Bisphosphonates in the treatment of osteoporosis (1998)

The bisphosphonates are synthetic compounds characterized by a P-C-P bond and therefore analogues of the normally occurring substances containing P-0-P. By substituting the hydrogens on the C atom. it is possible to sythesize a variety of bisphosphonates, each of them with its distinct physical-chemical, biological, therapeutic and toxicological characteristics. The first description of their action on calcium phosphate was published by our group in 1968–69.The bisphosphonates are characterized by a strong affinity to calcium phosphates and hence to bone mineral. Once bound they inhibit both formation and dissolution of the crystals. The former effect explains why, when given in large amounts. bisphosphonates can inhibit mineralization in vivo.Many of the bisphosphonates inhibit bone resorption, the newest compounds being 10000 times more active in this respect than the first ones described. In contrast to the effect on mineralizion, the antiresorbing effect is cell mediated. the exact mechanism being still unknown. It seems likely that part of the action is due to a direct effect on the osteoclasts which become inhibited after engulfing the compounds during the process of dissolution of drug-containing mineral. Another part of the effect appears to be mediated throug the osteoblasts, which are induced to produce an inhibitor of osteoclast recruitment. Bisphosphonates have been investigated extensively in animals in view of a possible use in diseases with increased bone resorption. In the growing rat, the inhibition of resorption is accompanied by an increase in intestinal absorption and an increased balance of calcium. They also prevent various types of experimental osteoporosis. such as after immobilization. ovariectomy, orchidectomy, administration of corticosterids, or low calcium diet. Furthermore, bisphosphonates prevent bone destruction induced by various tumor models.The P-C-P bond of the bisphosphonates is completely resistant to enzymatic hydrolysis. The bisphosphonates studied up to now. such as alendronate, clodronate, etidronate, pamidronate, risedronate and tiludronate, are absorbed. stored and excreted unaltered.In humans, bisphosphonates are used successfully in diseases with increased bone turnover. such as Paget's disease. tumoral bone disease, as well as in osteoporosis. They are today the therapy of choice in the former two and are becoming an important addition in the treatment of the latter.Indeed, various bisphosphonates, among them alendronate, clodronate, etidronate. ibandronate and pamidronate not only prevent the loss of bone, but induce an increase in bone mineral density in postmenopausal. as well as in elderly women. Furthermore they prevent the bone loss during corticosteroid treatment. Of great clinical relevance is the fact that. at least alendronate, also decreases the occurence of vertebral and non vertebral fractures. The main bisphosphonates clinically available are alendronate and etidronate.Lastly, etidronate is used with more or less success in prevention of ectopic mineralization and ossification.In humans, the side effects of bisphosphonates depend upon the compound and the amount given. In the case of etidronate. practically the only one is an inhibition of mineralization at high doses, but not at those given in osteporosis. At the beginning of treatment, the amino-derivatives, when given intravenously in larger doses, induce for a period of 2–3 days a syndrome with pyrexia, which resembles an acute phase reaction. Again this effect is not seen at the oral doses used in osteoporosis. Lastly, bisphosphonates, especially the amino-derivatives, can induce gastrointestinal disturbances. especially when given orally in too high doses or with too little water.