Vitamin A. Vitamin A and its analogues are often used in the treatment of neoplastic and dermatologic diseases. Hypervitaminosis A can rarely be complicated by hypercalcaemia. The mechanisms proposed include either an increased bone resorption due to the fact that osteoclasts and osteoblasts express retinoic acid receptors or an action of vitamin A on calcium release following lysosomal degradation. The susceptibility to develop hypervitaminosis A is highly variable, and the daily intake up to 50 000 UI is safe. Effective treatments, when needed later after discontinuation of vitamin A, include hydration, bisphosphonates, and glucocorticoids.
Oestrogen receptor modulators. Hypercalcaemia is rarely seen in women with breast cancer, in the early phase of treatment with tamoxifen, a selective oestrogen receptor modulator. The exact mechanism is not completely understood, and it is thought to be related to the presence of oestrogen receptor on cancer cells. Hypercalcaemia is generally transient and, in some cases, may be moderate to severe.
Lithium. Lithium, effectively used worldwide in the management of patients with bipolar disorders, has been shown to interfere with thyroid and parathyroid functions. There are many studies that demonstrate that lithium can associated with a biochemical pro file similar to that of PHPT. Lithium competes with calcium for the binding to the CaSR in the parathyroid glands, leading to a shift to the right of the calcium set- point and hypersecretion of PTH. This effect is transient and resolves after lithium discontinuation, when used for limited time, but persists when lithium is chronically used. In a few cases treatment with lithium has been associated with the development of parathyroid adenomas and, therefore, a ‘true’ PHPT. The optimal treatment is surgical as suggested in other forms of PHPT. Recently calcimimetics have been shown to be effective in lowering hypercalcaemia due to lithium treatment.
Thiazides. Treatment with thiazides has been associated with hypercalcaemia in 2% of cases and this side effect has been known for decades, even if the exact pathogenetic mechanism is poorly understood. Two possible triggers are the volume depletion induced by thiazides and the possible inhibition of the transient receptor potential cation channel subfamily V member 5 (TRVP5), a specific calcium selective channel. Hypercalcaemia due to thiazides is generally mild and resolves after thiazides withdrawal. However, some cases of occult PHPT and persistent hypercalcaemia after drug discontinuation have been described. This can be due to the fact that thiazides may worsen hypercalcaemia and reveals the presence of a previously undiagnosed mild PHPT characterized by normal or intermittently mildly elevated serum calcium.
