Recent studies have reported the presence of acetylcholine (ACh) receptor subtypes in bone tissue, and have demonstrated that inhibition of the ACh receptors has negative effects on bone mass and fracture healing capacity. However, little is known about the potential clinical effects that increased ACh signaling might have on bone. Accordingly, this study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate ACh receptors and are used to treat Alzheimer's disease (AD), is associated with a decreased risk of hip fracture in AD patients. To accomplish this objective, a case-control analysis was performed using the AD population, aged above 75 years, based in the local health area of the Carlos Haya Hospital, in Malaga, Spain. The cases were 80 AD patients that suffered a hip fracture between January 2004 and December 2008. The controls were 2178 AD patients without hip fracture followed at our health care area during the same period of time. Compared with patients who did not use AChEIs, the hip fracture adjusted odds ratio (OR) for users of AChEIs was 0.42 (95% confidence interval [CI], 0.24-0.72), for users of rivastigmine was 0.22 (95% CI, 0.10-0.45), and for users of donepezil was 0.39 (95% CI, 0.19-0.76). Data were adjusted for the following parameters: body mass index, fall risk, smoking habits, cognition, dependence, degree of AD, comorbidity score, treatment with selective serotonin reuptake inhibitors, age, and gender. Our data suggests that use of AChEIs donepezil and rivastigmine is associated with a reduced risk of fractures in AD patients. Many elderly patients with AD disease who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEIs donepezil and rivastigmine. ß