in the gene encoding the ClCN7 chloride channel in all 12 ADO II families analysed. Additionally, a patient with the severe, autosomal recessive, infantile form of osteopetrosis (ARO) was identified as being homozygous for a ClCN7 mutation. From genotype-phenotype correlations, it seems that ADO II reflects a dominant negative effect, whereas loss-of-function mutations in ClCN7 do not cause abnormalities in heterozygous individuals. Because some ARO patients have mutations in both copies of the ClCN7 gene, ADO II is allelic with a subset of ARO cases.
Abstract: BACKGROUND: Many adult patients in chronic hemodialysis exhibit malnourishment and muscle wasting, which in some may be due partly to blockage of the biological action of growth hormone and the somatomedines. Growth hormone (GH) promotes protein synthesis, and long-term treatment with growth hormone has induced an augmentation in lean body-mass (LBM) in normal elderly persons, in persons with GH deficiency as well as growth improvement in uremic children. The purpose of this study was to evaluate the effect of long-term GH treatment on soft tissues in hemodialyzed patients by dual-energy X-ray absorptiometry (DXA) with special regard to the improvement in lean body mass and fat mass (FM). DESIGN: The study was double-blinded, randomized, and placebo-controlled. Twenty enfeebled patients in chronic hemodialysis were treated by subcutaneous injections of biosynthetic human GH (4 IU/m2 per day) or placebo, given every evening for 6 months. Soft tissues as LBM and FM, were measured by DXA scan, and height, and weight were recorded before, and after 6 months treatment. Serum concentration of insulin-like growth factor (IGF-I) and type III collagen N-terminal propeptide (PIIINP) were analyzed at baseline and after 2, 4 and 6 months. RESULTS: Six months of GH therapy induced a total FM reduction of 3.05 +/- 0.75 kg (mean +/- SEM) (p < 0.001) (n = 9) corresponding to 25% of the total fat mass. The reduction in fat was most marked at the trunk, i.e. 1.39 +/- 0.41 kg (p < 0.001) corresponding to 40% of the total FM reduction. Total LBM increased by 3.14 +/-0.41 kg (p < 0.001) in the GH group. Regional changes for arm, truncus and leg in GH group amounted to 0.22 +/- 0.06 kg (p < 0.001), 1.64 +/- 0.37 kg (p < 0.001) and 0.51 +/- 0.06 kg (p < 0.001), respectively. In contrast, total body weight remained unchanged. Serum IGF-I increased from 199 +/- 14.8 microg/l to 527 +/- 111 microg/l (p < 0.0001) at month 6, and the serum PIIINP from 7.8 +/- 1.3/microg/l to 14.3 +/- 2.1 microg/l (p < 0.001) in the GH-treated group. In the placebo group (n = 11) there were no significant changes in FM, LBM or PIIINP while serum IGF-I decreased from 285 +/- 36 microg/l to 219 +/- 35 microg/l (p < 0.01) after 6 months treatment. CONCLUSIONS: Six months of GH therapy to patients with chronic renal failure resulted in marked changes of the soft tissue with an increase in LBM, and reduction of FM particularly at the trunk. The data imply that GH-induced changes in body composition are maintained with long-term therapy. Very few side-effects of GH treatment were observed, and no serious ones were encountered, though the dosage were 2 to 3 times higher than the one given to GH-insufficient, non-uremic persons, and the serum IGF-I concentrations during treatment equalized those seen in acromegalia. This indicates the existence of a reduced biological effect of GH and IGF-I in uremic persons.
Abstract: The importance of cigarette smoking in relation to bone mass remains uncertain, especially in younger women. In a recent meta-analysis including 10 studies in premenopausal women no effect was seen in this age group. We used baseline data from a large national cohort study (Danish Osteoporosis Prevention Study [DOPS]) to study the cumulated effect of pre- and perimenopausal smoking on bone mineral density (BMD) measured shortly after the cessation of cyclic bleedings. Baseline observations on 2015 recently menopausal women were available. Eight hundred thirty-two women were current smokers and 285 were exsmokers. Significant negative associations of cigarette smoking coded as current, ex-, or never smoking were seen on bone mass in the lumbar spine (P = 0.012), femoral neck (P<0.001), and total body (P<0.001). Quantitatively, the differences between current smokers and never smokers were limited to 1.6, 2.9, and 1.9%, respectively. A statistical interaction was found between smoking and fat mass, indicating that women in the highest tertile of fat mass were unaffected by cigarette smoking. Serum vitamin D levels and osteocalcin were inversely related to the number of cigarettes smoked per day (r = 0.11 and P<0.001; r = 0.17 and P = 0.04), respectively. Bone alkaline phosphatase (BALP) and urinary hydroxyproline (U-OHP) were unaffected by current smoking. The average cumulated effect of premenopausal smoking on bone is small but biologically significant. Reduced body mass in smokers explains part of the negative effect on the skeleton and a complex interaction between smoking and fat mass on the skeleton is indicated. Serum levels of 25-hydroxyvitamin D (25-OHD) and osteocalcin are lower in smokers, which may effect rate of bone loss.
Abstract: The proinflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-6 may play a central role in the acceleration of postmenopausal bone loss, but observational studies have led to contradictory results. Estrogen-dependent changes in the production of IL-1 receptor antagonist (IL-1ra) and the soluble IL-6 receptor (sIL-6R) potentially modify cytokine bioactivity. We therefore assessed the impact of menopause and hormone replacement therapy (HRT) on cytokines and activity modifiers in serum within a 5-year longitudinal study. One hundred sixty perimenopausal women (age 50.1 +/- 2.8 years) were randomized to HRT or no treatment. Serum IL-6 increased with age (r = 0.16; p < 0.05), but cytokines did not correlate with baseline bone mineral density (BMD). HRT led to small increases in IL-1ra (p < 0.001) and IL-6 (p < 0.05), with a decrease in sIL-6R (p < 0.01) and no change in IL-1 beta. No changes were observed in the control group. IL-1ra was inversely correlated with bone loss at the ultradistal forearm (r = 0.29; p < 0.05) and to a lesser degree at the spine (r = 0.20; p = 0.09). In addition, there was a weak positive correlation between sIL-6R and bone loss at the ultradistal forearm (r = 0.26; p < 0.05). High IL-6 levels were associated with slower bone loss (spine r = 0.31, p < 0.01) and controlling for age did not diminish this association. The percent change in sIL-6R during HRT was correlated with the bone loss at the femoral neck (r = -0.29; p < 0.01) and weakly with bone loss in the spine (r = -0.16; p = 0.17). In conclusion, serum IL-1ra and sIL-6R are influenced by HRT and are associated with the rate of bone loss in perimenopausal women.
Abstract: OBJECTIVES: To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. METHODS: Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. RESULTS: After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years. CONCLUSIONS: It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.
Abstract: A BsmI restriction enzyme polymorphism in the vitamin D receptor (VDR) gene has been reported to be associated with bone mineral density (BMD) and bone turnover. However, findings in other studies suggest the presence of considerable interaction by race, body size, and environmental factors. Therefore, we VDR BsmI genotyped 200 healthy perimenopausal Danish white women (mean age 50.8 years, mean calcium intake 900 mg/day) in a comprehensive, longitudinal, community-based population study. Bone loss was assessed by dual-energy X-ray absorptiometry (DXA) using cross-calibrated Hologic QDR-1000W and QDR-2000 densitometers, with a mean follow-up period of 4 years (range 1-5 years). Despite a distribution of genotypes similar to that of other white populations (28% bb, 49% Bb, 23% BB), VDR genotypes were not associated with lumbar or femoral baseline BMD, subsequent bone loss rates, or biochemical markers of bone metabolism (bone-specific alkaline phosphatase, urinary hydroxyproline, and serum osteocalcin). Controlling for body size, calcium intake, and serum levels of 25-hydroxyvitamin D3 [25(OH)D3] did not alter this finding. The possible existence of a threshold effect was subsequently investigated by restricting analysis to women with low serum 25(OH)D3 levels or low calcium intake. VDR BsmI genotypes showed no significant impact on bone density or bone loss in healthy Danish early postmenopausal women, even when allowance was made for calcium intake, serum 25(OH)D3, and body size.
Abstract: To study the effects of treatment with glucocorticoid and calcitriol on biochemical markers of calcium and bone metabolism, 48 normal male volunteers (aged 21-54 years) were randomized to treatment for 7 days with either (A) prednisolone, 10 mg twice daily, (B) prednisolone, 10 mg twice daily, and calcitriol, 1 microg twice daily, (C) calcitriol 1 mg twice daily, or (D) placebo. The study period was 28 days. Renal calcium excretion increased (mean maximal increase +44.7%, p < 0.01) as well as serum parathyroid hormone (PTH) (max. +18.5%, p < 0.01) during prednisolone treatment. Concomitant treatment with calcitriol or calcitriol alone equally enhanced renal calcium excretion (max. +185.2%, p < 0.001) and decreased serum PTH (max. -43.1%, p < 0.001). Prednisolone administration was followed by prompt declines in markers of bone formation [serum osteocalcin (max. -34.7%, p < 0.001) and serum procollagen type I C-terminal propeptide (PICP) (max. -25.9%, p < 0.05)], whereas serum bone alkaline phosphatase (bone AP) remained unchanged. Calcitriol in combination with prednisolone attenuated the decrease in PICP (max. -8.9%, not significant), but it had no effect on osteocalcin (max. -40.1%, p < 0.001), and decreased bone AP (max. -22.2%, p < 0.05). Calcitriol alone increased osteocalcin (max. +37.8%, p < 0.03) and PICP (max. +26.0%, p < 0.05). Among markers of bone degradation, prednisolone suppressed serum C-terminal telopeptide of type I collagen (ICTP) (max. -28.4%, p < 0.001), but not the fasting renal excretion of hydroxyproline (OHP) and collagen type I N-terminal telopeptide (NTx). Calcitriol partially antagonized the decrease in ICTP (max. -17.2%, p < 0.001). Calcitriol alone had no effect on resorptive markers. Extraosseous matrix synthesis was suppressed by prednisolone evaluated by serum procollagen type III N-terminal propeptide (max. -30.8%, p < 0.001) and was not affected by concomitant treatment with calcitriol or calcitriol alone. In conclusion, short-term administration of prednisolone to healthy men leads to fast and protracted suppression of biochemical markers of bone formation and extraosseous connective tissue metabolism. The effect on bone was partially antagonized by simultaneous calcitriol treatment, and points toward a potential role of calcitriol in the prevention of steroid induced osteoporosis.
Abstract: BACKGROUND: Uraemia and chronical haemodialysis are associated with an abnormal growth hormone (GH)-insulin-like growth factor (IGF) axis which may contribute to malnutrition and renal bone disease. Short-term studies have shown a beneficial effect of treatment with recombinant human growth hormone (rhGH) on nutritional status in patients on haemodialysis. In the present study, we evaluated the effect of rhGH on bone and mineral metabolism. METHODS: Twenty chronic malnourished patients on haemodialysis took part in a double-blind, placebo controlled trial with subcutaneous injections of rhGH (4 IU/m2/day) or placebo for 6 months. RESULTS: During rhGH treatment, serum IGF-1 increased 264 +/- 52% (mean +/- SEM) (P < 0.008). There were no significant changes in biochemical markers of mineral metabolism (serum ionized calcium, phosphate and parathyroid hormone). Among markers of bone metabolism, there was a significant increase in serum procollagen type I C-terminal propeptide (maximum 155 +/- 8%, P < 0.001) and no significant changes in serum alkaline phosphatase. Bone densitometry showed a significant decrease in whole body bone mineral content (95.7 +/- 1.2%) after 6 months treatment. The effects on the proximal femur were not significant. CONCLUSION: The effects of 6 months treatment with rhGH seen in this study are best explained by a GH- or IGF-1-induced increased bone turnover. Long-term treatment in larger cohorts followed by bone densitometry and, preferentially, bone histomorphometry are needed to evaluate whether this is a beneficial effect in haemodialysis patients.
Abstract: We investigated the effect of cooling blood to 20 degrees C on the reactions and dialysis efficiency in a model using pigs. Eighteen uremic pigs were hemodialyzed. Nine pigs were hemodialyzed cooling the blood in the dialysis filter and rewarmed using microwaves to body temperature before being returned to the pigs; no heparin was added. Nine pigs (control group) were dialyzed using heparin without blood cooling. A significant decrease in the number of leukocytes was observed after 15 min in the control group, whereas no change was observed in the hypotherm-dialyzed group. We conclude that heparin-free hemodialysis performed at 20 degrees C with microwave rewarming is possible, improving biocompatibility significantly.
Abstract: Albers-Schönberg disease, the classical form of osteopetrosis, is an autosomal dominant condition with generalized increased skeletal density due to reduced bone resorption. Characteristic radiological findings are generalized osteosclerosis, with, most typically, end-plate sandwichlike thickening of the vertebrae (Rugger-Jersey spine) and the bone-within-bone (endobones) phenomenon. We studied an extended kindred with Albers-Schönberg disease and found linkage with several markers from chromosome 1p21. The Albers-Schönberg gene is located in a candidate region of approximately 8.5 cM flanked by markers D1S486 and D1S2792. A maximum LOD score (Z(max)) of 4.09 was obtained in multipoint analysis at loci D1S239/D1S248. Possible linkage of osteopetrosis to this chromosomal region was analyzed because the CSF-1 gene, which is mutated in the op/op mouse model for osteopetrosis, is located in 1p21. However, SSCP and mutation analysis in patients did not reveal any abnormality, which excludes the CSF-1 gene as the disease-causing gene. This was confirmed by refined physical mapping of the CSF-1 gene outside the candidate region for the Albers-Schönberg gene. The identification of the molecular defect underlying Albers-Schönberg disease will therefore be dependent on the isolation of other genes from an 8.5-cM candidate region on chromosome 1p21.
Abstract: OBJECTIVES: To evaluate whether introduction of treatment alternatives would improve compliance with hormonal replacement therapy (HRT) as primary osteoporosis prevention in women not tolerating the first line osteoporosis prevention schedule. MATERIAL AND METHODS: Follow-up in four hospitals participating in the Danish Osteoporosis Prevention Study. A total of 706 peri- and postmenopausal women aged 45-57 years between 3 and 24 months from last menstrual bleeding took part, 489 women were randomised to HRT and 217 received HRT by personal choice. A total of 135 (19%) women were hysterectomised. HRT was given as oral or transdermal oestradiol supplemented with progestogen. If the initial treatment allocation was not acceptable several alternatives were available in a pragmatic approach. RESULTS: Compliance with first treatment schedule was lower in women with intact uterus (at 5 years: 48.3 +/- 2.4% compliance) than in hysterectomised (64.7 +/- 5.8%, P < 0.001 in a Cox analysis) but did not differ after the introduction of HRT alternatives (67.0 +/- 2.9 vs 77.8 +/- 5.9, P = 0.12). Compliance decreased with increasing age at treatment start (RR = 1.11, P < 0.001) in women with intact uterus but not in hysterectomised women (P = 0.96). Headache/migraine was more frequent among women with intact uterus on oral sequential oestrogen plus progestogen than among hysterectomised women receiving oral continuous oestrogen (RR = 11.3, P < 0.01). CONCLUSIONS: It seems possible to maintain a high HRT compliance by a pragmatic approach including offering alternative HRT formulations to women not tolerating the primary HRT. Further research into long-term compliance with HRT and cost-benefit is warranted.
Abstract: To evaluate the effects of short-term treatment with calcitriol on biochemical markers of calcium and bone metabolism, 36 normal male volunteers (aged 21-54 years) were randomized to oral treatment for 7 days with either (A) calcitriol, 1 microgram twice daily, (B) calcitriol, 0.5 microgram twice daily, or (C) placebo twice daily. Serum calcium increased slightly in a dose-dependent manner (maximal increase 2.5%, p < 0.05) followed by a heavy increase in both 24 h (max. 156.1%, p < 0.001) and fasting urinary calcium excretion (max. 123.1%, p < 0.001), and a striking reduction in serum PTH (max. -43.1%, p < 0.001). Biochemical markers of osteoblast activity and bone formation increased immediately in a dose-dependent manner [serum osteocalcin (max. 37.8%, p < 0.03) and serum procollagen type I C-terminal propeptide (PICP) (max. 26.0%, p < 0.05)], whereas there was no effect on serum bone alkaline phosphatase. Calcitriol treatment had no effect on biochemical markers of bone resorption [serum C-terminal telopeptide of type I collagen (ICTP) and fasting urinary excretion of hydroxyproline/creatinine (OHP)]. Extraosseous collagen matrix synthesis was not affected evaluated by serum procollagen type III N-terminal propeptide (PIIINP). In the follow-up period (15 weeks) no unequivocal changes were observed. The fast and protracted increase in biochemical markers of osteoblast activity and bone formation, without affecting bone resorption and extraosseous connective tissue metabolism points toward a selective effect of calcitriol on bone matrix formation.
Abstract: The development of Graves' disease as evidenced by diagnostic imaging and appearance of TSH receptor antibodies is described in a 49-year-old woman 6 months after onset of subacute thyroiditis. The HLA typing indicated that the patient had a genetic predisposition to hyperthyroid Graves' disease as well as subacute thyroiditis. A possible causal relationship is discussed.
Abstract: Replacement of dual energy X-ray densitometry (DXA) equipment may be necessary in many labs with time, or new equipment may be added. In this context we compared patient scans between a Hologic QDR-1000W and a QDR-2000 (n = 29-43, depending on anatomic region) and between QDR-2000 single beam (SB) and fan beam (FB) modes (n = 40-62) as a quality control measure. A total of 83 subjects (79 females and four males) with a wide range of bone mineral densities (BMD) were studied. There was a linear relationship between results with the QDR-1000W and QDR-2000 in SB mode, and between SB and FB mode on the QDR-2000, but the magnitude of the coefficients and constants differed for the different anatomic regions. In SB mode the QDR-2000 underestimated whole body and forearm BMD by 3% relative to the QDR-1000W, even after cross calibration using a spine phantom. Femoral total BMD was slightly, but not significantly, underestimated. Thus, additional postanalysis correction had to be applied to forearm and whole-body scans. In FB with the QDR-2000, spine and whole-body BMD was underestimated by 3%, but femur total and neck BMD was overestimated by 2.2 and 2.8%, respectively, compared with SB scans on the same device. Soft-tissue composition with FB (enhanced analysis protocol) on the QDR-2000 differed greatly from that obtained using SB (standard protocol). Lean tissue mass was 4 kg lower and fat mass 4 kg higher in FB mode.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Bone mineral content (BMC) and density (BMD) were measured by dual-energy X-ray absorptiometry in two subtypes of autosomal dominant osteopetrosis (ADO). Both types have been radiologically characterized by diffuse symmetrical osteosclerosis, but with characteristic differences. Increased thickness of the cranial vault is a typical finding in type I ADO, whereas endobones in the pelvis and end-plate thickening in the spine are obligate findings in type II. Eleven patients with type I from three kindreds, and seven patients with type II, one family participated in the study, and were compared with 18 age- and sex-matched normal controls. Whole-body BMC and BMD were measured, and regions of special interest were selected: head, axial, and appendicular skeleton. Moreover, lumbar spine and femoral neck scans were performed. Whole-body BMC and BMD, mostly reflecting cortical bone, were markedly increased in both types compared with normals. A pronounced osteosclerosis was present in the axial as well as the appendicular skeleton. Median BMD was markedly increased in the axial skeleton by 51% (44-56) and 42% (33-56), (median differences with 95% CI), respectively, for types I and II compared to normal controls, and in the appendicular skeleton by 48% (37-59) and 38% (16-45). No overlap between observed ranges of patients and controls was observed. A positive correlation between age and whole-body BMD was demonstrated in ADO, but not in the control group, indicating progressive osteosclerosis with age. Median BMD of the lumbar spine, which mostly reflects trabecular bone, showed increased densities in both types, 71% (51-84) and 59% (37-93), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The biological variations of serum (S-) magnesium and urinary (U-) magnesium concentrations and excretions have been investigated. Serum samples, 24-h and fasting urinary samples were collected from each of 60 supposedly healthy male volunteers. In addition, 12 volunteers collected additional samples 7 and 112 days after the initial sample. The reference interval for S-magnesium was 0.765-0.997 mmol l-1. The biological variation for S-magnesium was 3.2% within subjects and 7.4% between subjects. This indicated an index of indivduality of 0.5, which means that significant changes in S-magnesium can occur within the limits of the reference interval, and that serial determinations of S-magnesium might prove useful as an indicator of changes in whole body magnesium status. It is, on the other hand, unlikely that a single determination of S-magnesium can be used in assessing whole-body magnesium status in the individual. The reference interval for the 24-h U-magnesium excretion, corrected for surface area, was 1.306-4.762 mumol min-1 1.73 m-2. The 24-h U-magnesium excretion exhibited a biological within-subject variation of 36% and a between-subject variation of 26%. The 24-h U-magnesium excretion did not correlate with S-magnesium, and only slightly (r = 0.58) with the fasting U-magnesium/creatinine concentration. This, and the very large coefficients of variation, make it unlikely that the renal magnesium excretion can be used as a measure of whole body magnesium status, or that changes in the renal magnesium excretion can be used as a measure of changes in whole body magnesium status.
Abstract: OBJECTIVE: In active acromegaly body composition is characteristically altered by an increase in lean body mass and a corresponding reduction in fat mass. These changes are induced by an excessive secretion of GH and insulin-like growth factor I (IGF-I). Growth hormone is an anabolic hormone and leads to stimulation of protein synthesis and an increased lipolysis in adipose tissue. Treatment with the somatostatin analogue, octreotide, has been shown to reduce GH levels causing reduced hormonal effects on target tissues. We have studied changes in body composition during short-term reduction in GH level by octreotide in active acromegaly. DESIGN: Octreotide was compared to placebo in a double-blind, cross-over trial. Dual-energy X-ray absorptiometry scanning was employed to calculate body composition. Relations between body composition parameters and clinical signs of acromegaly (finger circumference and foot volume) were studied. PATIENTS: Twelve patients with active acromegaly, confirmed by lack of GH suppression during oral glucose loading, were included. All had pituitary adenomas diagnosed by computed tomography. MEASUREMENTS: Serum GH and IGF-I. Lean body mass, fat mass and total weight, foot volume and finger circumference. RESULTS: Four weeks of octreotide treatment caused a 75% decrease in GH levels (n = 10), a reduction in IGF-I from 476 +/- 51.9 (mean +/- SEM) to 233 micrograms/l +/- 46.3 (P < 0.005) and a corresponding decrease in both body weight (2.51 kg +/- 0.41) (P < 0.005) and lean body mass (2.44 kg +/- 0.48) (P < 0.005). No significant changes in fat mass were observed. These findings were paralleled by significant reductions in foot volume (44.50 ml +/- 17) (P < 0.05) and finger circumference (1.3 mm +/- 0.3) (P < 0.05). CONCLUSIONS: Short-term octreotide therapy reduces growth hormone levels leading to a significant reduction in lean body mass as assessed by dual-energy X-ray absorptiometry. Alterations in lean body mass were positively correlated with reductions in foot volume. Thus, simple clinical tests may be valuable in judging the effects of treatment in active acromegaly.
Abstract: The performance of the Hologic QDR-2000 DXA osteodensitometer was critically evaluated at four centers, using at all four centers one bone equivalent humanoid spine phantom supplied by the manufacturer. Results were compared with results from Hologic QDR-1000/W using that phantom tested at the same centers. It appears that the concept of fan-beam scanning--as used in the QDR-2000: a fan-beam, a linear array detector above the phantom, and an x-ray tube located rather close to the spine below the phantom--creates problems due to the magnification effect of the fan beam. The effect of decreasing the distance between the "vertebrae" of the phantom and the couch are: bone mineral content (BMC) increases by 2.8% per cm, projected area (Area) by 2.8% per cm, and bone mineral density (BMD) is unchanged. When QDR-1000/W is upgraded to QDR-2000, BMD is relatively constant, but there are shifts of BMC and Area which are partly due to the magnification effect of the fan-beam. Replacement of a QDR-1000/W with a QDR-2000 can invalidate longitudinal measurements, even for BMD, unless the proportionality factors of the QDR-2000 are checked and, if necessary, changed. This is true for switching from QDR-1000/W to pencil-beam mode of QDR-2000 or to fan-beam mode of QDR-2000. Even with pencil-beam mode, the long-term precision error with phantoms is higher for QDR-2000 than for QDR-1000/W (for BMD, 0.47% versus 0.35%).
Abstract: Serum concentration of fetal antigen 2 (FA2) in patients with hyperthyroidism (n = 18) (median: 12.9 mAU/l; range: 3.2-22.4 mAU/l) was significantly (p < 0.002) higher than in age- and sex-matched healthy controls (median: 4.1 mAU FA2/l; range: 2.4-10.0 mAU FA2/l). Serum FA2 was positively correlated with thyroxine (T4) (Rs = 0.51; p < 0.05), triiodothyronine (T3) (Rs = 0.64; p < 0.01), bone-Gla protein (BGP) (Rs = 0.70; p < 0.01), total alkaline phosphatase (total-AP) (Rs = 0.62; p < 0.01), bone isoenzyme alkaline phosphatase (bone-AP) (Rs = 0.63; p < 0.01), N-terminal procollagen type III (PIIINP) (Rs = 0.65; p < 0.01) and urine OH-proline (OHP) (Rs = 0.79; p < 0.01). In patients with hyperparathyroidism the pretreatment levels of FA2 (n = 8) (median: 17.6 mAU/l; range: 5.2-35.0 mAU/l) were significantly (p < 0.001) higher than those of age- and sex-matched controls (median: 3.7 mAU FA2/l; range: 3.4-9.0 mAU/l). The pretreatment level of FA2 was positively correlated with the parathyroid hormone (PTH) (Rs = 0.80; p < 0.05). Following surgical treatment the serum concentrations of FA2, PTH, and BGP decreased compared to pretreatment levels and the fall in these three parameters revealed parallelism. These data indicate that serum FA2 can be used as a marker in the evaluation of metabolic bone diseases.
Abstract: Serum levels of creatine kinase isoenzyme BB (CK-BB) were measured spectrophotometrically and by electrophoresis in 17 patients with autosomal dominant osteopetrosis (ADO) and compared with those of age- and sex-matched controls. Eight patients had ADO type 1 and nine patients had ADO type II. CK-BB was significantly increased (p less than 0.002) in type II but normal in type I compared with controls. This finding supports heterogeneity of ADO, and it may indicate a potential role for CK-BB as a marker of immature osteoclasts.
Abstract: A number of in vitro studies suggest an immunoregulatory role of 1 alpha,25 Dihydroxyvitamin D3 (1,25-(OH)2D3). The hormone inhibits production of interleukin-2 and immunoglobulin, and it blocks lymphocyte proliferation. Diverse effects on monocyte functions have been reported. However, immunological effects of 1,25-(OH)2D3 have not been substantiated in vivo. Six healthy male volunteers, aged 28-45 yr, were treated orally with 1,25-(OH)2D3 (tabl. Rocaltrol), 1 microgram twice daily for 7 days. Blood and urine samples were collected before and 7 days after initiation of treatment. Blood mononuclear cells from individuals treated with 1,25-(OH)2D3 showed a significantly reduced production of both interleukin-1 alpha (45%) and tumor necrosis factor-alpha (58%) (both measured by ELISA). Interleukin-6, production, measured by the B9 cell assay, was reduced in five individuals (78%), and unchanged in one. There was no effect on the release of interleukin-1 beta. There was no measurable effect on interleukin-2, interferon gamma or immunoglobulin production, or on mitogen-induced proliferation of blood mononuclear cells. Serum-osteocalcin and urine excretion of calcium were increased to 131 and 173%, respectively. The serum-calcium and serum-phosphate levels were unchanged.
Abstract: To investigate the stimulatory effect of vitamin D on biochemical markers of bone remodeling, 15 normal men (aged 26-45 years, mean 33.2) were treated orally with 1,25-dihydroxyvitamin D3, 2 micrograms daily for 7 days, and followed for a total of 16 weeks. Serum concentrations of 1,25-dihydroxyvitamin D3 rose 43% during the first week (p less than 0.01), with no significant alteration in the level of 25-hydroxyvitamin D3. Serum level of immunoreactive parathyroid hormone (1-84) (iPTH) decreased markedly (p less than 0.02), and the maximal renal reabsorption capacity of phosphate (TmP/GFR) increased (p less than 0.05), both indicating the impact of the raised vitamin D level on target tissues. Serum phosphate and serum calcium increased during the treatment week (p less than 0.05), as did the fasting renal excretion of phosphate and calcium (p less than 0.01). However, a gradual fall in the excretion of hydroxyproline was seen in the observation period. The serum activity of acid phosphatase increased in the first weeks after vitamin D treatment, reaching significance at the end of week 2 (p less than 0.05). Acid phosphatase activity was still increased at the end of the observation period (p less than 0.02). These observations suggest a synchronization and recruitment of new bone resorptive cells. The immediate response to 1,25-dihydroxyvitamin D administration on the biochemical markers of formative bone cells was a marked increase in the serum level of osteocalcin (BGP), (p less than 0.002) with a gradually fall during the next weeks. A secondary increase, however, was observed in the last two months of the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To investigate bone collagen metabolism during vitamin D treatment, 15 healthy males (aged 28-45 years, median 34) were treated orally with calcitriol, 2 micrograms daily for 7 days and followed for a total of 2 weeks. The serum concentration of calcitriol rose markedly (median difference and 95% confidence limits: 49% (5-82), p less than 0.005) during treatment, whereas serum levels of calcidiol, and calcium remained unchanged. The serum level of procollagen type I C-terminal propeptide rose 15% (7-33, p less than 0.003), whereas no alterations were observed concerning serum procollagen type III N-terminal propeptide, and serum hyaluronan. The serum concentration of osteocalcin rose concomitantly (26% (12-45), p less than 0.003). All values returned to baseline levels within seven days after the treatment week. The serum levels of osteocalcin and procollagen type I C-terminal propeptide were positively correlated (rs = 0.71, p less than 0.004) during the study. Serum procollagen type I C-terminal propeptide and serum osteocalcin did not correlate with serum procollagen type III N-terminal propeptide or serum hyaluronan either at baseline or after treatment. It is concluded that a short course of calcitriol administration to healthy males stimulates the biosynthesis of bone-related matrix proteins. By contrast, connective tissue components of predominantly extraosseous origin are not affected.
Abstract: Drug consumption was studied in 87 persons with occult fasting hyperglycaemia and compared with sex- and age-matched non-diabetic controls all selected by screening a well-defined population aged 60-74 years. The daily use of prescribed and nonprescribed drugs was established by questionnaires and interviews. Sixty-nine percent of subjects with fasting hyperglycaemia used drugs daily compared with 46% of controls (P less than 0.005). The difference was most pronounced among men. The median use of defined daily doses in those using drugs was not significantly different in the two groups. The main drug usage in both subjects with fasting hyperglycaemia and controls was in the cardiovascular medication group. More than half (59%) of the subjects with fasting hyperglycaemia used cardiovascular drugs compared with 27% of controls (P less than 0.0001). There were no significant differences in the other medication groups. Our results may reflect an increased morbidity from cardiovascular diseases among the elderly with occult fasting hyperglycaemia, and they seem to be comparable with the results on drug consumption found in the elderly with known diabetes.
Abstract: A total of 106 out of 267 patients admitted with acute gastroenteritis to Medical Department C, Odense Hospital, during the period 1977-1988 had acquired the condition abroad. This group was investigated retrospectively. During the period of investigation, the number of patients with "traveller's diarrhoea" increased but compurized constantly approximately 40% of the patients admitted with acute gastroenteritis. The patients were investigated routinely for pathogenic intestinal bacteria and parasites and the etiology could be determined in 72%. Salmonella infections were found in 50% and 1/5 of these were caused by Salmonella typhi or Salmonella paratyphi. Double and triple infections occurred. 51% of the infections were acquired in Asia and Africa although less than 7% of Danish package tours visit these regions. Five patients (5%) developed serious complications.
Abstract: Carbonic anhydrase localized in bone resorptive cells generates the protons necessary for bone resorption. Inhibition of the enzyme is a potential mechanism for decreasing bone resorption. Eight healthy post-menopausal women received oral acetazolamide 250 mg twice daily for 28 d. Bone resorption, evaluated by serum acid phosphatase activity and the renal excretion of hydroxyproline, was unaltered, as was bone formation estimated by serum levels of alkaline phosphatase and osteocalcin. The fasting renal excretion of calcium was increased, whereas serum ionized calcium was unchanged. The maximal renal reabsorption of phosphate decreased, but it was not an effect of PTH as it decreased significantly during the treatment period. In conclusion, no significant effect on biochemical markers of bone remodelling could be detected during the study period. The observed changes in calcium and phosphate metabolism may be secondary to the renal effect of acetazolamide.
Abstract: The drug use in 228 persons with diabetes was studied and compared with that of sex- and age-matched non-diabetic controls--all of whom were found by the screening of a well-defined Danish population aged 60-74 years. Ninety per cent of the diabetics had non-insulin-dependent diabetes mellitus (NIDDM), as evaluated by a glucagon-C-peptide test. Information on daily use of prescribed and non-prescribed drugs was obtained by questionnaires and interviews. More than 80% of the diabetics used drugs daily, compared to 55% of control subjects (P less than 0.00001). Among subjects using drugs diabetics, on average, used 70% more defined daily doses (DDD) than controls, even when antidiabetics were excluded. There was no difference in the number of drug users among subgroups of diabetics when divided according to antidiabetic treatment but tablet-treated diabetics, on average, used 20% fewer DDD than other diabetics. Cardiovascular drugs were the most commonly used drugs. Diabetics in all antidiabetic treatment groups used significantly more cardiovascular drugs than non-diabetics. Diabetics treated with oral antidiabetics used fewer cardiovascular drugs than insulin- and diet-treated diabetics. The estimated cost of drug therapy was more than 2.5 times higher for diabetics than for the control group. Our results reflect the increased morbidity among elderly diabetics and emphasise, together with other aspects of costs of diabetes in the elderly, the need for allocating resources for the prevention of NIDDM instead of the treatment of its complications.
