Postmenopausal women with normal BMD who have fractures have deteriorated bone microarchitecture: A prospective analysis from The OFELY study.

Most postmenopausal women who sustain fragility fracture (Fx) have their areal bone mineral density (BMD) above the osteoporosis threshold. A sizeable proportion of them have normal aBMD. This study aimed to prospectively investigate the association of fragility Fx with bone microarchitecture (MA) assessed by high-resolution peripheral computed tomography (HR-pQCT) in postmenopausal women without low BMD. At the 14th annual follow-up of the OFELY study, we measured bone MA at the distal radius and tibia with HR-pQCT in addition to areal BMD with DXA, in 586 postmenopausal women. Among them, 166 (29 %) women, mean (SD) age 65 (8) yr, had normal BMD defined as a T score ≥ -1 at the lumbar spine, femoral neck, and total hip. During a median [IQR] 15 [14-15] yr of follow-up, 46 of those women sustained incident fragility Fx, including 19 women with a major osteoporotic Fx (clinical spine, forearm, proximal humerus, hip). Women who sustained Fx did not differ for age, BMI, tobacco and alcohol use, diabetes, falls, FRAX®, aBMD, and TBS compared with women without incident Fx. In contrast, they had significant impairment of volumetric densities, cortical area (Ct. Ar) and thickness (Ct. Th), stiffness (K), and estimated failure load (FL) at the radius compared with women without incident Fx. At the radius, each SD decrease of volumetric densities, Ct.Ar, Ct.Th, K, and estimated FL were significantly associated with an increased risk of all fragility fractures with hazard ratios (HR) from 1.44 to 1.56 and of major osteoporotic fractures (HR from 1.66 to 2.57). Lesser impairment of bone MA was seen at the tibia. We conclude that even in women with normal areal BMD fragility fractures are associated with deterioration of bone microarchitecture.

Cost-effectiveness of treatment of women aged 70 years and older with both osteopenia and microstructural deterioration.

OBJECTIVE: Treatment is usually withheld from women with osteopenia even though they are the source of over 70% of all women having fragility fractures. As microstructural deterioration increases fracture risk and zoledronate reduces it, we aimed to determine whether identifying and treating women with osteopenia and severe microstructural deterioration is cost-effective. We also compared the health economic outcomes of 'global' versus 'targeted' treatment using SFS of women aged ≥70 years with osteopenia. DESIGN: We assessed the cost-effectiveness from using a Markov model that simulated 10-year follow up of women with osteopenia. Decision analysis compared measurement of distal radial microstructure using high resolution peripheral computed tomography (at a cost of USD $210) to target women with severe microstructural deterioration for zoledronate treatment, compared to standard care defined as measurement of bone mineral density (BMD) with treatment recommended when femoral neck BMD T score is ≤-2.5 SD with or without a prevalent fracture. In the 'global' treatment approach, high resolution peripheral quantitative tomography (HRpQCT) was not undertaken. SETTING: US healthcare system. PARTICIPANTS: A hypothetical cohort of 1000 women aged ≥70 years with osteopenia and no previous fractures was studied. MEASURES: Fractures, deaths, years of life lived, quality-adjusted life years (QALYs) lived and costs. Data inputs were obtained from published sources. A 3% annual discount rate was applied to future health benefits and costs. RESULTS: Women in the standard care group incurred 327 fractures during 7341.0 years and 4914.2 QALYs lived. Women in the intervention group incurred 300 fractures (number needed to treat 37) during 7359.2 years and 4928.8 QALYs lived. Net costs were USD $4,862,669 and $4,952,004, respectively, equating to 18.1 years of life saved and 14.6 QALYs saved, and incremental cost-effectiveness ratios of $4992 per year of life saved and $6135 per QALY saved. These ratios are well within the threshold considered to be cost-effective. Sensitivity analyses indicated the results were robust. Relative to standard of care, 'global' and 'targeted' treatment respectively resulted in 0.0364 vs. 0.0181 years of life (YoLS) saved per person, and 0.0292 and 0.0146 QALYs saved per person. The net costs per person for the respective approaches were $US 359 and $US 89. The incremental cost-effectiveness ratios were $9864 per YoLS and $12,290 per QALY saved for the 'global' approach and $4992 per YoLS and $6135 per QALY saved for the 'targeted' approach. CONCLUSION: Identifying and treating women ≥70 years of age with osteopenia and microstructural deterioration with zoledronate cost-effectively reduces the morbidity and mortality imposed by fragility fractures. This 'targeted' approach is more cost-effective than a 'global' approach and incurs only 25% of total costs. IMPLICATION: Women with osteopenia with bone fragility due to microstructural deterioration should be identified and targeted for treatment. SUMMARY: Women with osteopenia have 70% of fractures. Treating those with microstructural deterioration conferred an incremental cost-effectiveness ratio of $4992/year of life saved and $6135 per QALY saved.

The cartilage degradation marker, urinary CTX-II, is associated with the risk of incident total joint replacement in postmenopausal women. A 18 year evaluation of the OFELY prospective cohort.

OBJECTIVE: Identifying objective risk-indicators for total joint replacement (TJR) is useful to enrich population at high risk in OA clinical trials. We investigate the association of urinary CTX-II, a biochemical marker of cartilage breakdown, with the risk of TJR. METHOD: 478 postmenopausal women (mean age 65.5 ± 7.5 yr) from the OFELY cohort were studied. CTX-II, serum CTX-I (bone resorption) and PINP (bone formation), were measured at baseline. Association between CTX-II and incidence of TJR was assessed by Cox Hazard Regression. RESULTS: During a median (95%CI) 17.8 (15.0-18.1) years follow-up, 38 women sustained a TJR, including hip (n = 29) or knee (n = 9) replacement. CTX-II -but not CTX-I or PINP- was higher in patients with TJR (+34%, P = 0.001 vs women with no TJR). Increased baseline CTX-II levels were associated with a higher risk of TJR with a Hazard Ratio (HR) (95 CI) of 1.45 (1.13-1.85) per 1 SD increase after adjustment for age, BMI and total hip BMD. CTX-II remained significantly associated with the risk of TJR after further adjustment for total WOMAC, prevalent knee OA (KL ≥ 2) and self-reported hip OA [HR (95 CI): 1.31 (1.01-1.71), P = 0,04]. When women were categorized as low and high CTX-II (lower and above the 95 percentile of healthy premenopausal women, respectively), subjects with high levels had an age-BMI-hip BMD adjusted HR (95 CI) of 3.00 (1.54-5.85) compared to women with low levels which remained significant after further adjustment for WOMAC, knee and/or hip OA [HR (95 CI): 2.45 (1.25-4.89), P = 0.01]. CONCLUSION: CTX-II is an independent risk indicator of TJR in postmenopausal women suggesting that it may be useful to identify subjects at high risk of TJR.

Muscle mass is associated with incident fracture in postmenopausal women: The OFELY study.

The relationships between body composition and bone mineral density are well established but the contribution of body composition to the risk of fracture (Fx) has rarely been evaluated prospectively. We analyzed the risk of Fx by body composition in 595 postmenopausal women (mean age 66±8years) from a longitudinal cohort study (Os des Femmes de Lyon). We assessed the risk of the first incident fragility Fx according to body composition obtained from whole-body DXA: abdominal visceral (VFAT) and subcutaneous fat mass (SFAT), total body fat mass (FM), lean mass index (LMI) and appendicular skeletal muscle mass index (ASMI). During a median [IQ] follow-up of 13.1years [1.9], 138 women sustained a first incident Fx, including 85 women with a major osteoporotic Fx (MOP Fx: hip, clinical spine, humerus or wrist). After adjustment for age, women who sustained Fx had lower BMI (-4%, p=0.01), LMI (-6%, p=0.002) and ASMI (-3%, p=0.003), compared with women without Fx. After adjustment for age, prevalent Fx, physical activity, incident falls and FN BMD, each SD increase of baseline values of LMI and ASMI was associated with decreased Fx risk with adjusted hazard ratios of 0.76 for both of p≤0.02. Those associations were similar after accounting for the competing risk of death. VFAT and SFAT were associated with Fx risk in the multivariate model only for MOP Fx and the association did not persist after consideration of competing mortality. We conclude that lean mass and appendicular muscle mass indexes are associated with the risk of fracture in postmenopausal women independently of BMD and clinical risk factors.

Serum periostin is associated with prevalent knee osteoarthritis and disease incidence/progression in women: the OFELY study.

OBJECTIVE: Our aim was to investigate the relationships between serum periostin (POSTN) and both prevalence and incidence/progression of knee osteoarthritis (OA) in women. METHODS: We investigated 594 women (62.7 ± 11.2 yr) from the OFELY cohort. Knee radiographs were scored according to the Kellgren & Lawrence (KL) grading system at baseline and 4 years later. Spine, hip and hand OA were assessed at baseline. Prevalent knee OA was defined by a KL score higher or equal in 2. Progression of KL was defined as an increase of the KL score ≥1 during the 4 years follow-up. Serum POSTN was measured at baseline by ELISA. RESULTS: By non-parametric tests, POSTN was significantly lower in 83 women with a KL score ≥2 at baseline, compared to those with a KL score <2 (n = 511; 1101 ± 300 vs 1181 ± 294 ng/ml, P = 0.002) after adjustment for age, body mass index (BMI), treatments and diseases, prevalent hand OA and prevalent lumbar spine OA. By logistic regression analyses, the odds-ratio of knee OA incidence/progression was significantly reduced by 21% (P = 0.043) for each quartile increase in serum POSTN at baseline, after adjustment for age, BMI, prevalent knee OA, prevalent hand OA and prevalent lumbar spine OA. CONCLUSIONS: We show for the first time that serum POSTN is associated with prevalence and the risk of development/progression of knee OA in women.

Family resemblance of bone turnover rate in mothers and daughters--the MODAM study.

UNLABELLED: We studied bone turnover markers (BTM) and bone microarchitecture (using high-resolution peripheral quantitative computed tomography (HR-pQCT)) in 171 postmenopausal women and their 210 premenopausal daughters. BTM levels correlated positively between mothers and daughters. The mother-daughter pairs with high BTM levels had lower cortical density than those with low BTM levels. INTRODUCTION: We assessed the correlation of serum bone turnover markers (BTM) between postmenopausal mothers and their premenopausal daughters as well as possible determinants of this association and its impact on resemblance of bone microarchitecture between mothers and their daughters. METHODS: Cross-sectional analysis was performed in 171 untreated postmenopausal mothers (54 sustained fragility fractures) and their 210 premenopausal daughters. Intact N-terminal propeptide of type I collagen (PINP) and ß-isomerized C-terminal crosslinking telopeptide of type I collagen (CTX-I) were measured in the fasting status. Bone microarchitecture was assessed using HR-pQCT. RESULTS: After adjustment for age, weight, lifestyle factors, hormones, and mother's fracture status, BTM levels correlated positively between mothers and daughters (Intraclass Correlation Coefficient = 0.22-0.27, p <0.005). Average BTM levels were ∼ 0.6 SD higher among daughters of mothers in the highest BTM quartile vs. the ones in the lowest BTM quartile. The variability of BTM levels explained ≤ 10 and ≤ 14% of variability of bone microarchitecture in the daughters and mothers, respectively. Cortical density was lower by 2.3-2.9% (0.6 SD, p <0.05 to <0.005) in the daughters from the mother-daughter pairs with high BTM levels (defined by generation-specific quartiles) than in the daughters from the pairs with low BTM levels. Corresponding differences for the mothers were 4.5-4.8% (0.5 SD, p <0.05 to <0.01). CONCLUSION: BTM levels correlated between postmenopausal mothers and their premenopausal daughters after adjustment for age, weight, mother's fracture status, lifestyle, and hormonal factors. Family resemblance of BTM levels may contribute to family resemblance of some bone microarchitectural parameters, especially of cortical density.

How to predict fragility fracture beyond 10 years? The OFELY study.

CONTEXT: Low bone mineral density (BMD) is a major determinant of fragility fractures (Fx), but its very long-term prediction is poorly documented. OBJECTIVE: We analyzed the risk of Fx beyond 10 years in women. DESIGN: In a longitudinal cohort study (Os des Femmes de Lyon), we studied 867 women aged 40 years and older (mean age 59 ± 10 y) over 20 years. MAIN OUTCOME: We assessed the risk of the first incident Fx according to the baseline BMD obtained by dual-energy X-ray absorptiometry, clinical risk factors, and the Fracture Risk Assessment Tool (FRAX). RESULTS: During a median (interquartile range) follow-up of 20 years (3), 245 women sustained one or more incident fragility Fx. Women who sustained a first Fx beyond 10 years (Fx 10-20, n = 109) were younger and had lower values of FRAX compared with those in the first 10 years (Fx 0-10, n = 136). After adjustment for age, they still had greater grip strength and BMD. Parental hip Fx was associated with an increased risk of Fx 10-20 but contrasting with Fx 0-10, the risk of Fx 10-20 was not associated with age, previous Fx, and FRAX except in women younger than 70 years. Each SD decrease of BMD at the spine, femoral neck, total hip, and ultradistal radius was associated with an increased risk of Fx 10-20 with adjusted odds ratios [95% confidence interval (CI)] of 1.43 (95% CI 1.12-1.82), 1.39 (95% CI 1.08-1.82), 1.47 (95% CI 1.14-1.89), and 2.00 (95% CI 1.47-2.7). Women with osteoporosis had an increased risk of both Fx 0-10 and Fx 10-20 compared with women with normal BMD, whereas osteopenia was not associated with a higher risk of Fx beyond 10 years. CONCLUSIONS: Low BMD in women is significantly associated with an increased risk of Fx over 20 years. Beyond 10 years, the prediction conferred by baseline BMD was better than that from clinical risk factors.

Serum periostin is associated with fracture risk in postmenopausal women: a 7-year prospective analysis of the OFELY study.

PURPOSE: Periostin (POSTN) is a secreted γ-carboxyglutamic acid-containing protein expressed mainly in the periosteum in adult individuals. POSNT deficient mice develop periodontis and osteoporosis with decreased bone strength. The relationship between serum POSTN and bone metabolism and fracture risk in postmenopausal women is unknown. SUBJECTS AND METHODS: Serum POSTN was measured in 607 postmenopausal women (mean age 66.6 ± 8.4 y) from the Os des Femmes de Lyon cohort at the ninth annual follow-up visit (baseline visit of the current analysis). Nonvertebral and clinical vertebral incident fragility fractures were reported annually during 7 years. Areal bone mineral density (BMD; measured by dual energy X-ray absorptiometry) of the hip and bone markers (intact N-terminal propeptide of type I collagen, osteocalcin, and serum type I collagen C-telopeptide) were also measured. RESULTS: At baseline, serum POSTN did not correlate with age, bone markers, and BMD. After a median of 7 years of follow-up, 75 women sustained an incident clinical vertebral or nonvertebral fragility fracture. The proportion of women who had an incident fracture was significantly higher in women with levels of POSTN in the highest quartile than that of women in the three other quartiles (19.5% vs 10.1%, P = .018) after adjustment for age and prevalent fracture. The highest quartile of POSTN was associated with an increased risk of incident fracture with a relative risk (95% confidence interval) of 1.88 (1.1-3.2) after adjustment for age, prevalent fracture, and hip BMD T-score. Patients with both low hip BMD (T-score < -2.5) and high levels of POSTN (fourth quartile) had a relative risk of fracture of 7.1 (95% confidence interval 2.4-21.8) after adjustment for age. CONCLUSION: High serum POSTN levels are independently associated with increased fracture risk in postmenopausal women. These data suggest that serum POSTN could be useful to improve fracture risk assessment.

Severity of aortic calcification is positively associated with vertebral fracture in older men--a densitometry study in the STRAMBO cohort.

UNLABELLED: In older men, severe abdominal aortic calcification and vertebral fracture (both assessed using dual-energy X-ray absorptiometry) were positively associated after adjustment for confounders including bone mineral density. INTRODUCTION: Abdominal aortic calcification (AAC) is associated with higher fracture risk, independently of low bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA) can be used to assess both vertebral fracture and AAC and requires less time, cost, and radiation exposure. METHODS: We conducted a cross-sectional study of the association between AAC and prevalent vertebral fractures in 901 men≥50 years old. We used DXA (vertebral fracture assessment) to evaluate BMD, vertebral fracture, and AAC. RESULTS: Prevalence of vertebral fracture was 11%. Median AAC score was 1 and 12% of men had AAC score>6. After adjustment for age, weight, femoral neck BMD, smoking, ischemic heart disease, diabetes, and hypertension, AAC score>6 (vs ≤6) was associated with 2.5 (95% CI, 1.4-4.5) higher odds of vertebral fracture. Odds of vertebral fracture for AAC score>6 increased with vertebral fracture severity (grade 1, OR=1.8; grade 2, OR=2.4; grade 3, OR=4.4; trend p<0.01) and with the number of vertebral fractures (1 fracture, OR=2.0, >1 fracture, OR=3.5). Prevalence of vertebral fracture was twice as high in men having both a T-score<-2.0 and an AAC score>6 compared with men having only one of these characteristics. CONCLUSIONS: Men with greater severity AAC had greater severity and greater number of vertebral fractures, independently of BMD and co-morbidities. DXA can be used to assess vertebral fracture and AAC. It can provide a rapid, safe, and less expensive alternative to radiography. DXA may be an important clinical tool to identify men at high risk of adverse outcomes from osteoporosis and cardiovascular disease.

Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study.

SUMMARY: Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects. INTRODUCTION: Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk. METHODS: We investigated 572 postmenopausal women (mean age, 67 ± 8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum ß-isomerized C-terminal crosslinking of type I collagen (CTX), intact N-terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5-7 years) follow-up, 64 postmenopausal sustained an incident fracture. RESULTS: Serum sclerostin correlated positively with spine (r = 0.35, p < 0.0001) and total hip (r = 0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP (r = -0.10, p = 0.014) and CTX (r = -0.13, p = 0.0026) and with intact PTH (r = -0.13, p = 0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture. CONCLUSION: Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association.

Trabecular bone score improves fracture risk prediction in non-osteoporotic women: the OFELY study.

UNLABELLED: The use of areal bone mineral density (aBMD) for fracture prediction may be enhanced by considering bone microarchitectural deterioration. Trabecular bone score (TBS) helped in redefining a significant subset of non-osteoporotic women as a higher risk group. INTRODUCTION: TBS is an index of bone microarchitecture. Our goal was to assess the ability of TBS to predict incident fracture. METHODS: TBS was assessed in 560 postmenopausal women from the Os des Femmes de Lyon cohort, who had a lumbar spine (LS) DXA scan (QDR 4500A, Hologic) between years 2000 and 2001. During a mean follow-up of 7.8 ± 1.3 years, 94 women sustained 112 fragility fractures. RESULTS: At the time of baseline DXA scan, women with incident fracture were significantly older (70 ± 9 vs. 65 ± 8 years) and had a lower LS_aBMD and LS_TBS (both -0.4SD, p < 0.001) than women without fracture. The magnitude of fracture prediction was similar for LS_aBMD and LS_TBS (odds ratio [95 % confidence interval] = 1.4 [1.2;1.7] and 1.6 [1.2;2.0]). After adjustment for age and prevalent fracture, LS_TBS remained predictive of an increased risk of fracture. Yet, its addition to age, prevalent fracture, and LS_aBMD did not reach the level of significance to improve the fracture prediction. When using the WHO classification, 39 % of fractures occurred in osteoporotic women, 46 % in osteopenic women, and 15 % in women with T-score > -1. Thirty-seven percent of fractures occurred in the lowest quartile of LS_TBS, regardless of BMD. Moreover, 35 % of fractures that occurred in osteopenic women were classified below this LS_TBS threshold. CONCLUSION: In conclusion, LS_aBMD and LS_TBS predicted fractures equally well. In our cohort, the addition of LS_TBS to age and LS_aBMD added only limited information on fracture risk prediction. However, using the lowest quartile of LS_TBS helped in redefining a significant subset of non-osteoporotic women as a higher risk group which is important for patient management.

Impaired trabecular and cortical microarchitecture in daughters of women with osteoporotic fracture: the MODAM study.

UNLABELLED: We investigated the familial resemblance of bone microarchitecture parameters between postmenopausal mothers with fragility fracture and their premenopausal daughters using high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that daughters of women with fracture have lower total volumetric bone mineral density (vBMD), thinner cortices, and impaired trabecular microarchitecture at the distal radius and tibia, compared to controls. INTRODUCTION: Familial resemblance of areal bone mineral density (aBMD) in mothers and daughters has been widely studied, but not its morphological basis, including microarchitecture. METHODS: We compared aBMD, vBMD, bone size, and bone microarchitecture at the distal radius and tibia assessed by HR-pQCT in mothers and their premenopausal daughters. We included 115 women aged 43 ± 8 years whose mothers had sustained a fragility fracture and 206 women aged 39 ± 9 years whose mothers had never sustained a fragility fracture. RESULTS: Women whose mothers had fracture had significantly (p < 0.05) lower aBMD at the lumbar spine, total hip, femoral neck, mid-distal radius, and ultradistal radius compared to controls. In similar multivariable models, women whose mothers had a fracture had lower total vBMD at the distal radius (-5 %, 0.3 standard deviation [SD]; p < 0.005) and distal tibia (-7 %, 0.4 SD; p < 0.005). They also had lower cortical thickness and area at the distal radius (-5 %, 0.3 SD and -4 %, 0.2 SD, respectively; p < 0.005) and at the distal tibia (-6 %, 0.3 SD and -4 %, 0.3SD, respectively; p < 0.005). Trabecular vBMD was lower at the distal radius (-5 %, 0.3 SD; p < 0.05) and tibia (-8 %, 0.4 SD; p < 0.005), with a more spaced and heterogeneous trabecular network (4 and 7 % at the radius and 5 and 9 %, at the tibia, p < 0.05, for Tb.Sp and Tb.Sp.SD, respectively). CONCLUSION: Premenopausal daughters of women who had sustained fragility fracture have lower total and trabecular vBMD, thinner cortices, as well as impaired trabecular microarchitecture at the distal radius and tibia, compared with premenopausal daughters of women without fracture.

Local topological analysis at the distal radius by HR-pQCT: Application to in vivo bone microarchitecture and fracture assessment in the OFELY study.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is an in-vivo technique used to analyze the distal radius and tibia. It provides a voxel size of 82µm. In addition to providing the usual microarchitecture parameters, local topological analysis (LTA) depicting rod- and plate-like trabeculae may improve prediction of bone fragility. Thirty-three women with prevalent wrist fractures from the OFELY cohort were compared with age-matched controls. Bone microarchitecture, including the structural model index (SMI), was assessed by HR-pQCT, and micro-finite element analysis (µFE) was computed on trabecular bone images of the distal radius (XtremeCT, Scanco Medical AG). A new LTA method was applied to label each bone voxel as a rod, plate or node. Then the bone volume fraction (BV/TV*), the rod, plate and node ratios over bone volume (RV/BV*, PV/BV*, NV/BV*) or total volume (RV/TV*, PV/TV*, NV/TV*) and the rod to plate ratio (RV/PV*) were calculated. Associations between LTA parameters and wrist fractures were computed in a conditional logistic regression model. Multivariate models were tested to predict the µFE-derived trabecular bone stiffness. RV/TV* (OR=4.41 [1.05-18.62]) and BV/TV* (OR=6.45 [1.06-39.3]), were significantly associated with prevalent wrist fracture, after adjustment for ultra distal radius aBMD. Multivariate linear models including PV/TV* or BV/TV*+RV/PV* predicted trabecular stiffness with the same magnitude as those including SMI. Conversion from plates into rods was significantly associated with bone fragility, with a negative correlation between RV/PV* and trabecular bone stiffness (r=-0.63, p<0.0001). We conclude that our local topological analysis is feasible for a voxel size of 82µm. After further validation, it may improve bone fragility description.

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

UNLABELLED: 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. INTRODUCTION: Pentosidine has been described as an independent risk factor for hip and vertebral fracture in postmenopausal Japanese women. We investigated the prediction of urinary pentosidine on all fragility fracture risk in healthy untreated postmenopausal women from the OFELY cohort. METHODS: Urinary pentosidine was assessed at baseline in 396 healthy untreated postmenopausal women aged 63.3 +/- 8.4 years from the OFELY cohort using high-performance liquid chromatography method. Incident clinical fractures were recorded during annual follow-up and confirmed by radiographs, and vertebral fractures were assessed on radiographs performed every 4 years. Multivariate Cox's regression analysis was used to calculate the risk of urinary pentosidine levels after adjustment for age, prevalent fractures, and total hip bone mineral density (BMD). RESULTS: During a mean follow-up of 10 years, 88 of the 396 postmenopausal women have undergone incident vertebral (n = 28) and peripheral (n = 60) fractures. Fracture risk was higher in postmenopausal women with pentosidine in the highest quartile (p = 0.02), but it did not remain significant after adjustment for age, BMD, and prevalent fracture. CONCLUSIONS: Urine pentosidine concentration is not an independent risk factor of osteoporotic fracture in healthy postmenopausal women from the OFELY cohort.

Homocysteine and fracture risk in postmenopausal women: the OFELY study.

UNLABELLED: 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 mumol/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.

Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study.

INTRODUCTION: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. METHODS: 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. RESULTS: 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r(2)=0.023, p<0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. CONCLUSIONS: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health.

Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density.

CONTEXT: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. OBJECTIVE: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. DESIGN: A prospective population-based cohort was studied. SUBJECTS: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. MAIN OUTCOME MEASURE: The study measured incidents of vertebral and nonvertebral fractures. RESULTS: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. CONCLUSION: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.

Similar prevalence of vertebral fractures despite different approaches to define reference data.

Morphometric detection of vertebral fractures requires the use of reference normal values. In previous studies, normal values were obtained in young healthy adults or in adults of various ages in whom abnormal radiographs were excluded using trimming algorithms. We established four sets of normal values defined according to different approaches. We used a group of 102 young healthy women with normal spine radiographs and a population-based cohort of 260 women 51 to 85 years old (EVOS study) to select those with normal spine radiographs based on the semiquantitative method of Genant, the trimming algorithm defined by Melton, and the trimming algorithm defined by Black. Using the four sets of reference data, we applied two diagnostic criteria, the mean - 3SD and the 0.85 x mean to detect prevalent vertebral fractures in two groups of women: the population-based cohort of 260 women recruited for the EVOS study and 176 osteoporotic women 54 to 88 years old with at least one vertebral fracture. In the population-based cohort, the number of vertebral fractures varied from 53 to 57 for the 0.85 x mean cutoff and from 93 to 115 for the mean - 3SD cutoff. In the osteoporotic women, the number of vertebral fractures varied from 255 to 273 for the 0.85 x mean cutoff and from 372 to 404 for the mean - 3SD cutoff. In both groups, the number of vertebral fractures detected with the 0.85 x mean cutoff was close to the number detected by the semiquantitative method of Genant, which does not require a reference population. For the 0.85 x mean cutoff, agreement of diagnosis using different reference values was excellent (kappa = 0.96-0.99). For the mean - 3SD cutoff, agreement of vertebral fracture detection based on the four reference sets was good (kappa = 0.79-0.93). Agreement of diagnosis was lower when two cutoffs were compared using the same set of reference values (kappa = 0.60-0.81). In conclusion, reference data derived using different approaches give similar rates of prevalence of vertebral fractures. Compared to the semiquantitative assessment, the prevalence of vertebral fractures is similar for the 0.85 x mean cutoff, whereas it is considerably higher for the mean - 3SD cutoff.

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.