Exploiting and bypassing the bone remodeling cycle to optimize the treatment of osteoporosis.

Abstract

HE BISPHOSPHONATE ALENDRONATE is now widely used for the treatment of postmenopausal osteoporosis and has recently been approved for its prevention. Like many drugs, the mechanisms underlying alendronate’s therapeutic effect are not well understood. Alendronate treatment at a dose of 10 mg/day results in a 5% increase in spinal bone mineral density (BMD) over the first year. (1) BMD continues to increase, albeit at a slower rate, at this site during the second and third years of treatment. The magnitude and duration of the increase in BMD has led to speculation that alendronate is doing more than simply reducing remodeling space and that it may possess anabolic activity. Verification of this awaits the detailed results from histomorphometric analysis of bone biopsies taken before and after treatment. In the meantime, in an interesting paper that appears in this issue of JBMR, Heaney and colleagues (2) have performed a theoretical investigation of the mode of action of alendronate by applying data from the study of Liberman et al. (1) to a computer simulation of bone remodeling. (3) Using this model, an excellent fit to the observed clinical data was obtained by simulating a 36 ‐38% reduction in remodeling activation frequency, coupled with a positive balance in each remodeling unit of 1.1‐1.4%. By dint of closing down the remodeling space, the reduction in activation frequency accounts for the early and rapid increase in BMD, while the positive bone balance accounts for the continued, although smaller, gain in BMD observed in the second and third year of therapy. The model does not attempt to elucidate the structural or cellular basis for the positive bone balance at the level of the remodeling unit. A positive balance can be achieved either by reducing the depth of the resorption cavity without a decrease in the amount of bone deposited or by increasing the amount of bone deposited, leading to an increase in the thickness of the trabecular packet or, of course, by a combination of the two. The bisphosphonate etidronate reduced resorption depth in human iliac trabecular bone by almost 30% after 1 year of treatment, (4) but no such data are yet available for alendronate. Etidronate did not change the thickness of trabecular packets, but recent studies in osteoporotic women suggest that this is increased after 2 years of alendronate treatment at 10 and 20 mg/day. This result was not confirmed, however, after 3 years of treatment (P.J. Meunier, personal communication). A direct stimulatory effect of alendronate on bone formation in vivo is quite possible in view of the fact that it has been shown to increase the proliferation and functional activity (including matrix protein synthesis and mineralization) of cartilage and bone cells in vitro. (5‐9) Regardless of the underlying cellular mechanism(s), an increase in trabecular thickness, implying a positive bone balance at the level of the remodeling unit, has been reported in ovariectomized baboons treated with alendronate (10) and in humans treated with etidronate. (11)