Decimal Point — Osteoporosis Therapy at the 10-Year Mark
http://www.100md.com
《新英格兰医药杂志》
Osteoporosis takes an enormous toll among postmenopausal women. A 50-year-old woman in the United States has a 40 percent lifetime risk of an osteoporotic fracture. One woman in three and one man in nine older than 80 years of age will sustain a hip fracture at some point, and 15 to 20 percent of these patients will die from attendant complications. Osteoporosis is, to a remarkable degree, a disease of Western civilization, and we are now seeing the beginnings of a worldwide osteoporosis pandemic, as the population of the developing world ages and assumes a more Western lifestyle.
The past 10 years have witnessed the introduction of several new treatments for osteoporosis. The most widely used are antiresorptive agents, including the bisphosphonates alendronate and risedronate and the selective estrogen-receptor modulator raloxifene. By inhibiting bone resorption, these medications reduce the rate of bone turnover and prevent further bone loss. Anabolic therapy to induce the formation of new bone first became available with the introduction of teriparatide in 2002. Teriparatide is a recombinant peptide fragment of parathyroid hormone that restores bone in patients who have already had severe bone loss, although it must be administered by means of daily subcutaneous injection. Meunier et al.1 recently reported that strontium ranelate, a second anabolic agent, prevents osteoporotic fractures.
Because of their unique pharmacokinetics, bisphosphonates are targeted directly to osteoclasts, the cells that resorb bone. Analogues of inorganic pyrophosphate, bisphosphonates are bound to bone mineral when they are administered and are then slowly released as bone is resorbed by osteoclasts. Accordingly, osteoclasts are exposed to higher concentrations of bisphosphonates than are other cells. Nitrogen-containing bisphosphonates such as alendronate and risedronate block prenylation, the covalent modification with lipids of small GTPase signaling proteins that is a necessary step for the attachment of the proteins to cell membranes. In this manner, bisphosphonates are thought to block signals that organize the ruffled border, the organelle that resorbs bone (see Figure).
Figure. Mechanism of Action of Bisphosphonates.
Bisphosphonates bound to bone (red spheres) are released during bone resorption and taken up by osteoclasts. Bisphosphonates inhibit the formation of the ruffled border, the organ of active bone resorption, by preventing the prenylation of GTPase signaling proteins (blue spheres) that attach to membrane vesicles and direct the formation of the ruffled border.
Alendronate was the first orally active bisphosphonate introduced in the United States for the treatment of osteoporosis. In initial clinical trials, alendronate increased bone mineral density, decreased bone turnover, and reduced the risk of vertebral and hip fracture in postmenopausal women with osteoporosis. Follow-up studies have confirmed that the benefits of alendronate are maintained through seven years of therapy.
In this issue of the Journal, Bone et al. (pages 1189–1199) report on 10 years of experience with alendronate, an extension of the original 3-year randomized, controlled trials.2,3,4 Two groups of postmenopausal women received alendronate at a dose of 5 mg or 10 mg daily. Bone turnover, as measured by means of markers of bone formation and bone resorption, was reduced by more than 50 percent in women who received continuous alendronate therapy. Bone mineral density at the lumbar spine continued to increase throughout the 10-year period in both alendronate groups and was stable at other skeletal sites. A third group (the discontinuation group), who had initially received a 20 mg dose, was switched to 5 mg for years 3 through 5 and then to placebo for years 6 through 10. In this group, a small increase in bone turnover in years 6 through 10 was accompanied by a decrease in bone mineral density at most skeletal sites. The groups were too small to permit the detection of influences of treatment on the rate of fractures.
High bone turnover increases the risk of fracture, perhaps because of deleterious effects of rapid resorption on the microarchitecture of bone, such as the perforation of trabecular plates. Antiresorptive agents reduce fracture rates in part by reducing bone turnover rates. In short-term studies of antiresorptive therapy, the reduction in bone turnover explains more of the treatment-related reduction in the risk of fracture than does the increase in bone mineral density. The study of Bone et al. provides convincing evidence that the biochemical effects of alendronate on bone turnover remain stable over the course of 10 years of therapy, without any progression of its antiresorptive action or noticeable increase in the incidence of fractures. Long-term data on the safety and efficacy of bisphosphonates are particularly important because these agents reside in bone for long periods; in the current study, bone resorption was still inhibited by more than 50 percent five years after the discontinuation of alendronate therapy.
How does an antiresorptive agent like alendronate produce sustained, long-term increases in bone mineral density? The mineralization of newly formed bone proceeds in two phases: primary mineralization takes place when bone is formed during the bone-remodeling cycle, and secondary mineralization slowly and progressively increases the tissue mineral content of older bone. By slowing bone turnover, alendronate treatment allows secondary mineralization to progress, thereby increasing the tissue mineral content. Thus, the increase in bone mineral density after long-term alendronate therapy reflects primarily not an increase in bone mass (the tissue volume divided by the total volume), but an increase in tissue mineral content (the mineral level divided by the tissue volume). The measured increase in mineralization after three years of alendronate treatment did not exceed the normal range, however.
Is this increase in mineralization good or bad? It is good up to a point: the higher its tissue mineral content, the stiffer bone becomes, and the more peak stress it will tolerate. But when bone is highly mineralized and homogeneous, it becomes brittle and less tough, and cracks or microdamage can develop. Some studies in animals have found reductions in toughness and increased microdamage after exposure to high-dose bisphosphonates. We need better long-term data on the prevention of fractures during bisphosphonate treatment and better data on the material properties of bone after sustained bisphosphonate therapy. It should not be assumed that the apparent long-term safety of oral alendronate will pertain to other agents or other routes of administration (e.g., intravenous bisphosphonates).
Although 10 years of alendronate treatment appears to be safe, the optimal duration of treatment has not been established. Is there an eventual point at which the benefit of treatment with regard to protection from fractures will diminish? The inhibition of bone turnover is associated with the prevention of fractures, and bone turnover rates remain low for at least five years after alendronate therapy has been discontinued. How rapidly does the risk of fracture increase after bisphosphonate therapy is discontinued? Does a decrease in bone mineral density after the discontinuation of alendronate therapy, which is likely to reflect a decrease in mineralization rather than a decrease in bone mass, imply an increase in the risk of fracture? Could alendronate treatment be stopped after 10 or more years with persistent protection against fractures? Better data regarding the relative risk of fracture associated with continued treatment as compared with the discontinuation of treatment will be required for good clinical decision making.
Source Information
From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
References
Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-468.
Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC II. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996;101:488-501.
Devogelaer JP, Broll H, Correa-Rotter R, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone 1996;18:141-150.
Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1443.(Gordon J. Strewler, M.D.)
The past 10 years have witnessed the introduction of several new treatments for osteoporosis. The most widely used are antiresorptive agents, including the bisphosphonates alendronate and risedronate and the selective estrogen-receptor modulator raloxifene. By inhibiting bone resorption, these medications reduce the rate of bone turnover and prevent further bone loss. Anabolic therapy to induce the formation of new bone first became available with the introduction of teriparatide in 2002. Teriparatide is a recombinant peptide fragment of parathyroid hormone that restores bone in patients who have already had severe bone loss, although it must be administered by means of daily subcutaneous injection. Meunier et al.1 recently reported that strontium ranelate, a second anabolic agent, prevents osteoporotic fractures.
Because of their unique pharmacokinetics, bisphosphonates are targeted directly to osteoclasts, the cells that resorb bone. Analogues of inorganic pyrophosphate, bisphosphonates are bound to bone mineral when they are administered and are then slowly released as bone is resorbed by osteoclasts. Accordingly, osteoclasts are exposed to higher concentrations of bisphosphonates than are other cells. Nitrogen-containing bisphosphonates such as alendronate and risedronate block prenylation, the covalent modification with lipids of small GTPase signaling proteins that is a necessary step for the attachment of the proteins to cell membranes. In this manner, bisphosphonates are thought to block signals that organize the ruffled border, the organelle that resorbs bone (see Figure).
Figure. Mechanism of Action of Bisphosphonates.
Bisphosphonates bound to bone (red spheres) are released during bone resorption and taken up by osteoclasts. Bisphosphonates inhibit the formation of the ruffled border, the organ of active bone resorption, by preventing the prenylation of GTPase signaling proteins (blue spheres) that attach to membrane vesicles and direct the formation of the ruffled border.
Alendronate was the first orally active bisphosphonate introduced in the United States for the treatment of osteoporosis. In initial clinical trials, alendronate increased bone mineral density, decreased bone turnover, and reduced the risk of vertebral and hip fracture in postmenopausal women with osteoporosis. Follow-up studies have confirmed that the benefits of alendronate are maintained through seven years of therapy.
In this issue of the Journal, Bone et al. (pages 1189–1199) report on 10 years of experience with alendronate, an extension of the original 3-year randomized, controlled trials.2,3,4 Two groups of postmenopausal women received alendronate at a dose of 5 mg or 10 mg daily. Bone turnover, as measured by means of markers of bone formation and bone resorption, was reduced by more than 50 percent in women who received continuous alendronate therapy. Bone mineral density at the lumbar spine continued to increase throughout the 10-year period in both alendronate groups and was stable at other skeletal sites. A third group (the discontinuation group), who had initially received a 20 mg dose, was switched to 5 mg for years 3 through 5 and then to placebo for years 6 through 10. In this group, a small increase in bone turnover in years 6 through 10 was accompanied by a decrease in bone mineral density at most skeletal sites. The groups were too small to permit the detection of influences of treatment on the rate of fractures.
High bone turnover increases the risk of fracture, perhaps because of deleterious effects of rapid resorption on the microarchitecture of bone, such as the perforation of trabecular plates. Antiresorptive agents reduce fracture rates in part by reducing bone turnover rates. In short-term studies of antiresorptive therapy, the reduction in bone turnover explains more of the treatment-related reduction in the risk of fracture than does the increase in bone mineral density. The study of Bone et al. provides convincing evidence that the biochemical effects of alendronate on bone turnover remain stable over the course of 10 years of therapy, without any progression of its antiresorptive action or noticeable increase in the incidence of fractures. Long-term data on the safety and efficacy of bisphosphonates are particularly important because these agents reside in bone for long periods; in the current study, bone resorption was still inhibited by more than 50 percent five years after the discontinuation of alendronate therapy.
How does an antiresorptive agent like alendronate produce sustained, long-term increases in bone mineral density? The mineralization of newly formed bone proceeds in two phases: primary mineralization takes place when bone is formed during the bone-remodeling cycle, and secondary mineralization slowly and progressively increases the tissue mineral content of older bone. By slowing bone turnover, alendronate treatment allows secondary mineralization to progress, thereby increasing the tissue mineral content. Thus, the increase in bone mineral density after long-term alendronate therapy reflects primarily not an increase in bone mass (the tissue volume divided by the total volume), but an increase in tissue mineral content (the mineral level divided by the tissue volume). The measured increase in mineralization after three years of alendronate treatment did not exceed the normal range, however.
Is this increase in mineralization good or bad? It is good up to a point: the higher its tissue mineral content, the stiffer bone becomes, and the more peak stress it will tolerate. But when bone is highly mineralized and homogeneous, it becomes brittle and less tough, and cracks or microdamage can develop. Some studies in animals have found reductions in toughness and increased microdamage after exposure to high-dose bisphosphonates. We need better long-term data on the prevention of fractures during bisphosphonate treatment and better data on the material properties of bone after sustained bisphosphonate therapy. It should not be assumed that the apparent long-term safety of oral alendronate will pertain to other agents or other routes of administration (e.g., intravenous bisphosphonates).
Although 10 years of alendronate treatment appears to be safe, the optimal duration of treatment has not been established. Is there an eventual point at which the benefit of treatment with regard to protection from fractures will diminish? The inhibition of bone turnover is associated with the prevention of fractures, and bone turnover rates remain low for at least five years after alendronate therapy has been discontinued. How rapidly does the risk of fracture increase after bisphosphonate therapy is discontinued? Does a decrease in bone mineral density after the discontinuation of alendronate therapy, which is likely to reflect a decrease in mineralization rather than a decrease in bone mass, imply an increase in the risk of fracture? Could alendronate treatment be stopped after 10 or more years with persistent protection against fractures? Better data regarding the relative risk of fracture associated with continued treatment as compared with the discontinuation of treatment will be required for good clinical decision making.
Source Information
From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
References
Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-468.
Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC II. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996;101:488-501.
Devogelaer JP, Broll H, Correa-Rotter R, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone 1996;18:141-150.
Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1443.(Gordon J. Strewler, M.D.)