Hypercalcemia of malignancy occurs as the result of direct bone metastasis and via humoral mechanisms such as parathyroid hormone-related protein (PTHrP) or 1,25-dihydroxyvitamin D mediated pathways
ectopic secretion of parathyroid hormone (PTH) has been implicated
Hypercalcemia due to osteolytic bone lesions is common in multiple myeloma, leukemia, and breast cancer
Humoral hypercalcemia is predominant in squamous cell, renal cell and ovarian cancers, and lymphomas are associated with 1,25-dihydroxyvitamin D mediated hypercalcemia
20% of cases of hypercalcemia of malignancy and is frequently encountered in multiple myeloma, metastatic breast cancer, and to a lesser extent in leukemia and lymphoma
Physiologic bone turnover requires the complementary activity of osteoblasts – mesenchymal stem cell-derived bone-forming cells – and bone-resorbing cells of monocyte and macrophage lineage known as osteoclasts
In local osteolytic hypercalcemia, the RANKL/RANK interaction results in excessive osteoclast activation leading to enhanced bone resorption and thus hypercalcemia
In addition, osteoclast activation is also mediated by malignancy secreted cytokines, including interleukin-1, initially termed “osteoclast stimulating factor”
Macrophage inflammation protein 1-alpha (MIP 1-alpha)
hypercalcemia is through extra-renal 1,25-dihydroxyvitamin D (calcitriol) production
1% of cases
increased production of 1,25-dihydroxyvitamin D occurs nearly exclusively in Hodgkin and non-Hodgkin lymphoma with case reports of the same in ovarian dysgerminoma
1-α-hydroxylase in the kidney, a process regulated by PTH
in 1,25-dihydroxyvitamin D induced hypercalcemia, malignant cells likely recruit and induce adjacent macrophages to express 1-α-hydroxylase, converting endogenous calcidiol into calcitriol.31 Calcitriol then binds to receptors in the intestine leading to heightened enteric calcium reabsorption with resultant hypercalcemia
this mechanism of disease is best conceptualized as an absorptive form of hypercalcemia
Ectopic production of PTH by malignant cells has been described in a handful of cases involving cancer of the ovary and lung, as well as neuroendocrine tumors and sarcoma
primary hyperparathyroidism and malignancy comprising nearly 90% of cases of hypercalcemia
an initial panel consisting of PTH, PTHrP, phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D should be obtained
Lymphoma, a hypercalcemia due to 1,25-dihydroxyvitamin D mediated pathways, is implied by elevations in 1,25-dihydroxyvitamin D without concomitant elevations in 25-hydroxyvitamin D. In such cases, PTH is low and PTHrP undetectable
Treatment of hypercalcemia of malignancy is aimed at lowering the serum calcium concentration by targeting the underlying disease, specifically by inhibiting bone resorption, increasing urinary calcium excretion, and to a lesser extent by decreasing intestinal calcium absorption
mildly symptomatic disease
marked symptoms
hydration with isotonic fluid (if admitted), avoidance of thiazide diuretics, and a low-calcium diet
denosumab
Denosumab is an RANKL antibody that inhibits osteoclast maturation, activation, and function