Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

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Strength of bones depends on bone matrix volume (BMV), bone microarchitecture, but also bone mineralization, and we have recently shown in osteoporotic patients treated with alendronate that fracture risk and bone mineral density (BMD) were changed without modifications of BMV or bone microarchitecture. Mineralization of bone matrix implies two successive steps: a rapid primary mineralization on the calcification front followed by a slow process of secondary mineralization progressively adding about one-half of the mineral content on bone matrix. These two steps are clearly illustrated by microradiographs of compact and cancellous bone tissue from transiliac human biopsies. Our working hypothesis is based on the impact of changes in bone remodeling rate on the degree of mineralization of bone, i.e., on the BMD measured at the tissue level. Contact quantitative microradiography using a computerized microdensitometric method, is described and allows the measurement of the mean degree of mineralization of bone (MDMB). This parameter may be quantitatively evaluated by exposing an aluminum calibration step-wedge and a plane-parallel calcified tissue section simultaneously to the same beam of X-rays, then determining, from the resulting microradiograph, the thickness of aluminum that produces the same X-ray absorption as a given region of the bone tissue section. To be used as a control group, iliac bone samples were taken at necropsy from 43 subjects (30 women aged 48.4 +/- 3.7 years and 13 men aged 66.0 +/- 4.4 years) who died suddenly showing no apparent bone disease. A control MDMB, which does not change with age, and a control distribution of these values are thus established. These control values are necessary for interpreting the changes in MDMB observed in bone conditions untreated or treated.