Hypercalcemia of malignancy

Use calcium metabolism regulator (treatment of Paget s disease, hypercalcemia of malignancy)... 

May be superior to bisphosphonates for humoral hypercalcemia of malignancy (PTHrp)... 

FIGURE 96-4. Pathophysiology of the hypercalcemia of malignancy. PTHrP, parathyroid hormone-related protein TGF-P, transforming growth factor P TNF-a, tumor necrosis factor alpha Ca2+, calcium IL-1, interleukin 1 IL-2, interleukin 2. 

The antiresorptive therapy of choice for hypercalcemia of malignancy is a bisphosphonate. Because of poor oral bioavailability, only intravenous agents should be used. 

Ga Ga(N03)3 Hypercalcemia of malignancy Ganite. Possible anticancer agent. In clinical trials for use in lymphomas... 

Hypercalcemia of malignancy develops quickly and is associated with anorexia, nausea and vomiting, constipation, polyuria, polydipsia, and nocturia. Hypercalcemic crisis is characterized by acute elevation of serum calcium to greater than 15 mg/dL, acute renal failure, and obtundation. Untreated hypercalcemic crisis can progress to oliguric renal failure, coma, and life-threatening ventricular arrhythmias. 

Bisphosphonates are indicated for hypercalcemia of malignancy. Total serum calcium decline begins within 2 days and nadirs in 7 days. 

Hypercalcemia of malignancy (HCM) For the treatment of FICM (zoledronic acid) in conjunction with adequate hydration for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases (pamidronate patients with epidermoid or nonepidermoid tumors respond to pamidronate) for FICM that persists after adequate hydration has been restored (zoledronic acid). 

Dose The maximum recommended dose in hypercalcemia of malignancy (albumin-corrected serum calcium at least 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single dose IV infusion over not less than 15 minutes. Adequately rehydrate patients prior to administration of zoledronic acid. 

The bisphosphonates are the most effective compounds available to treat hypercalcemia of malignancy. Pamidronate (Aredia) and zoledronic acid (Zometa) can be infused intravenously and are the most effective compounds available for rapid reduction of serum calcium levels. 

Multiple bisphosphonates compounds are available for both oral and intravenous use. Some [alendronate (Fosamax) and etidronate (Didronel)] are used for osteoporosis, others [etidronate, tirludronate (Skelid), risedronate Actonel) for Paget s disease, and yet others [pamidronate Aredia), zoledronic acid] for the hypercalcemia of malignancy. 

Pamidronate, 60-90 mg, infused over 2-4 hours, and zole-dronate, 4 mg, infused over at least 15 minutes, have been approved for the treatment of hypercalcemia of malignancy and have largely replaced the less effective etidronate for this indication. The effects generally persist for weeks, but treatment can be repeated after a 7-day interval if necessary and if renal function is not impaired. Some patients experience a self-limited flu-like syndrome after the infusion. Repeated doses of these drugs have been linked to renal deterioration and osteonecrosis of the jaw, but this adverse effect is rare. 

Gallium nitrate is approved by the FDA for the management of hypercalcemia of malignancy. This drug acts by inhibiting... 

Sanders, JL, Chattopadhyay, N, Kifor, O, Yamaguchi, T and Brown, EM, 2000, Extracellular calciumsensing receptor (CaR) expression and its potential role in parathyroid hormone-related peptide (PTHrP) secretion in the H-500 rat Ley dig cell model of humoral hypercalcemia of malignancy, Biochem Biophys Res Commun 269 127 132... 

Hypercalcemia of malignancy Many forms of cancer accelerate bone resorption, leading to hypercalcemia Calcitonin, bisphosphonates... 

Osteolytic tumors may induce bone destruction either through local invasion, or by a secondary metastatic bone disease. The most frequent types of primary tumors that develop into metastatic bone disease are, in the order of prevalence breast, prostate, thyroid, kidney, and bronchial tumors, whereas esophageal, gastrointestinal and rectal tumors are much less metastatic [11]. Very often, the destruction of bone in a metastatic bone disease leads to hypercalcemia of malignancy, which also responds to BPs. In addition, hematological cancers such as... 

Pamidronate (Ciba Geigy) Hypercalcemia of malignancy Tumoral osteolysis Paget s disease Osteoporosis -100 1987 25, 312... 

Tiludronate (Sanofi Winthrop) Paget s disease Hypercalcemia of malignancy Tumoral osteolysis Osteoporosis -10 1995 31,350... 

Ibandronate (Boehringer Mannheim) Hypercalcemia of malignancy Tumoral osteolysis OsteoporosisPaget s disease -1000- -10 000 1996 32, 309... 

Alendronate is an aminobisphosphonate with general properties similar to those of the other bisphosphonates. It inhibits bone resorption and is nsed in osteoporosis and Paget s disease of bone. It has also been nsed in the treatment of bone metastases and hypercalcemia of malignancy. 

Clodronate is a bisphosphonate that has demonstrated efficacy in patients with a variety of disorders of enhanced bone resorption, including Paget s disease, osteolytic bone metastases, and hypercalcemia of malignancy (8,9). In preclinical studies, clodronate prevented bone loss during immobilization (10). 

Nussbaum SR, Younger J, Vandepol CJ, Gagel RE, Zubler MA, Chapman R, Henderson IC, MaUette LE. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993 95(3) 297-304. 

Daragon A, Peyron R, Serrurier D, Deshayes P. Treatment of hypercalcemia of malignancy with intravenous APD. Curr Ther Res 1991 50 10-21. 

Gallium nitrate has been used as an alternative to bisphosphonates in hypercalcemia of malignancy (11), in which it is effective but associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than the bisphosphonates. The pathophysiology and treatment of hypercalcemia of malignancy has been reviewed and the role of gallium nitrate considered (12,13). 

Major P, Lortholary A, Hon J, Abdi E, Mills G,Menssen HD, Yunus F, Bell R, Body J,Ouebe-Fehling E,etal.Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001 19 558-567. 

The potential therapeutic uses of calcitonin arc in the treatment of hyperparathyroidism, osteoporosis and other bone-disorders. hypercalcemia of malignancy, and idiopathic hypercalcemia. 

Indications Hypercalcemia of malignancy, Paget s disease Category Bisphosphonate Half-life 7 days... 

Hypercalcemia occurs in 10% to 20% of individuals with cancer. Tumors most commonly cause hypercalcemia by producing PTHrP, which is secreted into the circulation and stimulates bone resorptions and/or by invasion of the bone by metastatic tumor, which produces local factors that stimulate bone resorption. PTHrP binds to the PTH receptor and is the principal mediator of humoral hypercalcemia of malignancy (HHM). Cytokines such as lymphotoxin, interleukin-1, tumor necrosis factor, and PTHrP appear to be important mediators of hypercalcemia in multiple myeloma and other hematological malignancies. Some lymphomas associated with acquired immunodeficiency syndrome or HTLV [ infections cause hypercalcemia by producing 1,25(0H)2D. It is estimated that 5% of patients with hypercalcemic cancer have coexisting primary hyperparathyroidism. 

PTH and 1,25-dibydroxyvitamin D are the primary hormones regulating bone and mineral metabolism. Calcitonin has pharmacological actions, but a physiological role has not been established in adults. PTHrP is the principal mediator of hmnoral hypercalcemia of malignancy. 

Decreased 1,25 0H)2D Renal failure Hyperphosphatemia Hypomagnesemia Hypoparathyroidism Pseudohypoparathyroidism Vitamin D-dependent rickets, type I Hypercalcemia of malignancy Increased l,25(OH)2D Granulomatous diseases Primary hyperparathyroidism Lymphoma... 

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