Background The association of long-term bisphosphonate treatment for osteoporosis and related safety problems such as atypical fractures were not clearly defined.This study was to evaluate the structural,densitometric and biomechanical properties of the prolonged bisphosphonate-loaded bones.Methods Bone mineral density (BMD) at hip and femoral midshaft,bone cross-sectional area,moment of inertia of both femurs,bone formation and resorption biochemical markers were compared between 28 elderly with at least 4 years of bisphosphonate treatment from 2002 through 2006 and age-matched group of 37 elderly.Results The total hip BMD and t-score were found not different between two groups.However,bisphosphonate treated patients were found to have significantly lower bone mineral content in the femoral shaft (P ＜0.05); morphological study showed lower cross-sectional area in subtrochanteric and mid-diaphyseal region and thus significantly lower moment of inertia (P ＜0.01).High resolution-peripheral quantitative computed tomography showed significantly decreased trabecular density,bone volume ratio,trabecular number but increased trabecular spacing in tibia and distal radius.Finite element analysis further confirmed significantly lower stiffness and failure load in tibia.Biochemical studies also showed lower bone resorption and severely suppressed bone formation activity (P ＜0.001).Conclusions The unchanged total hip BMD between two groups confirmed the beneficial effects of bisphosphonate on trabecular bone,thus preventing osteoporotic fractures at large in previous studies.However,the inferior structural,densitometric and biomechanical properties at cortical bones,especially femur midshaft,need a special attention to look into the association between long-term bisphosphonate intake and the occurrence of stress fractures.When patients taking bisphosphonate complain of proximal thigh pain or discomfort,plain X-ray film can be the first line screening.All patients prescribed with bisphosphonate should be informed of such a complication though we must stress its rarity.