The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.

Calcitriol and calcium, used prophylactically with or without calcitonin, prevent corticosteroid-induced bone loss in the lumbar spine.

Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their anti-resorptive effects on the skeleton. However, since bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their anti-tumour action, particularly on cells outside of bone, remain unknown. Here we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumours, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumour-associated macrophages (TAMs), but not tumour cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumour of a patient and showed the resected tumour to be infiltrated with TAMs and to contain similar granular microcalcifications. These data represent the first compelling in vivo evidence that bisphosphonates can target cells in tumours outside the skeleton and that their anti-tumour activity is likely to be mediated via TAMs.

Genetic factors are major determinants of adult bone density, however, it is unknown how these effects may be mediated. Since bone mineral density is the net result of bone formation and bone resorption we studied biochemical indices of bone formation (serum osteocalcin) and resorption [fasting urinary calcium:creatinine (Ca/Crt) and hydroxyproline:creatinine (OH/Crt)] in adult female twins; 39 monozygotic (MZ) and 31 dizygotic (DZ) twin pairs (age, mean +/- SEM, MZ: 51.1 +/- 1.5 yrs; DZ: 46.5 +/- 1.5 yrs, P = NS). Of these subjects, 18 MZ twin pairs and 10 DZ twin pairs were postmenopausal. The MZ twin pair correlations (rMZ) for each index of bone turnover exceeded that between DZ pairs (rDZ), but this difference was only significant for osteocalcin (rMZ = 0.81, rDZ = 0.21, P less than 0.001). Similarly, in the postmenopausal group examined alone, the rMZ (r = 0.84) for serum osteocalcin was significantly greater than rDZ (r = -0.003, P less than 0.03). These osteocalcin data imply that 80% of the variance in serum osteocalcin could be explained by genetic factors. Although genetic effects on fasting urinary hydroxyproline:creatine and calcium:creatinine were not demonstrable, these indices may be less precise and specific. The data indicate that circulating osteocalcin, and therefore bone formation, is strongly genetically determined. These studies suggest at least one of the mechanisms of the genetic effect on bone mass relates to the regulation of bone turnover.

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To assess mechanisms that cause generalized osteoporosis in rheumatoid arthritis (RA), we measured bone mineral density (BMD) by dual photon absorptiometry in the lumbar spine and femoral neck of 111 patients with RA. BMD was significantly reduced at both sites in these patients. Physical activity correlated significantly with BMD in patients with RA, and was found, by multiple regression analysis, to be a significant predictor of femoral bone density in female patients. Multiparity exerted a protective effect on lumbar bone density. Prednisolone (mean dosage 8 mg/day) was not associated with significantly increased bone loss in women, whereas higher dosages in men (mean 10.3 mg/day) were associated with increased lumbar bone loss. Reduced physical activity leading to a form of disuse osteoporosis appears to be an important factor in axial bone loss in RA.

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.

Somatomedin-C (Sm-C) or insulin-like growth factor-I, GH and physical fitness decline with age. Physical fitness and muscle strength are important determinants of bone density, and the age-related decline in bone density may be related in part to a decline in fitness and muscle strength. Also, Sm-C has been shown to stimulate osteoblasts in vitro and may effect skeletal muscle mass. We postulated that the age-related decline in GH and Sm-C levels may be related to an age-related decline in physical fitness and/or muscle strength, and the effect of physical fitness and muscle strength on bone may be mediated by Sm-C. We, therefore, examined the relationship between circulating GH and Sm-C levels and physical fitness, as determined by predicted maximal oxygen uptake (VO2max) in 134 normal women, 34 of whom were postmenopausal. In a subgroup of 62 women overall muscle strength was estimated as the sum of the Z-sores for biceps, quadriceps, and grip strength. Overall muscle strength correlated with GH levels (r = 0.28; P less than 0.02), but not with Sm-C levels. There was a significant positive relationship between plasma Sm-C levels and VO2max in all women (r = 0.47; P less than 0.001) and in the postmenopausal group alone (r = 0.05; P less than 0.01). Although there was a significant negative relationship between Sm-C and age (r = -0.36; P = 0.001), VO2max was a better independent predictor than age (r = 0.47; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)