Cinacalcet for Secondary Hyperparathyroidism in Hemodialysis Recipients
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《新英格兰医药杂志》
To the Editor: Block and colleagues1 (April 8 issue) found a significant reduction in intact parathyroid hormone levels in patients with uncontrolled secondary hyperparathyroidism who received cinacalcet. The primary end point of intact parathyroid hormone levels of 250 pg per milliliter as an upper cutoff is based on the work of Wang et al.,2 who reported a relationship between serum levels of intact parathyroid hormone and the histomorphometric characteristics of bone. Yet Wang et al. also suggested that the use of an upper level of 200 pg per milliliter permits the best discrimination between normal and high bone-turnover states, with a positive predictive value of 82 percent, a negative predictive value of 91 percent, and a sensitivity of 88 percent, in patients who receive hemodialysis, and that a level of 300 pg per milliliter is best for patients who receive peritoneal dialysis. Similarly, Hutchison et al.3 found that a level of 200 pg per milliliter had a positive predictive value of 88 percent with a sensitivity of 83 percent and a specificity of 88 percent. A major limitation to the study of Block et al. is that the chosen level of 250 pg per milliliter may not represent an adequate control. A level of 200 pg per milliliter might have been a better primary end point for use in identifying a positive effect on the histomorphometric characteristics of bone and on the high prevalence of secondary hyperparathyroidism.4
Ali K. Owda, M.D.
Muhammad G. Alam, M.D., M.P.H.
Jayant Kumar, M.D.
University of Arkansas for Medical Science
Little Rock, AR 72205
alikowda@hotmail.com
References
Block GA, Martin KJ, de Francisco ALM, et al. Cinacalcet hydrochloride for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516-1525.
Wang M, Hercz G, Sherrard DJ, Maloney NA, Serge GV, Pei Y. Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 1995;26:836-844.
Hutchison AJ, Whitehouse RW, Boulton HF, et al. Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease. Kidney Int 1993;44:1071-1077.
Owda A, Elhwairis H, Narra S, Towery H, Osama S. Secondary hyperparathyroidism in chronic hemodialysis patients: prevalence and race. Ren Fail 2003;25:595-602.
To the Editor: Block et al. showed that cinacalcet administration was associated with a serum parathyroid hormone level of 250 pg per milliliter or less in 43 percent of patients, confirming previous results.1,2 Cinacalcet reduced parathyroid hormone levels independently of the severity of disease; in addition, the severity of secondary hyperparathyroidism cannot be assessed on the basis of the parathyroid hormone level alone. Parathyroid hormone levels greater than 600 pg per milliliter are often associated with adynamic bone disease in patients with uremia who are treated with vitamin D derivatives,3,4 as were approximately 65 percent of the patients in the study by Block et al. In the absence of bone histology, neither the severity of the bone disease nor the skeletal response to high parathyroid hormone levels is clear. The dose response to the calcimimetic agent was not discussed. The time of administration of calcimimetics is critical; for example, administration at the beginning of dialysis will decrease calcium levels two to four hours later. Together with hypokalemia, dehydration, and alkalosis, decreased calcium levels could trigger cardiac arrhythmias, and we wonder whether electrocardiographic changes, such as a prolonged QT interval or arrhythmia, were present among the patients treated with cinacalcet.
Pablo A. Ure?a Torres, M.D.
Clinique de l'Orangerie
93300 Aubervilliers, France
urena.pablo@wanadoo.fr
Jacques Chanard, M.D.
Centre Hospitalier Universitaire de Reims
51029 Reims, France
References
Quarles LD, Sherrard DJ, Adler S, et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14:575-583.
Lindberg JS, Moe SM, Goodman WG, et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 2003;63:248-254.
Goodman WG, Ramirez JA, Belin TR, et al. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 1994;46:1160-1166.
Ure?a P, Bernard-Poenaru O, Cohen-Solal M, de Vernejoul MC. Plasma bone-specific alkaline phosphatase changes in hemodialysis patients treated by alfacalcidol. Clin Nephrol 2002;57:261-273.
The authors reply: Dr. Owda and colleagues suggest that an intact parathyroid hormone level of 250 pg per milliliter or less may not represent an adequate level of control in evaluating a possible positive effect on the histomorphometric characteristics of bone. Our trial was not designed to evaluate the effect of cinacalcet on bone histomorphometry. However, we agree that this important outcome measure needs to be addressed in long-term studies. It is incorrect, however, to assume that an intact parathyroid hormone level of 250 pg per milliliter or less does not represent adequate control. The effect of calcimimetic agents on the time course of parathyroid hormone suppression is quite distinct from the effect of vitamin D sterols, owing to the immediate effect of cinacalcet, which is to inhibit parathyroid hormone secretion.1 Thus, parathyroid hormone levels 24 hours after dosing represent an underestimation of the extent of suppression during the previous 24 hours. The elevated bone-specific alkaline phosphatase levels at baseline suggest the presence of high-turnover bone disease, and the ability of cinacalcet to reduce both intact parathyroid hormone and bone-specific alkaline phosphatase levels is consistent with a favorable effect on bone turnover.
The dose of cinacalcet or placebo was adjusted on the basis of achievement of the primary outcome. At the end of the study, patients were distributed across all dose levels (30 to 180 mg once daily). Patients with higher baseline intact parathyroid hormone levels tended to require higher doses.
The administration of cinacalcet does not lower serum calcium levels within the time frame suggested by Drs. Ure?a Torres and Chanard. Rather, the nadir in serum calcium levels occurs approximately 8 to 12 hours after single doses of cinacalcet. However, once cinacalcet levels have reached a steady state (after seven days at the same dose), serum calcium levels remain constant.2 At week 18 of once-daily administration, there was no temporal reduction in serum calcium levels in relation to cinacalcet administration (unpublished data). We found no significant differences between patients who received placebo and those who received cinacalcet with regard to arrhythmia. Previous work has shown that cinacalcet administration does not alter the known relationship between serum calcium and the QT interval corrected for heart rate (QTc). In our analysis, there was no difference between the placebo group and the cinacalcet group in the proportion of patients with an increase in the QTc of more than 60 msec at the end of the study, nor was the proportion of patients with an absolute QTc greater than 500 msec (unpublished data).
Geoffrey A. Block, M.D.
Denver Nephrologists
Denver, CO 80218
gablock@denverneph.net
William G. Goodman, M.D.
David Geffen School of Medicine at UCLA
Los Angeles, CA 90095
References
Goodman WG, Hladik GA, Turner SA, et al. The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002;13:1017-1024.
Quarles LD, Sherrard DJ, Adler S, et al. The calcimetric AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14:575-583.
Ali K. Owda, M.D.
Muhammad G. Alam, M.D., M.P.H.
Jayant Kumar, M.D.
University of Arkansas for Medical Science
Little Rock, AR 72205
alikowda@hotmail.com
References
Block GA, Martin KJ, de Francisco ALM, et al. Cinacalcet hydrochloride for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516-1525.
Wang M, Hercz G, Sherrard DJ, Maloney NA, Serge GV, Pei Y. Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 1995;26:836-844.
Hutchison AJ, Whitehouse RW, Boulton HF, et al. Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease. Kidney Int 1993;44:1071-1077.
Owda A, Elhwairis H, Narra S, Towery H, Osama S. Secondary hyperparathyroidism in chronic hemodialysis patients: prevalence and race. Ren Fail 2003;25:595-602.
To the Editor: Block et al. showed that cinacalcet administration was associated with a serum parathyroid hormone level of 250 pg per milliliter or less in 43 percent of patients, confirming previous results.1,2 Cinacalcet reduced parathyroid hormone levels independently of the severity of disease; in addition, the severity of secondary hyperparathyroidism cannot be assessed on the basis of the parathyroid hormone level alone. Parathyroid hormone levels greater than 600 pg per milliliter are often associated with adynamic bone disease in patients with uremia who are treated with vitamin D derivatives,3,4 as were approximately 65 percent of the patients in the study by Block et al. In the absence of bone histology, neither the severity of the bone disease nor the skeletal response to high parathyroid hormone levels is clear. The dose response to the calcimimetic agent was not discussed. The time of administration of calcimimetics is critical; for example, administration at the beginning of dialysis will decrease calcium levels two to four hours later. Together with hypokalemia, dehydration, and alkalosis, decreased calcium levels could trigger cardiac arrhythmias, and we wonder whether electrocardiographic changes, such as a prolonged QT interval or arrhythmia, were present among the patients treated with cinacalcet.
Pablo A. Ure?a Torres, M.D.
Clinique de l'Orangerie
93300 Aubervilliers, France
urena.pablo@wanadoo.fr
Jacques Chanard, M.D.
Centre Hospitalier Universitaire de Reims
51029 Reims, France
References
Quarles LD, Sherrard DJ, Adler S, et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14:575-583.
Lindberg JS, Moe SM, Goodman WG, et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 2003;63:248-254.
Goodman WG, Ramirez JA, Belin TR, et al. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 1994;46:1160-1166.
Ure?a P, Bernard-Poenaru O, Cohen-Solal M, de Vernejoul MC. Plasma bone-specific alkaline phosphatase changes in hemodialysis patients treated by alfacalcidol. Clin Nephrol 2002;57:261-273.
The authors reply: Dr. Owda and colleagues suggest that an intact parathyroid hormone level of 250 pg per milliliter or less may not represent an adequate level of control in evaluating a possible positive effect on the histomorphometric characteristics of bone. Our trial was not designed to evaluate the effect of cinacalcet on bone histomorphometry. However, we agree that this important outcome measure needs to be addressed in long-term studies. It is incorrect, however, to assume that an intact parathyroid hormone level of 250 pg per milliliter or less does not represent adequate control. The effect of calcimimetic agents on the time course of parathyroid hormone suppression is quite distinct from the effect of vitamin D sterols, owing to the immediate effect of cinacalcet, which is to inhibit parathyroid hormone secretion.1 Thus, parathyroid hormone levels 24 hours after dosing represent an underestimation of the extent of suppression during the previous 24 hours. The elevated bone-specific alkaline phosphatase levels at baseline suggest the presence of high-turnover bone disease, and the ability of cinacalcet to reduce both intact parathyroid hormone and bone-specific alkaline phosphatase levels is consistent with a favorable effect on bone turnover.
The dose of cinacalcet or placebo was adjusted on the basis of achievement of the primary outcome. At the end of the study, patients were distributed across all dose levels (30 to 180 mg once daily). Patients with higher baseline intact parathyroid hormone levels tended to require higher doses.
The administration of cinacalcet does not lower serum calcium levels within the time frame suggested by Drs. Ure?a Torres and Chanard. Rather, the nadir in serum calcium levels occurs approximately 8 to 12 hours after single doses of cinacalcet. However, once cinacalcet levels have reached a steady state (after seven days at the same dose), serum calcium levels remain constant.2 At week 18 of once-daily administration, there was no temporal reduction in serum calcium levels in relation to cinacalcet administration (unpublished data). We found no significant differences between patients who received placebo and those who received cinacalcet with regard to arrhythmia. Previous work has shown that cinacalcet administration does not alter the known relationship between serum calcium and the QT interval corrected for heart rate (QTc). In our analysis, there was no difference between the placebo group and the cinacalcet group in the proportion of patients with an increase in the QTc of more than 60 msec at the end of the study, nor was the proportion of patients with an absolute QTc greater than 500 msec (unpublished data).
Geoffrey A. Block, M.D.
Denver Nephrologists
Denver, CO 80218
gablock@denverneph.net
William G. Goodman, M.D.
David Geffen School of Medicine at UCLA
Los Angeles, CA 90095
References
Goodman WG, Hladik GA, Turner SA, et al. The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002;13:1017-1024.
Quarles LD, Sherrard DJ, Adler S, et al. The calcimetric AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14:575-583.