Correspondence
Ten Years of Alendronate Treatment for Osteoporosis in Postmenopausal Women
N Engl J Med 2004; 351:190-192July 8, 2004
- Article
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.
5 ReferencesNina H. Bjarnason, M.D.
Institute for Rational Pharmacotherapy, 2300 S Copenhagen, Denmark
nbj@dkma.dk 1
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
Full Text | Web of Science | Medline2
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
CrossRef | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
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
CrossRef | Web of Science | Medline5
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
Web of Science | Medline
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
4 ReferencesAndrew S. Chan, M.D.
Kaiser Panorama City Medical Center, Panorama City, CA 914021
Plotnikoff GA ,Quigley JM . Prevalence of severe hypovitaminosis D in patients with persistent nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463-1470
CrossRef | Web of Science | Medline2
Hochwald O ,Harman-Boehm I ,Castel H . Hypovitaminosis D among inpatients in a sunny country. Isr Med Assoc J 2004;6:82-87
Web of Science | Medline3
Smith RL . Calcium and vitamin D supplementation in nursing home residents. J Am Med Dir Assoc 2003;4:Suppl 2:S23-S31
CrossRef | Medline4
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
Web of Science | Medline
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.
5 ReferencesSusan M. Ott, M.D.
University of Washington, Seattle, WA 98195
smott@u.washington. edu 1
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
Full Text | Web of Science | Medline2
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
Full Text | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
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
Full Text | Web of Science | Medline5
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
Full Text | Web of Science | Medline
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.2-4 This possible complication of impaired intraoral bone healing in patients receiving long-term bisphosphonate therapy warrants close surveillance.
4 ReferencesSalvatore 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 1
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
CrossRef | Web of Science | Medline2
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
Web of Science | Medline3
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;5:613-6204
Kapitola J ,Zak J . Effect of pamidronate on bone blood flow in oophorectomized rats. Physiol Res 1998;47:237-240
Web of Science | Medline
Author/Editor Response
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.1-3 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.
3 ReferencesHenry G. Bone, M.D.
Michigan Bone and Mineral Clinic, Detroit, MI 48236Arthur C. Santora, M.D., Ph.D.
Merck Research Laboratories, Rahway, NJ 070651
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
Full Text | Web of Science | Medline2
Cranney A ,Guyatt G ,Griffith L , et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:496-578
CrossRef | Web of Science | Medline3
Fosamax prescribing information. In: Physicians' Desk Reference. 58th ed. Montvale, N.J.: Medical Economics, 2004:1986-92.
- Citing Articles (6)
Citing Articles
1
Davide Ruffoni, Peter Fratzl, Paul Roschger, Roger Phipps, Klaus Klaushofer, Richard Weinkamer. (2008) Effect of Temporal Changes in Bone Turnover on the Bone Mineralization Density Distribution: A Computer Simulation Study. Journal of Bone and Mineral Research 23:12, 1905-1914
CrossRef2
Stuart L. Silverman, Michael Maricic. (2007) Recent Developments in Bisphosphonate Therapy. Seminars in Arthritis and Rheumatism 37:1, 1-12
CrossRef3
P. Milillo, A. P. Garribba, G. Favia, G. C. Ettorre. (2007) Jaw osteonecrosis in patients treated with bisphosphonates: MDCT evaluation. La radiologia medica 112:4, 603-611
CrossRef4
Martha Bass, M Allison Ford, Barry Brown, Andy Mauromoustakos, Roseanne S. Keathley. (2006) Variables for the Prediction of Femoral Bone Mineral Status in American Women. Southern Medical Journal 99:2, 115-122
CrossRef5
E. Merigo, M. Manfredi, M. Meleti, D. Corradi, P. Vescovi. (2005) Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. Journal of Oral Pathology and Medicine 34:10, 613-617
CrossRef6
Harmon Katz. (2005) Endodontic Implications of Bisphosphonate-Associated Osteonecrosis of the Jaws: A Report of Three Cases. Journal of Endodontics 31:11, 831-834
CrossRef
