Ten Years of Alendronate Treatment for Osteoporosis in Postmenopausal Women
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In their report on 10 years of alendronate therapy for osteoporosis in postmenopausal women, Bone et al. (March 18 issue)1 mention the long retention time of alendronate in bone as an advantage. This view is based on the fact that the large reduction in bone turnover is present five years after the discontinuation of treatment. The authors claim that histomorphometric analysis confirmed long-term bone safety,2,3 but the study they cite followed treatment for only two to three years in a small group of patients receiving 20 mg of alendronate.2 What the present study actually shows is that two years of therapy with 20 mg of alendronate followed by three years' treatment with 5 mg suppresses bone turnover to a degree from which it may not recover. This result is consistent with data from a study in Danish women, which showed that two years of treatment with 20 mg of alendronate led to a reduction in bone turnover that did not return to baseline five years after the discontinuation of therapy.4 In contrast, with two years of therapy with 2.5 mg or 5 mg of alendronate,5 bone turnover returned to placebo levels two years after discontinuation. Thus, the long-term safety with 20 mg of alendronate has not been established.
Nina H. Bjarnason, M.D.
Institute for Rational Pharmacotherapy
2300 S Copenhagen, Denmark
nbj@dkma.dk
References
Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 1997;100:1475-1480.
Boivin GY, Chavassieux PM, Santora AC, Yates AJ, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 2000;27:687-694.
Bagger YZ, Tanko LB, Alexandersen P, Ravn P, Christiansen C. Alendronate has a residual effect on bone mass in postmenopausal Danish women up to 7 years after treatment withdrawal. Bone 2003;33:301-307.
Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the Early Postmenopausal Intervention Cohort study. Ann Intern Med 1999;131:935-942.
To the Editor: The design of the study by Bone et al. permitted but did not require vitamin D supplementation. I question the wisdom of this approach. Since there is a high prevalence of vitamin D deficiency in community-dwelling,1 hospitalized,2 and nursing-home3 populations, controlling for adequate body stores of vitamin D seems fundamental and necessary for this type of study. The groups with the two different dosages of alendronate may have had an even greater increase in bone mineral density, and the discontinuation group may have had a lesser decline. An additional baseline characteristic for all the study groups should have been a 25-hydroxyvitamin D level greater than 20 to 30 ng per milliliter (50 to 75 nmol per liter).4
Andrew S. Chan, M.D.
Kaiser Panorama City Medical Center
Panorama City, CA 91402
References
Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463-1470.
Hochwald O, Harman-Boehm I, Castel H. Hypovitaminosis D among inpatients in a sunny country. Isr Med Assoc J 2004;6:82-87.
Smith RL. Calcium and vitamin D supplementation in nursing home residents. J Am Med Dir Assoc 2003;4:Suppl 2:S23-S31. [Medline]
Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210.
To the Editor: The optimal dose of bisphosphonates for preventing fractures has not yet been determined. With alendronate, there were no significant differences in the rate of fracture between the 5-mg and 10-mg daily doses, either during the first three years (rate of vertebral fracture, 2.9 percent and 2.8 percent per year, respectively)1 or during years 6 to 10 (rate of symptomatic nonvertebral fracture, 4.1 per 100 subject-years and 3.1 per 100 subject-years).2 These fracture rates are difficult to evaluate because the baseline prevalence of vertebral fracture was 30.8 percent in the 5-mg group and only 17.5 percent in the 10-mg group. The risk of vertebral fracture increases by a factor of four in women who have a prevalent fracture, as compared with women who do not, even after adjustment for age and bone mineral density.3 In a study in which 5445 women with osteoporosis were evaluated, the incidence of hip fracture was significantly decreased with 2.5 mg of risedronate daily but was not significantly decreased with 5 mg daily.4
Fractures are more important than bone density. Despite the reassuring data from the report by Bone et al., questions remain about possible brittleness of the bones in the second decade of bisphosphonate use. Patients with bisphosphonate accumulation may lose their capacity to benefit from newer anabolic agents.5 Thus, I see no clear advantage of using the higher doses and suggest prescribing alendronate at a dose of 35 mg per week.
Susan M. Ott, M.D.
University of Washington
Seattle, WA 98195
smott@u.washington.edu
Editor's note: Dr. Ott reports having received a research grant from Proctor & Gamble.
References
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.
Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
Black DM, Arden NK, Palermo L, et al. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. J Bone Miner Res 1999;14:821-828.
McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333-340.
Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-1215.
To the Editor: In their discussion of the safety profile of bisphosphonate therapy, Bone et al. do not mention a potential complication: oral osteonecrosis. Recently at our institution, there has been growing concern about delayed bone healing and osteonecrosis of the jaws in association with the use of bisphosphonates. The typical presentation is a nonhealing tooth-extraction socket or exposed jawbone, both of which appear to be refractory to conservative débridement and antibiotic therapy. Except for the presence of maxillary-bone involvement, the clinical presentation is similar to that of osteoradionecrosis. Bisphosphonate treatment was the only common factor in all 63 of the cases we have reported.1 Sixty patients were receiving intravenous bisphosphonate therapy for the treatment of bone metastases. Examination of biopsy specimens of the jaw lesions showed no evidence of metastatic disease. Ten patients in this series were receiving bisphosphonates (oral preparations in eight and intravenous preparations in two) for the treatment of osteoporosis. The pathogenesis of jaw lesions may be related to potent osteoclastic inhibition, altered blood flow in bone, or localized antiangiogenesis.2,3,4 This possible complication of impaired intraoral bone healing in patients receiving long-term bisphosphonate therapy warrants close surveillance.
Salvatore L. Ruggiero, D.M.D., M.D.
Bhoomi Mehrotra, M.B., B.S.
Long Island Jewish Medical Center
New Hyde Park, NY 11040
ruggiero@lij.edu
References
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-534.
Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:6538-6544.
Mashiba T, Hirano T, Turner CH, et al. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2001;5:613-620.
Kapitola J, Zak J. Effect of pamidronate on bone blood flow in oophorectomized rats. Physiol Res 1998;47:237-240.
The authors reply: Dr. Bjarnason expresses concern about the effects of protracted therapy with alendronate at a dose of 20 mg daily. That dose was included in the first two years of our study but offered no apparent advantage over lower doses, and thus it is not recommended. Dr. Ott suggests that alendronate at a dose of 35 mg weekly be used for the treatment of osteoporosis. That is currently the recommended dose for the prevention of osteoporosis. However, the approved dose for the treatment of osteoporosis is 10 mg daily or 70 mg weekly.1,2,3 Our study did not have adequate statistical power to compare fracture rates between doses of 5 mg and 10 mg daily, so we limited our analyses to the turnover and bone-density end points, which appeared to favor the 10-mg regimen. Dr. Chan notes the prevalence of vitamin D deficiency in elderly patients and suggests that adequate vitamin D may be necessary for an optimal response. We agree that ensuring adequate vitamin D intake is important for all patients with osteoporosis. When our study was initiated, in 1992, we did exclude patients with vitamin D deficiency.1
Drs. Ruggiero and Mehrotra refer to their report of osteonecrosis in persons treated with bisphosphonates, most of whom received high-dose intravenous bisphosphonates for multiple myeloma or other cancers that had metastasized to bone. Chemotherapy, recent dentoalveolar procedures, glucocorticosteroid exposure, and oral infections are possible risk factors, and such conditions appear to have been present in most of those patients. More detailed clinical information would be helpful, particularly concerning any patients treated only with oral bisphosphonates in the absence of cancer or other predisposing conditions. No similar cases were identified in our study or other clinical trials of alendronate. Osteonecrosis was not observed in preclinical studies of alendronate, which included much higher exposures than those used to treat osteoporosis in humans. In view of the very large number of persons who have been treated with alendronate (for an estimated 20 million patient-years), a careful, systematic, epidemiologic approach will be needed to distinguish between chance association and a causal relationship.
Henry G. Bone, M.D.
Michigan Bone and Mineral Clinic
Detroit, MI 48236
Arthur C. Santora, M.D., Ph.D.
Merck Research Laboratories
Rahway, NJ 07065
References
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.
Cranney A, Guyatt G, Griffith L, et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:496-578.
Fosamax prescribing information. In: Physicians' Desk Reference. 58th ed. Montvale, N.J.: Medical Economics, 2004:1986-92.
Nina H. Bjarnason, M.D.
Institute for Rational Pharmacotherapy
2300 S Copenhagen, Denmark
nbj@dkma.dk
References
Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 1997;100:1475-1480.
Boivin GY, Chavassieux PM, Santora AC, Yates AJ, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 2000;27:687-694.
Bagger YZ, Tanko LB, Alexandersen P, Ravn P, Christiansen C. Alendronate has a residual effect on bone mass in postmenopausal Danish women up to 7 years after treatment withdrawal. Bone 2003;33:301-307.
Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the Early Postmenopausal Intervention Cohort study. Ann Intern Med 1999;131:935-942.
To the Editor: The design of the study by Bone et al. permitted but did not require vitamin D supplementation. I question the wisdom of this approach. Since there is a high prevalence of vitamin D deficiency in community-dwelling,1 hospitalized,2 and nursing-home3 populations, controlling for adequate body stores of vitamin D seems fundamental and necessary for this type of study. The groups with the two different dosages of alendronate may have had an even greater increase in bone mineral density, and the discontinuation group may have had a lesser decline. An additional baseline characteristic for all the study groups should have been a 25-hydroxyvitamin D level greater than 20 to 30 ng per milliliter (50 to 75 nmol per liter).4
Andrew S. Chan, M.D.
Kaiser Panorama City Medical Center
Panorama City, CA 91402
References
Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463-1470.
Hochwald O, Harman-Boehm I, Castel H. Hypovitaminosis D among inpatients in a sunny country. Isr Med Assoc J 2004;6:82-87.
Smith RL. Calcium and vitamin D supplementation in nursing home residents. J Am Med Dir Assoc 2003;4:Suppl 2:S23-S31. [Medline]
Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210.
To the Editor: The optimal dose of bisphosphonates for preventing fractures has not yet been determined. With alendronate, there were no significant differences in the rate of fracture between the 5-mg and 10-mg daily doses, either during the first three years (rate of vertebral fracture, 2.9 percent and 2.8 percent per year, respectively)1 or during years 6 to 10 (rate of symptomatic nonvertebral fracture, 4.1 per 100 subject-years and 3.1 per 100 subject-years).2 These fracture rates are difficult to evaluate because the baseline prevalence of vertebral fracture was 30.8 percent in the 5-mg group and only 17.5 percent in the 10-mg group. The risk of vertebral fracture increases by a factor of four in women who have a prevalent fracture, as compared with women who do not, even after adjustment for age and bone mineral density.3 In a study in which 5445 women with osteoporosis were evaluated, the incidence of hip fracture was significantly decreased with 2.5 mg of risedronate daily but was not significantly decreased with 5 mg daily.4
Fractures are more important than bone density. Despite the reassuring data from the report by Bone et al., questions remain about possible brittleness of the bones in the second decade of bisphosphonate use. Patients with bisphosphonate accumulation may lose their capacity to benefit from newer anabolic agents.5 Thus, I see no clear advantage of using the higher doses and suggest prescribing alendronate at a dose of 35 mg per week.
Susan M. Ott, M.D.
University of Washington
Seattle, WA 98195
smott@u.washington.edu
Editor's note: Dr. Ott reports having received a research grant from Proctor & Gamble.
References
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.
Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.
Black DM, Arden NK, Palermo L, et al. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. J Bone Miner Res 1999;14:821-828.
McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333-340.
Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-1215.
To the Editor: In their discussion of the safety profile of bisphosphonate therapy, Bone et al. do not mention a potential complication: oral osteonecrosis. Recently at our institution, there has been growing concern about delayed bone healing and osteonecrosis of the jaws in association with the use of bisphosphonates. The typical presentation is a nonhealing tooth-extraction socket or exposed jawbone, both of which appear to be refractory to conservative débridement and antibiotic therapy. Except for the presence of maxillary-bone involvement, the clinical presentation is similar to that of osteoradionecrosis. Bisphosphonate treatment was the only common factor in all 63 of the cases we have reported.1 Sixty patients were receiving intravenous bisphosphonate therapy for the treatment of bone metastases. Examination of biopsy specimens of the jaw lesions showed no evidence of metastatic disease. Ten patients in this series were receiving bisphosphonates (oral preparations in eight and intravenous preparations in two) for the treatment of osteoporosis. The pathogenesis of jaw lesions may be related to potent osteoclastic inhibition, altered blood flow in bone, or localized antiangiogenesis.2,3,4 This possible complication of impaired intraoral bone healing in patients receiving long-term bisphosphonate therapy warrants close surveillance.
Salvatore L. Ruggiero, D.M.D., M.D.
Bhoomi Mehrotra, M.B., B.S.
Long Island Jewish Medical Center
New Hyde Park, NY 11040
ruggiero@lij.edu
References
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-534.
Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:6538-6544.
Mashiba T, Hirano T, Turner CH, et al. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2001;5:613-620.
Kapitola J, Zak J. Effect of pamidronate on bone blood flow in oophorectomized rats. Physiol Res 1998;47:237-240.
The authors reply: Dr. Bjarnason expresses concern about the effects of protracted therapy with alendronate at a dose of 20 mg daily. That dose was included in the first two years of our study but offered no apparent advantage over lower doses, and thus it is not recommended. Dr. Ott suggests that alendronate at a dose of 35 mg weekly be used for the treatment of osteoporosis. That is currently the recommended dose for the prevention of osteoporosis. However, the approved dose for the treatment of osteoporosis is 10 mg daily or 70 mg weekly.1,2,3 Our study did not have adequate statistical power to compare fracture rates between doses of 5 mg and 10 mg daily, so we limited our analyses to the turnover and bone-density end points, which appeared to favor the 10-mg regimen. Dr. Chan notes the prevalence of vitamin D deficiency in elderly patients and suggests that adequate vitamin D may be necessary for an optimal response. We agree that ensuring adequate vitamin D intake is important for all patients with osteoporosis. When our study was initiated, in 1992, we did exclude patients with vitamin D deficiency.1
Drs. Ruggiero and Mehrotra refer to their report of osteonecrosis in persons treated with bisphosphonates, most of whom received high-dose intravenous bisphosphonates for multiple myeloma or other cancers that had metastasized to bone. Chemotherapy, recent dentoalveolar procedures, glucocorticosteroid exposure, and oral infections are possible risk factors, and such conditions appear to have been present in most of those patients. More detailed clinical information would be helpful, particularly concerning any patients treated only with oral bisphosphonates in the absence of cancer or other predisposing conditions. No similar cases were identified in our study or other clinical trials of alendronate. Osteonecrosis was not observed in preclinical studies of alendronate, which included much higher exposures than those used to treat osteoporosis in humans. In view of the very large number of persons who have been treated with alendronate (for an estimated 20 million patient-years), a careful, systematic, epidemiologic approach will be needed to distinguish between chance association and a causal relationship.
Henry G. Bone, M.D.
Michigan Bone and Mineral Clinic
Detroit, MI 48236
Arthur C. Santora, M.D., Ph.D.
Merck Research Laboratories
Rahway, NJ 07065
References
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.
Cranney A, Guyatt G, Griffith L, et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:496-578.
Fosamax prescribing information. In: Physicians' Desk Reference. 58th ed. Montvale, N.J.: Medical Economics, 2004:1986-92.