Dirk Vanderschueren

Physiology of Calcium Homeostasis and Bone Remodeling

Calcium homeostasis is dependent on three major organs (intestine, kidney, bone) and three major hormones: parathyroid hormone (PTH), 1,25-(OH)2-D3, and calcitonin. Bone composition is complex and contains matrix with minerals and proteins (collagen and others). Bone is continuously turned over by osteoclasts and osteoblasts, during growth by modeling and during adulthood by remodeling. The receptor activator for the nuclear factor KB (RANK) ligand and its decoy receptor osteoprotegerin (OPG) are key regulatory factors of bone resorption produced by osteoblastic stromal cells, which respectively stimulate and inhibit osteoclast differentiation via interaction with the RANK receptor of osteoclast precursors.

Sex steroid deficiency alters renal calcium transporter expression independently of its effect on bone resorption

It is well established that sex steroid deficiency induces bone loss, resulting in osteoporosis. Consequently, global androgen receptor knock out (ARKO) mice have trabecular and cortical osteopenia. Bone cell-specific ARKOs however, have a much less pronounced bone phenotype, suggesting that androgens have an influence on processes in other systems or organs which in turn have an impact on bone metabolism. The kidney is a likely candidate, as it plays an important role in calcium homeostasis, through reabsorption/excretion and synthesis of vitamin D. Therefore, we hypothesize that androgens regulate renal calcium homeostasis, hereby indirectly affecting bone resorption. To test this hypothesis, adult male C57BL6/J mice were orchidectomized (ORX vs SHAM) and treated with the antiresorptive drug risedronate (RIS vs vehicle), in order to study the effects of sex steroid depletion on renal calcium homeostasis independent of bone resorption. Orchidectomy resulted in a decreased kidney weight (2 weeks post-ORX), hypercalciuria (1 week post-ORX) which was normalized 2 weeks post-ORX along with normal serum levels of calcium, 1.25(OH)2D3, PTH, and FGF23. Orchidectomy combined with prior bone antiresorptive treatment abolished the early hypercalciuric phase and even resulted in transiently decreased serum calcium levels 1 week post-ORX. Compared to control mice, a significant upregulation of renal calcium transporters (TRPV5, PMCA, NCX1, CaBP9K and CaBP28K) was observed in both the ORX and ORX+RIS group, while intestinal calcium transporters (TRPV5, TRPV6, PMCA, CaBP9K) remained unchanged, suggesting that sex steroid deficiency might impact renal calcium homeostasis independent of its effect on bone resorption.

Pharmacologic and Non-pharmacologic Strategies to Prevent Hip Fracture in Old Age

Strategies for the prevention of hip fracture should focus on the frequency of falling as well as on the prevalence of compromised femoral integrity as a consequence of bone loss. Given the high prevalence of falls among the elderly, a performance-oriented functional assessment should be targeted at all patients over 75 years of age. As the risk of falling increases with the number of risk factors, risk may be reduced by modifying even a few contributing factors. Intervention studies have indicated the need to provide adequate supply of both calcium (1500mg daily) and vitamin D (400–800 IU daily) in old age, particularly in housebound elderly and nursing home residents. Bisphosphonate treatment reduces the risk of hip fracture among elderly women with confirmed osteoporosis but is not more effective than calcium and vitamin D alone in women identified primarily on the basis of risk factors other than low BMD.

Androgens and Skeletal Homeostasis

Males deprived of androgen action, due to a lack of functional androgen receptors, have a female and not male phenotype (1,2), indicating that the development of the male phenotype depends on androgen action. The skeletal male phenotype is characterized by stronger bones than in females, primarily because male bones have greater size and not because they contain more mineral for similar size (3,4). It would seem logical, therefore, to assume that androgen action is particularly important for gender differences in bone size. Theoretically, androgen action may affect male skeletal homeostasis in utero, during the neonatal period, as well as before and after puberty. Females, on the other hand, do not secrete sex steroids before early puberty. Therefore, it is unlikely that sex steroids affect skeletal homeostasis before early puberty in the female.