An overview of the use of the fracture risk assessment tool (FRAX) in osteoporosis.

FRAX®, a simple-to-use fracture risk calculator, was first released in 2008 and since then has been used increasingly worldwide. By calculating the 10-year probabilities of a major osteoporotic fracture and hip fracture, it assists clinicians when deciding whether further investigation, for example a bone mineral density measurement (BMD), and/or treatment is needed to prevent future fractures. In this review, we explore the literature around osteoporosis and how FRAX has changed its management. We present the characteristics of this tool and describe the use of thresholds (diagnostic and therapeutic). We also present arguments as to why screening with FRAX should be considered. FRAX has several limitations which are described in this review. This review coincides with the release of a version, FRAXplus, which addresses some of these limitations.

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.

FRAX-based intervention thresholds for Pakistan.

We compared, for women in Pakistan, the utility of intervention thresholds either at a T-score ≤ - 2.5 or based on a FRAX probability equivalent to women of average body mass index (BMI) with a prior fragility fracture. Whereas the FRAX-based intervention threshold identified women at high fracture probability, the T-score threshold was less sensitive, and the associated fracture risk decreased markedly with age. PURPOSE: The fracture risk assessment algorithm FRAX® has been recently calibrated for Pakistan, but guidance is needed on how to apply fracture probabilities to clinical practice. METHODS: The age-specific 10-year probabilities of a major osteoporotic fracture were calculated in women with average BMI to determine fracture probabilities at two potential intervention thresholds. The first comprised the age-specific fracture probabilities associated with a femoral neck T-score of - 2.5. The second approach determined age-specific fracture probabilities that were equivalent to a woman with a prior fragility fracture, without bone mineral density (BMD). The parsimonious use of BMD was additionally explored by the computation of upper and lower assessment thresholds for BMD testing. RESULTS: When a BMD T-score ≤ - 2.5 was used as an intervention threshold, FRAX probabilities in women aged 50 years were approximately two-fold higher than in women of the same age but with no risk factors and average BMD. The relative increase in risk associated with the BMD threshold decreased progressively with age such that, at the age of 80 years or more, a T-score of - 2.5 was actually protective. The 10-year probability of a major osteoporotic fracture by age, equivalent to women with a previous fracture, rose with age from 2.1% at the age of 40 years to 17%, at the age of 90 years, and identified women at increased risk at all ages. CONCLUSION: Intervention thresholds based on BMD alone do not effectively target women at high fracture risk, particularly in the elderly. In contrast, intervention thresholds based on fracture probabilities equivalent to a 'fracture threshold' target women at high fracture risk.

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)).

Osteoporosis and fractures in women: the burden of disease.

Osteoporosis is a disease characterized by impaired bone microarchitecture and reduced bone mineral density (BMD) resulting in bone fragility and increased risk of fracture. In western societies, one in three women and one in five men will sustain an osteoporotic fracture in their remaining lifetime from the age of 50 years. Fragility fractures, especially of the spine and hip, commonly give rise to increased morbidity and mortality. In the five largest European countries and Sweden, fragility fractures were the cause of 2.6 million disability-adjusted life years in 2016 and the fracture-related costs increased from €29.6 billion in 2010 to €37.5 billion in 2017. In the European Union and the USA, only a small proportion of women eligible for pharmacological treatment are being prescribed osteoporosis medication. Secondary fracture prevention, using Fracture Liaison Services, can be used to increase the rates of fracture risk assessment, BMD testing and use of osteoporosis medication in order to reduce fracture numbers. Additionally, established primary prevention strategies, based on case-finding methods utilizing fracture prediction tools, such as FRAX, to identify women without fracture but with elevated risk, are recommended in order to further reduce fracture numbers.

Fracture risk assessment by the FRAX model.

The introduction of the FRAX algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. FRAX integrates the influence of several well-validated risk factors for fracture with or without the use of bone mineral density. Since age-specific rates of fracture and death differ across the world, FRAX models are calibrated with regard to the epidemiology of hip fracture (preferably from national sources) and mortality (usually United Nations sources). Models are currently available for 73 nations or territories covering more than 80% of the world population. FRAX has been incorporated into more than 80 guidelines worldwide, although the nature of this application has been heterogeneous. The limitations of FRAX have been extensively reviewed. Arithmetic procedures have been proposed in order to address some of these limitations, which can be applied to conventional FRAX estimates to accommodate knowledge of dose exposure to glucocorticoids, concurrent data on lumbar spine bone mineral density, information on trabecular bone score, hip axis length, falls history, type 2 diabetes, immigration status and recency of prior fracture.

Romosozumab efficacy on fracture outcomes is greater in patients at high baseline fracture risk: a post hoc analysis of the first year of the frame study.

This study aimed to determine the interaction between baseline FRAX® fracture probability and romosozumab efficacy. Using an ITT approach, it was determined that the efficacy of romosozumab on clinical fracture, osteoporotic fracture, and major osteoporotic fracture is significantly greater in patients at high baseline fracture risk, when compared with placebo. INTRODUCTION: Post hoc analyses of placebo-controlled osteoporosis treatment studies have shown significantly greater reductions of fracture incidence for higher fracture risk patients. This study determined the interaction between baseline FRAX® fracture probability and romosozumab efficacy in the placebo-controlled first year of the phase 3 FRAME study (NCT01575834). METHODS: Using an ITT approach, an extension of Poisson regression analysis studied the relationship between treatment, FRAX® 10-year probability of major osteoporotic fracture (MOF, calculated without BMD) and risk of first incident fracture (adjusting for age and follow-up time). Treatment interactions considered outcomes of all clinical fractures, osteoporotic fractures, MOF, clinical vertebral fractures, and morphometric vertebral fractures. Two-sided p value of < 0.1 for the interaction between treatment and FRAX® was considered significant. RESULTS: Compared with placebo, romosozumab reduced the incidence of all fracture outcomes in the first year (range: 32% reduction in MOF [p = 0.07] to 80% reduction in clinical vertebral fractures [p = 0.038]). Significant interactions were observed between efficacy and baseline FRAX® probability for composite outcomes of clinical fractures, osteoporotic fractures, and MOF (p = 0.064-0.084), but not vertebral fractures (p > 0.3). For example, romosozumab decreased all clinical fractures by 22% at the 25th centile of FRAX® probability but the reduction was 41% at the 75th centile. Exclusion of vertebral fractures from each composite fracture outcome (i.e. only nonvertebral fractures included) showed even stronger interactions with baseline FRAX® probability (p = 0.036-0.046). CONCLUSIONS: Efficacy of romosozumab on clinical fracture, osteoporotic fracture, and MOF is significantly greater in patients at high baseline fracture risk compared with placebo.

Fracture risk assessment in celiac disease: a registry-based cohort study.

Celiac disease is associated with an increased fracture risk but is not a direct input to the FRAX® calculation. When celiac disease is considered as a secondary osteoporosis risk factor or BMD is included in the FRAX assessment, FRAX accurately predicts fracture risk. INTRODUCTION: The fracture risk assessment tool (FRAX®) uses clinical factors and bone mineral density (BMD) measurement to predict 10-year major osteoporotic (MOF) fracture probability. The study aim was to determine whether celiac disease affects MOF risk independent of FRAX score. METHODS: The Manitoba BMD Registry includes clinical data, BMD measurements, 10-year probability of MOF calculated for each individual using the Canadian FRAX tool and diagnosed celiac disease. Using linkage to population-based healthcare databases, we identified incident MOF diagnoses over the next 10 years for celiac disease and general population cohorts. RESULTS: Celiac disease (N = 693) was associated with increased fracture risk adjusted for FRAX score computed without secondary osteoporosis or BMD (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.11-1.86). Celiac disease was no longer a significant risk factor for fracture when secondary osteoporosis or BMD were included in the FRAX calculation (p > 0.1). In subjects with celiac disease, each SD increase in FRAX score (calculated with and without secondary osteoporosis or BMD) was associated with higher risk of incident MOF (adjusted HR 1.66 to 1.80), similar to the general population (p-interaction > 0.2). Including celiac disease as secondary osteoporosis or including BMD in FRAX 10-year MOF probability calculations (10.1% and 8.6% respectively) approximated the observed cumulative 10-year MOF probability (10.8%, 95% CI 7.8-13.9%). CONCLUSIONS: Celiac disease is associated with an increased risk of major osteoporotic fractures. When celiac disease is considered as a secondary osteoporosis risk factor or BMD is included in FRAX assessment, FRAX accurately predicts fracture risk.

An assessment of intervention thresholds for very high fracture risk applied to the NOGG guidelines : A report for the National Osteoporosis Guideline Group (NOGG).

The National Osteoporosis Guideline Group (NOGG) has developed intervention thresholds based on FRAX® to characterise patients at high and very high risk of fracture. INTRODUCTION: Guidelines for the assessment of fracture risk have begun to categorise patients eligible for treatment into high and very high risk of fracture to inform choice of therapeutic approach. The aim of the present study was to develop intervention thresholds based on the hybrid assessment model of NOGG. METHODS: We examined the impact of intervention thresholds in a simulated cross-sectional cohort of women age 50 years or more from the UK with the distribution of baseline characteristics based on that in the FRAX cohorts. The prevalence of very high risk using the hybrid model was compared with age-dependent thresholds used by the International Osteoporosis Foundation and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (IOF/ESCEO). The appropriateness of thresholds was tested based on the populations treated with anabolic agents. RESULTS: With an upper intervention threshold using the IOF/ESCEO criteria, 56% of women age 50 years or more would be characterised at very high risk. This compares with 36% using the IOF/ESCEO criteria and an age-specific intervention threshold over all ages. With an upper intervention threshold of 1.6 times the pre-existing intervention threshold, 10% of women age 50 years or more would be characterised at very high risk. The data from phase 3 studies indicate that most trial participants exposed to romosozumab or teriparatide would fall into the very high-risk category. CONCLUSIONS: Proposals for FRAX-based criteria for very high risk for the NOGG hybrid model categorise a small proportion of women age 50 years or more (10%) in this highest risk stratum. The level of risk identified was comparable to that of women enrolled in trials of anabolic agents.

Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women.

This paper explores use of metrics that combine fracture outcomes that add power to phase 3 studies and provide a surrogate outcome for regulatory agencies. INTRODUCTION: The aim of this study was to develop an analytic framework that would combine information from all fracture outcomes (including radiographic vertebral fractures) in phase 3 studies to provide a metric for the assessment of treatment efficacy. METHODS: Data from the phase 3 study of denosumab were used as an exemplar comparing the effects of active intervention with placebo on the risk of all fractures associated with osteoporosis. Fracture outcomes were assigned utility weights drawn from the published literature and applied to age-specific health state values of the general population. For each fracture outcome in each arm of the study, cumulative disutility was computed to serve as the principal end point. The hypothesis tested was that treatment with denosumab results in a significant reduction in mean fracture-related disutility. RESULTS: Treatment with denosumab was associated with significantly lower utility loss compared with placebo. For patients treated with denosumab, mean utility loss was 42% less than with placebo (4.5 vs. 7.5 QALYs/1000 patient years, respectively, p < 0.001). CONCLUSIONS: Denosumab significantly decreased utility loss. The use of metrics that combine fracture outcomes may provide added power to phase 3 studies and provide a surrogate outcome for regulatory agencies.

Global impact of COVID-19 on non-communicable disease management: descriptive analysis of access to FRAX fracture risk online tool for prevention of osteoporotic fractures.

The COVID-19 pandemic, and its management, is markedly impacting the management of osteoporosis as judged by access to online FRAX fracture risk assessments. Globally, access was 58% lower in April than in February 2020. Strategies to improve osteoporosis care, with greater use of fracture risk assessments, offer a partial solution. INTRODUCTION: The COVID-19 pandemic is having a significant detrimental impact on the management of chronic diseases including osteoporosis. We have quantified the global impact by examining changes in the usage of online FRAX fracture risk assessments before and after the declaration of the pandemic (11 March 2020). METHODS: The study comprised a retrospective analysis using GoogleAnalytics data on daily sessions on the FRAX® website ( www.sheffield.ac.uk/FRAX ) from November 2019 to April 2020 (main analysis period February-April 2020), and the geographical source of that activity. RESULTS: Over February-April 2020, the FRAX website recorded 460,495 sessions from 184 countries, with 210,656 sessions in February alone. In March and April, the number of sessions fell by 23.1% and 58.3% respectively, a pattern not observed over the same period in 2019. There were smaller reductions in Asia than elsewhere, partly related to earlier and less-marked nadirs in some countries (China, Taiwan, Hong Kong, South Korea and Vietnam). In Europe, the majority of countries (24/31, 77.4%) reduced usage by at least 50% in April. Seven countries showed smaller reductions (range - 2.85 to - 44.1%) including Poland, Slovakia, Czech Republic, Germany, Norway, Sweden and Finland. There was no significant relationship between the reduction in FRAX usage and measures of disease burden such as COVID-attributed deaths per million of the population. CONCLUSION: This study documents a marked global impact of the COVID-19 pandemic on the management of osteoporosis as reflected by FRAX online fracture risk assessments. The analysis suggests that impact may relate to the societal and healthcare measures taken to ameliorate the pandemic.

Fracture prediction from FRAX for Canadian ethnic groups: a registry-based cohort study.

We identified large between-ethnicity calibration differences in the Canadian FRAX® tool which substantially overestimated the major osteoporotic fracture (MOF) risk in Asian women and Black women, and overestimated hip fracture risk in Asian women. PURPOSE: FRAX® is calibrated using population-specific fracture and mortality data. The need for FRAX to accommodate ethnic diversity within a country is uncertain. We addressed this question using the population-based Manitoba Bone Mineral Density (BMD) Program registry and self-reported ethnicity. METHODS: The study population was women aged 40 years or older with baseline FRAX assessments (Canadian and other ethnic calculators), fracture outcomes, and self-reported ethnicity (White N = 68,907 [referent], Asian N = 1910, Black N = 356). Adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to MOF and hip fracture were estimated. We examined candidate variables from DXA that might contribute to ethnic differences including skeletal size, hip axis length (HAL), trabecular bone score (TBS), and estimated body composition. RESULTS: Adjusted for baseline risk using the Canadian FRAX tool with BMD, Asian women compared with White women were at much lower risk for MOF (HR 0.46, 95% CI 0.35-0.59) and hip fracture (0.16, 95% CI 0.08-0.34). Black women were also at lower MOF risk (HR 0.58, 95% CI 0.32-1.00); there were no hip fractures. The US ethnic-specific FRAX calculators accounted for most of the between-ethnicity differences in MOF risk (86% for Asian, 92% for Black) but only partially accounted for lower hip fracture risk in Asian women (40%). The candidate variables explained only a minority of the effect of ethnicity. Gradient of risk in analyses was similar (p-interactions ethnicity*FRAX non-significant). CONCLUSIONS: We identified significant ethnic differences in performance of the Canadian FRAX tool with fracture probability overestimated among Asian and Black women. The US ethnic calculators helped to address this discrepancy for MOF risk assessment, but not for hip fracture risk among Asian women.

The effect on subsequent fracture risk of age, sex, and prior fracture site by recency of prior fracture.

The risk of a recurrent fragility fracture varies by age and sex, as by site and recency of sentinel fracture. INTRODUCTION: The recency of prior fractures affects subsequent fracture risk. Variable recency may obscure other factors that affect subsequent fracture risk. The aim of this study was to quantify the effect of a sentinel fracture by site, age, and sex where the recency was held constant. METHODS: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture incidence was compared to that of the general population determined at fixed times after a sentinel fracture (humeral, clinical vertebral, forearm, hip, and minor fractures). Outcome fractures comprised a major osteoporotic fracture and hip fracture. RESULTS: Sentinel osteoporotic fractures were identified in 9504 men and women. Of these, 3616 individuals sustained a major osteoporotic fracture as the first subsequent fracture, of whom 1799 sustained a hip fracture. Hazard ratios for prior fracture were consistently higher in men than in women and decreased progressively with age. Hazard ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus, forearm, or minor osteoporotic fracture. CONCLUSION: The risk of a recurrent fragility fracture varies by age, sex, and site of sentinel fracture when recency is held constant.

The use of 2-, 5-, and 10-year probabilities to characterize fracture risk after a recent sentinel fracture.

The increase in fracture risk associated with a recent fragility fracture is more appropriately captured using a 10-year fracture probability than 2- or 5-year probabilities. INTRODUCTION: The recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 2-, 5-, and 10-year probability of fracture. METHODS: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) occurring within the previous 2 years and probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios were used to adjust fracture probabilities over a 2-, 5-, and 10-year time horizon. RESULTS: As expected, probabilities decreased with decreasing time horizon. Probability ratios varied according to age and the site of sentinel fracture. Probability ratios to adjust for a prior fracture within the previous 2 years were higher the shorter the time horizon, but the absolute increases in fracture probabilities were much reduced. Thus, fracture probabilities were substantially lower with time horizons less than 10 years. CONCLUSION: The 10-year probability of fractures is the appropriate metric to capture the impact of the recency of sentinel fractures. The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures, adjustments which can readily inform clinical decision-making.

Fracture risk following high-trauma versus low-trauma fracture: a registry-based cohort study.

Prior high-trauma fractures identified through health services data are associated with low bone mineral density (BMD) and future fracture risk to the same extent as fractures without high-trauma. INTRODUCTION: Some have questioned the usefulness of distinguishing high-trauma fractures from low-trauma fractures. The aim of this study is to compare BMD measurements and risk of subsequent low-trauma fracture in patients with prior high- or low-trauma fractures. METHODS: Using a clinical BMD registry for the province of Manitoba, Canada, we identified women and men age 40 years or older with fracture records from linked population-based healthcare data. Age- and sex-adjusted BMD Z-scores and covariate-adjusted hazard ratios (HR) with 95% confidence intervals (CI) for incident fracture were studied in relation to prior fracture status, categorized as high-trauma if associated with external injury codes and low-trauma otherwise. RESULTS: The study population consisted of 64,428 women and men with no prior fracture (mean age 63.7 years), 858 with prior high-trauma fractures (mean age 65.1 years), and 14,758 with prior low-trauma fractures (mean age 67.2 years). Mean Z-scores for those with any prior high-trauma fracture were significantly lower than in those without prior fracture (P < 0.001) and similar to those with prior low-trauma fracture. Median observation time for incident fractures was 8.8 years (total 729,069 person-years). Any prior high-trauma fracture was significantly associated with increased risk for incident major osteoporotic fracture (MOF) (adjusted HR 1.31, 95% CI 1.08-1.59) as was prior low-trauma fracture (adjusted HR 1.55, 95% CI 1.47-1.63), and there was no significant difference between the two groups (prior trauma versus low-trauma fracture P = 0.093). A similar pattern was seen when incident MOF was studied in relation to prior hip fracture or prior MOF, or when the outcome was incident hip fracture or any incident fracture. CONCLUSIONS: High-trauma and low-trauma fractures showed similar relationships with low BMD and future fracture risk. This supports the inclusion of high-trauma fractures in clinical assessment for underlying osteoporosis and in the evaluation for intervention to reduce future fracture risk.

Adjusting conventional FRAX estimates of fracture probability according to the recency of sentinel fractures.

The risk of a recurrent fragility fracture is particularly high immediately following the fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the site of a recent fracture. INTRODUCTION: The recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 10-year probability of fracture determined with FRAX. METHODS: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) from the hazards of death and fracture. Fracture probabilities were computed on the one hand for sentinel fractures occurring within the previous 2 years and on the other hand, probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures. RESULTS: Probability ratios to adjust 10-year FRAX probabilities of a major osteoporotic fracture for recent sentinel fractures were age dependent, decreasing with age in both men and women. Probability ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus or forearm fracture. Probability ratios to adjust 10-year FRAX probabilities of a hip fracture for recent sentinel fractures were also age dependent, decreasing with age in both men and women with the exception of forearm fractures. CONCLUSION: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures.

Measured height loss predicts incident clinical fractures independently from FRAX: a registry-based cohort study.

During median follow-up 6.0 years in 11,495 individuals, prior absolute and annualized measured height loss was significantly greater in those with subsequent incident fracture compared with those without incident fracture. PURPOSE: FRAX® accepts baseline height and weight as input variables, but does not consider change in these parameters over time. AIM: To evaluate the association between measured height or weight loss on subsequent fracture risk adjusted for FRAX scores, risk factors, and competing mortality. METHODS: Using a dual-energy x-ray absorptiometry (DXA) registry for the Province of Manitoba, Canada, we identified women and men age 40 years or older with height and weight measured at the time of two DXA scans. Cox regression analyses were performed to test for a covariate-adjusted association between prior height and weight loss with incident fractures occurring after the second scan using linked population-based healthcare data. RESULTS: The study population consisted of 11,495 individuals (average age 68.0 ± 9.9 years, 94.6% women). During median follow-up 6.0 years, records demonstrated incident major osteoporotic fracture (MOF) in 869 individuals, hip fractures in 265, clinical vertebral fractures in 207, and any fracture in 1203. Prior height loss was significantly greater in individuals with fracture compared with those without fracture, regardless of fracture site. Mortality was greater in those with prior height loss (HR per SD 1.11, 95% CI 1.06-1.17) or weight loss (HR per SD 1.26, 95% CI 1.19-1.32). Each SD in height loss was associated with increased fracture risk (MOF 12-17%, hip 8-19%, clinical vertebral 28-37%, any fracture 14-19%). Prior weight loss was associated with 21-30% increased risk for hip fracture, but did not increase risk for other fractures. Height loss of 3.0 cm or greater more than doubled the risk for subsequent fracture. CONCLUSIONS: Prior height loss is associated with a small but significant increase in risk of incident fracture at all skeletal sites independent of other clinical risk factors and competing mortality as considered by FRAX. Prior weight loss only increases risk for subsequent hip fracture.

Fracture prediction from self-reported falls in routine clinical practice: a registry-based cohort study.

A simple question construct regarding number of falls in the previous year, ascertained by a single question, was strongly associated with incident fractures in routine clinical practice using a population-based dual-energy X-ray absorptiometry (DXA) registry. INTRODUCTION: There is conflicting evidence from research cohorts that falls independently increase fracture risk. We examined the independent effects of falls on subsequent fractures in a large clinical registry of bone mineral density (BMD) results for the Province of Manitoba, Canada that has been systematically collecting self-reported falls information since September 1, 2012. METHODS: The study population consisted of 24,943 women and men aged 40 years and older (mean age 65.5 ± 10.2 years) with fracture probability assessment (FRAX), self-reported falls for the previous year (categorized as none, 1, 2, or > 3) and fracture outcomes. Adjusted hazard ratios (HR) with 95 confidence intervals (CI) for time to fracture were estimated using Cox proportional hazards models. RESULTS: During mean observation time of 2.7 ± 1.0 years, 863 (3.5%) sustained one or more major osteoporotic fractures (MOF), 212 (0.8%) sustained a hip fracture, and 1210 (4.9%) sustained any incident fracture. Compared with no falls in the previous year (referent), there was a gradient of increasing risk for fracture with increasing number of falls (all P < 0.001). Results showed minimal attenuation with covariate adjustment. When adjusted for baseline fracture probability (FRAX score with BMD) the HR for MOF increased from 1.49 (95% CI 1.25-1.78) for one fall to 1.74 (1.33-2.27) for two falls to 2.62 (2.06-3.34) for ≥ 3 falls. HRs were similar for any incident fracture and slightly greater for prediction of hip fracture, reaching 3.41 (95% CI 2.19-5.31) for ≥ 3 previous falls. CONCLUSIONS: Self-report number of falls in the previous year is strongly associated with incident fracture risk in the routine clinical practice setting, and this risk is independent of age, sex, BMD, and baseline fracture probability. Moreover, there is dose-response with multiple falls (up to a maximum of 3) conferring greater risk than a single fall.

Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis.

Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment. INTRODUCTION: Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD). METHODS: We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value. RESULTS: Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046). CONCLUSION: The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

Risk-equivalent T-score adjustment for using lumbar spine trabecular bone score (TBS): the Manitoba BMD registry.

Lumbar spine trabecular bone score (TBS) can be used to modify the output from the fracture risk assessment tool, FRAX, to enhance fracture prediction. An alternative approach for using TBS in clinical practice, based upon an adjustment to the bone mineral density (BMD) T-score, may be helpful in regions where intervention guidelines and/or reimbursement are primarily based on BMD T-score. INTRODUCTION: The aim of this study is to develop an approach for using TBS in clinical practice based upon a "risk-equivalent" adjustment to the BMD T-score. METHODS: We identified 45,185 women age 40 years and older with baseline spine and hip DXA, TBS, and FRAX probabilities including femoral neck BMD. Incident major osteoporotic fractures (MOF, n = 3925) were identified from population-based health services data (mean follow-up 7.4 years comprising 335,910 person-years). Cox proportional hazards models adjusted for age and BMI were first used to estimate the risk for MOF from BMD T-score alone, then after including TBS and a multiplicative age interaction term. From the parameter estimates, we developed a TBS offset to the BMD T-score based upon change in TBS that would give the same risk as a unit change in BMD T-score for the femoral neck, total hip, and lumbar spine. RESULTS: All BMD measurements, TBS, and the age interaction term independently predicted MOF (p < 0.001). Measures of risk stratification and model fit were improved for the TBS-adjusted BMD T-score versus the unadjusted BMD T-score (p < 0.001). There was a high level of agreement between MOF probability estimated from TBS-adjusted MOF FRAX probability and FRAX probability using the "risk-equivalent" femoral BMD T-score: MOF probability r2 = 0.98, slope = 1.02, intercept = - 0.3; hip probability r2 = 0.95, slope = 1.07, intercept = 0.0. CONCLUSIONS: The BMD-independent effect of lumbar spine TBS on fracture risk can be estimated as a simple offset to the BMD T-score.