Hypercalcemia of Malignancy: Mechanisms and Therapeutic Implications of Concurrently Elevated PTHrP and Calcitriol

Although initially considered rare and associated with solid tumors, concurrent elevations in PTH-related peptide (PTHrP) and calcitriol have been increasingly detected in hypercalcemic patients with a variety of solid and hematologic malignancies. This review discusses the prevalence and pathophysiology and reevaluates the diagnostic and therapeutic implications of PTHrP and calcitriol co-mediated hypercalcemia of malignancy (HCM).

We searched PubMed using multiple combinations of "hypercalcemia of malignancy," PTHrP," "calcitriol," "combined causes," and "concurrent etiologies" and cross-referenced retrieved articles to identify 2 retrospective chart reviews and 17 HCM cases associated with concurrent elevations in PTHrP and calcitriol. Given the scarcity of articles pertaining to co-mediated cases, we contrasted these with literature regarding the pathophysiology, diagnosis, and treatment of isolated humoral and calcitriol-mediated HCM.

The true prevalence of concomitant PTHrP and calcitriol elevations is difficult to determine since these levels are seldom measured simultaneously when evaluating PTH-independent hypercalcemia and vary with tumor type. Malignant tissue is generally considered the source of PTHrP, but the source of calcitriol and the impact of PTHrP on calcitriol synthesis remain controversial. Although most reports suggest that co-mediated hypercalcemia is refractory to antiresorptive and glucocorticoid therapies, long-lasting resolution is associated with cancer remission.

Registry-based studies involving cohorts with thorough diagnostic evaluations and randomized control trials are indicated to clarify the prevalence and optimal approach to the management of PTHrP and calcitriol co-mediated HCM. Although IV bisphosphonates and glucocorticoids should be used to alleviate symptomatic hypercalcemia, cancer-targeted therapy is integral to prevent recurrence.