Closing the Osteoporosis Care Gap

Purpose of Review: This review outlines the scope of the problem in osteoporosis care and secondary fracture prevention and describes fracture prevention strategies, with a focus on the frail elderly. Recent Findings: Despite heightened awareness among patients and clinicians alike and the availability of efficacious anti-osteoporosis medications, osteoporosis is still underdiagnosed and undertreated. However, the introduction of systematic risk assessment and secondary fracture prevention programmes has gained momentum, and evidence of success is accumulating. Summary: We possess today the knowledge required to close the osteoporosis care gap. The basic components in a secondary prevention model are similar in all health care settings, number one being a dedicated fracture coordinator, with anti-osteoporosis medications and multifaceted falls prevention as cornerstones, particularly in the frailest, both in the near and long-term. Initiation of structured care pathways including the key elements – identification, investigation, intervention and follow-up of adherence – demonstrably reduces re-fracture rates and is cost-effective

Bone mass in Saudi women aged 20–40 years : the association with obesity and vitamin D deficiency

Summary: This study describes that low bone density is prevalent in premenopausal Saudi women, especially women of normal weight and vitamin D deficiency. Although BMD is higher in obese young women, this may not be beneficial later in life in conjunction with persistent vitamin D deficiency. Introduction: Not attaining peak bone mass is one crucial factor contributing to the risk of developing osteoporosis and suffering fractures in later life. The objectives of this study were to describe the normal range of bone mineral density (BMD) and bone mineral content (BMC) in premenopausal Saudi women in relation to obesity and vitamin D insufficiency. Methods: A cross-sectional study involving 312 healthy Saudi women aged 20–40. All women were clinically examined. BMD (g/cm2) and BMC (g) assessed at total body (TB), femoral neck (FN) and lumbar spine (LS) were performed using dual-energy X-ray absorptiometry (DXA). Obesity was defined as BMI ≥ 30 kg/m2 and vitamin D deficiency defined as 25(OH)D < 50 nmol/L. Results: Almost half of the studied women were obese, and the majority (86.2%) were deficient in vitamin D. Mean BMD in TB 1.060 ± 0.091, FN 0.918 ± 0.153 and LS 1.118 ± 0.123 g/cm2, while TB-BMC 2077 ± 272 g. When classified by BMI, the proportion with low bone density was 2–3 times higher among the normal weight compared to the obese women, p < 0.001. In the cohort overall, ~ 19% of these young premenopausal women had osteopenia or osteoporosis at the femoral neck, but 26% in normal weight, vitamin D deficient women. Conclusion: This study shows low bone density in premenopausal Saudi women, particularly those with normal weight. While obesity appears to confer some protection against vitamin D deficiency at this age, this is assumed to change in later life

Relation of alleles of the collagen type Iα1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women

Background Osteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Iα1, a bone- matrix protein. Methods We determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 1778 postmenopausal women using a polymerase- chain-reaction-based assay. We then related the genotypes to bone mineral density and the occurrence of osteoporotic fractures in these women. Results As compared with the 1194 women with the SS genotype, the 526 women with the Ss genotype had 2 percent lower bone mineral density at the femoral neck (P=0.003) and the lumbar spine (P=0.02), the 58 women with the ss genotype had reductions of 4 percent at the femoral neck (P=0.05) and 6 percent at the lumbar spine (P=0.005). These differences increased with age (P=0.01 for modification by age of the effect of COLIA1 on femoral-neck bone density, and P=0.004 for modification of the effect on lumbar-spine bone density). Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures (relative risk per copy of the s allele, 1.5; 95 percent confidence interval, 1.1 to 2.1). Conclusions The COLIA 1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures

Polymorphisms of the **CLCN7** gene are associated with BMD in women

UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects.INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population.MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age.RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site.CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects

The association between common vitamin D receptor gene variations and osteoporosis: A participant-level meta-analysis

Background : Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. Objective : To evaluate the relation between VDR polymorphisms, BMD, and fractures. Design : Prospective multicenter large-scale association study. Setting : The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. Participants : 26 242 participants (18 405 women). Measurements : Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. Results : Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). Limitations : The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. Conclusions : The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures

Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis:The GENOMOS study

INTRODUCTION: The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results.METHODS: We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures.RESULTS: There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05.CONCLUSIONS: This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies

The Association between Common Vitamin D Receptor Gene Variations and Osteoporosis: A Participant-Level Meta-Analysis

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures. Design: Prospective multicenter large-scale association study. Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. Participants: 26 242 participants (18 405 women). Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures