The conventional belief is that osteopenia is the major cause of vertebral fractures and that drug therapy must induce a substantial increase in vertebral bone mineral density (BMD) before the vertebral fracture rate (VFR) is decreased. We hypothesized that the increased bone turnover in osteoporosis also is a major cause of vertebral fractures because of its adverse effects on the microarchitecture of the vertebrae and, thus, that normalization of bone turnover by antiresorptive drug therapy will decrease VFR substantially. This hypothesis is supported by our reanalysis of data from previous clinical trials with fluoride and with estrogen therapy in postmenopausal osteoporotic women. As evident from computer-generated three-dimensional graphic plots of data from osteoporotic women treated with placebo, VFR increased as bone turnover increased or as vertebral BMD decreased. Estrogen therapy decreased the bone turnover rate to normal and eliminated the relationship between VFR and bone turnover, whereas the inverse relationship with vertebral BMD persisted. In osteoporotic women treated with fluoride, VFR decreased as vertebral BMD increased, provided that patients with high (toxic) serum fluoride levels were not included in the comparison. Over the range of values in the data set, increased vertebral BMD and decreased bone turnover had approximately equal effects in decreasing VFR. Thus, both formation-stimulating and resorption-inhibiting drugs can substantially decrease VFR but do so by different mechanisms.