Associations of Circulating Levels of Sphingosine 1-Phosphate with the Trabecular Bone Score and Bone Mineral Density in Postmenopausal Women

Despite the potential roles of sphingosine 1-phosphate (S1P) as a biomarker of osteoporotic fracture (OF), independent of bone mineral density (BMD) and clinical risk factors (CRFs), its association with bone microarchitecture, a key determinant of bone quality, have not been studied yet. We here investigated the association of S1P with the trabecular bone score (TBS), an index of the bone microarchitecture. The plasma S1P concentrations, TBS, and BMD were measured in the 339 postmenopausal women. The S1P level was inversely correlated with the TBS (γ=–0.096, p=0.049) and BMD at the femur neck (FN-BMD: γ=–0.122, p=0.025) and tended to be inversely correlated the BMD at the total hip (TH-BMD: γ=–0.096, p=0.079), but not at the lumbar spine (LS-BMD). After adjusting for fracture risk assessment tool probabilities of major OF from CRFs, the S1P level was inversely associated with the TBS (β=–0.096, p=0.049) and FN-BMD (β=–0.118, p=0.025) and tended to be inversely associated with the TH-BMD (β=–0.092, p=0.083). Compared with subjects in the lowest S1P tertile, those in the highest S1P tertile had a significantly lower TBS (p=0.032) and BMD at femur (p=0.004–0.036). These findings indicated that a high S1P level in postmenopausal women was inversely associated with the both bone mass and microarchitecture, reflecting the compromised bone strength.     

<Emphasis Type="Italic">Z</Emphasis>-score discordance and contributing factors in healthy premenopausal women with low bone mineral density: the Korean National Health and Nutrition Examination Survey 2008–9

The premenopausal period is important for bone health and prevention of future fractures, but measuring bone mineral density (BMD) at only one site may not be sufficient to determine therapeutic strategies for low BMD in premenopausal women due to the presence of Z-score discordance. In this study, we investigated Z-score discordance in addition to contributing factors of idiopathic low BMD in healthy premenopausal Korean women. We studied 3003 premenopausal women aged 18–50 years, without secondary causes for low BMD and history of fragility fracture, who had participated in the Fourth Korean National Health and Nutrition Examination Surveys (2008–2009). Low body mass index (BMI), low vitamin D level, and low body muscle mass were associated with low BMD even in premenopausal women. Risk factors differed depending on the anatomic site. Low BMI and low vitamin D level were risk factors for low femoral neck BMD (FN-BMD), but not for low lumbar spine BMD (LS-BMD). Only total muscle mass had a slight effect on low LS-BMD. Z-score discordance was much higher than expected, in 75 and 73.8 % of the low LS-BMD and low FN-BMD groups, respectively. Our findings suggest the need to consider BMD discordance in premenopausal women and also to provide information on correctable factors affecting low BMD in younger populations. Long-term follow-up is needed to evaluate the possible effect of Z-score discordance on the prognosis of osteoporosis and subsequent fracture risk.     

FRAX and Risk of Vertebral Fractures: The Fracture Intervention Trial

The validity of the WHO 10‐yr probability of major osteoporotic fracture model (FRAX) for prediction of vertebral fracture has not been tested. We analyzed how well FRAX for major osteoporotic fractures, with and without femoral neck BMD (FN BMD), predicted the risk of vertebral fracture. We also compared the predictive validity of FRAX, FN BMD, and prevalent vertebral fracture detected by radiographs at baseline alone or in combination to predict future vertebral fracture. We analyzed data from the placebo groups of FIT (3.8‐yr follow‐up, n = 3221) with ORs and areas under receiver operating characteristics (ROC) curves (AUC). FRAX with and without FN BMD predicted incident radiographic vertebral fracture. The AUC was significantly greater for FRAX with FN BMD (AUC = 0.71) than FRAX without FN BMD (AUC = 0.68; p = 0.002). Prevalent vertebral fracture plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture as well as a combination of prevalent vertebral fracture and FRAX with FN BMD (AUC = 0.75; p = 0.76). However, baseline vertebral fracture status plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture significantly better than FRAX with FN BMD (AUC = 0.71; p = 0.0017). FRAX for major osteoporotic fractures (with and without FN BMD) predicts vertebral fracture. However, once FN BMD and age are known, the eight additional risk factors in FRAX do not significantly improve the prediction of vertebral fracture. A combination of baseline radiographic vertebral fracture, FN BMD, and age is the strongest predictor of future vertebral fracture.     

Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.

Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.     

An approach for identifying postmenopausal women age 50–64 years at increased short-term risk for osteoporotic fracture

SUMMARY: Using data from NORA, we used 18 potential risk factors in a classification and regression tree analysis to build two algorithms. These algorithms correctly identified postmenopausal women between the ages of 50 and 64 years who were at the highest risk of osteoporotic fracture within 36 months. INTRODUCTION: The objective was to develop algorithms that best predict short-term fracture risk (3 years) in postmenopausal women 50-64 years old. METHODS: Data were from 91,652 women who responded to follow-up surveys as part of National Osteoporosis Risk Assessment (NORA) study. Peripheral bone mineral density (BMD) and risk factors obtained at baseline; incident osteoporotic fractures obtained from follow-up surveys. Eighteen risk factors were entered into a classification and regression tree analysis to build two algorithms, one with and one without BMD. RESULTS: Two thousand and seven (2.2%) women reported new osteoporotic fractures. Prior fracture, a peripheral BMD T-score 相似文献   

Validation of FRC, a fracture risk assessment tool, in a cohort of older men: the Osteoporotic Fractures in Men (MrOS) Study

We evaluated the performance of the Fracture Risk Calculator (FRC) in 5893 men who participated in the baseline visit (March 2000-April 2002) of the Osteoporotic Fractures in Men Study. FRC estimates for 10-yr hip and major osteoporotic (hip, clinical spine, forearm, and shoulder) fractures were calculated and compared with observed 10-yr fracture probabilities. Possible enhancement of the tool's performance when bone mineral density (BMD) was included was evaluated by comparing areas under receiver operating characteristic curves and by Net Reclassification Improvement (NRI). A total of 5893 men were followed-up for an average of 8.4 yr. For most quintiles of predicted fracture risk, the ratios of observed to predicted probabilities were close to unity. Area under the curves improved when BMD was included (p<0.001; 0.79 vs 0.71 for hip fracture and 0.70 vs 0.66 for major osteoporotic fracture, respectively). Using National Osteoporosis Foundation clinical treatment thresholds, BMD inclusion increased NRI significantly, 8.5% (p<0.01) for hip and 4.0% (p=0.01) for major osteoporotic fracture. We conclude that the FRC calibrates well with hip and major osteoporotic fractures observed among older men. Further, addition of BMD to the fracture risk calculation improves the tool's performance.     

Anisotropy changes in post-menopausal osteoporosis: characterization by a new index applied to trabecular bone radiographic images

Bone intrinsic strength is conditioned by several factors, including material property and trabecular micro-architecture. Bone mineral density (BMD) is a good surrogate for material property. Architectural anisotropy is of special interest in mechanics-architecture relations and characterizes the degree of directional organization of a material. We have developed anisotropy indices from the Fast Fourier Transform (FFT) on bone radiographs. We have validated these indices in a cross-sectional uni-center case-control study including 39 postmenopausal women with vertebral fracture and 70 age-matched control cases. BMD was measured at the lumbar spine and femoral neck. A fractal analysis of texture was performed on calcaneus radiographs at three regions of interest (ROIs), and the result was expressed as the H parameter (fractal dimension =H-2). The anisotropy evaluation was based on the FFT spectrum of these three ROIs extracted on calcaneus radiographs. On the FFT spectrum, we have measured the spreading angle of the longitudinal trabeculae called the dispersion longitudinal index (DLI) and the spreading angle of the transversal trabeculae called the dispersion transversal index (DTI). From the measured parameters, an anisotropy index was derived, and the degree of anisotropy (DA) calculated with DLI and DTI. We have compared the results from the vertebral fracture cases and control cases. The best distinction was obtained for the largest ROI located in the great tuberosity of the calcaneus for all parameters ( P <10^-4). The DA parameter showed a higher value in vertebral fracture cases (1.746±0.169) than in control cases (1.548±0.136); P <10^-4, and the difference persisted after removal of the subjects with hormonal replacement therapy. The analysis of the receiver operating characteristics (ROC) has shown the best results with DA and Hmean: areas under curves (AUCs) respectively of 0.765 and 0.683, while AUCs associated to LS-BMD and FN-BMD were 0.614 and 0.591 lower, respectively. We determined the odds ratios (OR) by uni- and multivariate analysis. Crude ORs were respectively 3.91 (95% CI: 2.22–6.87) and 3.08 (95% CI: 1.72–5.52) for DA and Hmean. Crude ORs were respectively 1.71 (95% CI: 1.15–2.56) and 1.56 (95% CI: 1.05–2.31) for LS-BMD and FN-BMD. All ORs were statistically significant, and those associated to Hmean and anisotropy indices were higher than those of BMD measurements. From a multivariate analysis including anisotropy indices, Hmean, age and FN-BMD, the remaining significant ORs were respectively 6.33 (95% CI: 2.80–14.30) and 3.08 (95% CI: 1.48–6.37) for DA and Hmean. These data have shown that anisotropy indices on calcaneus radiographs can distinguish vertebral fracture cases from control cases. This analysis provides complementary information concerning the BMD and fractal parameter. These data suggest that we can improve the fracture risk evaluation by adding information related to the directional organization of trabecular bone derived from the FFT spectrum on conventional radiographic images.     

Effect of strontium ranelate on fracture healing in the osteoporotic rats

The aim of this study was to evaluate the effect of strontium ranelate (SrR) on fracture healing in the osteoporotic rat model. Forty female Sprague–Dawley rats aged 3 months were enrolled in the study. Osteoporosis was induced by bilateral ovariectomy and subsequent daily heparin injection started 1 week after surgery and lasted for 4 weeks. Osteoporosis was confirmed by a reduction of bone mineral density (BMD). Twenty of the osteoporotic rats were assigned to the SrR group and the remaining 20 to the control group. An open right tibial midshaft transverse fracture was created and then an intramedullary fixation was performed. SrR group was treated by 450 mg/kg/day SrR per oral. Six weeks after surgical induction of fracture, all animals were sacrificed. One animal from each group died after ovariectomy. Two tibiae from the control group failed to unite. SrR‐treated group showed higher mechanical strength and fracture stiffness when compared to the control group (p = 0.006, p = 0.001, respectively). SrR‐treated group had mature woven bone or predominantly woven bone compared with osteoporotic control group (p = 0.038). SrR‐treated group's callus maturity was significantly higher than control group (p = 0.001). SrR is associated with better fracture healing in the osteoporotic rat model. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:138–142, 2011     

The Effect of Abaloparatide‐SC on Fracture Risk Is Independent of Baseline FRAX Fracture Probability: A Post Hoc Analysis of the ACTIVE Study

Daily subcutaneous (SC) injections of the investigational drug abaloparatide‐SC (80 mcg) for 18 months significantly decrease the risk of vertebral and nonvertebral fracture compared with placebo in postmenopausal women. We examined the efficacy of abaloparatide‐SC as a function of baseline fracture risk, assessed using the FRAX tool. Baseline clinical risk factors (age, body mass index [BMI], prior fracture, glucocorticoid use, rheumatoid arthritis, and smoking) were entered into country‐specific FRAX models to calculate the 10‐year probability of major osteoporotic fractures, with or without femoral neck bone mineral density (BMD). The interaction between probability of a major osteoporotic fracture and treatment efficacy was examined by a Poisson regression. A total of 821 women randomized to placebo and 824 women to abaloparatide‐SC, mean age 69 years in both groups, were followed for up to 2 years. At baseline, the 10‐year probability of major osteoporotic fractures (with BMD) ranged from 2.3% to 57.5% (mean 13.2%). Treatment with abaloparatide‐SC was associated with a 69% (95% confidence interval [CI] 38–85%) decrease in major osteoporotic fracture (MOF) and a 43% (95% CI 9–64%) decrease in any clinical fracture compared with placebo. For all outcomes, hazard ratios tended to decrease (ie, greater efficacy) with increasing fracture probability. Whereas the interaction approached significance for the outcome of any fracture (p = 0.11), there was no statistically significant interaction for any of the fracture outcomes. Similar results were noted when FRAX probability was computed without BMD. Efficacy of abaloparatide‐SC to decrease the risk of major osteoporotic fracture or any clinical fracture in postmenopausal women with low BMD and/or prior fracture appears independent of baseline fracture probability. © 2017 American Society for Bone and Mineral Research.     

Prediction of Bone Mineral Density and Fragility Fracture by Genetic Profiling

Although the susceptibility to fracture is partly determined by genetic factors, the contribution of newly discovered genetic variants to fracture prediction is still unclear. This study sought to define the predictive value of a genetic profiling for fracture prediction. Sixty‐two bone mineral density (BMD)‐associated single‐nucleotide polymorphisms (SNPs) were genotyped in 557 men and 902 women who had participated in the Dubbo Osteoporosis Epidemiology Study. The incidence of fragility fracture was ascertained from X‐ray reports between 1990 and 2015. Femoral neck BMD was measured by dual‐energy X‐ray absorptiometry. A weighted polygenic risk score (genetic risk score [GRS]) was created as a function of the number of risk alleles and their BMD‐associated regression coefficients for each SNP. The association between GRS and fracture risk was assessed by the Cox proportional hazards model. Individuals with greater GRS had lower femoral neck BMD (p < 0.01), but the variation in GRS accounted for less than 2% of total variance in BMD. Each unit increase in GRS was associated with a hazard ratio of 1.20 (95% CI, 1.04 to 1.38) for fracture, and this association was independent of age, prior fracture, fall, and in a subset of 33 SNPs, independent of femoral neck BMD. The significant association between GRS and fracture was observed for the vertebral and wrist fractures, but not for hip fracture. The area under the receiver‐operating characteristic (ROC) curve (AUC) for the model with GRS and clinical risk factors was 0.71 (95% CI, 0.68 to 0.74). With GRS, the correct reclassification of fracture versus nonfracture ranged from 12% for hip fracture to 23% for wrist fracture. A genetic profiling of BMD‐ associated genetic variants could improve the accuracy of fracture prediction over and above that of clinical risk factors alone, and help stratify individuals by fracture status. © 2016 American Society for Bone and Mineral Research.     

Plasma phosphatidylcholine concentrations of polyunsaturated fatty acids are differentially associated with hip bone mineral density and hip fracture in older adults: the Framingham Osteoporosis Study

Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN‐BMD) (n = 765); (2) 4‐year change in FN‐BMD (n = 556); and (3) hip fracture risk (n = 765) over 17‐year follow‐up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN‐BMD over 4 years in women (p‐trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN‐BMD in women (p‐trend = 0.02), and increased hip fracture risk in women and men (p‐trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p‐trend = 0.12 and p‐trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN‐BMD in men (p‐trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN‐BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk. © 2012 American Society for Bone and Mineral Research.     

Serum Bone Alkaline Phosphatase and Calcaneus Bone Density Predict Fractures: A Prospective Study

The aim of this study was to assess the ability of serum bone-specific alkaline phosphatase (bone ALP), creatinine-corrected urinary collagen crosslinks (CTx) and calcaneus bone mineral density (BMD) to identify postmenopausal women who have an increased risk of osteoporotic fractures. Calcaneus BMD and biochemical markers of bone turnover (serum bone ALP and urinary CTx) were measured in 512 community-dwelling postmenopausal women (mean age at baseline 69 years) participating in the Hawaii Osteoporosis Study. New spine and nonspine fractures subsequent to the BMD and biochemical bone markers measurements were recorded over an average of 2.7 years. Lateral spinal radiographs were used to identify spine fractures. Nonspine fractures were identified by self-report at the time of each examination. During the 2.7-year follow-up, at least one osteoporotic fracture occurred in 55 (10.7%) of the 512 women. Mean baseline serum bone ALP and urinary CTx were significantly higher among women who experienced an osteoporotic fracture compared with those women who did not fracture. In separate age-adjusted logistic regression models, serum bone ALP, urinary CTx and calcaneus BMD were each significantly associated with new fractures (odds ratios of 1.53, 1.54 and 1.61 per SD, respectively). Multiple variable logistic regression analysis identified BMD and serum bone ALP as significant predictors of fracture (p = 0.002 and 0.017, respectively). The results from this investigation indicate that increased bone turnover is significantly associated with an increased risk of osteoporotic fracture in postmenopausal women. This association is similar in magnitude and independent of that observed for BMD. Received: 18 June 1999 / Accepted: 21 June 1999     

Improving Risk Assessment: Hip Geometry, Bone Mineral Distribution and Bone Strength in Hip Fracture Cases and Controls. The EPOS Study

Hip geometry and bone mineral density (BMD) have previously been shown to relate independently to hip fracture risk. Our objective was to determine by how much hip geometric data improved the identification of hip fracture. Lunar pencil beam scans of the proximal femur were obtained. Geometric and densitometric values from 800 female controls aged 60 years or more (from population samples which were participants in the European Prospective Osteoporosis Study, EPOS) were compared with data from 68 female hip fracture patients aged over 60 years who were scanned within 4 weeks of a contralateral hip fracture. We used Lunar DPX ‘beta’ versions of hip strength analysis (HSA) and hip axis length (HAL) applied to DPX(L) data. Compressive stress (Cstress), calculated by the HSA software to occur as a result of a typical fall on the greater trochanter, HAL, body mass index (BMI: weight/(height)²) and age were considered alongside femoral neck BMD (FN-BMD, g/cm²) as potential predictors of fracture. Logistic regression was used to generate predictors of fracture initially from FN-BMD. Next age, Cstress (as the most discriminating HSA-derived parameter), HAL and BMI were added to the model as potentially independent predictors. It was not necessary to include both HAL and Cstress in the logistic models, so the entire data set was examined without excluding the subjects missing HAL measurements. Cstress combined with age and BMI provided significantly better prediction of fracture than FN-BMD used alone as is current practice, judged by comparing areas under receiver operating characteristic (ROC) curves (p<0.001, deLong’s test). At a specificity of 80%, sensitivity in identification was improved from 66% to 81%. Identifying women at high risk of hip fracture is thus likely to be substantially enhanced by combining bone density with age, simple anthropometry and data on the structural geometry of the hip. HSA might prove to be a valuable enhancement of DXA densitometry in clinical practice and its use could justify a more pro-active approach to identifying women at high risk of hip fracture in the community. Received: 16 March 2001 / Accepted: 3 August 2001     

Association of Bone Density Monitoring in Routine Clinical Practice With Anti-Osteoporosis Medication Use and Incident Fractures: A Matched Cohort Study

Routine bone mineral density (BMD) monitoring of individuals during the initial 5 years of anti-osteoporosis treatment is controversial. Using a registry-based cohort from the Province of Manitoba, Canada, we compared anti-osteoporosis medication use and fracture outcomes in women with versus without BMD monitoring receiving anti-osteoporosis medication. We identified 4559 women aged 40 years and older receiving anti-osteoporosis therapy with serial BMD testing (monitoring) within 5 years (mean interval 3.2 years) and 4559 propensity score–matched women without BMD monitoring. We assessed anti-osteoporosis medication use over 5 years from a population-based retail pharmacy database. Incident fractures to 10 years from health services data. During median 10 years observation, 1225 (13.4%) women developed major osteoporotic fracture, including 382 (4.2%) with hip fractures. Monitored women had significantly better fracture-free survival for major osteoporotic fracture (p = 0.040; 10-year cumulative risk 1.9% lower, 95% confidence interval [CI] 0.3–3.6%) and hip fracture ( p = 0.001; 10-year cumulative risk 1.8% lower, 95% CI 0.7–2.8%) compared with women who were not monitored. Hazard ratios (HRs) were significantly lower in monitored versus not monitored women for major osteoporotic fracture (HR = 0.89, 95% CI 0.80–0.98) and hip fracture (HR = 0.74, 95% CI 0.63–0.87). Days of medication use, medication persistence ratio, and treatment switching over 5 years were greater in monitored versus not monitored women. At the end of 5 years, more women in the monitored group persisted on treatment and more switched treatment, with switching behavior associated with an observed interval reduction in BMD. In conclusion, our findings suggest a possible role for BMD monitoring after initiating anti-osteoporosis therapy in the routine clinical practice setting. © 2019 American Society for Bone and Mineral Research.     

Potential Adverse Effect of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) on Bisphosphonate Efficacy: An Exploratory Post Hoc Analysis From a Randomized Controlled Trial of Clodronate

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have weak but beneficial effects on bone health, including fracture risk, but many epidemiological studies are likely confounded. We explored the relationship between NSAIDs and fracture risk in a post hoc analysis of a well-documented, randomized, placebo-controlled study of the bisphosphonate, clodronate, in which treatment reduced osteoporotic fracture risk by 23%. Concurrent medication use at baseline was used to identify those prescribed oral NSAIDs. Only verified, incident fractures were included in the analysis. A total of 1082 (20.8%) women reported use of NSAIDs at baseline. They were slightly, but significantly, younger (mean 79 versus 80 years, p = 0.004), heavier (mean 66.7 versus 64.7 kg, p < 0.001) than nonusers, with slightly higher femoral neck bone mineral density (FN-BMD, 0.66 versus 0.64 g/cm², p < 0.001). In an adjusted model, NSAID use was associated with a significant increase in osteoporotic fracture risk over the 3-year study period (hazard ratio [HR] 1.27; 95% confidence interval [CI], 1.01–1.62; p = 0.039). However, this increase in risk was not statistically significant in the placebo group (HR 1.11; 95% CI, 0.81–1.52). In women receiving clodronate, the effect of the bisphosphonate to reduce osteoporotic fracture risk was not observed in those receiving NSAIDs (HR 0.95; 95% CI, 0.65–1.41; p = 0.81) in contrast to those not using NSAIDs (HR 0.71; 95% CI, 0.58–0.89; p = 0.002). In a subset with hip BMD repeated at 3 years, BMD loss during clodronate therapy was greater in those women receiving NSAIDs than in nonusers (eg, total hip −2.75% versus −1.27%, p = 0.078; femoral neck −3.06% versus −1.12%, p = 0.028), and was not significantly different from that observed in women receiving placebo. The efficacy of the bisphosphonate, clodronate, to reduce fracture risk was largely negated in those receiving NSAIDs. Although the mechanism is unclear, this clinically significant observation requires exploration in studies of commonly used bisphosphonates. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Hepatitis C Co‐infection and Severity of Liver Disease as Risk Factors for Osteoporotic Fractures Among HIV‐Infected Patients

Osteoporosis is increasingly reported in the aging HIV‐positive population, and co‐infection with hepatitis C virus (HCV) may further increase the risk of osteoporosis. However, it remains unclear whether HCV‐related increased fracture risk is a function of the severity of liver disease. We calculated the time‐updated alanine aminotransferase to platelet ratio index (APRI) score (an indirect marker of hepatic fibrosis) in all HIV‐infected patients enrolled in the Veterans Affairs' Clinical Case Registry between 1984 and 2009. The association between HCV co‐infection and incident osteoporotic fracture (defined as closed wrist, vertebral, or hip fracture) was assessed in univariate and multivariate Cox survival models adjusting for traditional risk factors for osteoporosis and APRI score or the presence of cirrhosis. A total of 772 osteoporotic fractures were identified among 56,660 HIV‐infected patients (98.1% male; 31.3% HCV co‐infected; median age 44.0 years) contributing 305,237 patient‐years of follow‐up. Fracture rates were significantly higher among HIV/HCV patients than HIV‐only patients (2.57 versus 2.07/1000 patient‐years, relative risk = 1.24, p < 0.0001). In a Cox multivariable model including age, race, smoking, drug use, body mass index, and antiretroviral therapy, HCV co‐infection remained an independent predictor of osteoporotic fractures after controlling for presence of cirrhosis (hazard ratio [HR] = 1.32; p < 0.001) or APRI score (HR = 1.30; p = 0.003). Among HIV/HCV co‐infected patients, cirrhosis strongly predicted osteoporotic fractures (HR = 1.65; 95% confidence interval [CI] 1.11–2.44; p = 0.012), but APRI score was a weaker predictor (HR = 1.008; 95% CI 1.002–1.014; p = 0.015). In conclusion, among HIV‐infected patients, severity of liver disease partly explains the HCV‐associated increased risk of osteoporotic fractures. Other determinants of this increased risk remain to be defined. © 2013 American Society for Bone and Mineral Research.     

Family History of Appendicular Fracture and Risk of Osteoporosis: A Population-Based Study

Family and twin studies demonstrate a strong genetic component to osteoporosis, suggesting that a positive family history for this disease may be an important clinical risk factor. We have therefore explored the extent to which a history of wrist fracture in a female first-degree relative was associated with an increased risk of prevalent fracture at both appendicular and vertebral sites in a cross-sectional study design. One thousand and three Caucasian women (age range 45–64 years) were studied from a UK population cohort. Bone mineral density (BMD) was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Appendicular fractures (wrist and hip) were recorded by questionnaire and validated from radiographs and hospital records. Vertebral fractures were assessed using radiologic survey of the thoracolumbar spine and semi-automated morphometric analysis. A positive family history of osteoporotic fracture (hip and/or wrist) in either a mother and/or sister was reported in 138 of the 1003 women. When compared with those with a negative family history of fracture, BMD was significantly reduced in those with a positive history at both the spine (p = 0.02) and the hip (p = 0.02). In total, there were 63 validated fragility fractures found in the 1003 women (16 wrist, 6 hip and 41 vertebral). Family history of osteoporotic fracture was associated with an increased total risk for osteoporotic fracture, with an odds ratio (95% confidence interval) of 2.02 (1.02, 3.78). Site-specific analysis showed that a positive family history of wrist fracture was associated with a considerably elevated risk of wrist fracture, with an odds ratio of 4.24 (1.44, 12.67). These increases in risk remained after adjustment for BMD, suggesting that other genetic factors account for the familial risk of osteoporosis and fracture. Received: 20 August 1998 / Accepted: 25 January 1999     

WHO absolute fracture risk models (FRAX): Do clinical risk factors improve fracture prediction in older women without osteoporosis?

Bone mineral density (BMD) is a strong predictor of fracture, yet most fractures occur in women without osteoporosis by BMD criteria. To improve fracture risk prediction, the World Health Organization recently developed a country‐specific fracture risk index of clinical risk factors (FRAX) that estimates 10‐year probabilities of hip and major osteoporotic fracture. Within differing baseline BMD categories, we evaluated 6252 women aged 65 or older in the Study of Osteoporotic Fractures using FRAX 10‐year probabilities of hip and major osteoporotic fracture (ie, hip, clinical spine, wrist, and humerus) compared with incidence of fractures over 10 years of follow‐up. Overall ability of FRAX to predict fracture risk based on initial BMD T‐score categories (normal, low bone mass, and osteoporosis) was evaluated with receiver‐operating‐characteristic (ROC) analyses using area under the curve (AUC). Over 10 years of follow‐up, 368 women incurred a hip fracture, and 1011 a major osteoporotic fracture. Women with low bone mass represented the majority (n = 3791, 61%); they developed many hip (n = 176, 48%) and major osteoporotic fractures (n = 569, 56%). Among women with normal and low bone mass, FRAX (including BMD) was an overall better predictor of hip fracture risk (AUC = 0.78 and 0.70, respectively) than major osteoporotic fractures (AUC = 0.64 and 0.62). Simpler models (eg, age + prior fracture) had similar AUCs to FRAX, including among women for whom primary prevention is sought (no prior fracture or osteoporosis by BMD). The FRAX and simpler models predict 10‐year risk of incident hip and major osteoporotic fractures in older US women with normal or low bone mass. © 2011 American Society for Bone and Mineral Research     

Multiple gene polymorphisms can improve prediction of nonvertebral fracture in postmenopausal women

Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. In this study we investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1229 unrelated Korean postmenopausal women, 39 single‐nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis‐related traits, such as BMD, osteoporosis, vertebral fracture (VF), nonvertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (Model I) GRSs only; (Model II) BMD only; (Model III) CRFs only; (Model IV) CRFs and BMD; and (Model V) CRFs, BMD, and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis‐related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (p ranging from <0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (p ranging from 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (p = 0.049). In terms of predicting NVF, the area under the receiver operating characteristic curve (AUC) for Model I was 0.55, which was lower than the AUCs of Models II (0.60), III (0.64), and IV (0.65). Adding GRS to Model IV (in Model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (p = 0.014). In terms of predicting any fracture, the AUC of Model V (0.68) was similar to that of Model IV (0.68), and Model V did not significantly improve the accuracy of any fracture classification (p = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold. © 2013 American Society for Bone and Mineral Research.