Current Pharmaceutical Design - Volume 8, Issue 23, 2002

Bone growth is regulated by circulating hormones and locally generated factors. Understanding their mechanisms of action enables us to obtain a better appreciation of the cellular and molecular basis of bone remodelling, and could therefore be valuable in approaches to new therapies. In this review, we consider the actions on bone tissue of the peptide hormones amylin and adrenomedullin, known to circulate at picomolar concentrations. Adrenomedullin is also produced locally in bone. Amylin and adrenomedullin are related peptides with some homology to both calcitonin and calcitonin gene-related peptide. These peptides have recently been found to stimulate the proliferation of osteoblasts in vitro, and to increase indices of bone formation when administered either locally or systemically in vivo. In addition, amylin inhibits bone resorption. Both amylin and adrenomedullin have also been found to act on chondrocytes, stimulating their proliferation in culture and increasing tibial growth plate thickness when administered systemically to adult mice.Like the peptides themselves, the receptors for the calcitonin family are also related to each other. Each peptide seems to act through its own distinct high affinity receptor, as well as through other receptors for the family, usually with lower affinity. Characterisation of the putative receptors expressed in osteoblasts, has provided some understanding of the physiological effects of amylin and adrenomedullin in these cells.Studies of structure-activity relationships have demonstrated that osteotropic effects of amylin and adrenomedullin can be retained in peptide fragments of the molecule whilst losing the parent molecule's effects on carbohydrate metabolism or vasodilatory properties respectively. Thus, these small peptides, or their analogues, are attractive candidates as anabolic therapies for osteoporosis.

Potent antiresorptive agents have been developed for the treatment of osteoporosis and bone disorders. There are few agents available that stimulate bone formation. Recently, treatment with parathyroid hormone was found to induce a potent increase in hip and lumbar bone mineral density (BMD). The present review focus on growth hormone (GH) / growth hormone secretagogues (GHSs). GH / GHSs stimulates bone turnover, thereby increasing bone mass and density.

The proton pump expressed on the plasma membrane of bone resorbing osteoclasts, and which mediates the acidification of the extracellular environment in resorption lacuna, belongs to the family of vacuolar H+-ATPases, which are enzymes ubiquitously distributed among all cells and are evolutionary conserved. These pumps have two functional domains: a peripherally associated cytoplasmatic section, and a proton channel composed of several subunits one of which, the 116 kDa subunit, is expressed exclusively in osteoclasts and confers unique functional and pharmacological properties to the osteoclast V-ATPase.It was demonstrated that inhibition of this pump can abolish bone resorption, therefore, osteoclast-selective inhibitors could provide novel and useful agents for the treatment of osteoporosis. This paper reviews the medicinal chemistry approaches that have allowed to obtain such new agents, most of which have been designed starting from the natural macrolide antibiotic bafilomycin A1, a potent and selective inhibitor of all V-ATPases. Identification of SAR and of minimal structural requirements for bafilomycin activity have allowed to obtain (2Z,4E)-5-(5,6-dichloroindolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl )-2,4- pentadienamide (SB-242784) which inhibits the osteoclastic proton pump and bone resorption in vitro. Although it inhibits the activity of non-osteoclastic proton pumps as well, it appears to have reasonable selectivity and its administration for 6 months prevented the loss of femoral and vertebral BMD in ovariectomized rats, without any significant renal effects in control and acid-loaded animals. Other independent approaches that did not start from bafilomycin have led to the discovery of a different class of VATPase inhibitors, among which 4-(2,6-dichlorobenzoyl)amino-2-trifluoromethyl(benzoimidazol-1-yl)acetyl morpholine (FR177995) was the most effective in preventing bone resorption in an ovariectomized rat model of osteoporosis.These compounds are of great pharmaceutical and medical interest because they allow to target a specific function of the osteoclast, however, only clinical trials might demonstrate whether they have significant advantages over other inhibitors of bone resorption for the treatment of osteoporosis.

The dynamic and highly regulated processes of bone remodeling involve two major cells, osteoclasts and osteoblasts, both of which command a multitude of cellular signaling pathways involving protein kinases. Of the possible kinases in these cells, Src tyrosine kinase stands out as a promising therapeutic target for bone disease as validated by Src knockout mouse studies and in vitro cellular experiments, suggesting a regulatory role for Src in both osteoclasts (positive) and osteoblasts (negative). Advances in structural studies involving both Src and non-Src family kinases, in activated and unactivated protein states, have uncovered key binding site interactions that have led to the design of potent Src inhibitors. The lead compounds originate from a variety of synthetic templates and have demonstrated nM potency in enzymatic / binding assays and efficacy in animal models of bone disease. This review will provide a current understanding of critical Src signalling pathways in osteoclasts and osteoblasts, while detailing the structure-based design and screening-based lead discovery of Src inhibitors to be developed as therapeutic agents for bone disease.

Parathyroid hormone (PTH) is the key endocrine factor regulating systemic Ca2+ homeostasis. Elevated levels of circulating PTH increase bone turnover and, depending on the duration of elevation, will result in net anabolic or catabolic effects on the skeleton. Secretion of PTH from the parathyroid glands is regulated by small changes in circulating levels of Ca2+ which are detected by a Ca2+ receptor on the surface of parathyroid cells. This G protein-coupled receptor is the primary molecular entity used by parathyroid cells to regulate secretion of PTH. As such, the Ca2+ receptor is a unique molecular target for new drugs capable of increasing or decreasing circulating levels of PTH. Compounds which activate the Ca2+ receptor are termed calcimimetics and they inhibit the secretion of PTH, a calcimimetic compound is in late stage clinical trials for the treatment of both primary and secondary hyperparathyroidism. Conversely, calcilytic compounds, which are Ca2+ receptor antagonists, stimulate secretion of PTH, a calcilytic compound is in early clinical development for the treatment of osteoporosis.

Estrogens are known as important modulators of development, growth and maintenance of primary sexual physiology. The medical field has also grown increasingly appreciative of the effects of estrogens on non-traditional target tissues such as bone, cardiovascular tissue and the CNS. Postmenopausal women have been the beneficiaries of estrogen supplementation regimes, but the proliferative actions of estrogens on uterine and breast tissue have raised concerns. Combining estrogens with progestins (HRT) has succeeded in blunting the uterine effects of estrogen but not the effects of estrogens on breast tissue, and breakthrough bleeding induced by HRT regimes continues to present compliance issues. The discovery by Jordan and coworkers in 1987 that the “antiestrogens” tamoxifen and raloxifene showed estrogenic effects in preventing bone loss in ovariectomized rats revolutionized the way we have come to the think of nuclear receptor functioning. Since that time, broad insights have been garnered into both the mechanisms involved in the primary, ligand activated nuclear transcription pathway as well as other, non-traditional pathways via which estrogens may exert their effects. The recent discovery of a second estrogen receptor ERβ has provided additional possibilities for investigation and therapeutic intervention. Even though raloxifene (Evista) has been approved for the treatment and prevention of osteoporosis in postmenopausal women, there is room for improvement. For example, normal HRT alleviates hot flush and urogenital complaints, raloxifene does neither. Inaddition raloxifene does not raise overall HDL (while HRT does) but does increase venous thromboembolisms. The ideal SERM will maximize all of the positive estrogen attributes while minimizing the negatives, and to that end, there has been considerable activity in the medicinal chemistry community dedicated towards the modification of the SERM structure to achieve compounds with preferable profiles. What we have witnessed, so far, is an evolutionary march of compounds with potential clinical benefit over raloxifene, although the ideal SERM remains to be realized.