Hypercalcemia

Over the past 20 years, the use of biphosphonates in disorders of calcium metabolism has generated much interest. Several biphosphonates have undergone extensive clinical trials in Europe, but only etidronate disodium (Didronel) has been approved by the U.S. Food and Drug Administration. Currently accepted indications for etidronate are the following: treatment of symptomatic Paget's disease, prevention and treatment of heterotopic ossification, and treatment of hypercalcemia of malignancy that cannot be adequately managed by dietary modification, oral hydration and diuresis.

Etidronate has been used investigationally in cancer treatment, especially in cases of breast cancer with bony metastasis, as a means of relieving pain, preventing fracture and forestalling hypercalcemia.(1) Recent interest has focused on the use of etidronate in the management of osteoporosis.(1,2) Because fluoride has failed as a satisfactory therapy for osteoporosis, the biphosphonates are becoming more important, particularly in the management of severe and refractory cases.(3)

Chemistry

Biphosphonates are inorganic pyrophosphate analogs in which the phosphate-oxygen-phosphate structure has been changed to a backbone of phosphatecarbon-phosphate Figure 1). The substitution of a carbon for an oxygen provides resistance to circulating alkaline and acid phosphatase. Etidronate is the disodium salt of diphosphonic acid. It is also known as EHDP, an abbreviation of its chemical name (ethane-l-hydroxy-1, 1-diphosphonate).

Etidronate is available in 200-mg and 400-mg tablets. An intravenous preparation comes in 6-mL ampules containing a 5 percent solution of 300 mg of etidronate in water. This solution must be diluted in at least 250 mL of sterile normal saline solution and infused over at least two hours.

The side chains of some newer biphosphonates have been altered in an attempt to confer greater oral absorption and to decrease side effects. (4) Clodrinate and pamidronate (APD) are among the newer biphosphonates Figure 2). In the future, these biphosphonates may become the preferred agents, because they cause fewer bone demineralization problems than etidronate.

Mechanism of Action

Bone remodeling occurs in an orderly fashion because of the coupling of old bone resorption and new bone synthesis and mineralization. Biphosphonates may inhibit bone resorption by several mechanisms.(5) They bind to hydroxyapatite crystals, forming a complex that persists in the body for at least six months, and perhaps for as long as two years. Biphosphonates serve as bone stabilizers, much like calcitonin and mithramycin (plicamycin; Mithracin).

Bone biopsies show that etidronate also reduces the number of osteoclasts in active bone turnover sites.(6) The mechanism of this action is not known. However, it is believed that biphosphonates are gradually released from the hydroxyapatite crystals and internalized into osteoclasts.(6)

Beyond their effect on osteoclasts, etidronate and, to a lesser extent, the newer biphosphonates prevent osteoblasts from laying down new bone properly. The exact mechanism is unknown, but an increase in osteoid has been demonstrated by bone biopsy, especially with higherdose etidronate therapy. This change can lead to osteomalacia, an unwanted side effect of etidronate.

Pharmacokinetics

Absorption of oral biphosphonates is low; only about 1 to 10 percent of an oral dose is absorbed. The amount absorbed increases with increasing doses. At a dosage of 5 mg per kg per day, about 1 percent of etidronate is absorbed; at 10 mg per kg per day, about 2.5 percent is absorbed, and at 20 mg per kg per day, 6 percent is absorbed.(7) The remainder is excreted in feces.

Absorption of etidronate is complete two hours after an oral dose, and the plasma half-life is about six hours. Following rapid clearance from the blood, 50 percent of the absorbed dose goes to the bone and finds a reservoir there, while 50 percent is excreted unchanged in the urine. Etidronate does not accumulate in other tissues. Because a decrease in glomerular filtration rate could significantly increase blood levels, a reduced dosage must be given in patients with renal failure, although no definite guidelines exist. Etidronate should not be used in patients with serum creatinine levels greater than 5 mg per dL (440/(micro)mol per L).

Biphosphonates are preferentially absorbed into areas of bone that are undergoing active osteogenesis, such as active pagetic lesions.(6) The half-life in bone is greater than 90 days and may be as long as two years.

Absorption of etidronate is reduced by food, milk and divalent cations. Therefore, etidronate should be taken on an empty stomach, about two hours before or two hours after a meal. It may be taken with water or fruit juice. Vitamins with mineral supplements or antacids may interfere with absorption. In patients receiving nephrotoxic drugs, etidronate can further impair renal function. Clinical Use

PAGET'S DISEASE

Etidronate therapy prevents fractures and reduces bone pain from Paget's disease. High-output cardiac failure as a result of increased bone turnover in Paget's disease also responds to etidronate. The drug can also prevent neurologic sequelae from bony erosion surrounding neural structures, and it may be given prior to bone surgery in Paget's disease to promote postoperative healing. Etidronate provides an oral alternative to calcitonin and can induce a long period of remission, with few systemic side effects. There is no proven advantage to using etidronate in combination with calcitonin.

Etidronate therapy is started in a dosage of 5 to 10 mg per kg per day, given orally for up to six months. In at attempt to minimize the side effect of osteomalacia, some physicians start with 2.5 mg per kg per day for six months. The high-dose regimen consists of 11 to 20 mg per kg per day for up to three months. This regimen should be used only in patients who do not respond to lower dosages.

An etidronate-free interval of at least 90 days is necessary between treatment courses. If the patient has responded well to low-dose etidronate therapy but must be treated again, another low-dose course may be used. The need for more than one course of treatment per year may indicate that the patient is becoming resistant to etidronate.(6)

HYPERCALCEMIA OF MALIGNANCY

Etidronate can significantly improve the quality of life in patients with hypercalcemia of malignancy. One treatment course may result in normocalcemia for months, much longer than the period of normocalcemia that occurs with calcitonin therapy. Etidronate lacks the systemic side effects of mithramycin and glucocorticoids. Supportive measures such as hydration and loop diuretics should be used along with etidronate, because there can be a lag time of 48 to 72 hours before the hypercalcemia is corrected.

In hypercalcemia of malignancy, etidronate is effective even when bony metastasis cannot be found and humoral mechanisms are believed to be responsible for the hypercalcemia.(8) Etidronate is not approved for use in hypercalcemia of primary hyperparathyroidism.

Biphosphonates have also been used recently to decrease bone pain from cancer metastases. For this purpose, the newer biphosphonates appear superior to etidronate.(9-11)

The recommended dosage of etidronate for the management of hypercalcemia of malignancy is 7.5 mg per kg per day, given intravenously for three days. If the serum calcium level again becomes elevated, the regimen may be repeated after seven days. On the day after the last infusion, oral etidronate may be started at a dosage of 20 mg per kg per day for 30 days. Oral therapy can be continued for up to 90 days. Whether the oral medication is necessary to maintain normocalcemia is unknown; the oral form of etidronate appears to be less effective than the intravenous form in maintaining normocalcemia.

HETEROTOPIC OSSIFICATION

Heterotopic ossification occurs after a variety of insults, including spinal cord injury and total hip replacement. It is present in up to 50 percent of patients with spinal cord injury, but is clinically significant in only one-third of cases.

After hip replacement, risk factors for the development of heterotopic ossification include male sex, osteoarthritis, previous hip surgery and previous formation of ectopic bone. Heterotopic ossification is clinically significant in only a small percentage of cases. Etidronate has bee used prophylactically in patients though to be at high risk. (12)

In selected patients having total hip replacement, the dosage of etidronate is 20 mg per kg per day for one month preoperatively and three months postoperatively. For patients with spinal cord injury, etidronate should be started as soon as possible after the injury at a dosage of 20 mg per kg per day for two weeks, followed by 10 mg per kg per day for 12 weeks.

OSTEOPOROSIS

Senile osteoporosis affects both corfical and trabecular bone and involves synthesis of mineralized bone, whereas postmenopausal osteoporosis is characterized by an accelerated rate of trabecular bone loss due to increased resorption. In the past, etidronate was studied as a treatment for osteoporosis, but its use was abandoned because of concern about increased fracture rates. Recently, cyclical etidronate therapy has been used for osteoporosis in menopausal women. For this purpose, a two-week course of etidronate, 400 mg orally daily, is followed by an etidronate-free period of ten to 13 weeks.(1,2)

Theoretically, osteoclast breakdown of bone is inhibited during the treatment period, while osteoblast mineralization of bone occurs during the etidronate-free period. During the etidronate-free period, 500 mg of calcium is given to ensure adequate amounts of calcium for mineralization. In one study,(2)vitamin D, 400 IU per day, was given during the etidronate free period. This approach was found to result in a significant decrease in the rate of new vertebral fractures and an increase in bone mineral content.(1,2)

Adverse Reactions

Editronate is associated with few systemic side effects, and these are usually minor. The most common side effects are gastrointestinal complaints such as nausea, vomiting and diarrhea. These symptoms often can be alleviated by dividing the dose. Dizziness and alteration in taste, including a metallic taste in the mouth, can occur. Rare allergic reactions, including rash and urticaria, have been reported.

Occasional mild to moderate abnormalities in renal function have been associated with the use of intravenous etidronate in the treatment of hypercalcemia of malignancy. Renal function should be monitored during therapy. Etidronate should not be given when the serum creatinine level is greater than 5 mg per dL (440 (micro)mol per L). Hydration and diuresis must be established before the etidronate infusion is started.

Hyperphosphatemia from a direct increase in renal phosphate resorption occurs with oral dosages of 10 to 20 mg per kg per day. Phosphate levels must therefore be monitored.(7) Fasting serum phosphate levels greater than 4.0 mg per dL (1.30 mmol per L) or a rise greater than 0.5mg per dL(O.15 mmol per L) should be avoided. The serum phosphate level usually returns to normal within two to four weeks of discontinuing etidronate. Hypocalcemia during etidronate therapy has not been clinically significant. Even overdoses produce only mild hypocalcemia. Patients should be given supplemental calcium during etidronate therapy, except when it is being used to control hypercalcemia.

Etidronate (parenteral or oral) has not been extensively studied in pregnant or lactating women and is not recommended in such patients. Etidronate has been administered in children to prevent heterotopic ossification or soft tissue calcification; in such cases, its use has been associated with a reversible rachitic syndrome.

Osteomalacia, which results in an increased amount of demineralized bone, is one of the most significant side effects of prolonged therapy with oral etidronate. Increased bone pain, an increased fracture rate and mineralization defects on radiographs (including the classic "etidronate lesion," a bubble-like bone defect) have been reported with etidronate therapy.(6) Some of the radiologic findings have been shown to reverse after discontinuation of etidronate.

The fear of an increased fracture rate with etidronate has spurred the development of newer biphosphonates. Because etidronate may persist in the bone for up to two years, some physicians do not use it in patients with significant Paget's disease of the femur in an attempt to avoid the devastating consequences of a femoral fracture.(6) Some physicians also withhold etidronate in patients with a long bone fracture, fearing decreased healing. However, etidronate does not interfere with the healing of spinal fractures when it is given to prevent heterotopic ossification. The drug is also used prophylactically after total hip replacement.

Potential Uses

In Europe, the newer biphosphonates are used regularly. In the United Kingdom, pamidronate is approved for use in hypercalcemia of malignancy, and it is also used extensively in Paget's disease.(13) The most important advantage of the newer biphosphonates is that they provide more effective inhibition of osteoclastic activity in hypercalcemia of malignancy and less inhibition of osteoblastic bone mineralization in Paget's disease of bone.

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COPYRIGHT 1991 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group