Alendronate or Alfacalcidol in Glucocorticoid-Induced Osteoporosis
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《新英格兰医药杂志》
To the Editor: De Nijs et al. (Aug. 17 issue)1 report that alendronate was more effective in the prevention of glucocorticoid-induced bone loss than was alfacalcidol. This is a well-done study, but we are concerned that the authors did not address the fact that glucocorticoid therapy can have rapid effects on bone. It has been reported that the negative influence of glucocorticoid agents may be most pronounced in the first months of therapy.2 In patients with Crohn's disease, significant bone loss at the hip was detected after 2 months of such treatment.3 Therefore, because the study by de Nijs et al. involved patients who began glucocorticoid therapy within 12 weeks before enrollment in the study, it is possible that the findings may have been biased by this rapid glucocorticoid-induced effect.
Mitsumasa Kishimoto, M.D.
Ai Oishi, M.D.
Shinji Motojima, M.D.
Kameda Medical Center
Kamogawa 296-8602, Japan
kishimotomitsumasa@yahoo.co.jp
References
de Nijs RNJ, Jacobs JWG, Lems WF, et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 2006;355:675-684.
LoCascio V, Bonucci E, Imbimbo B, et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990;8:39-51.
Tobias JH, Sasi MR, Greenwood R, Probert CSJ. Rapid hip bone loss in active Crohn's disease patients receiving short-term corticosteroid therapy. Aliment Pharmacol Ther 2004;20:951-957.
To the Editor: De Nijs et al. conclude that alfacalcidol is not effective in preventing a glucocorticoid-induced decrease in bone mineral density, even though their study shows that the vitamin induces a positive uncoupling of the two processes of bone remodeling. We should therefore presume that the events occurring at the cellular level after the administration of alfacalcidol are not followed by a process of full mineralization. The authors also define hypercalcemia as a calcium level above 10.8 mg per deciliter. In adults, the upper limit of the normal range is now set at 10.2 mg per deciliter.1 Therefore, it would be interesting to know how many patients would have been defined as having persistent hypercalcemia if the latter value had been used to define hypercalcemia. It is also surprising that the results obtained concerning N-telopeptide excretion as measured in urine samples obtained during the second void of the day are reported as concentrations without correction for urinary creatinine, thus disregarding the effect of simple dilution.
Salvatore Minisola, M.D.
University of Rome
00161 Rome, Italy
salvatore.minisola@fastwebnet.it
Alfredo Scillitani, M.D.
Ospedale Casa Sollievo della Sofferenza
71013 San Giovanni Rotondo, Italy
Elisabetta Romagnoli, M.D.
University of Rome
00161 Rome, Italy
References
Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research, 2006.
The authors reply: We agree with Kishimoto and colleagues that glucocorticoids may have deleterious effects on bone within the first months of treatment. In our study, however, mean bone mineral density at baseline was still within the normal range, and the difference between the two groups of subjects was not significant. Most patients received treatment well within 2 months after starting glucocorticoid therapy. Without a delay in treatment, bone mineral density at 18 months might have been slightly higher in both groups, but we do not believe that this possibility affected the conclusions of our study.
Minisola and colleagues suggest that alfacalcidol uncouples the two processes of bone remodeling but that such an effect is not followed by full mineralization of bone. In a meta-analysis of active vitamin D treatment in patients receiving glucocorticoids, we indeed found only a minor increase in bone mineral density; however, patients had a 44% reduction in the risk of vertebral fracture.1 We think this finding can be attributed to improvements in bone architecture and bone strength, as shown in studies in animals,2 rather than to the small increase in bone mineral density. It will be of interest to analyze the long-term effects of the medication used in our study on vertebral fracture.
Because of the multicenter setting of the trial, the standardization of calcium measurements was performed centrally (Covance Virtual Central Laboratory). This central facility used 10.8 mg per deciliter as the upper limit of the normal range for calcium, corrected for albumin. If one were to use 10.2 mg per deciliter as the upper limit of the normal range, as suggested by Minisola et al., the numbers of patients with transient hypercalcemia would be 11 in the alendronate group and 15 in the alfacalcidol group, and the numbers of patients with hypercalcemia at two or more consecutive measurements in the two groups would be 2 and 7, respectively. Thus, as expected, lowering the upper limit of the normal range for calcium would increase the number of patients defined as having hypercalcemia in our study, especially in the alfacalcidol group. The results of the enzyme-linked immunosorbent assay we used for the measurement of N-telopeptide excretion in second-void urine is expressed in nanomoles per liter, without correction for urinary creatinine. Since this method was used in both treatment groups, it should not, in our opinion, bias the conclusions of our study.
Ron N.J. de Nijs, M.D., Ph.D.
Johannes W.G. Jacobs, M.D., Ph.D.
Johannes W.J. Bijlsma, M.D., Ph.D.
University Medical Center Utrecht
3584 CX Utrecht, the Netherlands
r.denijs@mmc.nl
References
de Nijs RN, Jacobs JW, Algra A, Lems WF, Bijlsma JW. Prevention and treatment of glucocorticoid-induced osteoporosis with active vitamin D3 analogues: a review with meta-analysis of randomized controlled trials including organ transplantation studies. Osteoporos Int 2004;15:589-602.
Aerssens J, Van Audekercke R, Talalaj M, et al. Effect of 1 alpha-vitamin D3 on bone strength and composition in growing rats with and without corticosteroid treatment. Calcif Tissue Int 1994;55:443-450.
Mitsumasa Kishimoto, M.D.
Ai Oishi, M.D.
Shinji Motojima, M.D.
Kameda Medical Center
Kamogawa 296-8602, Japan
kishimotomitsumasa@yahoo.co.jp
References
de Nijs RNJ, Jacobs JWG, Lems WF, et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 2006;355:675-684.
LoCascio V, Bonucci E, Imbimbo B, et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990;8:39-51.
Tobias JH, Sasi MR, Greenwood R, Probert CSJ. Rapid hip bone loss in active Crohn's disease patients receiving short-term corticosteroid therapy. Aliment Pharmacol Ther 2004;20:951-957.
To the Editor: De Nijs et al. conclude that alfacalcidol is not effective in preventing a glucocorticoid-induced decrease in bone mineral density, even though their study shows that the vitamin induces a positive uncoupling of the two processes of bone remodeling. We should therefore presume that the events occurring at the cellular level after the administration of alfacalcidol are not followed by a process of full mineralization. The authors also define hypercalcemia as a calcium level above 10.8 mg per deciliter. In adults, the upper limit of the normal range is now set at 10.2 mg per deciliter.1 Therefore, it would be interesting to know how many patients would have been defined as having persistent hypercalcemia if the latter value had been used to define hypercalcemia. It is also surprising that the results obtained concerning N-telopeptide excretion as measured in urine samples obtained during the second void of the day are reported as concentrations without correction for urinary creatinine, thus disregarding the effect of simple dilution.
Salvatore Minisola, M.D.
University of Rome
00161 Rome, Italy
salvatore.minisola@fastwebnet.it
Alfredo Scillitani, M.D.
Ospedale Casa Sollievo della Sofferenza
71013 San Giovanni Rotondo, Italy
Elisabetta Romagnoli, M.D.
University of Rome
00161 Rome, Italy
References
Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research, 2006.
The authors reply: We agree with Kishimoto and colleagues that glucocorticoids may have deleterious effects on bone within the first months of treatment. In our study, however, mean bone mineral density at baseline was still within the normal range, and the difference between the two groups of subjects was not significant. Most patients received treatment well within 2 months after starting glucocorticoid therapy. Without a delay in treatment, bone mineral density at 18 months might have been slightly higher in both groups, but we do not believe that this possibility affected the conclusions of our study.
Minisola and colleagues suggest that alfacalcidol uncouples the two processes of bone remodeling but that such an effect is not followed by full mineralization of bone. In a meta-analysis of active vitamin D treatment in patients receiving glucocorticoids, we indeed found only a minor increase in bone mineral density; however, patients had a 44% reduction in the risk of vertebral fracture.1 We think this finding can be attributed to improvements in bone architecture and bone strength, as shown in studies in animals,2 rather than to the small increase in bone mineral density. It will be of interest to analyze the long-term effects of the medication used in our study on vertebral fracture.
Because of the multicenter setting of the trial, the standardization of calcium measurements was performed centrally (Covance Virtual Central Laboratory). This central facility used 10.8 mg per deciliter as the upper limit of the normal range for calcium, corrected for albumin. If one were to use 10.2 mg per deciliter as the upper limit of the normal range, as suggested by Minisola et al., the numbers of patients with transient hypercalcemia would be 11 in the alendronate group and 15 in the alfacalcidol group, and the numbers of patients with hypercalcemia at two or more consecutive measurements in the two groups would be 2 and 7, respectively. Thus, as expected, lowering the upper limit of the normal range for calcium would increase the number of patients defined as having hypercalcemia in our study, especially in the alfacalcidol group. The results of the enzyme-linked immunosorbent assay we used for the measurement of N-telopeptide excretion in second-void urine is expressed in nanomoles per liter, without correction for urinary creatinine. Since this method was used in both treatment groups, it should not, in our opinion, bias the conclusions of our study.
Ron N.J. de Nijs, M.D., Ph.D.
Johannes W.G. Jacobs, M.D., Ph.D.
Johannes W.J. Bijlsma, M.D., Ph.D.
University Medical Center Utrecht
3584 CX Utrecht, the Netherlands
r.denijs@mmc.nl
References
de Nijs RN, Jacobs JW, Algra A, Lems WF, Bijlsma JW. Prevention and treatment of glucocorticoid-induced osteoporosis with active vitamin D3 analogues: a review with meta-analysis of randomized controlled trials including organ transplantation studies. Osteoporos Int 2004;15:589-602.
Aerssens J, Van Audekercke R, Talalaj M, et al. Effect of 1 alpha-vitamin D3 on bone strength and composition in growing rats with and without corticosteroid treatment. Calcif Tissue Int 1994;55:443-450.