Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: the OFELY study

Several epidemiological studies have identified clinical factors that predict the risk of hip fractures in elderly women independently of the level of bone mineral density (BMD), such as low body weight, history of fractures, and clinical risk factors for falls. Their relevance in predicting all fragility fractures in all postmenopausal women, including younger ones, is unknown. The objective of this study was to identify independent predictors of all osteoporosis-related fractures in healthy postmenopausal women. We prospectively followed for 5.3 +/- 1.1 years a cohort of 672 healthy postmenopausal women (mean age 59.1 +/- 9.8 years). Information on social and professional conditions, demographic data, current and past medical history, fracture history, medication use, alcohol consumption, caffeine consumption, daily calcium intake, cigarette smoking, family history of fracture, and past and recent physical activity was obtained. Anthropometric and total hip bone mineral density measurements were made. Incident falls and fractures were ascertained every year. We observed 81 osteoporotic fractures (annual incidence, 21 per 1000 women/year). The final model consisted of seven independent predictors of incident osteoporotic fractures: age > or = 65 years, odds ratio estimate (OR), 1.90 [95% confidence interval (CI) 1.04-3.46], past falls, OR, 1.76 (CI 1.00-3.09), total hip bone mineral density (BMD) < or = 0.736 g/cm(2), OR, 3.15 (CI 1.75-5.66), left grip strength < or = 0.60 bar, OR, 2.05 (CI 1.15-3.64), maternal history of fracture, OR, 1.77 (CI 1.01-3.09), low physical activity, OR, 2.08 (CI 1.17-3.69), and personal history of fragility fracture, OR, 3.33 (CI 1.75-5.66). In contrast, body weight, weight loss, height loss, smoking, neuromuscular coordination assessed by three tests, and hormone replacement therapy were not independent predictors of all fragility fractures after adjustment for all variables. We found that some--but not all--previously reported clinical risk factors for skeletal fragility predicted all fragility fractures independently of BMD in healthy postmenopausal women, although they differed somewhat from those predicting specifically hip fractures in elderly women. These risk factors appear to reflect quality of bone structure (previous fragility fracture), lifestyle habits (physical activity), muscle function and health status (grip strength), heredity (maternal history of fracture), falls, and aging. Measurements of these variables should be included in the clinical assessment of the risk of osteoporotic fractures in postmenopausal women.     

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.     

Homocysteine and fracture risk in postmenopausal women: the OFELY study

Summary Homocysteine has recently been described as an independent risk factor for osteoporotic fractures in the elderly. We prospectively followed 671 postmenopausal women belonging to the OFELY study, mean age 62 years, during a mean follow-up of 10 years. After adjustment for age, there was no significant relation between the plasma level of homocysteine and the subsequent risk of fracture. Introduction Plasma homocysteine increases with age. Recent studies have described homocysteine as an independent risk factor for osteoporotic fractures in elderly. We investigated the role of plasma homocysteine in the subsequent risk of fractures in healthy ambulatory postmenopausal women. Methods Homocysteine was measured at baseline in 671 postmenopausal women from the OFELY cohort (mean age 62.2 ± 9 years). Incident clinical fractures were recorded during annual follow-up and vertebral fractures were evaluated with radiographs every four years. A cox proportional hazards model based on time to first fracture was used to calculate hazard ratios for quartiles of homocysteine values. Results Mean homocysteine was 10.6 ± 3.4 μmol/l, increasing with age. After adjustment for age, homocysteine was significantly associated with physical activity, calcium intake, serum albumin and serum creatinine but not with bone turnover markers and bone mineral density. During a mean follow-up of 10 years, 183 fractures occurred among 134 women. After adjustment for age, the overall relative risk of fracture for each 1 SD increment of homocysteine was 1.03 (95%CI 0.87–1.31). Fracture risk was higher in women with homocysteine in the highest quartile without adjustment but no longer after adjustment for age. Conclusions Homocysteine is not an independent risk factor of osteoporotic fractures in healthy postmenopausal women from the OFELY cohort with a broad age range.     

Vertebral body morphology is associated with incident lumbar vertebral fracture in postmenopausal women. The OFELY study

Summary

We investigate the predictive role of vertebral anterior cortical curvature and height heterogeneity in the occurrence of vertebral fractures in postmenopausal women. Women who will fracture had shorter vertebral height, greater heterogeneity of height than those who will not fracture, and their anterior vertebral body edge was less concave.

Introduction

Vertebral morphology has been demonstrated to be associated with further risk of fracture. The aim of this study was to analyze vertebral anterior cortical curvature (Ct.curv) and vertebral height heterogeneity in postmenopausal women before the occurrence of a vertebral fracture.

Methods

This case–control study included 29 postmenopausal women who have underwent incident lumbar vertebral fractures (mean age 71?±?9 years, mean time to fractures 9?±?4 years), age-matched with 57 controls. From lateral X-rays of lumbar spine radiographs (T12 to L4), the following parameters were measured: (1) the posterior, middle, and anterior vertebral heights; (2) the heterogeneity of heights evaluated by the coefficient of variation of these three variables; (3) antero-posterior width, a 2D estimator of cross-sectional area; and (4) Ct.curv.

Results

Mean vertebral heights were significantly lower among women who fractured than in controls (p?<?0.05). The anterior and middle heights were significantly lower at L4 and L3 levels in fracture group (p?=?0.02). The heterogeneity of vertebral height was significantly greater in the fracture group (p?=?0.003). In addition, fractured patients had a significantly higher Ct.curv on L3 (p?=?0.04). After adjustment for bone mineral density (BMD), only the heterogeneity of vertebral height remained significant (p?=?0.005).

Conclusion

The current case–control study confirmed the association between vertebral height and occurrence of future vertebral fracture in postmenopausal women. The vertebrae with the smallest Ct.curv tended to fracture less often, and the heterogeneity of vertebral heights was associated with future fracture independently of BMD. An additional validation in a prospective study would be needed to confirm these initial results.

     

Multiple vertebral fractures are associated with refractory reflux esophagitis in postmenopausal women

We examined the frequency of multiple vertebral fractures (MVFs) and esophageal hiatal hernia (HH) in 18 Japanese postmenopausal women (74.1 ± 9.9 years, mean ± SD), with refractory reflux esophagitis (RRE) that had needed a proton pump inhibitor for more than 6 months to suppress symptoms such as heartburn and acid regurgitation, as well as in 57 control subjects without RE (71.4 ± 5.9 years). MVFs (two or more VFs), HH, and both features were found in 11 (61%), 16 (89%), and 11 (61%) subjects, respectively, in the RRE group. All 11 patients with MVFs also had HH, suggesting their strong association. On the other hand, MVFs, HH, and both were found in 15 (26%), 23 (40%), and 8 (14%) subjects, respectively, in those without RE. The differences in frequencies of MVFs, HH, and both between the two groups were significant (² = 7.3, 12.9, and 16.0; P = 0.015, 0.0009, and 0.0002, respectively). When univariate logistic regression analysis was performed with the presence of RRE as a dependent variable and the presence of MVFs, HH, and both as independent variables, MVFs, HH, and both were selected as indices affecting the presence of RRE (age-adjusted odds ratios: 4.34, 11.07, and 10.30; 95% confidential intervals: 1.40–13.45, 2.30–53.22, and 2.96–35.86; P = 0.0109, 0.0027, and 0.0002, respectively). These results show that the presence of MVFs is associated with the presence of RRE in Japanese postmenopausal women, and this association becomes more significant when HH is present. Thus, a kyphotic lumbar spine with MVFs may cause HH and RE by raising the intraabdominal pressure. As recent therapeutic agents for osteoporosis, alendronate and risedronate, are known to be very effective for suppressing the occurrence of new VFs, these agents may also prevent gastrointestinal disorders such as HH and RRE in osteoporotic women when administered to subjects without VFs.     

Disc space narrowing is associated with an increased vertebral fracture risk in postmenopausal women: the OFELY Study.

We have analyzed the relationship between spine osteoarthritis and fractures in the OFELY cohort. Despite a higher BMD associated with spine OA, the risk of fragility fractures is not reduced. Disc space narrowing is associated with an increased risk of vertebral fracture. These data indicate that the risk of osteoporotic fracture should not be underestimated in women with spine OA. INTRODUCTION: Although osteoarthritis (OA) and osteoporosis both increase with age, their co-existence is uncommon. A higher BMD in OA is well documented, but a reduction of the fracture risk is still controversial. Our objective was to analyze the risk of fracture in postmenopausal women with spine OA. MATERIALS AND METHODS: In a cross-sectional study, spine OA was evaluated by lateral radiographs according to the method of Lane, and BMD was measured by DXA in 559 postmenopausal women from the OFELY cohort (mean age, 68 +/- 8 years; range, 58-94 years) 8 years after their inclusion into the study. Previous fragility fractures, all confirmed by radiographs, were prospectively registered during the annual follow-up for 8 years, and vertebral fractures were evaluated with spine radiographs. Severity of OA was assessed by scoring on osteophytes and disc narrowing on a four-point scale from 0 (normal) to 3 (severe) and graded as 0 (normal), 1 (mild osteophyte and/or narrowing), or 2 (moderate or severe osteophyte and/or narrowing). RESULTS: Osteophytes and disc narrowing were present in 75% and 64%, respectively, of women at the lumbar spine and in 88% and 51%, respectively, at the thoracic spine, increasing with age. BMD of the spine, hip, and whole body increased with the severity of osteophytosis, whereas severity of narrowing was associated with a higher BMD only at the spine. Ninety-six fractures, including 48 vertebral fractures, occurred before OA assessment. No significant association was found between spine OA and all fragility fractures. In contrast, disc narrowing was associated with an increased risk of vertebral fracture with an odds ratio (95% CI) of 3.2 (1.1-9.3) after adjusting for age, body mass index, and BMD. The risk of vertebral fracture increased with the severity of disc narrowing. In comparison with the score 0, the odds ratio increased from 2.8 (0.9-8.7) to 4.6 (1.2-16.9) in women with mild to severe disc narrowing score. CONCLUSIONS: Despite a higher BMD, women with spine OA do not have a reduced risk of fracture. Disc narrowing is associated with a significant increased vertebral fracture risk.     

High-normal free thyroxine levels are associated with low trabecular bone scores in euthyroid postmenopausal women

Summary

Trabecular bone scores (TBS) have recently been developed as a diagnostic tool to assess bone texture. We studied thyroid status and TBS in a population-based cohort and demonstrated that high-normal thyroxine levels are associated with low TBS in healthy euthyroid postmenopausal women.

Introduction

Increased thyroid hormone levels affect bone mineral density (BMD) and, if untreated, increase the risk of fracture. However, the relationship between thyroid function and bone microarchitecture has not yet been established. Trabecular bone scores (TBS) are gray-level textural measurements of dual energy X-ray absorptiometry (DXA) images. The TBS has been proposed as an indirect index of bone microarchitecture. The goal of this study was to characterize the relationship between thyroid function and TBS in euthyroid men and postmenopausal euthyroid women.

Methods

A total of 1376 euthyroid subjects (648 postmenopausal women and 728 men) were recruited from a community-based cohort in Korea. Free thyroxine (fT4) levels, thyroid stimulating hormone (TSH) levels, BMD, and TBS were measured and compared.

Results

There was no significant relationship between either fT4 or TSH levels and BMD in men and women. Multiple linear regression analysis showed that high-normal fT4 levels were negatively correlated with TBS (β?=??0.111; P?=?0.002, after adjusting for both age and body mass index [BMI]) in postmenopausal women. In men, however, there was no significant correlation between fT4 levels and TBS. TSH levels were not significantly associated with TBS in either men or women.

Conclusion

Higher fT4 levels within the normal reference range are associated with deterioration of trabecular microarchitecture in healthy euthyroid postmenopausal women.

     

Two new regions of interest to evaluate separately cortical and trabecular BMD in the proximal femur using DXA

To differentiate changes in trabecular and cortical bone density at a skeletal site bearing body weight, the main goal of this retrospective study was to develop and characterize two new regions of interest (ROIs) for DXA at the hip, one mainly focusing on trabecular bone and another mainly focusing on cortical bone. Specific aims were to maximize the precision of the ROIs and to characterize their usefulness for monitoring age-related bone loss and discriminating controls from fracture cases in a cross-sectional study population and to compare them with earlier ROIs designed by our group. The study used populations from two different previous studies conducted in our laboratory, with one comprising cohorts of healthy premenopausal women, healthy postmenopausal women, and postmenopausal osteoporotic women with at least one spinal fracture (Spine Fx Study) and the other one comprising two cohorts of age-matched postmenopausal women, in whom cases had sustained a hip fracture (Hip Fx study). The new ROI for trabecular bone (CIRCROI) tries to improve on the earlier custom-designed Central ROI, which was also targeted at trabecular bone. CIRCROI consists of an approximate largest circle that can fit inside the femoral proximal metaphysis without touching the superior and inferior endocortical walls. The new ROI for cortical bone (CORTROI) at a site bearing body weight is defined as a horizontal rectangular box crossing the femoral shaft below the lesser trochanter. CORTROI BMD cohort means were significantly higher than all other ROIs, and CIRCROI BMD cohort means were lower than standard ROIs with the exception of Wards ROI. CIRCROI BMD was highly correlated with total femur BMD (r=0.94) and Central BMD (r=0.93), whereas CORTROI BMD correlations were lower (highest with total femur BMD (r=0.86)). Fracture discrimination odds ratios (ORs) of all ROIs were significant for the Hip Fx Study, with CIRCROI BMD having the highest, and CORTROI BMD the lowest, OR (4.83 and 2.49 per SD, respectively, compared with 3.69 for Wards ROI as the highest OR of standard ROIs). For the Spine Fx Study, only spinal and trochanteric BMD had significant OR. The new trabecular ROI had good short-term precision, comparable to the standard ROIs at the hip, but improving on that of Wards triangle, the only standard ROI only including the anterior and posterior cortical walls and therefore more predominantly consisting of trabecular bone than other standard ROIs. The precision of the new cortical ROI was lower than standard DXA ROIs, except for Wards triangle, but provides unique information on purely cortical bone at a skeletal site bearing body weight.     

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

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.     

Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women

Typically, in the milder form of primary hyperparathyroidism (PHPT), now seen in most countries, bone density by dual‐energy X‐ray absorptiometry (DXA) and detailed analyses of iliac crest bone biopsies by histomorphometry and micro–computed tomography (µCT) show detrimental effects in cortical bone, whereas the trabecular site (lumbar spine by DXA) and the trabecular compartment (by bone biopsy) appear to be relatively well preserved. Despite these findings, fracture risk at both vertebral and nonvertebral sites is increased in PHPT. Emerging technologies, such as high‐resolution peripheral quantitative computed tomography (HRpQCT), may provide additional insight into microstructural features at sites such as the forearm and tibia that have heretofore not been easily accessible. Using HRpQCT, we determined cortical and trabecular microstructure at the radius and tibia in 51 postmenopausal women with PHPT and 120 controls. Individual trabecula segmentation (ITS) and micro–finite element (µFE) analyses of the HRpQCT images were also performed to further understand how the abnormalities seen by HRpQCT might translate into effects on bone strength. Women with PHPT showed, at both sites, decreased volumetric densities at trabecular and cortical compartments, thinner cortices, and more widely spaced and heterogeneously distributed trabeculae. At the radius, trabeculae were thinner and fewer in PHPT. The radius was affected to a greater extent in the trabecular compartment than the tibia. ITS analyses revealed, at both sites, that plate‐like trabeculae were depleted, with a resultant reduction in the plate/rod ratio. Microarchitectural abnormalities were evident by decreased plate‐rod and plate‐plate junctions at the radius and tibia, and rod‐rod junctions at the radius. These trabecular and cortical abnormalities resulted in decreased whole‐bone stiffness and trabecular stiffness. These results provide evidence that in PHPT, microstructural abnormalities are pervasive and not limited to the cortical compartment, which may help to account for increased global fracture risk in PHPT. © 2013 American Society for Bone and Mineral Research.     

Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures.

Fractures and subsequent morbidity determine the impact of established postmenopausal osteoporosis. Health-related quality of life (HRQOL) has become an important outcome criterion in the assessment and follow-up of osteoporotic patients. As part of the baseline measurements of the Multiple Outcomes of Raloxifene Evaluation (MORE) study, HRQOL was assessed in 751 osteoporotic (bone mineral density [BMD] T score > or = -2.5) women from Europe with or without vertebral fractures (VFX). This was done using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), Nottingham Health Profile (NHP) and the EQ-5D (former EuroQol). QUALEFFO contains questions in five domains: pain, physical function, social function, general health perception, and mental function. Each domain score and QUALEFFO total scores are expressed on a 100-point scale, with 0 corresponding to the best HRQOL. In comparison with patients without VFX, those with VFX were older (66.2 +/- 5.9 years vs. 68.8 +/- 6.3 years; p < 0.001), had higher prevalence of nonvertebral fractures (25% vs. 36%; p = 0.002), and higher QUALEFFO scores (worse HRQOL; total score, 26 +/- 14 vs. 36 +/- 17; p < 0.001). QUALEFFO scores increased progressively with increasing number of VFX, especially lumbar fractures (p < 0.001). Patients with a single VFX already had a significant increase in QUALEFFO scores (p < 0.05). Similar, though weaker, associations were seen for NHP and EQ-5D scores. This study confirms decreased HRQOL for patients with prevalent VFX. In osteoporotic patients, QUALEFFO scores change in relation to the number of VFX. QUALEFFO is suitable for clinical studies in patients with postmenopausal osteoporosis.     

Urinary levels of pentosidine and the risk of fracture in postmenopausal women: the OFELY study

Summary  

The aim of the study was to investigate prospectively whether the levels of urinary pentosidine could predict fractures in postmenopausal women from the OFELY cohort. The results of the study suggest that urine pentosidine concentration is not an independent risk factor for fractures in postmenopausal women from a French cohort.     

Rate of forearm bone loss is associated with an increased risk of fracture independently of bone mass in postmenopausal women: the OFELY study.

BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. In 671 postmenopausal women from the OFELY cohort, we found that the rate of bone loss was significantly associated with fracture risk independently of other well-known predictors including BMD and previous fractures. INTRODUCTION: The level of BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. MATERIALS AND METHODS: In the OFELY study, we analyzed the risk of fracture in 671 postmenopausal women (mean age, 62.2 +/- 9 years), according to the rate of bone loss. BMD was measured annually by DXA at the forearm, with a mean number of measurements of 10.3 +/- 2.6. Peripheral fractures, all confirmed by radiographs, were prospectively registered, and vertebral fractures were evaluated with spine radiographs every 4 years. RESULTS: During a median (interquartile range [IQ]) of 11.2 years (11-12.3 years) of follow-up, 183 incident fragility fractures including 53 vertebral and 130 nonvertebral fractures were recorded in 134 women. The annual median +/- IQ rate of bone loss, calculated from the slope, was -0.30 +/- 0.76% at the mid-radius, -0.55 +/- 0.79% at the distal radius, and -0.40 +/- 0.96% at the ultradistal radius. Women with incident fracture had a rate of bone loss (before fracture) higher by 38-53% than those without fracture (p = 0.0003-0.016). Using multivariate Cox regression models, we found that bone loss in the highest tertile at the mid-radius, distal radius, and ultradistal radius was associated with a significant increased risk of all fractures with an hazard ratio from 1.45 to 1.70 (p = 0.02 to p = 0.009 after adjusting for age, previous fractures, maternal history of fracture, physical activity, grip strength, falls, and baseline BMD). CONCLUSIONS: The rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD and history of fractures.     

Association of the OSCAR promoter polymorphism with BMD in postmenopausal women.

In an effort to identify genetic polymorphisms in potential candidate genes for osteoporosis, 10 variants were identified in the OSCAR gene using direct DNA sequencing, and 560 postmenopausal women were genotyped at five SNP loci, using the TaqMan method. The rare allele (G allele) of OSCAR-2322A>G (SNP in the 5' flanking region) showed significant association with lower BMD at various bone sites in postmenopausal women (n = 560). INTRODUCTION: BMD is the major factor for determining bone strength and osteoporotic fracture risk and is determined by both environmental and multiple genetic factors. The osteoclast-associated receptor (OSCAR) plays a critical role in osteoclast differentiation and thus is an important candidate gene for the modulation of BMD. MATERIALS AND METHODS: Through direct sequencing in 24 Korean individuals, 10 sequence variants were identified: 2 in the 5' flanking region, 7 in the exons (including 6 nonsynonymous single-nucleotide polymorphisms [SNPs]), and 1 in an intron. Five of these polymorphisms were selected for larger-scale genotyping in postmenopausal women (n = 560). Areal BMD (g/cm2) of the anterior-posterior lumbar spine and the nondominant proximal femur was measured using DXA (Lunar Expert XL and Hologic QDR 4500-A). Lateral thoracolumbar radiographs were obtained in all subjects. RESULTS: Using multiple regression analysis and controlling for age, years since menopause, height, weight, and evaluation machine as covariates, the rare allele (G allele) of OSCAR-2322A>G showed significant association with lower BMD at various bone sites in postmenopausal women. CONCLUSION: These findings suggest that the promoter variant in OSCAR gene (OSCAR-2322A>G) might be one of genetic determinants of BMD in postmenopausal women.     

Four-month treatment with GLP-2 significantly increases hip BMD: A randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD

We have previously shown that repeated dosing of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women for 14 days results in a dose-dependent decrease in the nocturnal bone resorption, as assessed by s-CTX. In contrast, bone formation, as assessed by serum osteocalcin, appeared to be unaffected by treatment with exogenous GLP-2, at least over 14 days.The present study extends the observation period to four months. The study was a double-blind placebo-controlled dose-ranging trial comparing three different doses of GLP-2 (0.4 mg, 1.6 mg and 3.2 mg GLP-2, administered nightly) against a saline control injection. We examined safety and tolerability, and the effects on biochemical markers of bone turnover and the effect on bone mineral density.Injection of 0.4 mg, 1.6 mg and 3.2 mg GLP-2 resulted in similar reduction in the nocturnal rise of s-CTX, at Treatment Day 120 the mean difference to placebo was approximately − 150%  h at AUC_0–10H (P < 0.01). Osteocalcin levels were unaffected in the 10-hour period after injection indicating that injections of 0.4 mg, 1.6 mg and 3.2 mg GLP-2 do not exert any acute stimulatory or inhibitory effect on bone formation.Treatment with GLP-2 resulted in a significant dose-dependent increase in total hip BMD over the course of the study that for the 3.2 mg GLP-2 group reached 1.1% (P = 0.007) from baseline.The overall rates of adverse events in the 4 treatment groups were similar and there were no signs of tachyphylaxis or antibodies against GLP-2.The results indicate that GLP-2 produces a substantial decrease in bone resorption without suppression of bone formation thereby changing the bone remodeling balance in favor of bone formation, particularly at the hip.     

Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography

The deterioration of trabecular microarchitecture induced by elevated bone turnover is increasingly recognized as a factor in the pathogenesis of osteoporotic fractures. We investigated the effect of the reduction of turnover with risedronate on trabecular architecture in postmenopausal women with osteoporosis. Iliac crest bone biopsy specimens taken before and after 3 years of treatment from patients receiving risedronate 5 mg daily (n = 21) or placebo (n = 17) were analyzed using 3-D microcomputed tomography. We found a significant correlation between baseline bone turnover and bone loss in the placebo group, providing evidence that higher turnover induced higher bone loss leading to a greater degree of architectural degradation. When patients were classified into two groups based on baseline bone turnover (MS/BS less than or greater than the median value for the entire cohort), significant decreases in trabecular bone volume (BV/TV, P = 0.009) and trabecular thickness (Tb.Th*, P = 0.008) and an increase in marrow star volume (Ma.St.V, P = 0.008), a measure of trabecular porosity, were observed in the higher turnover (MS/BS> median) placebo-treated patients. The trabecular structure shifted from plates to rods as shown by an increase in structure model index (SMI, P = 0.028) and bone surface to bone volume ratio (BS/BV, P = 0.006). The changes from baseline in the lower turnover (MS/BS相似文献   

Calcaneal ultrasound predicts early postmenopausal fractures as well as axial BMD. A prospective study of 422 women

Low calcaneal ultrasound measurement (quantitative ultrasound, QUS) has been shown to predict fractures in elderly women. However, only a few studies have examined its ability to predict perimenopausal and early postmenopausal fractures. We conducted a prospective population-based cohort study to assess the capability of QUS as compared to axial BMD measurement to predict early postmenopausal fractures at that age. Four hundred and twenty-two women (mean age 59.6, range 53.7–65.3) from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) were randomly chosen to undergo a calcaneal ultrasound measurement. In all, 9.4% of these women were premenopausal at the time of measurement. Thirty-two follow-up fractures were reported during the mean follow-up of 2.6 years (SD 0.7). These were validated with patient record perusal. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were significantly lower among women with than without fracture (P-values 0.028, 0.001 and 0.001, respectively). Mean T-score adapted from SI was –1.5 (95% CI –1.7 to –1.2) for fracture group and –1.0 (95% CI –1.1 to –0.9) for the non-fracture group. All QUS measurements predicted fractures even after adjusting for age, weight, height, previous fracture history, femoral neck BMD and use of hormone replacement therapy according to Cox regression. The adjusted hazard ratios (HR, 95% confidence interval) of a follow-up fracture for a 1 SD decrease were 1.80 (1.27–2.56), 1.72 (1.21–2.45) and 1.43 (1.01–2.03) for SOS, SI and BUA, respectively. Similarly, the adjusted HR for a 1 SD decrease of spinal BMD was 1.27 (0.85–1.94) and for that of femoral neck BMD 1.14 (0.78–1.70). In receiver operator analyses, the area under the curve (AUC) was greatest for QUS measurements: SOS (AUC=0.68), stiffness (AUC=0.67), BUA (AUC=0.62) and least for lumbar BMD (AUC=0.56), while and femoral neck BMD (AUC=0.59). The difference between AUCs was statistically significant between SI and lumbar BMD (P=0.02, Duncans P=0.07). We conclude that low calcaneal QUS predicts early postmenopausal fractures as well as or even better than axial BMD.     

Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: the OFELY prospective study.

The Asp1211 residue of the 1209AHDGGR1214 sequence of the C-terminal cross-linking telopeptide of type I collagen (CTX) can undergo spontaneous post-translational modifications, namely, racemization and isomerization, which result in the formation of four isomers: the native form (alpha-L) and three age-related forms, that is, an isomerized form (beta-L), a racemized form (alpha-D), and an isomerized/racemized (beta-D) form. Previous studies have suggested that changes in the pattern of type I collagen racemization/isomerization, which can be assessed in vivo by measuring the degradation products of the CTX isoforms, may be associated with alterations of bone structure. The aim of this study was to examine prospectively the value of the different urinary CTX isoforms and their related ratio in the prediction of osteoporotic fractures in 408 healthy untreated postmenopausal women aged 50-89 years (mean, 64 years) who were part of the OFELY cohort. During a median 6.8 years follow-up, 16 incident vertebral fractures and 55 peripheral fractures were recorded in 65 women. The baseline levels of the four CTX isoforms in women who subsequently had a fracture were compared with those of the 343 women who did not fracture. At baseline, women with fractures had increased levels of ratios of native alpha-L-CTX to age-related isoforms (beta-L, alpha-D, and beta-D) compared with controls (p < 0.01). In logistic regression analysis after adjustment for age, prevalent fractures, and physical activity, women with levels of alpha-L/beta-L, alpha-L/alpha-D, and alpha-L/beta-D-CTX ratios in the highest quartile had a 1.5- to 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 2.0 (1.2-3.5), 1.8 (1.02-2.7), and 1.5 (0.9-2.7), respectively. Adjustment of alpha-L/beta-L and alpha-L/alpha-D-CTX ratios by the level of bone turnover assessed by serum bone alkaline phosphatase (ALP)- or femoral neck bone mineral density (BMD) decreased slightly the RR, which remained significant for the alpha-L/beta-L-CTX ratio (RR [95%] CI, 1.8 [1.1-3.2] after adjustment for bone ALP, 1.8 [1.03-3.1] after adjustment for BMD, and 1.7 [0.95-2.9] after adjustment for both bone ALP and BMD). Women with both high alpha-L/beta-L-CTX ratio and high bone ALP had a 50% higher risk of fracture than women with either one of these two risk factors. Similarly, women with both increased CTX ratio and low femoral neck BMD (T score < -2.5) had a higher risk of fracture with an RR (95% CI) of 4.5 (2.0-10.1). In conclusion, increased urinary ratio between native and age-related forms of CTX, reflecting decreased degree of type I collagen racemization/isomerization, is associated with increased fracture risk independently of BMD and partly of bone turnover rate. This suggests that alterations of type I collagen isomerization/racemization that can be detected by changes in urinary CTX ratios may be associated with increased skeletal fragility.     

Deterioration of trabecular plate-rod and cortical microarchitecture and reduced bone stiffness at distal radius and tibia in postmenopausal women with vertebral fractures

Postmenopausal women with vertebral fractures have abnormal bone microarchitecture at the distal radius and tibia by HR-pQCT, independent of areal BMD. However, whether trabecular plate and rod microarchitecture is altered in women with vertebral fractures is unknown. This study aims to characterize the abnormalities of trabecular plate and rod microarchitecture, cortex, and bone stiffness in postmenopausal women with vertebral fractures. HR-pQCT images of distal radius and tibia were acquired from 45 women with vertebral fractures and 45 control subjects without fractures. Trabecular and cortical compartments were separated by an automatic segmentation algorithm and subjected to individual trabecula segmentation (ITS) analysis for measuring trabecular plate and rod morphology and cortical bone evaluation for measuring cortical thickness and porosity, respectively. Whole bone and trabecular bone stiffness were estimated by finite element analysis. Fracture and control subjects did not differ according to age, race, body mass index, osteoporosis risk factors, or medication use. Women with vertebral fractures had thinner cortices, and larger trabecular area compared to the control group. By ITS analysis, fracture subjects had fewer trabecular plates, less axially aligned trabeculae and less trabecular connectivity at both the radius and the tibia. Fewer trabecular rods were observed at the radius. Whole bone stiffness and trabecular bone stiffness were 18% and 22% lower in women with vertebral fractures at the radius, and 19% and 16% lower at the tibia, compared with controls. The estimated failure load of the radius and tibia were also reduced in the fracture subjects by 13% and 14%, respectively. In summary, postmenopausal women with vertebral fractures had both trabecular and cortical microstructural deterioration at the peripheral skeleton, with a preferential loss of trabecular plates and cortical thinning. These microstructural deficits translated into lower whole bone and trabecular bone stiffness at the radius and tibia. Our results suggest that abnormalities in trabecular plate and rod microstructure may be important mechanisms of vertebral fracture in postmenopausal women.