Efficacy of Oral Cinacalcet in Non-PTH Nonmalignant Hypercalcemia from Excess 1,25-Dihydroxyvitamin D

Elevated 1,25-dihydroxyvitamin D (1,25(OH)₂D) is a rare cause of non-parathyroid hormone (PTH)-mediated hypercalcemia seen in granulomatous disease, malignancy (most often lymphoma), or genetic mutations. Therapeutic options are limited. We report the case of a 67-year-old White man with nonmalignant, nongranulomatous, 1,25(OH)₂D-mediated hypercalcemia treated successfully with cinacalcet. At presentation, he had hypercalcemia, hypercalciuria with recurrent nephrolithiasis, low PTH, elevated 1,25(OH)₂D, and normal 25-hydroxyvitamin D. The 1,25(OH)₂D levels were inappropriate in the setting of hypercalcemia with low PTH. Evaluations for sarcoidosis, tuberculosis, and malignancy were negative. Genetic testing showed biallelic variants in the CYP24A1 gene. Cinacalcet was trialed and showed normalization of calcium levels. On cinacalcet, biochemical indices showed a slight increase in 1,25(OH)₂D and 24-hour urine calcium and mild decrease in PTH. He briefly experienced symptomatic hypocalcemia that resolved after reducing cinacalcet dose. Due to limited symptomatic benefit, he opted to stop cinacalcet. Additional follow-up showed intermittently elevated serum calcium levels after stopping cinacalcet, most recently 10.3 mg/dL. Cinacalcet may be a therapeutic option in nonmalignant, 1,25(OH)₂D-mediated hypercalcemia. Further study is necessary to confirm efficacy, understand risks and benefits, and elucidate mechanism(s) of action.