FREM predicts 10-year incident fracture risk independent of FRAX® probability: a registry-based cohort study.

The Danish Fracture Risk Evaluation Model (FREM) was found to predict fracture risk independent of 10-year fracture probability derived with the FRAX® tool including bone mineral density from DXA. INTRODUCTION: FREM was developed from Danish public health registers without DXA information to identify high imminent risk of major osteoporotic fracture (MOF) and hip fracture (HF), while FRAX® estimates 10-year fracture probability from clinical risk factors and femoral neck bone mineral density (BMD) from DXA. The FREM algorithm showed significant 1- and 2-year fracture risk stratification when applied to a clinical population from Manitoba, Canada. We examined whether FREM predicts 10-year fracture risk independent of 10-year FRAX probability computed with BMD. METHODS: Using the Manitoba BMD Program registry, we identified women and men aged ≥ 45 years undergoing baseline BMD assessment. We calculated FREM and FRAX scores, and identified incident fractures over 10 years. Hazard ratios (HRs) for incident fracture were estimated according to FREM quintile, adjusted for FRAX probability. We compared predicted with observed 10-year cumulative fracture probability estimated with competing mortality. RESULTS: The study population comprised 74,446 women, mean age 65.2 years; 7945 men, mean age 67.5 years. There were 7957 and 646 incident MOF and 2554 and 294 incident HF in women and men, respectively. Higher FREM scores were associated with increased risk for MOF (highest vs middle quintile HRs 1.49 women, 2.06 men) and HF (highest vs middle quintile HRs 2.15 women, 2.20 men) even when adjusted for FRAX. Greater mortality with higher FREM scores attenuated its effect on 10-year fracture probability. In the highest FREM quintile, observed slightly exceeded predicted 10-year probability for MOF (ratios 1.05 in women, 1.49 in men) and HF (ratios 1.29 in women, 1.34 in men). CONCLUSIONS: Higher FREM scores identified women and men at increased fracture risk even when adjusted for FRAX probability that included BMD; hence, FREM provides additional predictive information to FRAX. FRAX slightly underestimated 10-year fracture probability in those falling within the highest FREM quintile.

Prediction of imminent fracture risk in Canadian women and men aged 45 years or older: external validation of the Fracture Risk Evaluation Model (FREM).

The Fracture Risk Evaluation Model (FREM) identifies individuals at high imminent risk of major osteoporotic fractures. We validated FREM on 74,828 individuals from Manitoba, Canada, and found significant fracture risk stratification for all FREM scores. FREM performed better than age alone but not as well as FRAX® with BMD. INTRODUCTION: The FREM is a tool developed from Danish public health registers (hospital diagnoses) to identify individuals over age 45 years at high imminent risk of major osteoporotic fractures (MOF) and hip fracture (HF). In this study, our aim was to examine the ability of FREM to identify individuals at high imminent fracture risk in women and men from Manitoba, Canada. METHODS: We used the population-based Manitoba Bone Mineral Density (BMD) Program registry, and identified women and men aged 45 years or older undergoing baseline BMD assessment with 2 years of follow-up data. From linked population-based data sources, we constructed FREM scores using up to 10 years of prior healthcare information. RESULTS: The study population comprised 74,828 subjects, and during the 2 years of observation, 1612 incident MOF and 299 incident HF occurred. We found significant fracture risk stratification for all FREM scores, with AUC estimates of 0.63-0.66 for MOF for both sexes and 0.84 for women and 0.65-0.67 for men for HF. FREM performed better than age alone but not as well as FRAX® with BMD. The inclusion of physician claims data gave slightly better performance than hospitalization data alone. Overall calibration for 1-year MOF prediction was reasonable, but HF prediction was overestimated. CONCLUSION: In conclusion, the FREM algorithm shows significant fracture risk stratification when applied to an independent clinical population from Manitoba, Canada. Overall calibration for MOF prediction was good, but hip fracture risk was systematically overestimated indicating the need for recalibration.

Validation of the Fracture Risk Evaluation Model (FREM) in predicting major osteoporotic fractures and hip fractures using administrative health data.

BACKGROUND: Prevention of osteoporotic fractures remains largely insufficient, and effective means to identify patients at high, short-term fracture risk are needed. The FREM tool is available for automated case finding of men and women aged 45 years or older at high imminent (1-year) risk of osteoporotic fractures, based on administrative health data with a 15-year look-back. The aim of this study was to validate the performance of FREM, and the effect of applying a shorter look-back period. We also evaluated FREM for 5-year fracture risk prediction. METHODS: Using Danish national health registers we generated consecutive general population cohorts for the years 2014 through 2018. Within each year and across the full time period we estimated the individual fracture risk scores and determined the actual occurrence of major osteoporotic fractures (MOF) and hip fractures. Risk scores were calculated with 15- and 5-year look-back periods. The discriminative ability was evaluated by area under the receiver operating curve (AUC), and negative predictive value (NPV) and positive predictive value (PPV) were estimated applying a calculated risk cut-off of 2% for MOF and 0.3% for hip fractures. RESULTS: Applying a 15-year look-back, AUC was around 0.75-0.76 for MOF and 0.84-0.87 for hip fractures in 2014, with minor decreases in the subsequent fracture cohorts (2015 to 2018). Applying a 5-year look-back generated similar results, with only marginally lower AUC. In the 5-year risk prediction setting, AUC-values were 0.70-0.72 for MOF and 0.81-0.84 for hip fractures. Generally, PPVs were low, while NPVs were very high. CONCLUSION: FREM predicts the 1- and 5-year risk of MOF and hip fractures with acceptable vs excellent discriminative power, respectively, when applying both a 15- and a 5-year look-back. Hence, the FREM tool may be applied to improve identification of individuals at high imminent risk of fractures using administrative health data.

Age at hip fracture and life expectancy in Denmark - Secular trends over two decades.

BACKGROUND: Recent improvements in the health of the oldest old coexist with a decline in hip fracture rates, in particular in women. We speculated that increased longevity with decreasing hip fracture rates would result in a delay in hip fracture. We conducted an analysis of time trends in the age at hip fracture, by type and gender, for the past two decades using national data. STUDY POPULATION AND METHODS: We used data from the Danish Hospital Discharge Register (1996-2017) to analyse the age distribution of femoral neck (FN) and pertrochanteric fractures (PT), allowing only the first fracture at each of these two sites to contribute to the analysis in each calendar year. Demographics for the background population at risk including life expectancy tabulations, were also obtained. RESULTS: The average age at FN fracture in women increased slowly but significantly by 0.035years - or 12.8 days - per calendar year [0.035, 95% CI (0.016; 0.054), p<0.001], resulting in an increase from 79.6 to 80.4 years. There were no significant changes in the age at FN fracture in men or the age at PT fracture in women and men. Further, increases in life expectancy were considerably faster than any change observed in the age at hip fracture. In 1996, the average age at FN or PT fracture exceeded the average life expectancy in both men and women whereas the opposite was the case from 2009 and onwards in men and 2015 and onwards in women. CONCLUSION: This study demonstrates a significant change in the demographics of hip fractures in Denmark over the past two decades. We observed a significant increase in the age at FN fracture in women but not in men, with no significant increase in the age at IT fracture and PT fracture. This developed much more slowly, however, than the increase in life expectancy in both sexes observed over the same period of time. Taken together, these changes resulted in a large decrease in the female to male incidence rate ratio from 2.6 and 2.5 (FN and PT, respectively) to 1.9 and 1.7.Additional effort is required to prevent hip fractures to ensure that the increasing life expectancy is matched by a similar increase in hip-fracture free life expectancy.

Hip fracture rates and time trends in use of anti-osteoporosis medications in Denmark for the period 2005 to 2015: Missed opportunities in fracture prevention.

BACKGROUND: Declining use of bisphosphonates (BP) in the United States and Europe may lead to a widening of the treatment gap for osteoporosis and an increase in fracture rates. However, a shift to non-bisphosphonates and to hospital administered i.v. BPs could lead to overestimation of the treatment gap if analyses are based exclusively on BP prescriptions. When a healthcare system successfully narrows the treatment gap by making appropriate use of anti-osteoporosis drugs, we would expect to see declining rates of osteoporotic fractures with much of the decrease being statistically attributable to medication uptake. We analysed a best-case scenario where all use of BPs, denosumab, raloxifene and PTH analogues - including the oncology area - was contrasted with the trend in hip fracture rates. This scenario also considered users of raloxifene and teriparatide as covered by osteoporosis drugs though the primary RCT for raloxifene showed no risk reduction in nonvertebral fractures and the RCT for teriparatide risk reductions for non-vertebral fractures but not hip fracture specifically. Sensitivity analyses were also done. METHODS: We used aggregate statistics on hip fracture events and total use of the above medications estimating the number of persons potentially covered. The reduction in hip fracture rates attributable to treatment was estimated using the absolute risk reduction (ARR) found in real-world users of oral alendronate in Denmark with the ARR in the FIT primary prevention arm as an alternative scenario. RESULTS: A plateau in use of osteoporosis medications occurred in 2014. Between 2005 and 2015, hip fracture rates declined by 30%. However, only up to 20% of the observed reduction in hip fracture rates was statistically attributable to treatment even in a best-case scenario. Sensitivity analyses where raloxifene and teriparatide were excluded did not impact on this finding. DISCUSSION: Anti-osteoporosis treatment in Denmark reached a plateau in 2014 even in a best-case scenario where all dispensations were assumed to be for osteoporosis. Future studies may be able to distinguish between the oncology area and the osteoporosis indication as well as provide a delineation of age and gender demographics among users of hospital administered osteoporosis medications. About 80% of the decline in hip fracture rates appears to be due to factors other than osteoporosis medication. The plateau in use of osteoporosis treatment at a level that is too low to make a meaningful impact on societal fracture burden is problematic given the predicted increased age-specific hip fracture rates.