Correspondence
Suppressed Bone Turnover during Alendronate Therapy for High-Turnover Osteoporosis
N Engl J Med 2006; 355:2048-2050November 9, 2006
- Article
To the Editor:
Bisphosphonates are the most widely used agents to prevent and treat osteoporosis.1 Although their safety has been tested in randomized trials (for up to 10 years),2 reports of previously unnoticed complications, such as severe suppression of bone turnover3 and osteonecrosis of the jaw,4 have emerged with long-term use.
A 35-year-old man was referred to our Bone Health Program in 1996 because of wrist and pelvic fractures after mild trauma. The z scores for bone mineral density (BMD) on dual-energy x-ray absorptiometry were −4.9 at the spine and −1.7 at the femoral neck. Biopsy of the right iliac crest showed reduced trabecular bone volume and trabecular connectivity (Figure 1AFigure 1
Bone-Biopsy Specimens Obtained before and after Alendronate Treatment.), an increased amount of osteoid over the trabecular surface (Figure 1B), and increased osteogenesis (as seen after fluorescent tetracycline double labeling) at the entire interface between osteoid and mineralized bone (Figure 1C). These findings were consistent with the presence of high-turnover osteoporosis.The results of an additional radiologic workup and a biochemical workup for secondary causes of bone loss were negative, with the following biochemical values: 25-hydroxyvitamin D, 22 ng per milliliter (normal range, 10 to 55); calcium, 9.5 mg per deciliter (normal range, 8.8 to 10.3); parathyroid hormone, 44 pg per milliliter (normal range, 10 to 55); urinary cortisol, 30 μg in a 24-hour period (normal range, 9 to 53); testosterone, 529 ng per deciliter (normal range, 270 to 1070); thyrotropin, 3.2 μU per milliliter (normal range, 0.4 to 6.2); osteocalcin, 25 μg per liter (normal range, 2 to 15); and the ratio of N-telopeptide (in nanomoles) to creatinine (in millimoles), 49 (normal range, 13 to 86).
On the basis of these tests, the patient received a diagnosis of idiopathic osteoporosis and began to receive 10 mg of alendronate daily and 1000 mg of calcium daily. After 5 years of treatment, he was discovered to have new thoracic vertebral compression fractures, despite having had improvement in his serial BMD measurements (with z scores of −2.9 at the spine and −0.8 at the femoral neck). The patient discontinued alendronate on his own after 6 years of treatment. One year later, he had a subtrochanteric fracture of the right femur after mild trauma. A bone biopsy showed severely decreased trabecular connectivity, with many small islands of bone (Figure 1D), decreased marrow cellularity, a lack of osteoid on trabecular surfaces (Figure 1E), and an absence of tetracycline labeling (Figure 1F), suggesting marked suppression of bone turnover. At the time of this report, his fracture had not completely healed.
Bisphosphonates effectively prevent vertebral and hip fractures. However, there is growing concern that long-term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage, thus potentially offsetting their beneficial effects with regard to the prevention of fractures.5 Our finding of fracture in an unusual site (i.e., the femoral metaphysis, which is primarily composed of cortical bone), associated with a biopsy-proven conversion from high turnover of bone to suppressed turnover after 6 years of alendronate treatment, is consistent with this picture. The identification of factors that may increase the risk of such complications should help define the proper balance between beneficial effects and potential risks of bisphosphonates in the context of long-term suppression of remodeling.
5 ReferencesReina Armamento-Villareal, M.D.
Nicola Napoli, M.D.
Washington University School of Medicine, St. Louis, MO 63110
rvillare@im.wustl. edu Vinita Panwar, M.D.
St. Luke's Hospital, St. Louis, MO 63017Deborah Novack, M.D., Ph.D.
Washington University School of Medicine, St. Louis, MO 631101
Rosen CJ . Postmenopausal osteoporosis. N Engl J Med 2005;353:595-603
Full Text | Web of Science | Medline2
Bone HG ,Hosking D ,Devogelaer J , 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
Odvina CV ,Zerwekh JE ,Rao DS ,Maalouf N ,Gottschalk FA ,Pak CY . Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301
CrossRef | Web of Science | Medline4
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 | Medline5
Ott SM . Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005;90:1897-1899
CrossRef | Web of Science | Medline
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R. Rizzoli, K. Åkesson, M. Bouxsein, J. A. Kanis, N. Napoli, S. Papapoulos, J.-Y. Reginster, C. Cooper. (2011) Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporosis International 22:2, 373-390
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Andrea Giusti, Neveen A.T. Hamdy, Socrates E. Papapoulos. (2010) Atypical fractures of the femur and bisphosphonate therapy. Bone 47:2, 169-180
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Bo Abrahamsen. (2010) Adverse Effects of Bisphosphonates. Calcified Tissue International 86:6, 421-435
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Black, Dennis M., Kelly, Michael P., Genant, Harry K., Palermo, Lisa, Eastell, Richard, Bucci-Rechtweg, Christina, Cauley, Jane, Leung, Ping Chung, Boonen, Steven, Santora, Arthur, de Papp, Anne, Bauer, Douglas C., . (2010) Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur. New England Journal of Medicine 362:19, 1761-1771
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N. Napoli, D. Novack, R. Armamento-Villareal. (2010) Bisphosphonate-associated femoral fracture: implications for management in patients with malignancies. Osteoporosis International 21:4, 705-708
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Clarita V. Odvina, Shiri Levy, Sudhir Rao, Joseph E. Zerwekh, D. S. Rao. (2010) Unusual mid-shaft fractures during long-term bisphosphonate therapy. Clinical Endocrinology 72:2, 161-168
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Robert D. Bunning, Robert J. Rentfro, James S. Jelinek. (2010) Low-Energy Femoral Fractures Associated With Long-Term Bisphosphonate Use in a Rehabilitation Setting: A Case Series. PM&R 2:1, 76-80
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Jung-Gwan Park, Kwang-Sup Song, Ho-Joong Jung, Jae-Sung Lee, Tae-Jin Lee, Ki-Seong Kim. (2010) Bilateral Femoral Subtrochanteric Insufficiency Fractures after Long-term Bisphosphonate Therapy. Journal of the Korean Orthopaedic Association 45:2, 146
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Kuntheavy Ing-Lorenzini, Jules Desmeules, Olivier Plachta, Domizio Suva, Pierre Dayer, Robin Peter. (2009) Low-Energy Femoral Fractures Associated with the Long-Term Use of Bisphosphonates. Drug Safety 32:9, 775-785
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Reina Armamento-Villareal, Nicola Napoli, Kathryn Diemer, Marcus Watkins, Roberto Civitelli, Steven Teitelbaum, Deborah Novack. (2009) Bone Turnover in Bone Biopsies of Patients with Low-Energy Cortical Fractures Receiving Bisphosphonates: A Case Series. Calcified Tissue International 85:1, 37-44
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Bruno Frediani, Luca Cavalieri, Giovanni Cremonesi. (2009) Clodronic Acid Formulations Available in Europe and their Use in Osteoporosis. Clinical Drug Investigation 29:6, 359-379
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Luigi Gennari, John P Bilezikian. (2009) Glucocorticoid-induced osteoporosis: hope on the HORIZON. The Lancet 373:9671, 1225-1226
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Ali Zamani, Gholamhossein R. Omrani, Masoud Mousavi Nasab. (2009) Lithium's effect on bone mineral density. Bone 44:2, 331-334
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Seth M Arum. (2008) New developments surrounding the safety of bisphosphonates. Current Opinion in Endocrinology, Diabetes and Obesity 15:6, 508-513
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Michael Samoszuk, Michael Leuther, Nicholas Hoyle. (2008) Role of serum P1NP measurement for monitoring treatment response in osteoporosis. Biomarkers in Medicine 2:5, 495-508
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Michael P Whyte, William H McAlister, Deborah V Novack, Karen L Clements, Perry L Schoenecker, Deborah Wenkert. (2008) Bisphosphonate-Induced Osteopetrosis: Novel Bone Modeling Defects, Metaphyseal Osteopenia, and Osteosclerosis Fractures After Drug Exposure Ceases. Journal of Bone and Mineral Research 23:10, 1698-1707
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M. T. Drake, B. L. Clarke, S. Khosla. (2008) Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clinic Proceedings 83:9, 1032-1045
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Ernest Beng Kee Kwek, Seo Kiat Goh, Joyce Suang Bee Koh, Meng Ai Png, Tet Sen Howe. (2008) An emerging pattern of subtrochanteric stress fractures: A long-term complication of alendronate therapy?. Injury 39:2, 224-231
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Deborah V. Novack, Steven L. Teitelbaum. (2008) The Osteoclast: Friend or Foe?. Annual Review of Pathology: Mechanisms of Disease 3:1, 457-484
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T. Matsunaga, M. Shigetomi, T. Hashimoto, H. Suzuki, T. Gondo, H. Tanaka, T. Sugiyama, T. Taguchi. (2007) Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats. Osteoporosis International 18:11, 1531-1540
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Takahiro Hashimoto, Mitsunori Shigetomi, Teruyasu Ohno, Tsunemitsu Matsunaga, Keiichi Muramatsu, Hiroshi Tanaka, Toshihiro Sugiyama, Toshihiko Taguchi. (2007) Sequential Treatment with Intermittent Low-Dose Human Parathyroid Hormone (1-34) and Bisphosphonate Enhances Large-Size Skeletal Reconstruction by Vascularized Bone Transplantation. Calcified Tissue International 81:3, 232-239
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S. Reinsdorf, B. Habermann, K. Hochmuth, A.A. Kurth. (2007) Bisphosphonate in der Osteoporosetherapie. Der Orthopäde 36:2, 110-117
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