Invited Symposium: Regulators of Skeletal Growth and Integrity in Health and Disease
The maintenance of skeletal mass throughout adult life is critical to the prevention of osteoporosis and its chief complication, fracture. The determinants of bone mass in childhood and early adolescence are in large part heritable. These factors may act alone, but also interact with and respond to important environmental factors such as diet and physical activity. Thus opportunities exist for modifying behaviours, leading to improvements in bone mass acquisition and maintenance, with the potential for substantial reductions in overall fracture rates.
At present, the decline in bone mineral density (BMD) that occurs as a function of aging and specifically as a consequence of hormone deficiency (particularly in women) provide the most practical opportunity for therapeutic intervention, and thus maintenance of skeletal integrity. With our current undestanding of the physiology of bone remodelling, and the changes observed throughout life cycles, the major successes to date have been with those agents that preferentially inhibit bone resorption. This component is clearly enhanced and accelerated in the most common condition associated with bone loss (primary osteoporosis). Therapeutic interventions directly aimed at increasing bone formation have been less effective, but novel agents or combination approaches may provide new opportunities in the future.
Calcium plays a critical role in skeletal health and function. Nevertheless, the requirements for calcium change over the lifetime of an individual. Those factors that govern calcium and mineral balance also vary between ethnic groups, and are gender specific. With respect to the former, differences in calcium absorption may be racially determined, by virtue of heritable or other factors, and in regards to the latter, estrogen plays an important role in maintaining calcium balance, by promoting intestinal calcium absorption, and reducing renal calcium excretion. Calcium supplementation as a therapeutic modality to maintain BMD has been the subject of considerable investigation. It is clear that normal calcium intake is important for normal skeletal bone growth and development, and calcium mineral deficiencies, for any variety of reasons early in life, have been shown to lead to suboptimal bone mass acquisition. While a net negative calcium balance is a feature of the aging process, with the attendant features of increased bone turnover and loss, attempted correction of such a deficit by aggressive calcium supplementation alone has not been shown in most studies to substantially prevent increased bone resorption, retard bone loss, and more importantly reliably reduce fracture rates.
Several recent studies have suggested that in the elderly, calcium supplementation may improve bone mass and even prevent some fractures. The responses reported may however not account for the correction of a variety of other nutritional interventions, specifically the contribution of Vitamin D. Deficiencies or abnormalities in the metabolism of this important vitamin may result in a profound bone deficit (e.g. osteomalacia), but there is increasing recognition that chronic Vitamin D insufficiency is an under recognized factor in the maintenance of skeletal integrity in the elderly. Recent data suggests that this may also apply to younger subjects, with significant seasonal variation in those latitudes with prolongued periods of reduced sun exposure. In combination with calcium supplements, this is an inexpensive and potentially effective therapeutic intervention, particularly in an elderly population, but probably applicable to all ages. The contributions of other nutritional factors in bone health have been investigated, including the impact of protein and sodium intake. It would appear that excessive animal protein intake, in the absence of adequate calcium and vitamins (D and K), may have potential deliterious effects, but further studies are needed. It is also apparent that in the elderly population, protein malnutrition may contribute to accelerated bone loss and impaired muscle function, which together increase the risk for fracture. Bone loss under these circumstances may be mediatd by certain cytokines, specifically the insulin-like growth factor (IGF-1), which may also play an important role in promoting bone mass accumulation.
Anti-resorptive drugs include Estrogen and related synthetic agents (Selective Estrogen Receptor Modulators or SERMs), Bisphosphonates, and Calcitonin. They target the osteoclast, inhibiting resorption and at least stabilizing BMD. The net effect is often an increase in bone mass, as osteoblast function is generally maintained. These agents are particularly effective during periods of rapid bone turnover (e.g. postmenopausally), but also during the entire period of age related bone loss. In addition, several of these agents have also demonstrated efficacy in preventing secondary bone loss (eg as a result of corticosteroid use). Ovarian Hormone therapy (OHT) remains the mainstay of treatment for post menopausal osteoporosis, but the acceptance of this intervention is limited by the aggregate potential for unwanted short as well as long term side effects. As a result, successful long term administration is generally limited. Nevertheless, OHT may offer many significant benefits in addition to those specifically related to maintaining bone mass. More emphasis is now placed on effective decision making strategies, so that appropriate individual choices with respect to OHT can be made.
Anti-estrogens or SERMs may provide an important alternative for women who seek some of the benefits of estrogen but are concerned because of the long term risk of breast cancer associated with OHT. The recent release of Raloxifene provides an additional, perhaps more attractive option than Tamoxifen, with a better side effect profile (with regards to endometrial hyperpalsia) and bone mass maintenance, including the potential for fracture rate reduction. Combination therapy with other non-hormonal agents may be an even more effective furture strategy. Bisphophonates have been extensively studied and found to be effective treatments for preventing bone loss, improving bone mass in osteoporotic patients, and reducing fracture rates. The specificity of their action (almost exclusively bone), relatively modest side effect profile, and an increasing list of preparations that can be administered orally or parenterally provide an attractive alternative to OHT. These factors, as well as investigations examining the utility of combination therapies (OHT and Bisphophonates), intermittent dosing administration regimens for increased convenience (in addition to the standard cyclical regimen for the oldest bisphosphonate-Etidronate), have combined to push bisphosphonates to the forefront of treatment regimens worldwide. In addition, they have demonstrated efficacy use in the treatment of secondary conditions associated with bone loss, particualrly related to corticosteroid use.
Calcitonin is a naturally derived thyroid hormone that inhibits bone resorption. It is available in injectable forms and nasal aerosol, and has long been approved for the treatment of postmenopausal osteoporosis. It has shown efficacy in preventing bone loss, and in some but not all studies of fracture reduction.
Agents that stimulate bone formation include Flouride, anabolic steroids, and Vitamin D analogues. These drugs target the osteoblast to stimulate collagen formation and bone mineralizaton. This approach has been less commonly used in general, as a result of a variety of factors such as regional variations in effectiveness, side effects profiles, risks related to prolongued administration, and less acceptable administration regimens. The importance however of adequate vitamin D status as mentioned above has been increasingly appreciated. Efforts to ensure appropriate supplementation are likely to yield large scale benefits. The use of active vitamin D analogues may be necessary in those situations requiring more effective intestinal absorption and direct osteoblast stimulation,and may be combined with anti-resorptive agents to achieve greater responses than the latter alone.
Several other phamacologic agents are under investigation for their utility in preserving and increasing bone mass. These include synthetic analogues of the active component of parathyroid hormone, growth hormone and insulin like growth factors. Preliminary studies suggest that these agents hold significant promise. Alone, or more likely in combination with other drugs mentioned above, novel regimens will become available to substantially maintain or where indicated improve bone mass and reduce fractures in the future.
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|Rubin, L.A.; (1998). Pharmacological and Dietary Agents that Stimulate Skeletal Maintenance in Adults. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/atkinson/rubin0527/index.html|
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