Hypercalcemia bisphosphonates

Ehevention and treatment efforts usually include adequate calcium and vitamin D intake, adherence to pancreatic enzymes, correction of hypogonadism, exercise, potential use of GH in children whose height is below the tenth percentile, and when possible, reductions in glncocorticoid use. Calcitriol may be needed to overcome vitamin D malabsorption problems, bnt needs to be monitored for hypercalcemia. Bisphosphonates are generahy not recommended for children. 

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

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

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

Hypercalcemia can be treated by (1) administering 0.9% NaCl solution plus furosemide (if necessary) renal excretion (2) the osteoclast inhibitors calcitonin, plicamycin, or clodro-nate (a bisphosphonate) bone calcium mobilization i (3) the Ca +chelators EDTA sodium or sodium citrate as well as (4) glucocorticoids. 

Bisphosphonates structurally mimic endogenous pyrophosphate, which inhibits precipitation and dissolution of bone minerals. They retard bone resorption by osteoclasts and, in part, also decrease bone mineralizatioa Indications include tumor osteolysis, hypercalcemia, and Paget s disease. Qinical trials with etidronate, administered as an intermittent regimen, have yielded favorable results in osteoporosis. With the newer drugs clodronate, pamidronate, and alendronate, inhibition of osteoclasts predominates a continuous regimen would thus appear to be feasible. 

The bisphosphonates are synthetic organic compounds that are incorporated directly into the hydroxyapatite of bone and then inhibit osteoclastic bone resorption. This antiresorptive action makes them useful in the pharmacological treatment of hypercalcemia, osteoporosis, and Paget s disease. 

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. 

Calcitonin is also effective in reducing serum calcium levels in life-threatening hypercalcemia however, it is not as rapid or as effective as the bisphosphonates. Subcutaneous administration of salmon (Calcimar) or human (Cibacalcin) calcitonin reduces serum calcium levels within 3 to 5 days in 75 to 90% of malignant hypercalcemias. 

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. 

Etidronate and the other bisphosphonates exert a variety of effects on bone mineral homeostasis. In particular, bisphosphonates are useful for the treatment of hypercalcemia associated with malignancy, for Paget s disease, and for osteoporosis (see Newer Therapies for Osteoporosis). Contrary to expectations, some of the newer bisphosphonates appear to increase bone mineral density well beyond the 2-year period predicted for a drug whose effects are limited to blocking bone resorption. The bisphosphonates exert a variety of other cellular effects, including inhibition of l,25(OH)2D... 

Giving intravenous phosphate is probably the fastest and surest way to reduce serum calcium, but it is a hazardous procedure if not done properly. Intravenous phosphate should be used only after other methods of treatment (bisphosphonates, calcitonin, and saline diuresis) have failed to control symptomatic hypercalcemia. Phosphate must be given slowly (50 mmol or 1.5 g elemental phosphorus over 6-8 hours) and the patient switched to oral phosphate (1-2 g/d elemental phosphorus, as one of the salts indicated below) as soon as symptoms of hypercalcemia have cleared. The risks of intravenous phosphate therapy include sudden hypocalcemia, ectopic calcification, acute renal failure, and... 

This rather common disease, if associated with symptoms and significant hypercalcemia, is best treated surgically. Oral phosphate and bisphosphonates have been tried but cannot be recommended. Asymptomatic patients with mild disease often do not get worse and may be left untreated. The calcimimetic agent cinacalcet, discussed previously, has been approved for secondary hyperparathyroidism and is in clinical trials for the treatment of primary hyperparathyroidism. If such drugs prove efficacious, medical management of this disease will need to be reconsidered. 

The goal of treatment is to reduce bone pain and stabilize or prevent other problems such as progressive deformity, hearing loss, high-output cardiac failure, and immobilization hypercalcemia. Calcitonin and bisphosphonates are the first-line agents for this disease. Treatment failures may respond to plicamycin. Calcitonin is administered subcutaneously or intramuscularly in doses of 50-100 MRC (Medical Research Council) units every day or every other day. Nasal inhalation at 200-400 units per day is also effective. Higher or more frequent doses have been advocated when this initial regimen is ineffective. Improvement in bone pain and reduction in serum alkaline phosphatase and urine hydroxyproline levels require weeks to months. Often a patient who responds well initially loses the response to calcitonin. This refractoriness is not correlated with the development of antibodies. 

Morony S et al The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia and malignancy. Endocrinology 2005 146 3235. [PMID 15845617]... 

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

General Category Bisphosphonates Examples Alendronate (Fosamax) Etidronate (Didronel) Ibandronate (Boniva) Pamidronate (Aredia) Risedronate (Actonel) Treatment Rationale and Principal Indications Appear to block excessive bone resorption and formation is used to normalize bone turnover in conditions such as osteoporosis and Paget disease, and to prevent hypercalcemia resulting from excessive bone resorption in certain forms of cancer... 

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). 

Calcitonin inhibits osteoclastic bone resorption, increases the urinary excretion of calcium and phosphate, and reduces serum calcium. It is established in the treatment of disorders of high bone turnover, including Paget s disease and postmenopausal osteoporosis, but is less effective than the bisphosphonates. Calcitonin is less effective than other therapeutic measures in the treatment of acute hypercalcemia. Long-term administration of calcitonin reduces morbidity in cases of osteogenesis imperfecta... 

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). 

Dumon JC, Magritte A, Body JJ. Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia. Bone Miner 1991 15 257-266. 

Trade name Aredia (Novartis) Indications Hypercalcemia, Paget s disease Category Bisphosphonate Half-life 1.6 hours... 

Several bisphosphonates are available in the United States. Etidronate sodium (Didronel) is used for treatment of Paget s disease and may be used parenteraUy to treat hypercalcemia. Because etidronate is the only bisphospho-nate that inhibits mineralization, it has been supplanted largely by pamidronate and zoledronate for treating hypercalcemia. Pamidronate (Aredia) is approved for management of hypercalcemia but also is effective in other... 

Pamidronate disodium is a bisphosphonate that inhibits normal and abnormal bone resorption. It is indicated in the treatment of moderate to severe hypercalcemia associated... 

Intravenous bisphosphonates (pamidronate, zoled-ronate) have proven very effective in the management of hypercalcemia. These agents potently inhibit osteoclastic bone resorption. Oral bisphosphonates are less effective for treating hypercalcemia. Therefore, pamidronate (Aredia) is given as an intravenous infusion of 60 to 90 mg over 4 to 24 hours. With pamidronate, resolution of hypercalcemia occurs over several days, and the effect usually persists for several weeks. 

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