The goal of osteoporosis therapy is reduction of fracture risk. In randomized controlled trials, relative risk of fracture is determined by comparing the absolute fracture rate of a treatment group to a control group. Fracture risk cannot be measured in individual patients being treated for osteoporosis. Since osteoporosis is a silent disease, and some patients may not respond to therapy, a surrogate test for reduction of fracture risk is often used-most commonly a bone density test. A proposed definition of nonresponse is: A decrease in bone mineral density greater than the Least Significant Change at the 95% level of confidence. The Least Significant Change is a value based on bone density measurements in patients and calculated according to well-established standards. There are other candidates for measuring responsiveness to therapy, most notably biochemical markers of bone metabolism, but none is as well validated or standardized as bone density testing. Causes of nonresponse include poor adherence, co-morbid conditions, calcium and vitamin D deficiency, malabsorption, metabolic factors, wrong dose, wrong dosing interval, and lack of efficacy. A bone density increase or stability of bone density is associated with fracture risk reduction in approved osteoporosis therapies, while a bone density decrease is cause for clinical concern. The proposed definition of nonresponse identifies a subset of patients who may require a change of therapy and/or additional medical intervention. More data are needed to develop guidelines for clinicians. Further study is suggested.