Treatment of immobilization-related hypercalcaemia with denosumab.

Abstract

Hypercalcaemia has been reported to occur in ∼1–4% of the general adult population, and in 0.5–3% of hospitalized adult patients [1]. Hypercalcaemia results when the entry of calcium (Ca) into the extracellular fluid exceeds excretion in the urine or deposition in bone. This occurs when there is accelerated bone resorption, excessive gastrointestinal absorption or decreased renal excretion of Ca. Under most pathologic conditions, hypercalcaemia results from increased skeletal resorption or intestinal absorption with normal or decreased renal excretion. In some disorders more than one mechanism may be involved. As an example, in primary hyperparathyroidism, elevated parathyroid hormone (PTH) levels increase bone resorption, tubular Ca reabsorption and, indirectly, intestinal Ca absorption (by increasing renal synthesis of calcitriol). Among all causes of hypercalcaemia, primary hyperparathyroidism and malignancy are the most common, accounting for >90% of cases [2]. The differential diagnosis of hypercalcaemia may be broadly divided into PTH-mediated and non-PTH-mediated hypercalcaemia [3] (Table 1). PTH-mediated hypercalcaemia is associated most frequently with primary hyperparathyroidism. The most common cause of non-PTH-mediated hypercalcaemia is that of malignancy. Hypercalcaemia in patients with cancer is primarily due to increased bone resorption and the release of Ca from bone. There are three major mechanisms by which this can occur: osteolytic metastases with local release of cytokines which stimulates the differentiation of osteoclast precursors into mature osteoclasts and activates bone resorption (mainly breast cancer, myeloma and lymphomas), tumour secretion of PTH-related protein (PTHrP) (mainly solid tumours, such as squamous cell carcinomas and renal carcinomas) and tumour production of calcitriol (mainly lymphomas). In the latter condition, hypercalcaemia results from the increase of either bone resorption or intestinal absorption. Ectopic PTH secretion has been documented in single cases of small cell and squamous cell lung cancer, ovarian carcinoma, papillary thyroid carcinoma, hepatocellular carcinoma and undifferentiated neuroendocrine neoplasia. Non-PTH-mediated hypercalcaemia may be caused also by different endocrine disorders such as thyrotoxicosis and adrenal insufficiency. In hyperthyroidism, hypercalcaemia mainly results from increased bone resorption. Hypercalcaemia is a rare complication of pheochromocytoma. It can be due to concurrent hyperparathyroidism (in MEN, Type II) or to the pheochromocytoma itself due to tumoural production of PTHrp. Granulomatous diseases (such as sarcoidosis, and focal or disseminated tuberculosis) can cause hypercalcaemia by overproduction of 1,25-dihydroxyvitamin D. Immobilization is a rare cause of hypercalcaemia. For the diagnosis of immobilization-related hypercalcaemia, all the other causes of PTH- and vitamin D-dependent hypercalcaemia should be carefully excluded (Table 1). In this issue of CKJ, de Beus and Boer [4] report the case of a patient with chronic renal failure and immobilization-related hypercalcaemia successfully treated with denosumab, a monoclonal antibody with affinity for the receptor activator of nuclear factor-kB (RANK) ligand (RANKL). Prolonged immobilization uncouples bone remodelling because of the lack of mechanical stress. The greater deceleration in bone formation than in bone resorption results in a net efflux of Ca from bone that induces hypercalciuria and suppression of the parathyroid-1,25-vitamin D axis [5]. Hypercalcaemia develops when the efflux of Ca from bone exceeds the capacity of the kidney to excrete Ca. Immobilized patients with pre-existing states of high bone turnover (e.g. adolescents and patients with Paget's disease, thyrotoxycosis or primary hyperparathyroidism), and/or reduced renal function are at particular risk of developing severe hypercalcaemia [6–8] Table 1. Causes of hypercalcaemia