The Use of Calcimimetics for the Treatment of Secondary Hyperparathyroidism: A 10 Year Evidence Review Mariano Rodrıguez,* William G. Goodman,† Vassilios Liakopoulos,‡ Piergiorgio Messa,§ Andrzej Wiecek,¶ and John Cunningham**
rdoba, Spain, †Amgen, Inc., Thousand *Servicio de Nefrologia, IMIBIC, Hospital Universitario Reina Sofia, Co Oaks, California, ‡Division of Nephrology and Hypertension, 1st Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece, §Division of Nephrology and Dialysis, di Milano, Milan, Italy, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita ¶Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland, and **Centre for Nephrology, UCL Medical School, Royal Free Campus, London, United Kingdom
ABSTRACT Until the discovery of calcimimetics, the management of secondary hyperparathyroidism (SHPT) relied exclusively on treatment with phosphate binders, vitamin D derivatives or surgical parathyroidectomy with limited success. The therapeutic use of calcimimetic agents, together with a better understanding of the pivotal role of the calciumsensing receptor (CaSR) in the physiological regulation of parathyroid gland function, substantially advanced the management of hyperparathyroidism in dialysis practice. Calcimimetics bind selectively to the CaSR receptor in parathyroid tissue and enhance the inhibitory effect of extracellular calcium ions on parathyroid hormone (PTH) secretion, thereby reducing PTH levels even when serum
calcium concentrations are normal or low. The availability of calcimimetic agents for clinical use has opened a new era in the management of patients with SHPT. Indeed, calcimimetic compounds have been shown to reduce PTH levels and to lower serum calcium concentrations in all forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Such findings underscore the critical importance of the CaSR as a therapeutic target in this family of clinical disorders. New calcimimetic agents are being developed that have the potential to offer improved efficacy and safety compared with currently available calcimimetic compounds.
Calcimimetic agents were introduced for clinical use more than 10 years ago. The first group of compounds with calcimimetic properties to be identified were phenylalkylamines, which were discovered incidentally some years earlier during screening for molecules that functioned as calcium-channel blockers (1). The phenylalkylamines were subsequently shown to act as allosteric activators of the calciumsensing receptor (CaSR) (1). The availability of calcimimetic agents for clinical use has provided a new and fundamentally different therapeutic option for patients with secondary hyperparathyroidism (SHPT) and disorders of mineral metabolism associated with chronic kidney disease (CKD). These
compounds have also been shown to be effective in patients with other forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Cinacalcet is the only currently approved calcimimetic agent, and it has been used most extensively for the treatment of SHPT among patients with CKD undergoing dialysis. A number of clinical trials have demonstrated the efficacy of cinacalcet in stabilizing several of the biochemical abnormalities that characterize SHPT and in attenuating the progression of vascular calcification among patients managed with hemodialysis. However, much remains to be learned, about the effect of cinacalcet on important clinical outcomes that include bone disease, skeletal fracture, cardiovascular events, and mortality. To date, results from clinical trials have yet to conclusively show that treatment with cinacalcet reduces the risk of death or the occurrence of major cardiovascular events among patients with SHPT (2). New calcimimetic compounds that can be administered intravenously, rather than orally, are in development. These new compounds may circumvent some of the treatment-related adverse effects
Address correspondence to: Mariano Rodrıguez, Hospital nides de Universitario Reina Sofia (M.R.), Instituto Maimo n Biome dica de Co rdoba, Avda. Mene ndez Investigacio rdoba 14004, Spain, Tel.: +34 (957) 011040, Pidal s/n, Co Fax: +34 (957) 010452, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 5 (September–October) 2015 pp. 497–507 DOI: 10.1111/sdi.12357 © 2015 Wiley Periodicals, Inc. 497
Rodrıguez et al.
498
associated with cinacalcet and may also improve medication adherence. Studies to address these issues are currently ongoing. Here, we provide an overview of the development of calcimimetic agents as a therapy for SHPT among patients with CKD receiving dialysis and offer an assessment of the impact of this class of drugs on the overall clinical management of patients with SHPT. The Causes and Consequences of Hyperparathyroidism Hyperparathyroidism occurs most commonly either as a primary endocrine disorder or as a secondary adaptive response to maintain calcium homeostasis in patients with CKD or under circumstances of calcium or vitamin D deficiency. It can also be a manifestation of parathyroid carcinoma or a consequence of unresolved, or persistent, SHPT after successful kidney transplantation. Primary hyperparathyroidism (PHPT) is an important cause of hypercalcemia in the general population. It affects approximately 3 per 1000 persons, but the incidence can be as high as 21 per 1000 in postmenopausal women (3,4). Frequently, patients with PHPT do not have overt signs or symptoms of kidney disease or bone disease, and the diagnosis is most often made by measuring the blood levels of selected biochemical parameters, including parathyroid hormone (PTH) and calcium. Classically, PHPT is characterized by persistent elevations in the levels of PTH in blood despite concurrent increases in serum calcium concentration. Early in the course of the disease, increases in PTH can be modest and intermittent thus posing a diagnostic challenge before overt hypercalcemia develops. In approximately 80% of cases, PHPT is due to a solitary adenoma located in one of the parathyroid glands. Diffuse four-gland hyperplasia, multiple adenomas, and parathyroid carcinoma account for 15%, 5%, and 1/10); common (>1/100 to 1/1,000 to 1/10,000 to 1000 pg/ml (106.0 pmol/l) and serum calcium >10.5 mg/l (2.6 mmol/l) on one occasion followed by prescription of commercial cinacalcet within 2 months; or, (iii) surgical parathyroidectomy (2,58). Despite such findings, the statistical treat-
504
Rodrıguez et al.
ment of these endpoints must be considered as descriptive only because they represent secondary endpoints from a clinical trial that did not demonstrate a statistically significant difference between groups on the primary study endpoint. The use of cinacalcet was evaluated among patients with SHPT due to CKD, stages 3–4, who were not receiving dialysis. Treatment effectively reduced PTH levels, but a larger proportion of subjects receiving cinacalcet experienced a serum calcium level
rdoba, Spain, †Amgen, Inc., Thousand *Servicio de Nefrologia, IMIBIC, Hospital Universitario Reina Sofia, Co Oaks, California, ‡Division of Nephrology and Hypertension, 1st Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece, §Division of Nephrology and Dialysis, di Milano, Milan, Italy, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita ¶Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland, and **Centre for Nephrology, UCL Medical School, Royal Free Campus, London, United Kingdom
ABSTRACT Until the discovery of calcimimetics, the management of secondary hyperparathyroidism (SHPT) relied exclusively on treatment with phosphate binders, vitamin D derivatives or surgical parathyroidectomy with limited success. The therapeutic use of calcimimetic agents, together with a better understanding of the pivotal role of the calciumsensing receptor (CaSR) in the physiological regulation of parathyroid gland function, substantially advanced the management of hyperparathyroidism in dialysis practice. Calcimimetics bind selectively to the CaSR receptor in parathyroid tissue and enhance the inhibitory effect of extracellular calcium ions on parathyroid hormone (PTH) secretion, thereby reducing PTH levels even when serum
calcium concentrations are normal or low. The availability of calcimimetic agents for clinical use has opened a new era in the management of patients with SHPT. Indeed, calcimimetic compounds have been shown to reduce PTH levels and to lower serum calcium concentrations in all forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Such findings underscore the critical importance of the CaSR as a therapeutic target in this family of clinical disorders. New calcimimetic agents are being developed that have the potential to offer improved efficacy and safety compared with currently available calcimimetic compounds.
Calcimimetic agents were introduced for clinical use more than 10 years ago. The first group of compounds with calcimimetic properties to be identified were phenylalkylamines, which were discovered incidentally some years earlier during screening for molecules that functioned as calcium-channel blockers (1). The phenylalkylamines were subsequently shown to act as allosteric activators of the calciumsensing receptor (CaSR) (1). The availability of calcimimetic agents for clinical use has provided a new and fundamentally different therapeutic option for patients with secondary hyperparathyroidism (SHPT) and disorders of mineral metabolism associated with chronic kidney disease (CKD). These
compounds have also been shown to be effective in patients with other forms of hyperparathyroidism, including primary hyperparathyroidism (PHPT) and parathyroid carcinoma. Cinacalcet is the only currently approved calcimimetic agent, and it has been used most extensively for the treatment of SHPT among patients with CKD undergoing dialysis. A number of clinical trials have demonstrated the efficacy of cinacalcet in stabilizing several of the biochemical abnormalities that characterize SHPT and in attenuating the progression of vascular calcification among patients managed with hemodialysis. However, much remains to be learned, about the effect of cinacalcet on important clinical outcomes that include bone disease, skeletal fracture, cardiovascular events, and mortality. To date, results from clinical trials have yet to conclusively show that treatment with cinacalcet reduces the risk of death or the occurrence of major cardiovascular events among patients with SHPT (2). New calcimimetic compounds that can be administered intravenously, rather than orally, are in development. These new compounds may circumvent some of the treatment-related adverse effects
Address correspondence to: Mariano Rodrıguez, Hospital nides de Universitario Reina Sofia (M.R.), Instituto Maimo n Biome dica de Co rdoba, Avda. Mene ndez Investigacio rdoba 14004, Spain, Tel.: +34 (957) 011040, Pidal s/n, Co Fax: +34 (957) 010452, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 5 (September–October) 2015 pp. 497–507 DOI: 10.1111/sdi.12357 © 2015 Wiley Periodicals, Inc. 497
Rodrıguez et al.
498
associated with cinacalcet and may also improve medication adherence. Studies to address these issues are currently ongoing. Here, we provide an overview of the development of calcimimetic agents as a therapy for SHPT among patients with CKD receiving dialysis and offer an assessment of the impact of this class of drugs on the overall clinical management of patients with SHPT. The Causes and Consequences of Hyperparathyroidism Hyperparathyroidism occurs most commonly either as a primary endocrine disorder or as a secondary adaptive response to maintain calcium homeostasis in patients with CKD or under circumstances of calcium or vitamin D deficiency. It can also be a manifestation of parathyroid carcinoma or a consequence of unresolved, or persistent, SHPT after successful kidney transplantation. Primary hyperparathyroidism (PHPT) is an important cause of hypercalcemia in the general population. It affects approximately 3 per 1000 persons, but the incidence can be as high as 21 per 1000 in postmenopausal women (3,4). Frequently, patients with PHPT do not have overt signs or symptoms of kidney disease or bone disease, and the diagnosis is most often made by measuring the blood levels of selected biochemical parameters, including parathyroid hormone (PTH) and calcium. Classically, PHPT is characterized by persistent elevations in the levels of PTH in blood despite concurrent increases in serum calcium concentration. Early in the course of the disease, increases in PTH can be modest and intermittent thus posing a diagnostic challenge before overt hypercalcemia develops. In approximately 80% of cases, PHPT is due to a solitary adenoma located in one of the parathyroid glands. Diffuse four-gland hyperplasia, multiple adenomas, and parathyroid carcinoma account for 15%, 5%, and 1/10); common (>1/100 to 1/1,000 to 1/10,000 to 1000 pg/ml (106.0 pmol/l) and serum calcium >10.5 mg/l (2.6 mmol/l) on one occasion followed by prescription of commercial cinacalcet within 2 months; or, (iii) surgical parathyroidectomy (2,58). Despite such findings, the statistical treat-
504
Rodrıguez et al.
ment of these endpoints must be considered as descriptive only because they represent secondary endpoints from a clinical trial that did not demonstrate a statistically significant difference between groups on the primary study endpoint. The use of cinacalcet was evaluated among patients with SHPT due to CKD, stages 3–4, who were not receiving dialysis. Treatment effectively reduced PTH levels, but a larger proportion of subjects receiving cinacalcet experienced a serum calcium level
