John A. Eisman

Genetic determinants of bone mass in adults. A twin study.

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.

Physical fitness is a major determinant of femoral neck and lumbar spine bone mineral density.

The relationship between physical fitness and bone mass in the femoral neck, lumbar spine, and forearm was studied in 84 normal women. Femoral neck and lumbar spine bone mineral density and forearm bone mineral content were estimated by absorptiometry. Fitness was quantitated from predicted maximal oxygen uptake. Femoral neck and lumbar bone mineral density were significantly correlated with fitness as well as age and weight. In the 46 postmenopausal subjects, fitness was the only significant predictor of femoral neck bone mineral density, and both weight and fitness predicted the lumbar bone mineral density. These data represent the first demonstration of a correlation between physical fitness, and, by implication, habitual physical activity, and bone mass in the femoral neck; they also support the previous reported correlation between lumbar bone mass and physical activity. The data suggest that increased physical fitness may increase bone mass at the sites of clinically important fractures in osteoporosis.

Osteoporosis in rheumatoid arthritis: safety of low dose corticosteroids.

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.

Genetic determinants of bone mass

Purpose of reviewThis review examines recent advances in the analysis of genetic determinants of bone mass. It addresses both human and animal linkage studies as well as genetic manipulations in animals, inbred mouse models, and candidate gene analyses. Recent findingsRecent studies have implicated novel regulatory pathways in bone biology including both the neuroendocrine system and metabolic pathways linked to lipid metabolism. Variations in the lipoprotein receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were independently identified by linkage in high and low bone mass families. Subsequently, other high bone mass syndromes have been shown to have mutations in this gene. Neural studies have shown the skeletal regulatory activity of leptin and neuropeptide Y receptors via the hypothalamus. Subsequently, the β-adrenergic pathway has been implicated, with important changes in bone mass. The lipoxygenase 12/15 pathway, identified through inbred mouse models and through pharmacologic studies with specific inhibitors, has also been shown to have important effects on bone mass. These studies exemplify the value of genetic models both to identify and then confirm pathways by mutational study and pharmacologic interventions. Continuing candidate gene studies often performed with multiple loci complement such discoveries. However, these studies have not focused on the clinical endpoint of fracture and few have included large enough groups to engender confidence in the associations reported, as such studies may require thousands of individuals. Interestingly, results often differ by ethnicity, age, or gender. A small proportion have examined whether relevant genes influence response to treatment. SummaryThe combinations of human and animal genetic linkage studies have advanced understanding of the regulation of bone mass. Studies ranging from linkage to pharmacology provide optimism for new targets and treatments for osteoporosis.

Vitamin D Metabolism

A decade or so ago the concept of vitamin D metabolism was deceptively simple. The vitamin was produced in the skin (vitamin D3, cholecalciferol) under the influence of the ultraviolet component of sunlight or was derived from some food sources (largely vitamin D2, ergocalciferol). These vitamins D were equally potent in man so the term vitamin D was commonly used. This vitamin, bound to a serum vitamin D binding protein (DBP), was transferred in the blood to the liver, where it was converted to 25-hydroxy- vitamin D (see Fig. 1). This metabolite also bound to the DBP was carried in blood to the kidney, which was the sole site of a further 1a-hydroxylation to produce the active hormonal form, 1, 25-dihydroxyvitamin D. The form of this hormone derived from vitamin D3 has been given the trivial name of calcitriol. However, clinically this was sometimes used to imply both 1, 25-dihydroxycholecalciferol and 1, 25-dihydroxyergocalciferol. The 24- hydroxylation pathway, which also existed in the kidney, was seen as an alternate to 1-hydroxylation and of uncertain significance. The hormone was considered to act like other steroidal hormones through a receptor but it had not been cloned and its structure was unknown. Despite this gap it was “clear” that the receptor existed in the vitamin D target organs, primarily bone and gut, and presumably not elsewhere.