ORIGINAL RESEARCH Delineating the Relationship Between Leptin, Fat Mass, and Bone Mineral Density: A Mediation Analysis Lan T. Ho-Pham 1 • Thai Q. Lai 2 • Uyen D. T. Nguyen 3 • Quoc V. Bui 3 • Tuan V. Nguyen 4,5,6 Received: 4 July 2016 / Accepted: 1 October 2016 Ó Springer Science+Business Media New York 2016 Abstract To test the hypothesis that the relationship between fat mass (FM) and bone mineral density (BMD) is mediated by leptin. The study involved 611 individuals aged 20–89 years who were randomly sampled from Ho Chi Minh City (Vietnam). BMD at the femoral neck (FN), lumbar spine (LS), and whole body (WB) was measured by DXA. Lean mass and FM were derived from the WB DXA scan. Leptin was measured by ELISA (DRG Diagnostics, Germany). The regression method was used to partition the variance of leptin and FM on BMD. The mediated effect of leptin was analyzed by the mediation analysis model. In the multiple linear regression, leptin, FM, and age collectively accounted for *34 % variation in FNBMD in men and women. However, only 0.5 % of this explained variance was due to leptin. Of the total effect of FM on FNBMD, the mediated effect of leptin accounted for 6.1 % (P = 0.38) in men and 7.1 % (P = 0.99) in women. The same trend was observed for LS and WBBMD. These data suggest that greater FM is associated with greater BMD, but the association is not mediated by leptin, and that leptin has a non-significant influence on bone mass. Keywords Osteoporosis Á Leptin Á Fat mass Á Bone mineral density Á Mediation analysis Introduction Fracture due to osteoporosis remains a significant health- care problem in the contemporary population, due largely to its high prevalence and association with reduced life expectancy [1]. Low bone mineral density (BMD) is the most robust risk factor for osteoporotic fracture, such that each standard deviation decrease in BMD is associated with a twofold increase in the risk of fracture [2]. The variation in BMD between individuals in a population is strongly associated with body weight [3], and body weight is in turn determined by fat mass and lean mass [4, 5]. Nevertheless, it is still not entirely clear which fac- tor(s) underlie the relationship between fat mass and BMD. This paper postulates that leptin is one such factor. Leptin, the product of the ob gene, is produced mainly by fat cells. There is in vitro evidence that leptin stimulates osteoprotegerin (OPG) expression and osteoblast prolifera- tion, and directly inhibits osteoclastogenesis [6]. The amount of leptin produced in the body is highly related to adiposity [7]. Adiposity is, in turn, strongly associated with bone mass, such that individuals with greater body mass index (BMI) having greater bone mineral density (BMD) [8] and reduced fracture risk [3]. Therefore, the link between leptin and bone metabolism has been a subject of intense research during the past two decades [7, 9–13], and results have shown that leptin is closely related to body fat mass, such that weight loss in obese individuals results in reduced levels of plasma leptin. & Lan T. Ho-Pham hophamthuclan@tdt.edu.vn 1 Bone and Muscle Research Group, Ton Duc Thang University, 19 Nguyen Huu Tho Street, Tan Phong Ward, Ho Chi Minh City, Vietnam 2 Department of Rheumatology, People’s Hospital 115, Ho Chi Minh City, Vietnam 3 Department of Internal Medicine, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam 4 Garvan Institute of Medical Research, Darlinghurst, Australia 5 School of Public Health and Community Medicine, UNSW Australia, Sydney, Australia 6 University of Technology Sydney, Ultimo, Australia 123 Calcif Tissue Int DOI 10.1007/s00223-016-0196-5