Body mass index and subsequent fracture risk: a meta-analysis to update FRAX®

The aim of this international meta-analysis was to quantify the predictive value of body mass index (BMI) for incident fracture and relationship of this risk with age, sex, follow-up time and bone mineral density (BMD). 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had femoral neck BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight:<18.5 kg/m2; Normal:18.5-24.9 kg/m2; Overweight:25.0-29.9 kg/m2; Obese I:30.0-34.9 kg/m2; Obese II:≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95%CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). HF risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26). Further adjustment for femoral neck BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, whilst overweight/obesity appeared protective base models, they became risk factors after additional adjustment for femoral neck BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX.