Calcium-Mediated Parathyroid Hormone Suppression to Assess Progression of Secondary Hyperparathyroidism During Treatment Among Incident Dialysis Patients

Hospital Universitario Reina Sofia (M.R.), Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba 14004, Spain
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 01/2013; 98(2). DOI: 10.1210/jc.2012-3246
Source: PubMed


Context:Parathyroid gland function is affected adversely by tissue hyperplasia and gland enlargement in hyperparathyroidism.Objective:We examined the effects of 2 treatment strategies on the progression of secondary hyperparathyroidism using measurements of the nonsuppressible component of calcium-regulated PTH secretion as an index of parathyroid mass.Design, Subjects, and Intervention:In this randomized, open-label study, subjects managed with hemodialysis for >3 but <12 months before entering the trial (mean, 7.2 months) who had baseline plasma PTH levels >300 pg/mL received cinacalcet and low-dose vitamin D sterols (Cin-D, n = 153) or larger, varying doses of calcitriol, or other vitamin D analogs (Flex-D, n = 151). Study drug doses were adjusted periodically based on PTH and serum total calcium determinations.Main Outcome Measures:The exploratory endpoint was calcium-regulated PTH release, assessed using a standardized PTH suppression test before and after 52 weeks of treatment and 4 weeks after withdrawing treatment. PTH and serum total calcium were measured before hemodialysis using high-calcium (3.5 mEq/L or 1.75 mmol/L) dialysate and after 150 and 180 minutes.Results:Mean (95% confidence interval) nonsuppressible calcium-regulated PTH release at baseline did not differ between Cin-D, 33.4% (25.9%, 40.9%), and Flex-D, 28.1% (23.2%, 32.9%). Corresponding values after 52 weeks of treatment were 34.3% (29.7%, 38.9%) and 42.0% (32.7%, 51.3%), not significant, and did not change measurably in either group when reevaluated 4 weeks after treatments were withdrawn.Conclusion:Disease progression over 12 months was not documented using a PTH suppression test in this population. Calcium-mediated PTH suppression was maintained fully, however, in Cin-D despite reductions in serum total calcium concentration, whereas values did not increase in Flex-D despite substantial increases in serum calcium.

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Available from: Pablo Antonio Ureña Torres, Mar 12, 2015
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    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 calcium-sensing 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. © 2015 Wiley Periodicals, Inc.
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    ABSTRACT: Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken. This was a prospective, multicenter, phase 4, randomized, open-label study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH >450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH <300 pg/ml or a ≥30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken. Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was -12.1% (-20.0% to -4.1%) in the cinacalcet arm and -7.0% (-14.9% to 0.8%) in the vitamin D analog arm, a difference of -5.0% (-15.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH≤300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction >30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P<0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm. Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels. Copyright © 2015 by the American Society of Nephrology.
    No preview · Article · Apr 2015 · Clinical Journal of the American Society of Nephrology