There is a need for the development of new drugs to prevent osteoporosis-related fractures. Fractures are projected to increase and the present drugs have modest efficacy, significant side-effects and poor compliance. To illustrate the difficulties in the development of new drugs, the author reviews the fate of several drugs that have failed to gain regulatory approval. These drugs include arzoxifene, lasofoxifene, MK-5442, roncalceret and odanacatib. Romosozumab and abaloparatide are the only new drugs presently in phase-3 development. It is anticipated that ongoing studies of the mechanisms and signaling pathways involved in the regulation of bone remodeling will open up new opportunities for targeted pharmacological interventions to increase bone strength. However, the perfect drug is still a long way off and will face many obstacles before approval.