The use of placebo control groups (e.g., subjects using calcium and vitamin D) in osteoporosis trials with subjects at high risk for fracture has been systematically questioned by institutional review boards (IRBs). Regulatory agencies, on the other hand, continue to not only recommend but also require that placebo-controlled trials be presented for the registration of new drugs for osteoporosis treatment. The Declaration of Helsinki and its updates have upheld the principle that protection of research subjects' rights is of primary concern. Nevertheless, even the Declaration keeps clearly opening the possibility of using placebo-control designs if it is justified for "compelling and scientifically sound methodological reasons." The use of intermediary endpoints or surrogates to establish the efficacy or safety of new medications in the management of osteoporosis is currently considered scientifically insufficient. This concept has led regulatory agencies, such as the Food and Drug Administration in the United States and the European Medicines Agency in the European Union, to require "fragility fracture reduction" as the primary endpoint in clinical trials for the registration of new drugs. Superiority or noninferiority trials are alternatives to placebo-controlled designs. However, factors such as sample size, cost, and statistical limitations render these models impractical for the registration of new medications for osteoporosis. We recommend collaboration among regulatory agencies, IRBs, scientists, and ethicists on the design of clinical trials for the registration of new medications for reduction of fracture risk. Delay in developing mutually acceptable models may impair scientific development in the field and possibly deprive patients of potentially beneficial treatments.