Familial Mediterranean fever (FMF) has episodic or subclinical inflammation that may lead to a decrease in bone mineral density (BMD). The aim of this study was to evaluate the effect of FMF on bone metabolism and to investigate the factors that can influence bone metabolism, such as body mass index (BMI), mutations in Mediterranean fever (MEFV) gene, osteoprotegerin (OPG), leptin and inflammatory cytokines, including interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha). OPG, a soluble protein produced by osteoblasts, favors increased bone mass. Leptin may influence bone metabolism by acting on differentiated osteoblasts, having anabolic effects on bone. Thirty-one FMF patients in attack-free period (12 females and 19 males; mean age 31.4 +/- 9.3 years) and 18 healthy controls (11 females and 7 males; mean age 34.6 +/- 9.5 years) were compared according to the above parameters. BMD (g/cm(2)) and standard deviation scores (Z-score) were measured at the lumbar spine L-1-L-4 (BMD-L1-4) and proximal femur by dual X-ray absorptiometry. Osteopenia is defined as a Z-score between -1 and -2.5 and osteoporosis is equal or below -2.5. FMF patients showed statistically significant reduction in BMD-L1-4 and Z-score-L1-4. Moreover, serum OPG concentration was significantly elevated in FMF patiens. In contrast, MEFV gene mutations, leptin and the inflammatory cytokines did not differ between the patient and control groups. In conclusion, BMD was decreased and OPG was increased in our FMF patients. The high OPG levels may reflect a preventive mechanism against bone loss; namely, OPG might protect the FMF patients from excessive osteoporosis.