Postmenopausal Osteoporosis and Strontium Ranelate
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Meunier et al. (Jan. 29 issue)1 studied the effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis in a placebo-controlled trial. We are surprised by their statement, "To date, no deleterious effects on the primary or secondary mineralization of bone in laboratory animals or humans have been reported." We found an association between increased levels of bone strontium and osteomalacia in patients undergoing dialysis.2 A worldwide epidemiologic study showed that patients undergoing dialysis were at risk for strontium accumulation.3 The role of strontium in the development of osteomalacia was demonstrated in a rat model of renal failure4,5 and was reproduced in vitro.6 These data are relevant because the target population of patients consists mainly of elderly women whose renal function is already reduced. As mentioned in the accompanying editorial by Fuleihan,7 the use of strontium for osteoporosis in the 1950s was associated with mineralization defects. Although strontium ranelate may have therapeutic potential, the risk of mineralization defects in patients with reduced renal function should be mentioned.
Patrick C. D'Haese, Ph.D.
University of Antwerp
B-2650 Antwerp, Belgium
Francisco Santacruz, M.D.
National University of Asuncion
1120 Asuncion, Paraguay
Marc E. De Broe, M.D., Ph.D.
University of Antwerp
B-2650 Antwerp, Belgium
marc.debroe@ua.ac.be
References
Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-468.
D'Haese PC, Schrooten I, Goodman WG, et al. Increased bone strontium levels in hemodialysis patients with osteomalacia. Kidney Int 2000;57:1107-1114.
Schrooten I, Elseviers MM, Lamberts LV, De Broe ME, D'Haese PC. Increased serum strontium levels in dialysis patients: an epidemiological survey. Kidney Int 1999;56:1886-1892.
Schrooten I, Cabrera W, Goodman WG, et al. Strontium causes osteomalacia in chronic renal failure rats. Kidney Int 1998;54:448-456.
Schrooten I, Behets GJ, Cabrera WE, et al. Dose-dependent effects of strontium on bone of chronic renal failure rats. Kidney Int 2003;63:927-935.
Verberckmoes SC, De Broe ME, D'Haese PC. Dose-dependent effects of strontium on osteoblast function and mineralization. Kidney Int 2003;64:534-543.
Fuleihan GE. Strontium ranelate: a novel therapy for osteoporosis or a permutation of the same? N Engl J Med 2004;350:504-506.
To the Editor: Meunier et al. bring strontium ranelate back to the forefront of the therapeutic armamentarium against osteoporosis. Since their data may affect more than 44 million persons — 55 percent of the population over the age of 50 years in the United States1 — clarification should be provided regarding the analysis performed. In the Methods section, the authors state that they calculated Kaplan–Meier product-limit estimates and used an unadjusted Cox regression model to compare the incidence of new vertebral fractures among subjects randomly assigned to receive strontium ranelate or placebo. However, the results of these analyses are not presented. A survival curve and hazard ratios for the incidence of vertebral fractures in the two groups would have been very useful for further characterizing the effectiveness of strontium ranelate therapy in the treatment of postmenopausal osteoporosis.
Ying Taur, M.D., M.P.H.
Long Island Jewish Medical Center
New Hyde Park, NY 11040
yingtaur@earthlink.net
Farrah Al-Tureihi, M.D.
Gisele Wolf-Klein, M.D.
Parker Jewish Institute for Health Care and Rehabilitation
New Hyde Park, NY 11040
References
America's bone health: the state of osteoporosis and low bone mass in our nation. Washington, D.C.: National Osteoporosis Foundation, February 2002. (Accessed April 16, 2004, at http://www.nof.org/advocacy/prevalence/index.htm.)
Dr. Meunier replies: Dr. D'Haese and colleagues have previously reported that strontium could be involved in delayed mineralization in vitro and in a model of renal failure in rats. In contrast, as we mentioned in our article, no deleterious effect of strontium ranelate on bone mineralization has been reported in laboratory animals with normal renal function, for an exposure similar to that in clinical trials. Data from patients with end-stage renal failure suggest that strontium may be a causal agent for osteomalacia in patients undergoing dialysis, who may be exposed to elevated strontium levels in dialysis fluids.1 However, the strontium content of bone in patients undergoing dialysis does not always correlate with defective mineralization, as indicated by reports of bone-biopsy results in patients with end-stage renal failure.2,3 Many other elements that accumulate in the bones of patients undergoing dialysis (e.g., aluminum and fluoride) may be responsible for mineralization defects.4,5 Therefore, any results suggesting that osteomalacia may be induced by strontium in patients with end-stage renal failure or patients undergoing dialysis should be interpreted with caution.
The target population we studied did not have severe renal failure (mean [±SD] serum creatinine level, 87.1±11.9 μmol per liter). I personally examined more than 200 bone-biopsy specimens from patients treated with strontium ranelate during the clinical development program, and I did not identify any signs of mineralization defects (an increased osteoid thickness or mineralization lag time or a decreased mineralization apposition rate). Thus, I would state that delayed mineralization has not been observed with strontium ranelate in an in vitro study, in intact animals, or in humans with moderate renal insufficiency.
In response to Dr. Taur and colleagues, the Cox model was used to compare groups for the occurrence of the first new vertebral fracture. The treatment effect was estimated with the use of hazard ratios — namely, relative risks, as stated in the article (i.e., a hazard ratio of 0.59 as an estimate of the treatment effect over a three-year period). Since radiographs were obtained yearly, not continuously, Kaplan–Meier estimates could be computed only from the assessments at months 12, 24, and 36, of which the assessments at months 12 (the earliest) and 36 (the one of particular clinical relevance) are given in the Results section and in Figure 2 of our article, with formal estimates given for months 12 and 36. For example, Kaplan–Meier estimates of the probability of vertebral fracture at month 36 — namely, 32.8 percent for placebo as compared with 20.9 percent for strontium ranelate — are given both in the Results section and in Figure 2.
Pierre J. Meunier, M.D.
Edouard Herriott Hospital
69437 Lyon, France
pierre.meunier@laennec.univ-lyon1.fr
References
D'Haese PC, Verberckmoes SC, Schrooten I, De Broe ME. Strontium and chronic renal failure. Kidney 2000;9:93-98.
Spasovski GB, Bervoets AR, Behets GJ, et al. Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis. Nephrol Dial Transplant 2003;18:1159-1166.
Cohen-Solal ME, Augry F, Mauras Y, Morieux C, Allain P, de Vernejoul MC. Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients. Nephrol Dial Transplant 2002;17:449-454.
D'Haese PC, Couttenye MM, Lamberts LV, et al. Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of end-stage renal failure patients. Clin Chem 1999;45:1548-1556.
Vanholder R, Cornelis R, Dhondt A, Lameire N. The role of trace elements in uraemic toxicity. Nephrol Dial Transplant 2002;17:Suppl 2:2-8.
Patrick C. D'Haese, Ph.D.
University of Antwerp
B-2650 Antwerp, Belgium
Francisco Santacruz, M.D.
National University of Asuncion
1120 Asuncion, Paraguay
Marc E. De Broe, M.D., Ph.D.
University of Antwerp
B-2650 Antwerp, Belgium
marc.debroe@ua.ac.be
References
Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-468.
D'Haese PC, Schrooten I, Goodman WG, et al. Increased bone strontium levels in hemodialysis patients with osteomalacia. Kidney Int 2000;57:1107-1114.
Schrooten I, Elseviers MM, Lamberts LV, De Broe ME, D'Haese PC. Increased serum strontium levels in dialysis patients: an epidemiological survey. Kidney Int 1999;56:1886-1892.
Schrooten I, Cabrera W, Goodman WG, et al. Strontium causes osteomalacia in chronic renal failure rats. Kidney Int 1998;54:448-456.
Schrooten I, Behets GJ, Cabrera WE, et al. Dose-dependent effects of strontium on bone of chronic renal failure rats. Kidney Int 2003;63:927-935.
Verberckmoes SC, De Broe ME, D'Haese PC. Dose-dependent effects of strontium on osteoblast function and mineralization. Kidney Int 2003;64:534-543.
Fuleihan GE. Strontium ranelate: a novel therapy for osteoporosis or a permutation of the same? N Engl J Med 2004;350:504-506.
To the Editor: Meunier et al. bring strontium ranelate back to the forefront of the therapeutic armamentarium against osteoporosis. Since their data may affect more than 44 million persons — 55 percent of the population over the age of 50 years in the United States1 — clarification should be provided regarding the analysis performed. In the Methods section, the authors state that they calculated Kaplan–Meier product-limit estimates and used an unadjusted Cox regression model to compare the incidence of new vertebral fractures among subjects randomly assigned to receive strontium ranelate or placebo. However, the results of these analyses are not presented. A survival curve and hazard ratios for the incidence of vertebral fractures in the two groups would have been very useful for further characterizing the effectiveness of strontium ranelate therapy in the treatment of postmenopausal osteoporosis.
Ying Taur, M.D., M.P.H.
Long Island Jewish Medical Center
New Hyde Park, NY 11040
yingtaur@earthlink.net
Farrah Al-Tureihi, M.D.
Gisele Wolf-Klein, M.D.
Parker Jewish Institute for Health Care and Rehabilitation
New Hyde Park, NY 11040
References
America's bone health: the state of osteoporosis and low bone mass in our nation. Washington, D.C.: National Osteoporosis Foundation, February 2002. (Accessed April 16, 2004, at http://www.nof.org/advocacy/prevalence/index.htm.)
Dr. Meunier replies: Dr. D'Haese and colleagues have previously reported that strontium could be involved in delayed mineralization in vitro and in a model of renal failure in rats. In contrast, as we mentioned in our article, no deleterious effect of strontium ranelate on bone mineralization has been reported in laboratory animals with normal renal function, for an exposure similar to that in clinical trials. Data from patients with end-stage renal failure suggest that strontium may be a causal agent for osteomalacia in patients undergoing dialysis, who may be exposed to elevated strontium levels in dialysis fluids.1 However, the strontium content of bone in patients undergoing dialysis does not always correlate with defective mineralization, as indicated by reports of bone-biopsy results in patients with end-stage renal failure.2,3 Many other elements that accumulate in the bones of patients undergoing dialysis (e.g., aluminum and fluoride) may be responsible for mineralization defects.4,5 Therefore, any results suggesting that osteomalacia may be induced by strontium in patients with end-stage renal failure or patients undergoing dialysis should be interpreted with caution.
The target population we studied did not have severe renal failure (mean [±SD] serum creatinine level, 87.1±11.9 μmol per liter). I personally examined more than 200 bone-biopsy specimens from patients treated with strontium ranelate during the clinical development program, and I did not identify any signs of mineralization defects (an increased osteoid thickness or mineralization lag time or a decreased mineralization apposition rate). Thus, I would state that delayed mineralization has not been observed with strontium ranelate in an in vitro study, in intact animals, or in humans with moderate renal insufficiency.
In response to Dr. Taur and colleagues, the Cox model was used to compare groups for the occurrence of the first new vertebral fracture. The treatment effect was estimated with the use of hazard ratios — namely, relative risks, as stated in the article (i.e., a hazard ratio of 0.59 as an estimate of the treatment effect over a three-year period). Since radiographs were obtained yearly, not continuously, Kaplan–Meier estimates could be computed only from the assessments at months 12, 24, and 36, of which the assessments at months 12 (the earliest) and 36 (the one of particular clinical relevance) are given in the Results section and in Figure 2 of our article, with formal estimates given for months 12 and 36. For example, Kaplan–Meier estimates of the probability of vertebral fracture at month 36 — namely, 32.8 percent for placebo as compared with 20.9 percent for strontium ranelate — are given both in the Results section and in Figure 2.
Pierre J. Meunier, M.D.
Edouard Herriott Hospital
69437 Lyon, France
pierre.meunier@laennec.univ-lyon1.fr
References
D'Haese PC, Verberckmoes SC, Schrooten I, De Broe ME. Strontium and chronic renal failure. Kidney 2000;9:93-98.
Spasovski GB, Bervoets AR, Behets GJ, et al. Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis. Nephrol Dial Transplant 2003;18:1159-1166.
Cohen-Solal ME, Augry F, Mauras Y, Morieux C, Allain P, de Vernejoul MC. Fluoride and strontium accumulation in bone does not correlate with osteoid tissue in dialysis patients. Nephrol Dial Transplant 2002;17:449-454.
D'Haese PC, Couttenye MM, Lamberts LV, et al. Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of end-stage renal failure patients. Clin Chem 1999;45:1548-1556.
Vanholder R, Cornelis R, Dhondt A, Lameire N. The role of trace elements in uraemic toxicity. Nephrol Dial Transplant 2002;17:Suppl 2:2-8.