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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.

Background: Estrogen deficiency increases body weight or total and central adiposity and decreases energy expenditure. Hypothalamic neuropeptide Y (NPY) expression is altered by estrogen deficiency in rodents, but the long-term consequences on energy homeostasis are unknown. Objective: To investigate the role of NPY in the changes in energy expenditure and physical activity, as well as the associated changes in body weight and composition in response to short-term and long-term estrogen deficiency. Design: Sham and ovariectomy (OVX) operations were performed at 8 weeks of age in wild-type (WT) and NPY −/− mice. Energy expenditure, physical activity, body composition and weight, as well as food intake were measured at 10–18 days (short-term) and 46–54 days (long-term) after OVX. Results: OVX influences energy homeostasis differently at early compared with later time-points. At the early but not the late time point, OVX in WT mice reduced oxygen consumption and energy expenditure and tended to reduce resting metabolic rate. Interestingly, these effects of short-term estrogen deficiency were ablated by NPY deletion, with NPY −/− mice exhibiting significant increases in energy expenditure and resting metabolic rate. In addition to these hypermetabolic effects, OVX NPY −/− mice exhibited significantly lower body weight and whole-body fat mass relative to OVX WT controls at the short-term but not the long-term time point. Food intake and physical activity were unaltered by OVX, but NPY −/− mice exhibited significant reductions in these parameters relative to WT. Conclusion: The effects of estrogen deficiency to reduce energy metabolism are transient, and NPY is critical to this effect as well as the early OVX-induced obesity.

Fear of inducing generalised osteoporosis is one reason why corticosteroids are withheld in patients with rheumatoid arthritis (RA). No studies, however, have directly measured bone density in such patients at clinically relevant sites. To assess this risk we measured bone mineral density in the lumbar spine and femoral neck by dual photon absorptiometry in 84 patients with RA, 44 of whom had been treated with low dose prednis(ol)one (mean dose +/- SE 8.0 +/- 0.5 mg/day; mean duration of treatment 89.6 +/- 12.0 months). There were significant reductions in bone mineral density in patients treated with corticosteroids (lumbar 9.6%, p less than 0.001; femoral 12.2%, p less than 0.001) and in those who had not received corticosteroids (lumbar 6.9%, p less than 0.01; femoral 8.9%, p less than 0.001), but the differences between the two groups were not significant. We conclude on the basis of these studies that low dose oral corticosteroids do not increase the risk of generalised osteoporosis in patients with rheumatoid arthritis.

Common vitamin-D-receptor (VDR) gene allelic variants predict bone mineral density. We analysed VDR alleles and rate of change of lumbar-spine bone mineral density over 18 months in 72 elderly subjects. 9 BB homozygotes lost bone mineral density but 26 homozygotes for the alternative genotype (bb) did not (mean change -2.3 [SE 1.0] vs 0.9 [0.7]% per year, p < 0.05), irrespective of calcium intake. Among 37 heterozygotes (Bb), however, change in bone mineral density correlated with calcium intake (r = 0.35, p < 0.03). This association between a genetic marker and rate of bone loss in the elderly suggests that the effect of calcium intake on maintenance of bone mass could relate to VDR gene polymorphisms.

The objective of the study was to determine the effects of modifiable risk factors on bone mineral density in postmenopausal Thai women. Dietary calcium intake (g/day), energy expenditure (kcal/day), and sunlight exposure (h/day) were assessed in 129 rural Thai women aged 63 years (range 50 to 84 years). Bone mineral density (BMD) at the femoral neck, lumbar spine, and distal radius were measured by dual-energy X-ray absorptiometry (DXA). The average dietary calcium intake was 236 +/- 188 g/day (mean +/- SD), while the energy expenditure was 2,118 +/- 656 kcal/day with 1.1 +/- 1.7 h of sunlight exposure. In multiple linear regression analysis, dietary calcium intake, energy expenditure, and years since menopause were significant and independent predictors of BMD at various sites. The three factors together accounted for between 35% and 45% of the variance of BMD. The prevalence of osteoporosis (defined as BMD T-scores < or =-2.5) was 33% at the femoral neck, 42% at the lumbar spine, and 35% at the distal radius. The risk of osteoporosis was higher in women with lower dietary calcium intake (< or =138 mg/day; prevalence rate ratio [PRR], 1.4; 95% confidence interval [CI], 1.0 to 1.9), lower energy expenditure (< or =1,682 kcal; PRR, 1.7; 95% CI, 1.2 to 2.3), and greater years since menopause (> or =6 years; PRR, 2.6; 95% CI, 1.2 to 5.8). The population attributable risk fraction of osteoporosis risk due to the three factors was 70%. These results suggest that in the Thai population, low dietary calcium intake and low physical activity together with advancing years since menopause were independent risk factors for low BMD.

Hip axis length (HAL) has been proposed as an independent predictor of hip fracture risk in Caucasian females. Femoral neck axis length (FNAL) is a similar measure of femoral geometry but does not include acetabular structures. The aim of this study was to examine the association between hip geometry, using FNAL, and hip fractures in elderly males and females in relation to other anthropometric data. The study group comprised 123 females (23 hip fracture patients and 100 age-matched controls) and 137 males (13 hip fracture patients, 65 age-matched controls and 59 current-height-matched controls). All subjects had femoral neck bone mineral density measured by dual-energy X-ray absorptiometry. From these scans, FNAL was measured as the linear distance from the base of the greater trochanter to the apex of the femoral head. FNAL was correlated significantly with current height (r = 0.47 and r = 0.56 for females and males respectively; p < 0.0001) and peak height (r = 0.45 and r = 0.57 for females and males respectively; p < 0.0001) in both sexes. In females, FNAL in the fracture patients (91.5 +/- 5.4 mm, mean +/- SD) was not significantly different from FNAL in controls (89.7 +/- 5.4 mm; p = 0.2). Fracture patients had the same current height as controls and a trend towards a greater peak height (163 +/- 6 cm vs 160 +/- cm; p = 0.09). After adjusting FNAL for current or peak height there was no difference in FNAL between fracture patients and controls. In males, FNAL in the fracture patients (103.9 +/- 3.9 mm) was not significantly different from that of age-matched controls (103.4 +/- 6.3 mm; p = 0.79). Fracture patients had a significantly lower current height (168 +/- 6 cm) than the age-matched controls (174 +/- 6 cm; p = 0.0008) but had the same peak height. When adjusted for peak height there were no significant differences between height of hip fracture patients (102.0 +/- 4.9 cm), age-matched controls (102.1 +/- 5.1 cm) and current-height-matched controls (102.6 +/- 5.3 cm). Fracture patients had a significantly greater height loss (peak height minus current height) than either control group. In logistic regression analyses peak height in females and height loss in males but not FNAL were independent predictors of hip fracture. The greater height, FNAL and presumably HAL in males versus females is not associated with increased hip fracture risk. However, in this study of elderly males and females, peak height (females) and height loss (males) were independent risk factors for hip fracture. Moreover, FNAL appears to have limited utility in the prediction of hip fracture risk and any role of HAL in the prediction of hip fracture does not relate to its major component of femoral neck length.

Abstract Objectives: To determine prospectively the rates of change in bone mineral density in elderly people and to examine the relation between lifestyle and demographic factors and these rates of change. Design: Longitudinal population based study. Setting: Dubbo, New South Wales, Australia. Subjects: Representative sample (n=769) of residents aged >=60 on 1 January 1989. Main outcome measure: Rates of change in bone mineral density measured prospectively (mean scan interval 2.5 years) at the femoral neck and lumbar spine by dual energy x ray absorptiometry. Results: Summary rates of loss in the femoral neck were 0.96% per year (95% confidence interval 0.64% to 1.28%) in women and 0.82% per year (0.52% to 1.12%) in men. Importantly, rates of loss at the femoral neck (both percentage and absolute) increased in both sexes with advancing age. No significant loss was evident in either sex at the lumbar spine, probably because of coexistent osteoarthritis. Lifestyle factors had only modest effects on rates of loss at either site. Conclusions: These data show that bone density of the femoral neck declines at an increasing rate in elderly people, and as this site is predictive of fracture suggest that treatment to minimise bone loss may be important even in very elderly people.

Low dose corticosteroids are effective in suppressing synovitis in rheumatoid arthritis (RA), but there remains concern about their side effects, particularly osteoporosis. To examine the effects of low dose corticosteroids on bone loss in RA bone mineral density (BMD) was measured in the lumbar spine and hip for up to two years in 15 patients treated with these agents (mean dose prednis(ol)one 6.6 mg/day). 15 patients not receiving them, and 15 age matched controls. The initial BMD at both skeletal sites was significantly reduced in both patient groups compared with controls. The mean change in bone density was 0.2, 0.1, and -0.1% a year in the spine and -2.0, -1.9, and -1.0% a year in the hip respectively for the three groups. These rates of bone loss were not significantly different between groups at either site. These findings suggest that low dose corticosteroid treatment in RA is not associated with an increased risk of osteoporosis.

Abstract Objectives: To investigate the possible association between vitamin D receptor genotype and bone mineral density in a large group of postmenopausal twins. Design: Cross sectional twin study. Setting: Twin population based in Britain. Subjects: 95 dizygotic (non-identical) pairs of twins and 87 monozygotic (identical) pairs of twins aged 50-69 years, postmenopausal, and free of diseases affecting bone, recruited from a national register of twins and with a media campaign. Main outcome measures: Bone mineral density measured at the hip, lumbar spine, forearm, and for the whole body by dual energy x ray absorptiometry in relation to differences in the vitamin D receptor genotype. Results: At all sites the values of bone density among dizygotic twins were more similar in those of the same vitamin D receptor genotype than in those of differing genotype, and the values in the former were closer to the correlations seen in monozygotic twins. Women with the genotype that made them at risk of osteoporotic fracture had an adjusted bone mineral density that was significantly lower by SD 0.5 to 0.6 at the hip, lumbar spine, and for the whole body. The results could not be explained by differences in age, weight, years since menopause, or use of hormone replacement therapy. Conclusions: The findings that in postmenopausal women in Britain bone density—particularly at the hip and spine—is genetically linked and specifically associated with the vitamin D receptor genotypes should lead to novel approaches to the prevention and treatment of osteoporosis. Key messages Key messages Vitamin D has an important role in the metabolism of calcium and bone, mediated through its receptor Common variants of the vitamin D receptor gene are responsible for 7-10% of the difference in bone density between women after the menopause This genetic marker is important because of its potential role in identifying individual women at increased risk of fracture before menopause and in selecting optimal treatment