Disrupted trabecular bone micro-architecture in middle-aged male HIV-infected treated patients.

OBJECTIVES: HIV-infected individuals are at increased risk of incident fractures. Evaluation of trabecular bone micro-architecture is an important tool to assess bone strength, but its use has not yet been reported in middle-aged HIV-infected male individuals. The aim of the study was to compare bone micro-architecture between HIV-infected and HIV-uninfected men. METHODS: In this cross-sectional study, 53 HIV-infected male individuals with a mean (± standard deviation) age of 49 ± 9 years who had been receiving antiretroviral therapy including tenofovir disoproxil fumarate (DF) for at least 60 months were compared with 50 HIV-uninfected male controls, matched for age and ethnic origin. We studied the volumetric bone density and micro-architecture of the radius and tibia using high-resolution peripheral quantitative computed tomography (HR-p QCT). RESULTS: Volumetric trabecular bone density was 17% lower in the tibia (P < 10(-4) ) and 16% lower in the radius (P < 10(-3) ) in HIV-infected patients compared with controls. By contrast, the cortical bone density was normal at both sites. The tibial trabecular micro-architecture differed markedly between patients and controls: bone volume/total volume (BV/TV) and trabecular number were each 13% lower (P < 10(-4) for both). Trabecular separation and inhomogeneity of the network were 18% and 24% higher in HIV-infected patients than in controls, respectively. The radial BV/TV and trabecular thickness were each 13% lower (P < 10(-3) and 10(-2) , respectively). Cortical thickness was not different between the two groups. CONCLUSIONS: The findings of lower volumetric trabecular bone density and disrupted trabecular micro-architectural parameters in middle-aged male HIV-infected treated patients help to explain bone frailty in these patients.

Bone status and fractures in 85 adults with Wilson's disease.

UNLABELLED: Wilson's disease is characterized by copper deposition, especially in the liver and central nervous system. We assessed the prevalent fractures and bone mineral density (BMD) and related risk factors in 85 patients. BMD was normal, but patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk for fractures. INTRODUCTION: Wilson's disease (WD) is characterized by copper deposition, especially in the liver and central nervous system. Two studies showed a high prevalence of osteoporosis in WD patients. We wanted to assess the prevalent fractures and bone mineral density (BMD) and to identify risk factors for bone loss and fractures in a large group of WD patients. METHODS: In this prospective cross-sectional survey at National center of reference for WD, we included 85 patients, 47 women, and 38 men, with a mean age of 35 ± 10 years, and mean time from diagnosis to study of 21 ± 9 years; 57 (67%) patients had neurological signs. Peripheral fractures, prevalent radiological vertebral fractures (VFx), and dual-energy X-ray absorptiometry BMD measurements at the femoral neck (FN) and lumbar spine (LS) were studied. RESULTS: Mean LS and FN Z-score was normal (-0.37 ± 1.20 at LS and -0.06 ± 1.20 at FN). BMI <19 kg/m(2) and amenorrhea were associated with low BMD. Prevalent peripheral fractures were noted in 43 (51%) and VF in 7 (8%) patients. Severity of neurological involvement and male sex was associated with peripheral fractures, whereas older age, severe neurological involvement, and low BMD and Z-score values were associated with VF. CONCLUSION: Our data showing normal BMD overall do not support routine bone status evaluation in adults with WD. However, patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk factors for fractures and may require specific monitoring.

ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion.

Mutations in the 2Cl(-)/1H(+)-exchanger ClC-7 impair osteoclast function and cause different types of osteoclast-rich osteopetrosis. However, it is unknown to what extent ClC-7 function has to be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clcn7(-/-) mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro. Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7(-/-) mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7-related osteopetrosis.

Effect of oral monthly ibandronate on bone microarchitecture in women with osteopenia-a randomized placebo-controlled trial.

UNLABELLED: We have examined the effect of oral monthly ibandronate on distal radius and tibia microarchitecture with high-resolution peripheral quantitative tomography compared with placebo, in women with osteopenia, and found that ibandronate did not significantly affect trabecular bone but improved cortical density and thickness at the tibia. METHODS: We have examined the effect of ibandronate on bone microarchitecture with peripheral high-resolution quantitative computed tomography (HR-pQCT) in a randomized placebo-controlled trial among 148 women with osteopenia. Patients received either oral 150 mg monthly ibandronate or placebo over 24 months. Bone microarchitecture was assessed at baseline, 6, 12, and 24 months, using HR-pQCT at the distal radius and tibia; areal bone mineral density (aBMD) was measured with DXA at the spine, hip, and radius. RESULTS: At 12 months, there was no significant difference in trabecular bone volume at the radius (the primary end point) between women on ibandronate (10.8 ± 2.5%) and placebo (10.5 ± 2.9%), p = 0.25. There was no significant difference in other radius trabecular and cortical microarchitecture parameters at 12 and 24 months. In contrast, at the tibia, cortical vBMD in the ibandronate group was significantly greater than in the placebo group at 6, 12, and 24 months, with better cortical thickness at 6, 12, and 24 months. With ibandronate, aBMD was significantly increased at the hip and spine at 12 and 24 months but at the radius was significantly superior to placebo only at 24 months. Most of the adverse events related to ibandronate were expected with bisphosphonate use, and none of them were serious. CONCLUSION: We conclude that 12 months of treatment with ibandronate in women with osteopenia did not affect trabecular bone microarchitecture, but improved cortical vBMD at the tibia at 12 and 24 months, and preserved cortical thickness at the tibia.

Osteoporosis in young adults: pathophysiology, diagnosis, and management.

Postmenopausal osteoporosis is mainly caused by increased bone remodeling resulting from estrogen deficiency. Indications for treatment are based on low areal bone mineral density (aBMD, T-score ≤ -2.5), typical fragility fractures (spine or hip), and more recently, an elevated 10-year fracture probability (by FRAX®). In contrast, there is no clear definition of osteoporosis nor intervention thresholds in younger individuals. Low aBMD in a young adult may reflect a physiologically low peak bone mass, such as in lean but otherwise healthy persons, whereas fractures commonly occur with high-impact trauma, i.e., without bone fragility. Furthermore, low aBMD associated with vitamin D deficiency may be highly prevalent in some regions of the world. Nevertheless, true osteoporosis in the young can occur, which we define as a T-score below -2.5 at spine or hip in association with a chronic disease known to affect bone metabolism. In the absence of secondary causes, the presence of fragility fractures, such as in vertebrae, may point towards genetic or idiopathic osteoporosis. In turn, treatment of the underlying condition may improve bone mass as well. In rare cases, a bone-specific treatment may be indicated, although evidence is scarce for a true benefit on fracture risk. The International Osteoporosis Foundation (IOF) convened a working group to review pathophysiology, diagnosis, and management of osteoporosis in the young, excluding children and adolescents, and provide a screening strategy including laboratory exams for a systematic approach of this condition.

Strontium ranelate decreases the incidence of new caudal vertebral fractures in a growing mouse model with spontaneous fractures by improving bone microarchitecture.

UNLABELLED: Young mice over-expressing Runx2 fail to gain bone relative to wild type mice with growth and present spontaneous fractures. It allows, for the first time in rodents, direct assessment of anti-fracture efficacy of strontium ranelate which was able to decrease caudal vertebrae fracture incidence through an improvement of trabecular and cortical architecture. INTRODUCTION: The aim was to investigate whether strontium ranelate was able to decrease fracture incidence in mice over-expressing Runx2, model of severe developmental osteopenia associated with spontaneous vertebral fractures. METHODS: Transgenic mice and their wild type littermates were treated by oral route with strontium ranelate or vehicle for 9 weeks. Caudal fracture incidence was assessed by repeated X-rays, resistance to compressive loading by biochemical tests, and bone microarchitecture by histomorphometry. RESULTS: Transgenic mice receiving strontium ranelate had significantly fewer new fractures occurring during the 9 weeks of the study (-60%, p < 0.05). In lumbar vertebrae, strontium ranelate improves resistance to compressive loading (higher ultimate force to failure, +120%, p < 0.05) and trabecular microarchitecture (higher bone volume and trabecular number, lower trabecular separation, +60%, +50%, -39%, p < 0.05) as well as cortical thickness (+17%, p < 0.05). In tibiae, marrow cavity cross-section area and equivalent diameter were lower (-39%, -21%, p < 0.05). The strontium level in plasma and bone was in the same range as the values measured in treated postmenopausal women. CONCLUSIONS: This model allows, for the first time, direct assessment of anti-fracture efficacy of strontium ranelate treatment in rodents. In these transgenic mice, strontium ranelate was able to decrease caudal vertebral fracture incidence through an improvement of trabecular and cortical architecture.

Bone mineral density in patients with rapidly destructive or common hip osteoarthritis.

BACKGROUND: Recent findings that subchondral insufficiency fracture in the femoral head may precede rapid chondrolysis suggest a role for systemic low bone mass in the genesis of rapidly destructive hip osteoarthritis (RDHOA). OBJECTIVE: To compare bone mineral density (BMD) in females with RDHOA and those with common hip osteoarth-ritis (OA). METHODS: This prospective case-control study involved 26 females with RDHOA recruited from our institution between March 2000 and November 2006. BMD was measured at the femoral neck and lumbar spine (L1-L4) by dual-energy x-ray absorptiometry. For comparison, BMD was measured in 33 women with common hip OA who were scheduled for primary total hip arthroplasty. RESULTS: Patients with RDHOA and those with common hip OA were similar in age (74.9+/-9.9 vs. 74.7+/-8.8 years) and BMI (26.3+/-4.3 vs. 26.3+/-5 g/m2) and did not differ in mean BMD at the lumbar spine (1.0+/-0.2 vs. 1.1+/-0.2 g/cm2; mean T-score: -0.6+/-1.3 vs. -0.8+/-1.5) or at the femoral neck (0.7+/-0.1 vs. 0.8+/-0.2 g/cm2; mean T-score: -1.5+/-1.1 vs. -1.4+/-1.4). CONCLUSION: The results of this study do not suggest a role for systemic low bone mass in the pathophysiology of RDHOA.

Bone mass does not correlate with the serum fibroblast growth factor 23 in hemodialysis patients.

Circulating fibroblast growth factor 23 (FGF23) increases renal phosphate excretion, decreases bone mineralization and is markedly increased in hemodialysis patients. Bone cells express fibroblast growth receptor 1, suggesting that FGF23 could alter bone mineralization by means of a direct effect on the skeleton and/or secondarily due to hypophosphatemia. To distinguish between these possibilities we measured serum concentrations of FGF23, parathyroid hormone, phosphate, calcium, and markers of bone remodeling, and assessed bone mineral density in 99 hemodialysis patients. FGF23 concentrations were increased in all hemodialysis patients, even in those without hyperphosphatemia, and positively correlated with serum phosphate but not with parathyroid hormone. Hemodialysis did not decrease the serum FGF23 concentration. We found no significant correlation between serum FGF23 levels and bone mineral density. Further analysis by gender or T-score did not modify these results. Serum markers of bone remodeling significantly correlated with parathyroid hormone but not with FGF23 levels. The increase in serum FGF23 concentration in hemodialysis patients cannot be solely ascribed to hyperphosphatemia. Our study suggests that the effects of FGF23 on bone mineralization are mainly due to hypophosphatemia and not a direct effect on bone.

The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation.

The monoamine serotonin (5-HT), a well-known neurotransmitter, is also important in peripheral tissues. Several studies have suggested that 5-HT is involved in bone metabolism. Starting from our original observation of increased 5-HT(2B) receptor (5-HT(2B)R) expression during in vitro osteoblast differentiation, we investigated a putative bone phenotype in vivo in 5-HT(2B)R knockout mice. Of interest, 5-HT(2B)R mutant female mice displayed reduced bone density that was significant from age 4 months and had intensified by 12 and 18 months. This histomorphometrically confirmed osteopenia seems to be due to reduced bone formation because 1) the alkaline phosphatase-positive colony-forming unit capacity of bone marrow precursors was markedly reduced in the 5-HT(2B)R mutant mice from 4 to 12 months of age, 2) ex vivo primary osteoblasts from mutant mice exhibited reduced proliferation and delayed differentiation, and 3) calcium incorporation was markedly reduced in osteoblasts after 5-HT(2B)R depletion (produced genetically or by pharmacological inactivation). These findings support the hypothesis that the 5-HT(2B)R receptor facilitates osteoblast recruitment and proliferation and that its absence leads to osteopenia that worsens with age. We show here, for the first time, that the 5-HT(2B)R receptor is a physiological mediator of 5-HT in bone formation and, potentially, in the onset of osteoporosis in aging women.

Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate.

OBJECTIVE: Strontium ranelate (SR) increases bone mineral density (BMD) in postmenopausal osteoporotic women and reduces vertebral and non-vertebral fracture incidence. Hip fracture reduction has also been observed during 3-year treatment with SR in osteoporotic women at high risk of hip fracture. The objective of this study is to analyse the association between BMD changes and hip fracture incidence during treatment with SR. MATERIAL AND METHODS: In this post-hoc analysis, 465 women aged over 74 years with low BMD at the femoral neck (T-score < or = -2.4 according to NHANES normative values) were selected from the population of a recently published study (the Treatment of Peripheral Osteoporosis Study - TROPOS). BMD was assessed at the femoral neck at baseline and after a follow-up of 3 years. Hip fractures were reported by study investigators. RESULTS: After adjusting for age, body mass index, femoral neck BMD at baseline and number of prevalent vertebral fractures, we found that for each 1% increase in femoral neck BMD observed after 3 years, the risk to experience a hip fracture after 3 years decreased by 7% (95% CI: 1-14%) (p = 0.04). In patients experiencing a hip fracture over 3 years of treatment with SR, femoral neck BMD increased by (mean [SE]) 3.41 (1.02)% compared to 7.23 (0.81)% in patients without hip fracture (p = 0.02). CONCLUSION: In this post-hoc analysis of women undergoing 3 years of SR treatment, an increase in femoral neck BMD is associated with a decrease in hip fracture incidence.

Complex segregation analysis accounting for GxE of bone mineral density in European pedigrees selected through a male proband with low BMD.

Osteoporosis is a common multifactorial disorder characterized by low bone mass (BMD) and high susceptibility to low-trauma fractures. Family and twin studies have found a strong genetic component in the determination of BMD, but the mode of inheritance of this trait is not yet fully understood. BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. Detection of potential gene-environment interactions is of great interest in the determination of bone health status. Here we have conducted segregation analyses, using the regressive class D models, in a sample of 100 European pedigrees (NEMO) with 713 subjects (524 measured for phenotypes) identified via a male with low BMD values at either the Lumbar Spine or the Femoral Neck. Segregation analyses were conducted on the residuals of LS-BMD and FN-BMD adjusted for gender, age and BMI. We tested for gene-covariate (GxE) interactions, and investigated the impact of significant GxE interactions on segregation results. Without GxE a major effect was found to be marginally significant in LS-BMD and highly significant in FN-BMD. For both traits the Mendelian hypothesis was rejected. Significant Age x gene and BMI x gene interactions were revealed. Accounting for GxE increased statistical evidence for a major factor in LS-BMD, and improved the fit of the data to the Mendelian transmission model for both traits. The best fitting models suggested a codominant major gene accounting for 45% (LS-BMD) and 44% (FN-BMD) of the adjusted BMDs. However, substantial residual correlations were also found, and these remained highly significant after accounting for the major gene.

A gene responsible for Ghosal hemato-diaphyseal dysplasia maps to chromosome 7q33-34.

Ghosal hemato-diaphyseal dysplasia is a rare autosomal recessive disorder characterized by a progressive sclerosing diaphyseal dysplasia and refractory anemia. The pathogenesis and genetic bases of this syndrome remain hitherto unknown. We have performed a genome wide search in two inbred families originating from Algeria and Tunisia. Here, we report on the mapping of a disease gene to chromosome 7q33-34 (Zmax = 4.21 at theta = 0 at locus D7S2513) in a 3.4 Mb defined by loci D7S2560 and AC091742. Ongoing studies will hopefully lead to identification of the disease-causing gene.

Over-expression of TIMP-1 in osteoblasts increases the anabolic response to PTH.

Intermittent PTH treatment induces structural changes that affect cancellous bone mass and have led to its indication for the treatment of osteoporosis. PTH is also known to upregulate the expression of matrix metalloproteinases (MMP) in osteoblasts. We wanted to find out whether inhibiting osteoblastic MMPs can affect the anabolic action of PTH in vivo. We had shown previously that mice over-expressing TIMP-1 (tissue inhibitor of MMPs) specifically in osteoblasts display an increase in bone mineral density and bone mass combined with an overall decrease in bone turnover. In the present study, 10-week-old wild-type (WT) and transgenic (TG) mice were treated with PTH at 40 microg/kg/day for 1.5 months. DEXA analysis was performed before and after treatment, and histomorphometric and molecular analysis were carried out at the end of the experiment. Our findings indicate that the transgene boosted the anabolic action of PTH. The femurs of PTH-treated TG mice displayed a greater increase in bone mineral density and trabecular bone volume than treated WT mice. Interestingly, the positive effect of the transgene on the action of PTH resulted from both reduced bone resorption activity and an increase in the bone formation rate. Osteoclastic surfaces that were increased in PTH-treated WT mice remained unchanged in TG mice, suggesting a decrease in osteoclastic differentiation. Histomorphometric data also indicate that PTH administration increased osteoblast activity in TG mice and affected the number of osteoblasts in WT mice. In conclusion, we demonstrate that inhibiting osteoblastic MMPs can potentiate the anabolic effect of PTH by decreasing osteoclast activity and increasing osteoblast activity. Our data also suggest that osteoblastic MMPs have some role in mediating the anabolic effects of PTH in vivo and indicate that inhibitors of MMPs could constitute a new therapy for degenerative diseases.

Estradiol inhibits adhesion and promotes apoptosis in murine osteoclasts in vitro.

Osteoporosis caused by estrogen deficiency is characterized by enhanced bone resorption mediated by osteoclasts. Adhesion to bone matrix and survival of differentiated osteoclasts is necessary to resorb bone. The aim of our study was to investigate the in vitro effects of estradiol on murine osteoclasts. RAW 264.7 cells treated with 30 ng/ml RANK-L were used as a model for osteoclastogenesis. Estradiol (10(-8)M) for 5 days induced an inhibition of osteoclast differentiation and beta3 expression. Estradiol inhibited significantly the adhesion of mature osteoclasts by 30%. Furthermore estradiol-induced apoptosis shown by with nuclear condensation and Bax/Bcl2 ratio. In addition, estradiol enhanced caspase-3, -8 and -9 activities. This effect completely disappeared using specific caspase-8 inhibitor. However, increased caspase-3 activity by estradiol was observed in the presence of caspase-9 inhibitor, indicating the preferential involvement of caspase-8 pathway. Fas and FasL mRNA expression was not regulated by estradiol. However, estradiol enhanced caspase-3 activity in Fas-induced apoptosis on mature osteoclasts, suggesting that this might interact with the Fas-signaling pathway. These data suggest that estradiol decreases bone resorption by several mechanisms including adhesion and apoptosis of osteoclasts.

Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II.

CONTEXT: Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density. OBJECTIVE: The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII. DESIGN: This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene. PARTICIPANTS: A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers. MAIN OUTCOME MEASURE(S): In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype. RESULTS: Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis. CONCLUSION: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.

[Calcimimetics, mechanisms of action and therapeutic applications]. / Les calcimimétiques, mécanismes d'action et applications thérapeutiques.

The extracellular calcium-sensing receptor (CaR) on the parathyroid cell surface negatively regulates secretion of parathyroid hormone (PTH). Its activation by small changes in the extracellular concentration of ionized calcium (ec[Ca2+]) decreases PTH secretion and secondarily bone turnover. CaR is an ideal target for compounds that may be developed to modulate its activity - activating calcimimetics and inhibiting calcilytics. Calcimimetics can amplify the sensitivity of the CaR to ec(Ca2+), thereby suppressing PTH levels and in turn reducing blood Ca++. They dose-dependently reduce the secretion of PTH in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia when given at the onset of the disease and stop cell proliferation if they are administered afterwards, when the hyperplasia already exists. They normalize plasma PTH levels and bone remodeling. In uremic patients undergoing hemodialysis, calcimimetics reduce plasma PTH concentrations in the short (12 weeks) and long (2 years) terms. They also reduce serum levels of calcium-phosphorus product. Calcimimetics are therefore an alternative for the treatment of secondary hyperparathyroidism, particularly in dialysis patients, when increased serum levels of calcium-phosphorus product, the attendant risk of cardiovascular calcification, and its lack of efficacy limit use of the standard treatment.

LRP5 gene polymorphisms and idiopathic osteoporosis in men.

Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have demonstrated the role of LRP5 in bone mass acquisition. LRP5 variants were recently reported to contribute to the population-based variance in vertebral bone mass and size in males. To investigate whether LRP5 variants are implicated in idiopathic male osteoporosis, we studied 78 men with low BMD (<2.5 T score or < -2 Z score) aged less than 70 years (mean +/- SD: 50 +/- 16 years) in whom secondary causes of osteoporosis had been excluded and 86 controls (51 +/- 10 years). Genotypes and haplotypes were based on LRP5 missense substitutions in exons 9 (c.2047G > A, p.V667M) and 18 (c.4037C > T, p.A1330V), and their association with osteoporosis evaluated after adjustment for multiple clinical and environmental variables using logistic regression. The presence of osteoporosis was significantly associated with LRP5 haplotypes (P = 0.0036) independent of age (P = 0.006), weight (P = 0.004), calcium intake (P = 0.002), alcohol (P = 0.005) and tobacco (P = 0.004) consumption. Accordingly, the odds ratio for osteoporosis was 3.78 (95% CI 1.27-11.26, P < 0.001) in male carriers of haplotype 3 (c.2047A-4037T, n = 20 cases and 12 controls) versus homozygous carriers of haplotype 1 (c.2047G-4037C, n = 42 cases and 61 controls). In conclusion, these data indicate beyond a significant role for environmental factors, an association between LRP5 variants and idiopathic osteoporosis in males, pointing to a role of LRP5 in this disease.

An intermediate form of juvenile Paget's disease caused by a truncating TNFRSF11B mutation.

Juvenile Paget's disease (JPD) is a rare condition with an autosomal recessive mode of inheritance. Typically presenting in infancy or early childhood, the disorder is characterized by a generalized widening of the long bones and thickening of the skull combined with sustained elevation of serum alkaline phosphatase levels. The extremely rapid bone turnover results in osteopenia, fractures, and progressive skeletal deformity. In 2002, mutations in TNFRSF11B, the gene encoding osteoprotegerin, were described as underlying JPD. We evaluated a patient with JPD at the clinical, biochemical, radiological, and molecular level. Mutation analysis of TNFRSF11B revealed a homozygous insertion/deletion in exon 5, predicted to result in truncation of the protein at amino acid 325. The residual activity of the mutated protein product was investigated by Western blotting and ELISA upon transient overexpression. Absence of the C-terminal domain abolished homodimerization and was shown to lead to a decreased capacity of the mutant protein to bind its ligand RANKL. We conclude that truncation of the C-terminal part of osteoprotegerin negatively affects functional activity. As a consequence, osteoclast formation and function are up-regulated, causing the increased bone turnover seen in this patient.

Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study.

BACKGROUND: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. METHODS: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. FINDINGS: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. CONCLUSION: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.