Suppressed Bone Turnover during Alendronate Therapy for High-Turnover Osteoporosis
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《新英格兰医药杂志》
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 1A), 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.
Figure 1. Bone-Biopsy Specimens Obtained before and after Alendronate Treatment.
Bone core biopsies of the iliac crest taken before alendronate treatment (Panels A, B, and C) and after alendronate treatment (Panels D, E, and F) were embedded in methyl methacrylate, as seen on von Kossa's staining (Panels A, B, D, and E) or fluorescence microscopy (Panels C and F).
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.
Reina 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 63017
Deborah Novack, M.D., Ph.D.
Washington University School of Medicine
St. Louis, MO 63110
References
Rosen CJ. Postmenopausal osteoporosis. N Engl J Med 2005;353:595-603.
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.
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.
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.
Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005;90:1897-1899.
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 1A), 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.
Figure 1. Bone-Biopsy Specimens Obtained before and after Alendronate Treatment.
Bone core biopsies of the iliac crest taken before alendronate treatment (Panels A, B, and C) and after alendronate treatment (Panels D, E, and F) were embedded in methyl methacrylate, as seen on von Kossa's staining (Panels A, B, D, and E) or fluorescence microscopy (Panels C and F).
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.
Reina 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 63017
Deborah Novack, M.D., Ph.D.
Washington University School of Medicine
St. Louis, MO 63110
References
Rosen CJ. Postmenopausal osteoporosis. N Engl J Med 2005;353:595-603.
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.
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.
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.
Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005;90:1897-1899.