Etidronate became available at approximately the same time as salmon calcitonin.43,44 Indeed, these two agents were the mainstays of therapy for this disorder for nearly 20 years, after which the newer and more potent bisphosphonates emerged. Etidronate is given orally at a dose of 5 mg/kg per day (400 mg in most patients), taken with a small amount of water or clear juice at a point midway through a 4-hour fast (e.g., between two meals at least 4 hours apart or at bedtime at least 2 hours after any food has been ingested). It is given for a treatment course of 6 months’ duration, typically achieving ˜50% reduction in elevated indices of pagetic bone turnover in most patients, as well as a relief of those symptoms likely to respond to decreased turnover as previously noted. Thus, in patients with mild disease, indices may return to normal and remain that way with continued symptom relief for several years after a single 6-month course.45 However, individuals with initial elevations of serum alkaline phosphatase more than three to four times the upper limit of normal typically continue to have biochemically elevated turnover indices despite the 50% or so reduction, even if symptoms improve. Such patients are typically retreated at the same dose in repeated cycles of 6 months on, 6 months off therapy, a program that has maintained a reduced level of turnover for up to 10 years in some patients,45 although others have experienced a loss of effectiveness with repeated cycles.46

The failure of indices to return to normal or near normal in most of the more severely affected patients has been suggested as one explanation for the finding of disease progression in many patients treated with etidronate.47 Interestingly, higher dosages of etidronate for longer treatment intervals produce greater degrees of biochemical suppression than the recommended regimen, but clearly such therapy often leads to clinically significant osteomalacia.43 This is the basis for the recommendation that the 400-mg dose be given for no longer than 6 months, followed by at least a 6-month etidronate-free interval, an approach that is generally quite safe. All bisphosphonates have the capacity to impair mineralization of newly forming bone if enough is given for a long enough time period (the process reverses itself once the agent is stopped), but, of the currently available bisphosphonates, only etidronate at excessive dosages is likely to do so. Etidronate has also been shown to be associated with progression of lytic disease in some patients with this manifestation of the disorder48; thus, the drug should not be used in individuals with advancing lytic disease in weight-bearing bone or in patients with healing fractures. As is noted later, the newer bisphosphonates do not appear to impair mineralization at the therapeutic doses that are highly effective in treating this disease.