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Chapter: Basic & Clinical Pharmacology : Agents That Affect Bone Mineral Homeostasis

Other Disorders of Bone Mineral Homeostasis

Paget’s disease is a localized bone disorder characterized by uncontrolled osteoclastic bone resorption with secondary increases in poorly organized bone formation.



Paget’s disease is a localized bone disorder characterized by uncon-trolled osteoclastic bone resorption with secondary increases in poorly organized bone formation. The cause of Paget’s disease is obscure, although some studies suggest that a slow virus may be involved. The disease is fairly common, although symptomatic bone disease is less common. The biochemical parameters of ele-vated serum alkaline phosphatase and urinary hydroxyproline are useful for diagnosis. Along with the characteristic radiologic and bone scan findings, these biochemical determinations provide good markers by which to follow therapy.

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.

Sodium etidronate, alendronate, risedronate, and tiludronate are the bisphosphonates currently approved for clinical use in Paget’s disease of bone in the USA. Other bisphosphonates, including pamidronate, are being used in other countries. The recommended dosages of bisphosphonates are etidronate, 5 mg/kg/d; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludronate, 400 mg/d. Long-term (months to years) remission may be expected in patients who respond to a bisphosphonate. Treatment should not exceed 6 months per course but can be repeated after 6 months if necessary. The principal toxicity of etidronate is the development of osteomal-acia and an increased incidence of fractures when the dosage is raised substantially above 5 mg/kg/d. The newer bisphosphonates such as risedronate and alendronate do not share this adverse effect. Some patients treated with etidronate develop bone pain similar in nature to the bone pain of osteomalacia. This subsides after stop-ping the drug. The principal adverse effect of alendronate and the newer bisphosphonates is gastric irritation when used at these high doses. This is reversible on cessation of the drug.

The use of a potentially lethal cytotoxic drug such as plicamycin in a generally benign disorder such as Paget’s disease is recom-mended only when other less toxic agents (calcitonin, alendronate) have failed and the symptoms are debilitating. Clinical data on long-term use of plicamycin are insufficient to determine its useful-ness for extended therapy. However, short courses involving 15–25 mcg/kg/d intravenously for 5–10 days followed by 15 mcg/kg intravenously each week have been used to control the disease.


Patients with short bowel syndromes and associated fat malabsorp-tion can present with renal stones composed of calcium and oxalate. Such patients characteristically have normal or low urine calcium levels but elevated urine oxalate levels. The reasons for thedevelopment of oxaluria in such patients are thought to be twofold: first, in the intestinal lumen, calcium (which is now bound to fat) fails to bind oxalate and no longer prevents its absorption; second, enteric flora, acting on the increased supply of nutrients reaching the colon, produce larger amounts of oxalate. Although one would ordinarily avoid treating a patient with calcium oxalate stones with calcium supplementation, this is precisely what is done in patients with enteric oxaluria. The increased intestinal calcium binds the excess oxalate and prevents its absorption. One to 2 g of calcium carbonate can be given daily in divided doses, with careful moni-toring of urinary calcium and oxalate to be certain that urinary oxalate falls without a dangerous increase in urinary calcium.

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