DRUG-INDUCED METABOLIC BONE-DISEASE

Osteoporosis is an insidious disorder of multifactorial etiology with a growing health impact on our aging society.(187) It is defined pathologically as an absolute decrease in total bone mass.(171) Because the loss of bone mineral content parallels that of bone protein matrix, the ratio of mineral to matrix remains normal. Diminished bone mass leads to reduced physical strength, microarchitectural derangement, and, most importantly, an increased susceptibility to fracture.(101,172) Bone is the site of substantial metabolic exchanges. Both cortical and trabecular bone undergo perpetual changes throughout life called bone remodeling.(149) At the cellular level, bone remodeling involves cycles of bone resorption, formation, and mineralization which follow a programmed sequence at discrete foci called bone multicellular units (BMU). In young adults, the resorption and formation phases are tightly coupled, and bone mass is maintained.(171) The regulatory process of remodeling can be disrupted in several ways. The number of bone-remodeling units can vary, the speed at which each BMU operates can vary, and an imbalance between resorption and formation can occur. Uncoupling of resorption and formation leading to an absolute or relative increase in resorption over formation results in a net negative balance per remodeling cycle and therefore bone loss.(149) Osteoporosis can therefore be caused by an increased frequency of activation or duration of activity of osteoclasts, by a decrease in activity or duration of the action of osteoblasts (leading to incomplete refilling of resorption spaces), or a combination of these. All three mechanisms have been observed, and osteoporosis is associated with low, normal, and high rates of bone turnover.(139,150,208) In addition, disintegration of the trabecular network in states characterized by high bone turnover and increased resorptive activity results from trabecular perforations.(151) Osteomalacia is a pathologic loss of mineralized bone due to a reduction of calcium phosphate levels below those required for normal mineralization of bone matrix. As a result, the bone mineral/matrix ratio is reduced, uncalcified matrix accumulates, and bone strength is reduced. In addition to age-related idiopathic osteoporosis,(131) secondary causes of metabolic bone disease frequently are related to pharmacologic agents. A multiplicity of compounds are associated with bone loss and mineralization defects. The drugs most commonly associated with osteoporosis are glucocorticoids, L-thyroxine, heparin, ethanol, caffeine, tobacco, gonadotropin-releasing hormone agonists, neuroleptic agents, cyclosporine, and cytotoxic agents, including methotrexate. The drugs most commonly associated with mineralization defects are anticonvulsant agents, diphosphonates, total parenteral nutrition, aluminum-binding antacids, and fluoride.