Abstract: Context: As awareness of osteoporosis in childhood has increased, so have pressures to consider use of the pharmacologic agents used to treat osteoporosis in adults. This review examines available research on the efficacy and safety of bisphosphonate therapy for pediatric osteoporosis. Evidence Acquisition: We reviewed the medical literature for key articles and consensus statements on the use of bisphosphonates in children through June, 2008. Evidence Synthesis: We compared reports using varying bisphosphonate agents, doses, duration of therapy to treat osteogenesis imperfecta and a variety of secondary causes of osteoporosis in children. Conclusions drawn from a recently published Cochrane analysis and the consensus statements from experts in the field were considered as well. Conclusions: Use of bisphosphonate therapy in pediatric patients remains controversial because of inadequate long-term efficacy and safety data. For this reason, many experts recommend limiting use of these agents to those children with recurrent extremity fractures, symptomatic vertebral collapse and reduced bone mass. Current data are inadequate to support the use of bisphosphonates in children to treat reductions in bone mass/density alone. More research is needed to define appropriate indications for bisphosphonate therapy and the optimal agent, dose, and duration of use in pediatric patients.
Abstract: The International Society for Clinical Densitometry Official Positions on reporting of densitometry results in children represent an effort to consolidate opinions to assist healthcare providers determine which skeletal sites should be assessed, which adjustments should be made in these assessments, appropriate pediatric reference databases, and elements to include in a dual energy X-ray absorptiometry (DXA) report. Skeletal sites recommended for assessment are the lumbar spine and total body less head, the latter being valuable as it provides information on soft tissue, as well as bone. Interpretation of DXA findings in children with growth or maturational delay requires special consideration; adjustments are required to prevent erroneous interpretation. Normative databases used as a reference should be based on a large sample of healthy children that characterizes the variability in bone measures relative to gender, age, and race/ethnicity, and should be specific for each manufacturer and model of densitometer and software. Pediatric DXA reports should provide relevant demographic and health information, technical details of the scan, Z-scores, and should not include T-scores. The rationale and evidence for development of the Official Positions are provided. Given the sparse data currently available in many of these areas, it is likely that these positions will change over time as new data become available.
Abstract: We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)(2) vitamin D (1x10(-7) M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 h. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR.
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.
