Fooling the Parathyroid Gland — Will There Be Health Benefits?
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《新英格兰医药杂志》
In people with a reduced glomerular filtration rate, the serum parathyroid hormone level is often secondarily elevated as a result of reduced serum levels of calcium and 1,25-dihydroxyvitamin D3 and an increased serum phosphate level (referred to as secondary hyperparathyroidism). The mean parathyroid hormone level is increased by a factor of more than seven in patients who are receiving hemodialysis.1 In addition to the well-described associated metabolic bone disease, secondary hyperparathyroidism and its treatments may play a role in the high rates of death and cardiovascular disease among patients with end-stage renal disease.2,3
The goal of current therapies to reduce the synthesis and secretion of parathyroid hormone by the hyperplastic parathyroid tissue in patients with secondary hyperparathyroidism is to decrease the serum phosphate level and supplement the levels of calcium and vitamin D. Approaches to phosphate lowering center on binding and reducing the intake of dietary phosphate. Calcium-based phosphate binders are inexpensive but entail the risk of increasing the serum calcium–phosphate product, which has been statistically associated with adverse outcomes.2,3 Non–calcium-based polymers (e.g., sevelamer) are more expensive to use than calcium-based binders, but they do not increase the serum calcium level and they may also avert the increases in calcium scores in the coronary arteries and aorta, calculated by means of electron-beam computed tomography,4 which have been associated with an increased risk of cardiovascular events and death in patients with one or more cardiac risk factors.5 Thus, these agents may be beneficial in patients who are receiving dialysis. Nonetheless, the polymers alone may not bring the parathyroid hormone level into the target range.6,7 Although aluminum-based binders are effective, they are generally avoided because of their potentially toxic effects. Relatively high doses of vitamin D analogues decrease parathyroid hormone levels by diminishing the transcription of the parathyroid hormone gene, but the effectiveness of this approach is limited by the accompanying elevations in serum calcium and phosphate and, thus, the calcium–phosphate product.
The discovery of the calcium-sensing receptor8 introduced the possibility that a therapy could be developed that would reduce the secretion of parathyroid hormone without inducing the adverse metabolic effects associated with supplemental calcium and vitamin D. The calcium-sensing receptor regulates the minute-to-minute secretion of parathyroid hormone and may also influence the development of parathyroid-gland hyperplasia. Calcimimetic compounds (e.g., cinacalcet) lower the threshold for the activation of calcium-sensing receptors in the parathyroid gland by serum calcium. In humans, these agents reduce serum parathyroid hormone levels not only in those with normal or reduced renal function, but also potentially in persons with primary hyperparathyroidism.9
Previous short studies demonstrated that calcimimetics dramatically reduce parathyroid hormone levels in patients receiving hemodialysis10 and also decrease the serum levels of both calcium and phosphorus. The mechanism for phosphate lowering is unclear. In this issue of the Journal, Block and colleagues11 report the results of two identical randomized, controlled trials of 26 weeks' duration involving a total of 741 patients who were receiving hemodialysis and whose plasma parathyroid hormone levels were at least 300 pg per milliliter (31.8 pmol per liter). During the first 12 weeks of the study, half the patients received escalating doses of oral cinacalcet once daily and the other half received a placebo. The patients continued to take the same agent for the next 14 weeks, which was considered the efficacy-assessment phase. Other therapies, including phosphate binders and vitamin D analogues, were continued as directed by the treating physician.
Dramatic reductions in the parathyroid hormone level and the serum calcium–phosphate product were seen in the cinacalcet group. The primary end point — a mean parathyroid hormone level of 250 pg per milliliter (26.5 pmol per liter) or less during the efficacy-assessment phase — was reached by 43 percent of the patients in the cinacalcet group, as compared with 5 percent of those in the placebo group. The secondary end point — a decrease from base line of at least 30 percent in mean parathyroid hormone levels — was reached by 64 percent of the patients in the cinacalcet group, as compared with 11 percent of those in the placebo group; this change was independent of the base-line parathyroid hormone level. The serum calcium–phosphate product did not change significantly in the placebo group but declined by 15 percent in the cinacalcet group; 89 percent of those who had a parathyroid hormone level of 250 pg per milliliter or less had a reduction in the calcium–phosphate product.
As expected with this type of study population, a substantial proportion of patients did not finish the study. Thirty-two percent of patients in the cinacalcet group and 22 percent of those in the placebo group dropped out before the end of the 26-week study. Over 90 percent of patients in both groups reported at least one adverse event, with nausea and vomiting being the two most common events as well as being more frequent in the cinacalcet group. Adverse events led to early withdrawal in 15 percent of patients in the cinacalcet group and 7 percent of those in the placebo group.
Several points deserve comment. First, considering that the mean duration of dialysis among the study subjects was six years, this was a relatively short-term study. During a two-year study of cinacalcet in 59 patients, long-term control of the parathyroid hormone level was achieved,12 suggesting that drug resistance does not develop over the long term. Second, despite their finding of substantial reductions in the parathyroid hormone level, Block et al. did not examine "hard" outcomes. There is insufficient information in the literature to determine whether reducing parathyroid hormone levels improves important outcomes such as the risk of death, cardiovascular events, and bone disease. Third, it is unlikely that the treating physicians were unaware of the patients' parathyroid hormone levels. For future studies of calcimimetics involving hard outcomes, algorithms should be developed for the use of phosphate binders and vitamin D supplementation. Fourth, the reasons for the differential responses among those who received cinacalcet deserve investigation and include the possibility of genetic influences and the use of different dosing schedules.
This study raises a number of important questions. What is the optimal target parathyroid hormone level in patients with a reduced glomerular filtration rate? Although the generally accepted guidelines published by the National Kidney Foundation13 recommend a serum parathyroid hormone level in the range of 150 to 300 pg per milliliter (15.9 to 30.9 pmol per liter) in patients who are receiving dialysis, the long-term implications need further study in patients with end-stage renal disease as well as in those with less severe renal dysfunction. What is the role of cinacalcet in patients who are receiving peritoneal dialysis or in renal-transplant recipients? What is the role of cinacalcet in children with renal disease? How long after the administration of a calcimimetic drug should the blood sample be drawn for the measurement of the parathyroid hormone level?
Will the use of calcimimetics alter our current understanding of the relationship between parathyroid hormone and bone disease? Treatment with calcimimetics may not eliminate the need for parathyroidectomy in patients with severe secondary or tertiary hyperparathyroidism, but will it lead to a drop in the rates? Does the use of a calcimimetic drug and vitamin D have an additive effect on the release of parathyroid hormone? Calcimimetics, in contrast to pharmacologic doses of vitamin D, reinstate serum calcium–induced physiologic control of parathyroid hormone secretion. This results in a more pulsatile pattern of secretion of parathyroid hormone, which, one hopes, will prevent or treat adynamic bone disease.
I believe that vitamin D supplementation will provide benefits in addition to those provided by calcimimetics and that it will continue to be commonly used in this population because at least low-dose supplementation is needed for optimal bone health, and the formulation may be related to the odds of survival. Finally, how will the availability of calcimimetics affect health care costs? Dialysis-related costs are substantial; thus, any new therapy deserves a cost–benefit analysis. In this case, it should be remembered that the cost of orally administered drugs is typically the patient's responsibility.
Calcimimetic drugs are a welcome and long-awaited addition to our options for treating secondary hyperparathyroidism. For patients with bone disease and disordered mineral metabolism resulting from secondary hyperparathyroidism associated with renal dysfunction, treatment can now be tailored to include a phosphate-binding agent to control phosphate levels, calcium supplementation to increase serum calcium levels, vitamin D for repletion of deficiency, and a calcimimetic to reduce the serum parathyroid hormone level. Although Block et al. report impressive reductions in parathyroid hormone levels in the cinacalcet group, studies of the effect of calcimimetics on hard outcomes are essential. Meanwhile, given what is known about the physiology of secondary hyperparathyroidism, maintaining the serum levels of calcium, phosphorus, and parathyroid hormone in the recommended ranges should remain a priority.
Source Information
From the Renal Division and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston.
References
Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003;349:446-456.
Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607-617.
Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-2138.
Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62:245-252.
Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291:210-215.
Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 1999;14:2907-2914.
Chertow GM, Dillon M, Burke SK, et al. A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium: strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients. Clin Nephrol 1999;51:18-26.
Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993;366:575-580.
Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:5644-5649.
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.
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.
Moe SM, Sprague SM, Cunningham J, et al. Long-term treatment of secondary hyperparathyroidism (HPT) with the calcimimetic cinacalcet HCl. J Am Soc Nephrol 2003;14:463A-464A. abstract.
Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42:Suppl 3:1-201.(Gary Curhan, M.D., Sc.D.)
The goal of current therapies to reduce the synthesis and secretion of parathyroid hormone by the hyperplastic parathyroid tissue in patients with secondary hyperparathyroidism is to decrease the serum phosphate level and supplement the levels of calcium and vitamin D. Approaches to phosphate lowering center on binding and reducing the intake of dietary phosphate. Calcium-based phosphate binders are inexpensive but entail the risk of increasing the serum calcium–phosphate product, which has been statistically associated with adverse outcomes.2,3 Non–calcium-based polymers (e.g., sevelamer) are more expensive to use than calcium-based binders, but they do not increase the serum calcium level and they may also avert the increases in calcium scores in the coronary arteries and aorta, calculated by means of electron-beam computed tomography,4 which have been associated with an increased risk of cardiovascular events and death in patients with one or more cardiac risk factors.5 Thus, these agents may be beneficial in patients who are receiving dialysis. Nonetheless, the polymers alone may not bring the parathyroid hormone level into the target range.6,7 Although aluminum-based binders are effective, they are generally avoided because of their potentially toxic effects. Relatively high doses of vitamin D analogues decrease parathyroid hormone levels by diminishing the transcription of the parathyroid hormone gene, but the effectiveness of this approach is limited by the accompanying elevations in serum calcium and phosphate and, thus, the calcium–phosphate product.
The discovery of the calcium-sensing receptor8 introduced the possibility that a therapy could be developed that would reduce the secretion of parathyroid hormone without inducing the adverse metabolic effects associated with supplemental calcium and vitamin D. The calcium-sensing receptor regulates the minute-to-minute secretion of parathyroid hormone and may also influence the development of parathyroid-gland hyperplasia. Calcimimetic compounds (e.g., cinacalcet) lower the threshold for the activation of calcium-sensing receptors in the parathyroid gland by serum calcium. In humans, these agents reduce serum parathyroid hormone levels not only in those with normal or reduced renal function, but also potentially in persons with primary hyperparathyroidism.9
Previous short studies demonstrated that calcimimetics dramatically reduce parathyroid hormone levels in patients receiving hemodialysis10 and also decrease the serum levels of both calcium and phosphorus. The mechanism for phosphate lowering is unclear. In this issue of the Journal, Block and colleagues11 report the results of two identical randomized, controlled trials of 26 weeks' duration involving a total of 741 patients who were receiving hemodialysis and whose plasma parathyroid hormone levels were at least 300 pg per milliliter (31.8 pmol per liter). During the first 12 weeks of the study, half the patients received escalating doses of oral cinacalcet once daily and the other half received a placebo. The patients continued to take the same agent for the next 14 weeks, which was considered the efficacy-assessment phase. Other therapies, including phosphate binders and vitamin D analogues, were continued as directed by the treating physician.
Dramatic reductions in the parathyroid hormone level and the serum calcium–phosphate product were seen in the cinacalcet group. The primary end point — a mean parathyroid hormone level of 250 pg per milliliter (26.5 pmol per liter) or less during the efficacy-assessment phase — was reached by 43 percent of the patients in the cinacalcet group, as compared with 5 percent of those in the placebo group. The secondary end point — a decrease from base line of at least 30 percent in mean parathyroid hormone levels — was reached by 64 percent of the patients in the cinacalcet group, as compared with 11 percent of those in the placebo group; this change was independent of the base-line parathyroid hormone level. The serum calcium–phosphate product did not change significantly in the placebo group but declined by 15 percent in the cinacalcet group; 89 percent of those who had a parathyroid hormone level of 250 pg per milliliter or less had a reduction in the calcium–phosphate product.
As expected with this type of study population, a substantial proportion of patients did not finish the study. Thirty-two percent of patients in the cinacalcet group and 22 percent of those in the placebo group dropped out before the end of the 26-week study. Over 90 percent of patients in both groups reported at least one adverse event, with nausea and vomiting being the two most common events as well as being more frequent in the cinacalcet group. Adverse events led to early withdrawal in 15 percent of patients in the cinacalcet group and 7 percent of those in the placebo group.
Several points deserve comment. First, considering that the mean duration of dialysis among the study subjects was six years, this was a relatively short-term study. During a two-year study of cinacalcet in 59 patients, long-term control of the parathyroid hormone level was achieved,12 suggesting that drug resistance does not develop over the long term. Second, despite their finding of substantial reductions in the parathyroid hormone level, Block et al. did not examine "hard" outcomes. There is insufficient information in the literature to determine whether reducing parathyroid hormone levels improves important outcomes such as the risk of death, cardiovascular events, and bone disease. Third, it is unlikely that the treating physicians were unaware of the patients' parathyroid hormone levels. For future studies of calcimimetics involving hard outcomes, algorithms should be developed for the use of phosphate binders and vitamin D supplementation. Fourth, the reasons for the differential responses among those who received cinacalcet deserve investigation and include the possibility of genetic influences and the use of different dosing schedules.
This study raises a number of important questions. What is the optimal target parathyroid hormone level in patients with a reduced glomerular filtration rate? Although the generally accepted guidelines published by the National Kidney Foundation13 recommend a serum parathyroid hormone level in the range of 150 to 300 pg per milliliter (15.9 to 30.9 pmol per liter) in patients who are receiving dialysis, the long-term implications need further study in patients with end-stage renal disease as well as in those with less severe renal dysfunction. What is the role of cinacalcet in patients who are receiving peritoneal dialysis or in renal-transplant recipients? What is the role of cinacalcet in children with renal disease? How long after the administration of a calcimimetic drug should the blood sample be drawn for the measurement of the parathyroid hormone level?
Will the use of calcimimetics alter our current understanding of the relationship between parathyroid hormone and bone disease? Treatment with calcimimetics may not eliminate the need for parathyroidectomy in patients with severe secondary or tertiary hyperparathyroidism, but will it lead to a drop in the rates? Does the use of a calcimimetic drug and vitamin D have an additive effect on the release of parathyroid hormone? Calcimimetics, in contrast to pharmacologic doses of vitamin D, reinstate serum calcium–induced physiologic control of parathyroid hormone secretion. This results in a more pulsatile pattern of secretion of parathyroid hormone, which, one hopes, will prevent or treat adynamic bone disease.
I believe that vitamin D supplementation will provide benefits in addition to those provided by calcimimetics and that it will continue to be commonly used in this population because at least low-dose supplementation is needed for optimal bone health, and the formulation may be related to the odds of survival. Finally, how will the availability of calcimimetics affect health care costs? Dialysis-related costs are substantial; thus, any new therapy deserves a cost–benefit analysis. In this case, it should be remembered that the cost of orally administered drugs is typically the patient's responsibility.
Calcimimetic drugs are a welcome and long-awaited addition to our options for treating secondary hyperparathyroidism. For patients with bone disease and disordered mineral metabolism resulting from secondary hyperparathyroidism associated with renal dysfunction, treatment can now be tailored to include a phosphate-binding agent to control phosphate levels, calcium supplementation to increase serum calcium levels, vitamin D for repletion of deficiency, and a calcimimetic to reduce the serum parathyroid hormone level. Although Block et al. report impressive reductions in parathyroid hormone levels in the cinacalcet group, studies of the effect of calcimimetics on hard outcomes are essential. Meanwhile, given what is known about the physiology of secondary hyperparathyroidism, maintaining the serum levels of calcium, phosphorus, and parathyroid hormone in the recommended ranges should remain a priority.
Source Information
From the Renal Division and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston.
References
Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003;349:446-456.
Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607-617.
Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-2138.
Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62:245-252.
Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291:210-215.
Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 1999;14:2907-2914.
Chertow GM, Dillon M, Burke SK, et al. A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium: strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients. Clin Nephrol 1999;51:18-26.
Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993;366:575-580.
Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:5644-5649.
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.
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.
Moe SM, Sprague SM, Cunningham J, et al. Long-term treatment of secondary hyperparathyroidism (HPT) with the calcimimetic cinacalcet HCl. J Am Soc Nephrol 2003;14:463A-464A. abstract.
Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42:Suppl 3:1-201.(Gary Curhan, M.D., Sc.D.)