Bisphosphonates are widely used to treat osteoporosis. They reduce the incidence of new fractures in patients with established osteoporosis (1, 2). In women with osteopenia, bisphosphonates prevent bone loss, and physicians prescribe them with the hope of preventing future fractures. These medications have profound effects on bone physiology, but the long-term consequences remain unknown. The longest duration of placebo-controlled trials is 6 yr; subjects in observational studies have used the newer amino-bisphosphonates for 10 yr. Some unadvertised aspects of bisphosphonates, including their long half-life and their effects on bone physiology, are not well recognized. Unlike most medications, bisphosphonates remain in the body for decades. These drugs are not metabolized, but are either excreted renally or deposited within the bones. The amount of drug within the bone will accumulate with use. There is no known method of removing the medication from the bones. The duration of physiological effect is still unknown. After taking alendronate for 5 yr, the bone resorption and formation markers remain suppressed for at least 5 yr after discontinuation (3).

The amino-bisphosphonates strongly inhibit osteoclastic bone resorption. During normal bone remodeling, osteoblastic bone formation follows resorption and occurs within the eroded cavities, so inhibition of bone resorption also results in inhibition of bone formation. Bone biopsy studies using double tetracycline labels show that the bone-forming surface is suppressed by 60–90% with usual doses of the bisphosphonates (4, 5). These drugs are certainly not anabolic! The volume of bone does not increase. The bone density as measured by dual-energy x-ray absorptiometry, however, does increase. This is because the bone is no longer remodeling, and so there is not much new bone. The older bone is denser than the newer bone; there is less water and more mineral in the bone, and the radiographic techniques thus measure the higher density. Osteoporotic bone is generally undermineralized, so some increase in mineralization (or hardening of the bone) may improve the bone strength (6).