Hypercalcaemia of malignancy

D5. de la Piedra, C., Toural, V., and Rapado, A., Osteocalcin and urinary hydroxyproline/creatinine ratio in the differential diagnosis of primary hyperparathyroidism and hypercalcaemia of malignancy. Scand. J. Clin. Lab. Invest. 47, 587-592 (1987). 

Bisphosphonates (see later). Pamidronate is infused according to the schedule in Table 38.1 it is active in a wide variety of hypercalcaemic disorders. Fall in serum calcium begins in 1-2 d, reaches a nadir in 5-6 d and lasts 20-30 d. Etidronate may be given i.v. in hypercalcaemia of malignant disease. It acts in 1-2 d and a dose lasts 3 weeks it may also provide benefit for neoplastic metastatic disease in bone. Clodronate (oral or i.v.) or zoledonic acid (i.v) are alternatives. 

Bisphosphonates are widely used for the prevention and treatment of osteopenia and osteoporosis and for the reduction of skeletal complications in patients with malignant bone disease. Several oral bisphosphonates, including alendronate, risedronate, and ibandronate, are approved worldwide for the treatment of osteoporosis in postmenopausal women, as are intravenous (i.v.) formulations of ibandronate (3 mg quarterly) and zoledronic acid (5 mg annually). Several i.v. bisphosphonates are available for the treatment of the skeletal complications that frequently occur in malignant disease, such as hypercalcaemia of malignancy (HCM), multiple myeloma, and bone metastases associated with solid tumours. Pamidronate is approved worldwide for the treatment of HCM, multiple myeloma, and breast cancer bone metastases. Although not registered for oncology indications in the United States, i.v. ibandronate is widely available elsewhere for HCM and breast cancer bone metastases. 

AE = Adverse event BC = Breast cancer CLOD = Clodronate EHDP = Etidronate HCM = Hypercalcaemia of malignancy IBN = Ibandronate i.v = Intravenous LC = Lung cancer MM = Multiple myeloma OST = Other solid tumours (renal, head and neck, thyroid, other) PDB = Paget s disease of bone PAM = Pamidronate PC = Prostatecancer PLA = Placebo PMO = Postmenopausal osteoporosis RIS = Risedronate ZOL = Zoledronicacid. 

Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995 72 1289-1293. 

Pecherstorfer M, Diel IJ. Rapid administration of ibandronate does not affect renal functioning evidence from clinical studies in metastatic bone disease and hypercalcaemia of malignancy. Support Care Cancer 2004 12 877-881. 

The commonest causes of hypercalcaemia are primary hyperparathyroidism and hypercalcaemia of malignancy. 

Hypercalcaemia will most likely be due to the presence of a parathyroid adenoma, or will be associated with a malignancy. In the former, serum PTH will be high or inappropriately detectable, whereas in hypercalcaemia of malignancy the high calcium suppresses parathyroid function and semm PTH is undetectable. 

Osteoporosis Rickets osteomalacia Paget s disease Primary hyperparathyroidism Hypercalcaemia of malignancy Gout Myeloma... 

Calcitonin is used clinically to treat hypercalcaemia associated with some forms of malignancy and Paget s disease. The latter condition is a chronic disorder of the skeleton in which bone grows abnormally in some regions. It is characterized by substantially increased bone turnover rates,... 

What treatment options are now available to Mrs CR and what are the goals of therapy for her with regard to (a) chemotherapy, (b) management of malignant hypercalcaemia/bone metastases, and (c) management of liver capsule pain ... 

The treatment of Mrs CR s hypercalcaemia is urgent and requires immediate administration of bisphosphonate therapy, the first choice therapy in cases of severe hypercalcaemia. Currently four bisphosphonates are available in the UK for the treatment of malignant hypercalcaemia - sodium clodronate, disodium pamidronate, zoledronic acid and ibandronic acid. The choice of which bisphosphonate to recommend will depend on which one is on the local hospital formulary. 

An adrenocortical steroid, e.g. prednisolone 20-40 mg/d orally, is effective in particular situations it reduces the hypercalcaemia of vitcimin D intoxication (which is due to excessive intestinal absorption of calcium) and of sarcoidosis (principally by its disease-modifying effect). Steroid may be effective in the h)q5ercalcaemia of malignancy where the disease itself is responsive, e.g. myeloma of lymphoma. Most patients with hyperparathyroidism do not respond. 

A subset of patients with hypercalcaemia related to a malignancy show no evidence of excess parathyroid hormone production or osseous metastases. PG have been implicated in the pathogenesis of malignancy-related hypercalcaemia, since PG enhance bone resorption, and are necessary for the synthesis of osteoclastic activating factor. Some patients with renal cell carcinoma and concomitant hypercalcaemia have been shown to have elevated renal PG levels which can be suppressed with indomethacin. 

Q7 The total serum calcium concentration is normally about 9.5 mg dl 1. Approximately half of this is bound to plasma protein, mostly to albumin. Most of the remainder is unbound or ionized calcium, which is the physiologically and clinically important form. Hypercalcaemia, normally defined as a serum concentration of >12 mgdl-1, may sometimes be caused by excessive consumption of calcium in the diet. More important pathologically is malignant disease. Hypercalcaemia occurs when there are bone metastases associated with breast or prostate cancer. However, many tumours can produce a PTH-like protein causing elevated serum calcium levels. Furthermore, intoxication and immobilization of vitamin D or excess vitamin D may also cause hypercalcaemia. 

Q9 The hypercalcaemia which occurs in hyperparathyroidism may be reduced by administration of a loop diuretic such as furosemide, which helps calcium excretion. Bisphosphonates, which prevent bone resorption and so reduce calcium release from bone, can be used to treat hypercalcaemia associated with malignancies. Calcitonin may also be useful in treating the hypercalcaemia associated with cancer, as it reduces calcium levels both by attenuating its renal reabsorption and by increasing calcium deposition in bone. 

Kanis JA, McCloskey EV, Paterson AH. Use of diphospho-nates in hypercalcaemia due to malignancy. Lancet 1990 335(8682) 170-1. 

A diagnostic decision chart is shown in Figure 1. Primary hyperparathyrouHsm is most often due to a single parathyroid adenoma which secretes PTH independently of feedback control by plasma calcium. Hypercalcaemia associated with malignancy is the commonest cause of a high calcium in a hospital population. Some tumours secrete a protein called PTHrP (parathyroid hormone-related protein) which has PTH-like properties. 

Pathological intracellular calcifications can also occur in conditions associated with hypercalcaemia [26] - excess levels of calcium in the blood, caused, e.g. by hyperparathyroidism (excess secretion of parathyroid hormone by overactive parathyroid glands which normally regulate calcium levels tightly) or malignancy [27]. Intramitochondrial cdcifications often precede necrosis, and fusion or rupture of calcified mitochondria results in calcareous masses in the cytoplasm or outside of the cell. Much progress has been made in the ultramicroscopic identification and systematic classification of these calcifications [28]. 

Some of the numerous adverse effects of aspirin on metabolism have been reviewed previously (136 ). Aspirin reduces the urinary excretion of prostaglandin metabolites, and may lower the serum calcium in patients with hypercalcaemia associated with malignancy (177). Sodium salicylate interferes with the synthesis of cartilage glycosamino-glycans and the question of long-term deleterious effects on articular cartilage has been raised (178). 

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