MANAGEMENT OF OSTEOPOROSIS AND PAGETS-DISEASE - AN APPRAISAL OF THE RISKS AND BENEFITS OF DRUG-TREATMENT

Osteoporosis is a major public health problem occurring primarily amon g the postmenopausal population. Osteoporosis is a preventable disease , but despite several advances in its prevention, treatment of the est ablished disease to date remains a major challenge to be managed by pr imary care physicians. Stabilisation of bone mass and prevention of fa lls are of paramount importance in any therapeutic programme for osteo porotic patients with established vertebral fractures. Drug therapy fo r osteoporosis can be divided operationally into 2 main categories; th ose that inhibit bone resorption, and thus reduce bone turnover, and t hose that stimulate bone formation, exerting an anabolic effect. Thera peutic agents that inhibit bone remodeling would appear to be best sui ted to those patients with high turnover osteoporosis (about 30%). Inc luded in this category are calcium, vitamin D and its metabolites, gon adal steroids, calcitonin, ipriflavone and bisphosphonates. Although e strogen replacement therapy has been proven to be effective in older f emales, calcitonin appears to be the treatment of choice for this popu lation since it stabilises or increases bone mass and also has reporte d analgesic properties. Drugs that stimulate bone remodeling or bone f ormation would be best suited to patients with low turnover osteoporos is (about 70%). The agent in this class that is widely used is sodium fluoride. New therapies include intermittent injections of synthetic p arathyroid hormone, and cyclic bisphosphonates to activate then depres s resorption and formation. Any attempts to stabilise the skeleton wit h any drug regimen must be accompanied by an adequate calcium supply, i.e. 1200 to 1500 mg/day). The theoretical basis of tailoring treatmen t for osteoporosis to the underlying histology has not yet been fully proven, but there is increasing experimental support to this approach. Drugs that inhibit bone turnover, such as calcitonin, appear to be ef fective in increasing bone mass for 1.5 to 2 years, about the time it would take to replenish the remodeling space in a patient with high tu rnover osteoporosis. In contrast, although bone mass appears to increa se for as long as 5 years in patients treated with sodium fluoride, th ere has been no consistent reduction in occurrence of vertebral or hip fractures. Paget' disease of bone is a focal disorder of the skeleton characterized by excessive resorption and subsequently disorganized f ormation of bone. The aetiology of the disease is unknown. Paget's dis ease may be mono-ostotic or polyostotic; pain and bone deformities due to enlargement of skeletal segments represent the main clinical aspec ts. However, in many patients the disease may be asymptomatic. The mai n goal in the therapy of Paget's disease is the reduction of bone turn over. Effective drugs such as calcitonin and bisphosphonates appear to act by reducing osteoclast activity and the generation of osteoclasts . The efficacy of calcitonin has been shown by the fall in serum alkal ine phosphatase and in urinary hydroxyproline excretion, along with re lief of bone pain and improvement of disability. The reduction of bone turnover has also been quantified in sequential bone biopsies by the decreases in osteoclast number, and in woven bone by the behaviour of serum osteocalcin. A more common response to calcitonin may be a plate au response, or acquired resistance. The most common adverse effects o f calcitonin are nausea and vomiting. At present, etidronic acid (etid ronate) is the most widely available bisphosphonate, and is extensivel y used in Paget's disease. Its use has resulted in a reduction of seru m alkaline phosphatase and urinary hydroxyproline. Histologically, ost eoclastic bone resorption significantly decreases in etidronic acid-tr eated patients. The duration of remission is variable. Many studies in dicate that prolonged high dosages of the drug may produce inhibition of bone mineralisation. Other bisphosphonates have had beneficial effe cts in Paget's disease. Combination therapy with calcitonin and a bisp hosphonate has been utilised to obtain additive suppressive effects on the disease with a reduction in adverse effects. Plicamycin (mithramy cin), oral calcium supplementation and gallium nitrate have also been proposed for the treatment of Paget's disease.