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A tale of two worlds in prescribing etidronate for osteoporosis
THE LANCET
COMMENTARY 6
7
Goodwin TM, Valenzuela G, Silver H, Hayashi R, Creasy GW, Lane ???. Treatment of preterm labor with the oxytocin antagonist atosiban. Am J Perinatol 1996; 13: 143–46. Danielsson BR, Danielson M, Reiland S, Rundqvist E, Dencker L, Regard CG. Histological and in-vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators. Teratology 1990; 41: 185–93.
A tale of two worlds in prescribing etidronate for osteoporosis The recent publication of three studies which demonstrated the efficacy of etidronate in preventing bone loss has highlighted a growing geographical difference The in prescribing anti-osteoporotic drugs.1–3 bisphosphonates are a class of agents that block bone resorption through inhibition of osteoclasts, thereby preserving bone mass. Although available for more than 20 years, the first two randomised placebo-controlled trials of etidronate in postmenopausal osteoporosis were not published until 1990.4,5 In both studies, cyclic etidronate significantly increased bone density and reduced new vertebral fractures in postmenopausal osteoporotic women after only 2 years of treatment. Almost overnight, cyclic etidronate became first-line therapy for osteoporosis. But, two events led to change in that prescribing pattern. First, 3-year follow-up data in the US multicentre trial revealed no difference in vertebral fracture rates between controls and etidronate-treated women.6 This finding, plus concern about osteomalacia, prompted the US Food and Drug Administration (FDA) to deny approval of etidronate for postmenopausal osteoporosis. Second, 2 years ago alendronate, a newer bisphosphonate, was reported to reduce vertebral fractures and increase spine and hip bone density after 3 years of treatment.7 Unlike etidronate, alendronate was not associated with osteomalacia and won speedy approval by the FDA. Soon thereafter, the Fracture Intervention Trial (FIT) showed that alendronate drastically reduced osteoporotic fractures in older postmenopausal women, with few adverse effects.8 The combination of US regulatory approval of alendronate, a strong media blitz, and proven efficacy in two multicentre placebo-controlled trials was sufficient to induce American practitioners to switch their off-label use of etidronate to alendronate. Meanwhile, etidronate was still prescribed outside the USA because of its excellent safety profile, its capacity to improve bone density, and its low cost. In the past 3 years, etidronate has won approval for the treatment of postmenopausal osteoporosis in 23 countries, and is the dominant bisphosphonate prescribed for this disease on three continents. These three new studies1–3 on etidronate reopen this prescribing dichotomy and raise more questions than answers in this tale of two worlds. The first question is whether the magnitude of increase in bone density indicates the degree of fracture-prevention efficacy. Alendronate produces a greater increment in bone density at all sites than does etidronate but recent studies provide ample evidence that fracture prevention does not necessarily correlate with the magnitude of increase in bone density. Second, is there a difference between alendronate and etidronate in prevention of bone loss for healthy postmenopausal women? The answer is probably no since all the bisphosphonates can slow bone loss during 1340
the menopause.2,3 Third, is alendronate safer than etidronate? If etidronate is used properly, the answer is no. Indeed, gastrointestinal tolerance is slightly better for etidronate than alendronate, and neither causes osteomalacia when prescribed properly.3,6,8 Fourth, does etidronate prevent fractures in postmenopausal women with osteoporosis? The answer to that question is unclear, since post-hoc analysis of the US multicentre trial showed that etidronate reduced vertebral fractures in women with the lowest bone density and previous fractures, while alendronate showed fracture efficacy in all postmenopausal cohorts under investigation.6,7,8 Unfortunately, the US etidronate trial was grossly underpowered for fracture efficacy, having enrolled only 450 women, some with minimal disease.6 Hence, this question will probably never be answered. Still, it is worth noting that severely osteoporotic women in that trial experienced the greatest benefit from etidronate and were nearly identical in respect to bone density and previous fractures as women who participated in FIT.6,8 Finally, are there more treatment failures among women receiving etidronate than those prescribed alendronate? In FIT, a decline in bone density was reported in fewer than 5% of treated women.8 In the etidronate trial, non-response was three to four fold higher.6 These and other questions will remain unanswered unless a randomised, placebo-controlled, comparative study in postmenopausal osteoporotic women is undertaken. Such a trial seems highly unlikely to be conducted since several new bisphosphonates will soon win regulatory approval. This leaves today’s clinician with an interesting choice of bisphosphonates. Which one the practitioner chooses must rest on his/her ability to interpret the published evidence, balance safety issues, consider the risk of treatment failure, weigh the cost of therapy, and foremost, heed the wishes of his/her patient. That, rather than geographic location, remains the art of medicine.
Clifford J Rosen Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Bangor, ME 04401, USA 1
2
3
4
5
6
7
8
Adachi JD, Bensen WD, Brown J, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382–87. Meunier PJ, Confavreauz E, Tupinon I, Hardouin C, Delmas PD, Balena R. Prevention of early postmenopausal bone loss with cyclical etidronate therapy. J Clin Endocrinol Metab 1997; 82: 2784–91. Herd RJ, Balena R, Blake GM, Ryan PJ, Fogelman I. Prevention of early postmenopausal bone loss by cyclical etidronate: a two year doubleblind placebo-controlled study. Am J Med 1997; 103: 92–99. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265–71. Watts NB, Harris ST, Genant HK, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73–79. Harris ST,Watts NB, Jackson RD, et al. Four year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med 1993; 95: 557–67. Liberman VA,Weiss SR, Broll J, et al. Effect of oral alendronate on bone density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333: 1437–43. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson ED. Randomized trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535–41.
Vol 350 • November 8, 1997
COMMENTARY 6
7
Goodwin TM, Valenzuela G, Silver H, Hayashi R, Creasy GW, Lane ???. Treatment of preterm labor with the oxytocin antagonist atosiban. Am J Perinatol 1996; 13: 143–46. Danielsson BR, Danielson M, Reiland S, Rundqvist E, Dencker L, Regard CG. Histological and in-vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators. Teratology 1990; 41: 185–93.
A tale of two worlds in prescribing etidronate for osteoporosis The recent publication of three studies which demonstrated the efficacy of etidronate in preventing bone loss has highlighted a growing geographical difference The in prescribing anti-osteoporotic drugs.1–3 bisphosphonates are a class of agents that block bone resorption through inhibition of osteoclasts, thereby preserving bone mass. Although available for more than 20 years, the first two randomised placebo-controlled trials of etidronate in postmenopausal osteoporosis were not published until 1990.4,5 In both studies, cyclic etidronate significantly increased bone density and reduced new vertebral fractures in postmenopausal osteoporotic women after only 2 years of treatment. Almost overnight, cyclic etidronate became first-line therapy for osteoporosis. But, two events led to change in that prescribing pattern. First, 3-year follow-up data in the US multicentre trial revealed no difference in vertebral fracture rates between controls and etidronate-treated women.6 This finding, plus concern about osteomalacia, prompted the US Food and Drug Administration (FDA) to deny approval of etidronate for postmenopausal osteoporosis. Second, 2 years ago alendronate, a newer bisphosphonate, was reported to reduce vertebral fractures and increase spine and hip bone density after 3 years of treatment.7 Unlike etidronate, alendronate was not associated with osteomalacia and won speedy approval by the FDA. Soon thereafter, the Fracture Intervention Trial (FIT) showed that alendronate drastically reduced osteoporotic fractures in older postmenopausal women, with few adverse effects.8 The combination of US regulatory approval of alendronate, a strong media blitz, and proven efficacy in two multicentre placebo-controlled trials was sufficient to induce American practitioners to switch their off-label use of etidronate to alendronate. Meanwhile, etidronate was still prescribed outside the USA because of its excellent safety profile, its capacity to improve bone density, and its low cost. In the past 3 years, etidronate has won approval for the treatment of postmenopausal osteoporosis in 23 countries, and is the dominant bisphosphonate prescribed for this disease on three continents. These three new studies1–3 on etidronate reopen this prescribing dichotomy and raise more questions than answers in this tale of two worlds. The first question is whether the magnitude of increase in bone density indicates the degree of fracture-prevention efficacy. Alendronate produces a greater increment in bone density at all sites than does etidronate but recent studies provide ample evidence that fracture prevention does not necessarily correlate with the magnitude of increase in bone density. Second, is there a difference between alendronate and etidronate in prevention of bone loss for healthy postmenopausal women? The answer is probably no since all the bisphosphonates can slow bone loss during 1340
the menopause.2,3 Third, is alendronate safer than etidronate? If etidronate is used properly, the answer is no. Indeed, gastrointestinal tolerance is slightly better for etidronate than alendronate, and neither causes osteomalacia when prescribed properly.3,6,8 Fourth, does etidronate prevent fractures in postmenopausal women with osteoporosis? The answer to that question is unclear, since post-hoc analysis of the US multicentre trial showed that etidronate reduced vertebral fractures in women with the lowest bone density and previous fractures, while alendronate showed fracture efficacy in all postmenopausal cohorts under investigation.6,7,8 Unfortunately, the US etidronate trial was grossly underpowered for fracture efficacy, having enrolled only 450 women, some with minimal disease.6 Hence, this question will probably never be answered. Still, it is worth noting that severely osteoporotic women in that trial experienced the greatest benefit from etidronate and were nearly identical in respect to bone density and previous fractures as women who participated in FIT.6,8 Finally, are there more treatment failures among women receiving etidronate than those prescribed alendronate? In FIT, a decline in bone density was reported in fewer than 5% of treated women.8 In the etidronate trial, non-response was three to four fold higher.6 These and other questions will remain unanswered unless a randomised, placebo-controlled, comparative study in postmenopausal osteoporotic women is undertaken. Such a trial seems highly unlikely to be conducted since several new bisphosphonates will soon win regulatory approval. This leaves today’s clinician with an interesting choice of bisphosphonates. Which one the practitioner chooses must rest on his/her ability to interpret the published evidence, balance safety issues, consider the risk of treatment failure, weigh the cost of therapy, and foremost, heed the wishes of his/her patient. That, rather than geographic location, remains the art of medicine.
Clifford J Rosen Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Bangor, ME 04401, USA 1
2
3
4
5
6
7
8
Adachi JD, Bensen WD, Brown J, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382–87. Meunier PJ, Confavreauz E, Tupinon I, Hardouin C, Delmas PD, Balena R. Prevention of early postmenopausal bone loss with cyclical etidronate therapy. J Clin Endocrinol Metab 1997; 82: 2784–91. Herd RJ, Balena R, Blake GM, Ryan PJ, Fogelman I. Prevention of early postmenopausal bone loss by cyclical etidronate: a two year doubleblind placebo-controlled study. Am J Med 1997; 103: 92–99. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265–71. Watts NB, Harris ST, Genant HK, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73–79. Harris ST,Watts NB, Jackson RD, et al. Four year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med 1993; 95: 557–67. Liberman VA,Weiss SR, Broll J, et al. Effect of oral alendronate on bone density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333: 1437–43. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson ED. Randomized trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535–41.
Vol 350 • November 8, 1997