We report clinical and bone morphometric findings in 18 osteoporotic patients who experienced stress fractures during fluoride therapy. Patients were treated with either sodium fluoride (n = 15), or sodium monofluorophosphate (n = 3). Oral calcium supplementation was given in 11 patients, and vitamin D in 13. Stress fractures occurred after 17.1 +/- 10.3 months of therapy (range: 5-41 months). Atraumatic sudden pain in a lower limb bone extremity, normal initial roentgenogram, high 99technetium uptake on early bone scan, and a 3 to 4 week delay in linear bone condensation area at the same site were characteristics of stress fracture. The most frequent sites were the tibial metaphysis (n = 13), femoral neck (n = 10), and calcaneus (n = 4). Biochemical data showed increased plasma alkaline phosphatase levels in 11 patients, and mild renal failure in 2. Bone histomorphometry was performed on an iliac crest specimen in 10 patients at the time of the stress fracture. Trabecular bone volume was normal, and formation parameters were increased. Features of osteomalacia were encountered in only 2 patients with decreased renal function. Trabecular resorption was increased, as assessed by the osteoclastic surface (1.01 +/- 1.15% bone surface), and the number of osteoclasts (0.44 +/- 0.49 per mm2 bone section). The clinical course was favorable in all patients who stopped fluoride, although 5 patients who continued the treatment had either completion of femoral neck stress fractures to hip fractures (n = 2), or recurrent stress fractures (n = 2), or both (n = 1). Fluoride appears to be a key factor in the pathogenesis of stress fractures, and may be associated with increased trabecular resorption in some treated patients.