Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Predictive performance of the Garvan Fracture Risk Calculator: a registry-based cohort study.

The G arvan Fracture Risk Calculator predicts risk of osteoporotic fractures. We evaluated its predictive performance in 16,682 women and 2839 men from Manitoba, Canada, and found significant risk stratification, with a strong gradient across scores. The tool outperformed clinical risk factors and bone mineral density for fracture risk stratification. INTRODUCTION: The optimal model for fracture risk estimation to guide treatment decision-making remains controversial. Our objective was to evaluate the predictive performance of the Garvan Fracture Risk Calculator (FRC) in a large clinical registry from Manitoba, Canada. METHODS: Using the population-based Manitoba Bone Mineral Density (BMD) registry, we identified women and men aged 50-95 years undergoing baseline BMD assessment from September 1, 2012, onwards. Five-year Garvan FRC predictions were generated from clinical risk factors (CRFs) with and without femoral neck BMD. We identified incident non-traumatic osteoporotic fractures (OFs) and hip fractures (HFs) from population-based healthcare data sources to March 31, 2018. Fracture risk was assessed from area under the receiver operating characteristic curve (AUROC). Cox regression analysis and calibration ratios (5-year observed/predicted) were assessed for risk quintiles. All analyses were sex stratified. RESULTS: We included 16,682 women (mean age 66.6 + / - SD 8.7 years) and 2839 men (mean age 68.7 + / - SD 10.2 years). During a mean observation time of 2.6 years, incident OFs were identified in 681 women and 140 men and HFs in 199 women and 22 men. AUROC showed significant fracture risk stratification with the Garvan FRC. Tool predictions without BMD were better than from age or decreasing weight, and the tool with BMD performed better than BMD alone. Garvan FRC with BMD performed better than without BMD, especially for HF prediction (AUROC 0.86 in women, 0.82 in men). There was a strong gradient of increasing risk across Garvan FRC quintiles (highest versus lowest, hazard ratios women 5.75 and men 3.43 for any OF; women 101.6 for HF). Calibration differences were noted, with both over- and underestimation in risk. CONCLUSIONS: Garvan FRC outperformed CRFs and BMD alone for fracture risk stratification, particularly for HF, but may require recalibration for accurate predictions in this population.

Development and validation of the risk engine for an Australian Health Economics Model of Osteoporosis.

The Australian Health Economics Model of Osteoporosis (AusHEMO) has shown good face, internal and cross validities, and can be used to assist healthcare decision-making in Australia. PURPOSE: This study aimed to document and validate the risk engine of the Australian Health Economics Model of Osteoporosis (AusHEMO). METHODS: AusHEMO is a state-transition microsimulation model. The fracture risks were simulated using fracture incidence rates from the Dubbo Osteoporosis Epidemiology Study. The AusHEMO was validated regarding its face, internal and cross validities. Goodness-of-fit analysis was conducted and Lin's coefficient of agreement and mean absolute difference with 95% limits of agreement were reported. RESULTS: The development of AusHEMO followed general and osteoporosis-specific health economics guidelines. AusHEMO showed good face validity regarding the model's structure, evidence, problem formulation and results. In addition, the model has been proven good internal and cross validities in goodness-of-fit test. Lin's coefficient was 0.99, 1 and 0.94 for validation against the fracture incidence rates, Australian life expectancies and residual lifetime fracture risks, respectively. CONCLUSIONS: In summary, the development of the risk engine of AusHEMO followed the best practice for osteoporosis disease modelling and the model has been shown to have good face, internal and cross validities. The AusHEMO can be confidently used to predict long-term fracture-related outcomes and health economic evaluations when costs data are included. Health policy-makers in Australia can use the AusHEMO to select which osteoporosis interventions such as medications and public health interventions represent good value for money.

Assessing the clinical utility of genetic profiling in fracture risk prediction: a decision curve analysis.

Using decision curve analysis on 2188 women and 1324 men, we found that an osteogenomic profile constructed from 62 genetic variants improved the clinical net benefit of fracture risk prediction over and above that of clinical risk factors and BMD. INTRODUCTION: Genetic profiling is a promising tool for assessing fracture risk. This study sought to use the decision curve analysis (DCA), a novel approach to determine the impact of genetic profiling on fracture risk prediction. METHODS: The study involved 2188 women and 1324 men, aged 60 years and above, who were followed for up to 23 years. Bone mineral density (BMD) and clinical risk factors were obtained at baseline. The incidence of fracture and mortality were recorded. A weighted individual genetic risk score (GRS) was constructed from 62 BMD-associated genetic variants. Four models were considered: CRF (clinical risk factors); CRF + GRS; Garvan model (GFRC) including CRF and femoral neck BMD; and GFRC + GRS. The DCA was used to evaluate the clinical net benefit of predictive models at a range of clinically reasonable risk thresholds. RESULTS: In both women and men, the full model GFRC + GRS achieved the highest net benefits. For 10-year risk threshold > 18% for women and > 15% for men, the GRS provided net benefit above those of the CRF models. At 20% risk threshold, adding the GRS could help to avoid 1 additional treatment per 81 women or 1 per 24 men compared with the Garvan model. At lower risk thresholds, there was no significant difference between the four models. CONCLUSIONS: The addition of genetic profiling into the clinical risk factors can improve the net clinical benefit at higher risk thresholds of fracture. Although the contribution of genetic profiling was modest in the presence of BMD + CRF, it appeared to be able to replace BMD for fracture prediction.

Impact of osteoporotic fracture type and subsequent fracture on mortality: the Tromsø Study.

Less is known about the impact of non-hip non-vertebral fractures (NHNV) on early death. This study demonstrated increased risk of dying following hip and NHNV fractures which was further increased by a subsequent fracture. This highlights the importance of early intervention to prevent both initial and subsequent fractures and improve survival. INTRODUCTION: Osteoporotic fractures are a major health concern. Limited evidence exists on their impact on mortality in ageing populations. This study examined the contribution of initial fracture type and subsequent fracture on mortality in a Norwegian population that has one of the highest rates of fractures. METHODS: The Tromsø Study is a prospective population-based cohort in Norway. Women and men aged 50+ years were followed from 1994 to 2010. All incident hip and non-hip non-vertebral (NHNV) fractures were registered. NHNV fractures were classified as either proximal or distal. Information on self-reported co-morbidities, lifestyle factors, general health and education level was collected. Multivariable Cox models were used to quantify mortality risk with incident and subsequent fractures analysed as time-dependent variables. RESULTS: Of 5214 women and 4620 men, 1549 (30%) and 504 (11%) sustained a fracture, followed by 589 (38%) and 254 (51%) deaths over 10,523 and 2821 person-years, respectively. There were 403 (26%) subsequent fractures in women and 68 (13%) in men. Hip fracture was associated with a two-fold increase in mortality risk (HR 2.05, 95% CI 1.73-2.42 in women and 2.49, 95% CI 2.00-3.11 in men). Proximal NHNV fractures were associated with 49% and 81% increased mortality risk in women and men (HR 1.49, 95% CI 1.21-1.84 and 1.81, 95% CI 1.37-2.41), respectively. Distal NHNV fractures were not associated with mortality. Subsequent fracture was associated with 89% and 77% increased mortality risk in women and men (HR 1.89, 95% CI 1.52-2.35 and 1.77, 95% CI 1.16-2.71), respectively. CONCLUSION: Hip, proximal NHNV and subsequent fractures were significantly associated with increased mortality risk in the elderly, highlighting the importance of early intervention.

Association between vertebral fractures and coronary artery calcification in current and former smokers in the ECLIPSE cohort.

In smokers and former smokers from the ECLIPSE cohort, there is an association between prevalent vertebral fractures (VFs) and coronary artery calcification (CAC). Chest CT scans provide the opportunity to evaluate VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions. INTRODUCTION: Prevalence of VFs among smokers and patients with chronic obstructive pulmonary disease (COPD) is high, and an association between CAC and osteoporosis has been described. We investigated the associations between VFs and CAC (expressed in Agatston score) in (former) smokers. METHODS: Current and former smokers from the ECLIPSE study (designed to determine underlying COPD progression mechanisms) were studied. Baseline Agatston score (zero (0), medium (1-400), or high (> 400)), baseline bone attenuation (BA), and prevalent and incident VFs (vertebrae T1-L1) were assessed on CT. RESULTS: A total of 586 subjects were included (mean age 59.8 ± 8.3; 62.3% men; 70.1% with COPD; 21.0% with prevalent VFs; 196 with zero, 266 with medium, and 124 with high Agatston score). Of these, 23.4% suffered incident VFs within 3 years. In multivariate models, prevalent VFs were associated with medium (1.83 [95% CI 1.01-3.30]) and with high (OR = 3.06 [1.45-6.47]) Agatston score. After adjustment for BA, prevalent VFs were still associated with high (OR = 2.47 [1.13-5.40]), but not significantly with medium Agatston score (OR = 1.57 [0.85-2.88]). Similarly, after adjustment for BA, high (OR = 2.06 [1.02-4.13]) but not medium Agatston score (OR = 1.61 [0.88-2.94]) was associated with prevalent VFs. Agatston score at baseline was not associated with short-term VF incidence. CONCLUSION: In (former) smokers, there was an association between prevalent VFs and Agatston score. Chest CT scans provide the opportunity to also evaluate for VFs and CAC, which are potentially important comorbidities, each of which is amenable to effective interventions.

Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study.

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

Worsening of soft tissue dystrophic calcification in an osteoporotic patient treated with teriparatide.

Teriparatide, used for treatment of osteoporosis in patients at high risk of fracture risk, sometimes results in mild and transient hypercalcemia. There have been two recent reports of worsening dystrophic calcification in patients with autoimmune disorders following teriparatide treatment. We report a patient with severe osteoporosis and without a pre-existing autoimmune disorder, who developed symptomatic worsening of dystrophic calcification 4 months after teriparatide was initiated. Symptoms resolved within 1 week of teriparatide cessation.

More-than-minimal-trauma fractures are associated with low bone density: an 8-year prospective study.

Few studies have examined the relationship between more-than-minimal-trauma fractures and bone density. This study demonstrated that more-than-minimal-trauma fractures are associated with lower bone density similar to that seen in minimal trauma fractures. Men and women over 50 years with a more-than-minimal-trauma fracture should be investigated to exclude low bone density. INTRODUCTION: The aim of this study was to assess the prevalence and predictors of low bone density in men and women with more-than-minimal-trauma fractures. METHODS: In an Australian hospital, 630 community-dwelling men and women, 20 years of age or older, sustained a fracture due to more-than-minimal-trauma (force greater than a fall from standing height but less than high trauma). We studied 349 individuals who agreed to have a bone mineral density (BMD) scan. These participants were compared with 472 men and women with minimal trauma fractures. RESULTS: Men and women with more-than-minimal-trauma fractures had significantly lower bone density than expected for their age, gender and weight (Z-scorespine = -0.4 SD, 95 % confidence interval (CI), -0.5 to -0.3; Z-scorehip = -0.5 SD, 95 % CI, -0.6 to -0.4). Almost 1 in 4 of those over 50 years of age had osteoporosis by BMD criteria. The independent predictors of low bone density (T-score <-2.0 SD) were age equal to or over 50 years (odds ratio (OR) = 5.97, 95 % CI, 3.34 to 10.65), low body weight <20 kg/m2 (OR = 3.44, 95 % CI, 1.32 to 8.94), a prior minimal trauma fracture (OR = 2.76, 95 % CI, 1.17-6.52) and in those over 50 years of age, an osteoporosis-associated condition (OR = 4.51, 95 % CI, 1.69 to 12.06). Men and women with more-than-minimal-trauma fractures had similar bone density (Z-score) compared to those with minimal trauma fractures. CONCLUSIONS: Men and women over 50 years with a more-than-minimal-trauma fracture, especially those with low body weight, prior minimal trauma fracture or an osteoporosis-associated condition, should be investigated to exclude low bone density and its associated risk of subsequent fractures.

Association between fat mass, lean mass, and bone loss: the Dubbo Osteoporosis Epidemiology Study.

UNLABELLED: Lower body fat mass is a risk factor for bone loss at lumbar spine in postmenopausal women, but not in men. Body lean mass and fat mass were not associated with femoral neck bone loss in either gender. INTRODUCTION: Bone density and body mass are closely associated. Whole body lean mass (LM) and fat mass (FM) together account for approximately 95 % of body mass. Bone loss is associated with loss of body mass but which of the components of body mass (FM or LM) is related to bone loss is not well understood. Therefore, in this study, we sought to assess whether baseline FM or LM has predictive value for future relative rate of bone mineral density (BMD) changes (%/year). METHODS: The present population-based cohort study was part of the ongoing Dubbo Osteoporosis Epidemiology Study (DOES). BMD, FM, and LM were measured with dual energy X-ray absorptiometry (GE-LUNAR Corp, Madison, WI). BMD measurements were taken in approximately every 2 years between 2000 and 2010. We only included the participants with at least two BMD measurements at the femoral neck and lumbar spine. In total, 717 individuals (204 men and 513 women) aged 50 years or older were studied. RESULTS: Rate of bone loss at femoral neck and lumbar spine was faster in women than in men (all P < 0.01). In bivariable regression analysis, each 5 kg greater FM in women was associated with 0.4 %/year (P = 0.003) lower bone loss at lumbar spine. This magnitude of association remained virtually unchanged after adjusting for LM and/or other covariates (P = 0.03). After adjusting for covariates, variation of FM accounted for ∼1.5 % total variation in lumbar spine bone loss. However, there was no significant association between FM and change in femoral neck BMD in either men or women. CONCLUSION: Lower FM was an independent but modest risk factor for greater bone loss at the lumbar spine in women but not in men. If further studies confirm our findings, FM can help predict lumbar spine bone loss in women.

Accelerated bone loss and increased post-fracture mortality in elderly women and men.

UNLABELLED: Bone loss, a fracture risk factor, may play a role in post-fracture mortality. We found accelerated bone loss (≥1.31 % bone loss/year for women and ≥1.35 % bone loss/year for men) associated with 44-77 % increased mortality. It remains unclear whether bone loss is a marker or plays a role in mortality. INTRODUCTION: Osteoporotic fractures are associated with increased mortality although the cause is unknown. Bone loss, a risk factor for osteoporotic fracture is also associated with increased mortality, but its role in mortality risk post-fracture is unclear. This study aimed to examine post-fracture mortality risk according to levels of bone loss. METHODS: Community-dwelling participants aged 60+ from Dubbo Osteoporosis Epidemiology Study with incident fractures were followed from 1989 to 2011. Kaplan-Meier survival curves were constructed according to bone loss quartiles. Cox proportional hazard models were used to determine the effect of bone loss on mortality. RESULTS: There were 341 women and 106 men with ≥2 BMD measurements. The rate of bone loss was similar for women and men (women mean -0.79 %/year, highest bone loss quartile -1.31 %/year; men mean -0.74 %/year, highest quartile -1.35 %/year). Survival was lowest for the highest quartile of bone loss for women (p < 0.005) and men (p = 0.05). When analysed by fracture type, the association of bone loss with mortality was observed for vertebral (highest vs lower 3 quartiles of bone loss, women p = 0.03 and men p = 0.02) and non-hip non-vertebral fractures in women (p < 0.0001). Bone loss did not play an additional role in mortality risk following hip fractures. Importantly, overall, rapid bone loss was associated with 44-77 % increased mortality risk after multiple variable adjustment. CONCLUSION: Rapid bone loss was an independent predictor of post-fracture mortality risk in both women and men. The association of bone loss and post-fracture mortality was predominantly observed following vertebral fracture in both women and men and non-hip non-vertebral fracture in women. It remains to be determined whether bone loss is a marker or plays a role in the mortality associated with fractures.

Abdominal obesity increases the risk of hip fracture. A population-based study of 43,000 women and men aged 60-79 years followed for 8 years. Cohort of Norway.

BACKGROUND: The question as to whether abdominal obesity has an adverse effect on hip fracture remains unanswered. The purpose of this study was to investigate the associations of waist circumference, hip circumference, waist-hip ratio, and body mass index with incident hip fracture. METHODS: The data in this prospective study is based on Cohort of Norway, a population-based cohort established during 1994-2003. Altogether 19,918 women and 23,061 men aged 60-79 years were followed for a median of 8.1 years. Height, weight, waist and hip circumference were measured at baseline using standard procedures. Information on covariates was collected by questionnaires. Hip fractures (n = 1,498 in women, n = 889 in men) were identified from electronic discharge registers from all general hospitals in Norway between 1994 and 2008. RESULTS: The risk of hip fracture decreased with increasing body mass index, plateauing in obese men. However, higher waist circumference and higher waist-hip ratio were associated with an increased risk of hip fracture after adjustment for body mass index and other potential confounders. Women in the highest tertile of waist circumference had an 86% (95% CI: 51-129%) higher risk of hip fracture compared to the lowest, with a corresponding increased risk in men of 100% (95% CI 53-161%). Lower body mass index combined with abdominal obesity increased the risk of hip fracture considerably, particularly in men. CONCLUSION: Abdominal obesity was associated with an increased risk of hip fracture when body mass index was taken into account. In view of the increasing prevalence of obesity and the number of older people suffering osteoporotic fractures in Western societies, our findings have important clinical and public health implications.

Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Impact of femoral neck and lumbar spine BMD discordances on FRAX probabilities in women: a meta-analysis of international cohorts.

There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX. We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS-FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS-FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort. The absolute ΔLS-FN was greater than 2 SD for 2.5% of women and between 1 and 2 SD for 21%. ΔLS-FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95% CI = 1.04-1.15). In reclassification analyses, only 2.3-3.2% of the women moved to a higher or lower risk category when using FRAX with ΔLS-FN compared with FN-derived FRAX alone. Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1-2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold.

Bone mineral density and association of osteoarthritis with fracture risk.

OBJECTIVE: High body mass index (BMI) is associated with increased risk of osteoarthritis (OA) and reduced risk of fragility fracture. However, the relationship between fragility fracture and OA remained unclear. This study sought to investigate the effect of bone mineral density (BMD) in the OA-fracture relationship. METHODS: Data from 2412 women and 1452 men aged >45 years in the Dubbo Osteoporosis Epidemiology Study (DOES) were analyzed. Individuals have been followed for up to 22 years (median: 7.5 years; range: 0.1-22 years). Femoral neck BMD (FNBMD) and lumbar spine BMD (LSBMD) was measured by dual energy X-ray absorptiometry (DXA) (GE LUNAR, Madison, WI). The presence of OA was ascertained at baseline by self-reported diagnosis. The incidence of low-trauma fracture was ascertained from X-ray reports. RESULTS: Overall, 29% of women and 26% of men had reported a diagnosis of OA. Fracture risk was significantly higher in women with OA than those without OA (Hazard ratio (HR) = 1.50; 95% confidence interval (CI), 1.28-1.76). However, the association was mainly observed in women with osteopenic BMD (HR = 1.74; 95% CI, 1.38-2.17) and normal-BMD (HR = 1.50; 95% CI, 1.06-2.13) and not in those with osteoporosis. Further analysis revealed that osteopenic women with OA had significant increase in risk of vertebral (HR = 1.85; 95% CI, 1.24-2.75) and limb fracture (HR = 2.49; 95% CI, 1.77-3.48), but not in hip fracture. In men, no comparable relationship was found before and after adjustment for covariates. CONCLUSION: Women with OA have an increased risk of fragility fracture, and the risk was mainly observed in non-osteoporotic group.

Osteochondral regeneration using a novel aragonite-hyaluronate bi-phasic scaffold in a goat model.

PURPOSE: The objective of this study was to examine whether different mechanical modifications and/or impregnation of hyaluronic acid (HA) might enhance aragonite-based scaffold properties for the regeneration of cartilage and bone in an animal model. METHODS: Bi-phasic osteochondral scaffolds were prepared using coralline aragonite with different modifications, including 1- to 2-mm-deep drilled channels in the cartilage phase (Group 1, n = 7) or in the bone phase (Group 2, n = 8), and compared with unmodified coral cylinders (Group 3, n = 8) as well as empty control defects (Group 4, n = 4). In each group, four of the implants were impregnated with HA to the cartilage phase. Osteochondral defects (6 mm diameter, 8 mm depth) were made in medial and lateral femoral condyles of 14 goats, and the scaffolds were implanted according to a randomization chart. After 6 months, cartilage and bone regeneration were evaluated macroscopically and histologically by an external laboratory. RESULTS: Group 1 implants were replaced by newly formed hyaline cartilage and subchondral bone (combined histological evaluation according to the ICRS II-2010 and O'Driscoll et al. 34 ± 4 n = 7). In this group, the cartilaginous repair tissue showed a smooth contour and was well integrated into the adjacent native cartilage, with morphological evidence of hyaline cartilage as confirmed by the marked presence of proteoglycans, a marked grade of collagen type II and the absence of collagen type I. The average scores in other groups were significantly lower (Group 2 (n = 8) 28.8 ± 11, Group 3 (n = 8) 23 ± 9 and Group 4 (empty control, n = 4) 19.7 ± 15). CONCLUSIONS: The implants with the mechanical modification and HA impregnation in the cartilage phase outperformed all other types of implant. Although native coral is an excellent material for bone repair, as a stand-alone material implant, it does not regenerate hyaline cartilage. Mechanical modification with drilled channels and impregnation of HA within the coral pores enhanced the scaffold's cartilage regenerative potential. The modified implant shows young hyaline cartilage regeneration. This implant might be useful for the treatment of both chondral and osteochondral defects in humans.

Association between hypertension and fragility fracture: a longitudinal study.

UNLABELLED: Hypertension is an independent risk factor for osteoporosis and osteoporotic fracture in postmenopausal women. INTRODUCTION: Although hypertension has been suggested to be associated with increased fracture risk, it is not clear whether the association is independent of bone mineral density (BMD). The present study sought to examine the interrelationships between hypertension, BMD, and fracture risk. METHODS: The study included 1,032 men and 1,701 women aged 50 years and older who were participants in the Dubbo Osteoporosis Epidemiology Study. BMD at the femoral neck and lumbar spine was measured by dual energy X-ray absorptiometry (GE-LUNAR Corp., Madison, WI, USA). The presence of hypertension was ascertained by direct interview and verification through clinical history. The incidence of fragility fractures was ascertained by X-ray report during the follow-up period (1989-2008). The Cox proportional hazards model was used to assess the association between hypertension and fracture risk. RESULTS: Women with hypertension had lower BMD at the femoral neck (0.79 versus 0.82 g/cm(2), P = 0.02) than those without the disease. After adjusting for BMD and covariates, hypertension was an independent risk factor for fragility fracture [hazard ratio (HR), 1.49; 95% CI, 1.13-1.96]. In men, hypertension was associated with higher femoral neck BMD (0.94 versus 0.92 g/cm(2), P = 0.02), but the association between hypertension and fracture risk did not reach statistical significance. CONCLUSION: Hypertension is associated with increased fracture risk in women, and the association is independent of BMD.