Bisphosphonates in the treatment of osteoporosis

Bisphosphonates are compounds derived from pyrophosphate, a byproduct of cellular cleavage of adenosine triphosphate (ATP), and are resistant to alkaline phosphatase by virtue of replacement of oxygen by carbon. The high affinity of the P-C-P structure for hydroxyapatite accounts for deposition in bone. Modification of the two side chains of carbon alters the potency of the drugs. Of those that have either completed or are undergoing clinical trials, the order of increasing potency for inhibition of bone resorption is etidronate, clodronate, tiludronate, pamidronate, alendronate, residronate and ibandronate (potency range: 1 to 10,000). Less than 5% of bisphosphonates are absorbed and the half life is a few hours. The drugs must be given on an empty stomach because food and beverages interfere with gastrointestinal absorption. Of the absorbed fraction, as much as 60% is taken up by the skeleton and the remainder is excreted unchanged in the urine. Etidronate, tiludronate, residronate, and alendronate are given orally, clodronate intravenously, and pamidronate and ibandronate by either route. At lower concentrations, bisphosphonates inhibit osteoclatic bone resorption, whereas at higher concentrations they may inhibit mineralization and cause osteomalacia. Inhibition of mineralization diminishes with increasing potency. In postmenopausal women, etidronate and alendronate for 3 yr were shown to inhibit bone resorption, increase bone mineral density (BMD) of the lumbar spine and hip, and prevent fractures without producing osteomalacia. Bone formation also is reduced as a consequence of diminished bone resorption but reduction is less than the reduction of bone resorption. In higher doses bisphosphonates may cause upper gastrointestinal disturbances but in recommended doses they generally are well tolerated and have an excellent safety profile.