Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades

Context: Thiazide diuretics, the antihypertensive agent prescribed most frequently worldwide, are commonly associated with hypercalcemia. However, the epidemiology and clinical features are poorly understood. Objective: To update the incidence of thiazide-associated hypercalcemia and clarify its clinical features. Patients and Methods: In a population-based descriptive study, Olmsted County, Minnesota, residents with thiazide-associated hypercalcemia were identified through the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System from 2002-2010 and were added to the historical cohort beginning in 1992. Main Outcome: Incidence rates were adjusted to the 2010 United States white population. Results: Overall, 221 Olmsted County residents were identified with thiazide-associated hypercalcemia an average of 5.2 years after initiation of treatment. Subjects were older (mean age, 67 years) and primarily women (86.4%). The incidence of thiazide-associated hypercalcemia increased after 1997 and peaked in 2006 with an annual incidence of 20 per 100 000, compared to an overall rate of 12 per 100 000 in 1992-2010. Severe hypercalcemia was not observed in the cohort despite continuation of thiazide treatment in 62.4%. Of patients discontinuing thiazides, 71% continued to have hypercalcemia. Primary hyperparathyroidism was diagnosed in 53 patients (24%), including five patients who underwent parathyroidectomy without thiazide discontinuation. Conclusions: Many patients with thiazide-associated hypercalcemia have underlying primary hyperparathyroidism. Additionally, a sharp rise in thiazide-associated hypercalcemia incidence began in 1998, paralleling the increase observed in primary hyperparathyroidism in this community. Case ascertainment bias from targeted osteoporosis screening is the most likely explanation.