BISPHOSPHONATES - PRECLINICAL ASPECTS AND USE IN OSTEOPOROSIS

The bisphosphonates are synthetic compounds characterized by a P-C-P b ond. They have a strong affinity to calcium phosphates and hence to bo ne mineral. In vitro they inhibit both formation and dissolution of th e latter. Many of the bisphosphonates inhibit bone resorption, the new est compounds being 10,000 times more active than etidronate, the firs t bisphosphonate described. The antiresorbing effect is cell mediated, partly by a direct action on the osteoclasts, partly through the oste oblasts, which produce an inhibitor of osteoclastic recruitment. When given in large amounts, some bisphosphonates can also inhibit normal a nd ectopic mineralization through a physical-chemical inhibition of cr ystal growth. In the growing rat the inhibition of resorption is accom panied by an increase in intestinal absorption and an increased balanc e of calcium. Bisphosphonates also prevent various types of experiment al osteoporosis, such as after immobilization, ovariectomy, orchidecto my, administration of corticosteroids, or low calcium diet. The P-C-P bond of the bisphosphonates is completely resistant to enzymatic hydro lysis. The: bisphosphonates studied up to now, such as etidronate, clo dronate, pamidronate, and alendronate, are absorbed, stored, and excre ted unaltered. The intestinal absorption of the bisphosphonates is low , between 1% or less and 10% of the amount ingested. The newer bisphos phonates are at the lower end of the scale. The absorption diminishes when the compounds are given with food, especially in the presence of calcium. Bisphosphonates are rapidly cleared from plasma, 20%-80% bein g deposited in bone and the remainder excreted in the urine. In bone, they deposit at sites of mineralization as well as under the osteoclas ts. In contrast to plasma, the half-life in bone is very long, partial ly as long as the half-life of the bone in which they are deposited. I n humans, bisphosphonates are used successfully in diseases with incre ased bone turnover, such as Paget's disease, tumoural bone disease, as well as in osteoporosis. Various bisphosphonates, such as alendronate , clodronate, etidronate, ibandronate, pamidronate, and tiludronate, h ave been investigated in osteoporosis. All inhibit bone loss in postme nopausal women and increase bone mass. Furthermore, bisphosphonates ar e also effective in preventing bone loss both in corticosteroid-treate d and in immobilized patients. The effect on the rate of fractures has recently been proven for alendronate. In humans, the adverse effects depend upon the compound and the amount given. For etidronate, practic ally the only adverse effect is an inhibition of mineralization. The a minoderivatives induce for a period of 2-3 days a syndrome with pyrexi a, which shows a similitude with an acute phase reaction. The more pot ent compounds can induce gastrointestinal disturbances, sometimes oeso phagitis, when given orally. Bisphosphonates are an important addition to the therapeutic possibilities in the prevention and treatment of o steoporosis.