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.
Similar content being viewed by others
References
Cummings SR, Melton LJ (2002) Epidemiology and outcomes of osteoporotic fractures. Lancet 359(9319):1761–1767
Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312(7041):1254–1259
Chan MY, Frost SA, Center JR, Eisman JA, Nguyen TV (2014) Relationship between body mass index and fracture risk is mediated by bone mineral density. J Bone Miner Res 29(11):2327–2335
Nguyen TV, Howard GM, Kelly PJ, Eisman JA (1998) Bone mass, lean mass, and fat mass: same genes or same environments? Am J Epidemiol 147(1):3–16
Ho-Pham LT, Nguyen ND, Lai TQ, Nguyen TV (2010) Contributions of lean mass and fat mass to bone mineral density: a study in postmenopausal women. BMC Musculoskelet Disord 11:59
Holloway WR, Collier FM, Aitken CJ, Myers DE, Hodge JM, Malakellis M et al (2002) Leptin inhibits osteoclast generation. J Bone Miner Res 17(2):200–209
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y et al (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1(11):1155–1161
Ho-Pham LT, Nguyen UD, Nguyen TV (2014) Association between lean mass, fat mass, and bone mineral density: a meta-analysis. J Clin Endocrinol Metab 99(1):30–38
Bartell SM, Rayalam S, Ambati S, Gaddam DR, Hartzell DL, Hamrick M et al (2011) Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice. J Bone Miner Res 26(8):1710–1720
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334(5):292–295
Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA et al (2004) Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA 101(9):3258–3263
Morberg CM, Tetens I, Black E, Toubro S, Soerensen TI, Pedersen O et al (2003) Leptin and bone mineral density: a cross-sectional study in obese and nonobese men. J Clin Endocrinol Metab 88(12):5795–5800
Sahin G, Polat G, Baethis S, Milcan A, Baethdatoethlu O, Erdoethan C et al (2003) Body composition, bone mineral density, and circulating leptin levels in postmenopausal Turkish women. Rheumatol Int 23(2):87–91
Blain H, Vuillemin A, Guillemin F, Durant R, Hanesse B, de Talance N et al (2002) Serum leptin level is a predictor of bone mineral density in postmenopausal women. J Clin Endocrinol Metab 87(3):1030–1035
Thomas T, Burguera B, Melton LJ 3rd, Atkinson EJ, O’Fallon WM, Riggs BL et al (2001) Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women. Bone 29(2):114–120
Yamauchi M, Sugimoto T, Yamaguchi T, Nakaoka D, Kanzawa M, Yano S et al (2001) Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women. Clin Endocrinol (Oxf) 55(3):341–347
Ruhl CE, Everhart JE (2002) Relationship of serum leptin concentration with bone mineral density in the United States population. J Bone Miner Res 17(10):1896–1903
Hadji P, Bock K, Gotschalk M, Hars O, Backhus J, Emons G et al (2003) The influence of serum leptin concentration on bone mass assessed by quantitative ultrasonometry in pre and postmenopausal women. Maturitas 44(2):141–148
Blum M, Harris SS, Must A, Naumova EN, Phillips SM, Rand WM et al (2003) Leptin, body composition and bone mineral density in premenopausal women. Calcif Tissue Int 73(1):27–32
Sato M, Takeda N, Sarui H, Takami R, Takami K, Hayashi M et al (2001) Association between serum leptin concentrations and bone mineral density, and biochemical markers of bone turnover in adult men. J Clin Endocrinol Metab 86(11):5273–5276
Slinker BK, Glantz SA (1985) Multiple regression for physiological data analysis: the problem of multicollinearity. Am J Physiol 249(1 Pt 2):R1–R12
Tu YK, Kellett M, Clerehugh V, Gilthorpe MS (2005) Problems of correlations between explanatory variables in multiple regression analyses in the dental literature. Br Dent J 199(7):457–461
Thomas T, Burguera B (2002) Is leptin the link between fat and bone mass? J Bone Miner Res 17(9):1563–1569
Baron RM, Kenny DA (1986) The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51(6):1173–1182
Tingley D, Yamamoto T, Hirose K, Keele L, Imai K (2014) Mediation: R package for causal mediation analysis. J Stat Softw 2014(5):1–38
Grömping U (2007) Estimators of relative importance in linear regression based on variance decomposition. Am Stat 61:139–147
R Development Core Team (2008) R: a language and environment for statistical computing, 2.7.0 edn. R Foundation for Statistical Computing, Vienna. http://www.R-project.org
Gromping U (2006) Relative importance for linear regression in R: the package relaimpo. J Stat Softw 17(1):1–27
Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT et al (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100(2):197–207
Reid IR, Plank LD, Evans MC (1992) Fat mass is an important determinant of whole body bone density in premenopausal women but not in men. J Clin Endocrinol Metab 75(3):779–782
Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D et al (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(5223):543–546
Felson DT, Zhang Y, Hannan MT, Anderson JJ (1993) Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res 8(5):567–573
Shapses SA, Riedt CS (2006) Bone, body weight, and weight reduction: what are the concerns? J Nutr 136(6):1453–1456
Pasco JA, Henry MJ, Kotowicz MA, Collier GR, Ball MJ, Ugoni AM et al (2001) Serum leptin levels are associated with bone mass in nonobese women. J Clin Endocrinol Metab 86(5):1884–1887
Zaidi M, Buettner C, Sun L, Iqbal J (2012) Minireview: the link between fat and bone: does mass beget mass? Endocrinology 153(5):2070–2075
Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P et al (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39(6):724–726
Guo Y, Liu H, Yang TL, Li SM, Li SK, Tian Q et al (2011) The fat mass and obesity associated gene, FTO, is also associated with osteoporosis phenotypes. PLoS One 6(11):e27312
Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89(6):2548–2556
Longcope C, Kato T, Horton R (1969) Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest 48(12):2191–2201
Hickey MS, Israel RG, Gardiner SN, Considine RV, McCammon MR, Tyndall GL et al (1996) Gender differences in serum leptin levels in humans. Biochem Mol Med 59(1):1–6
Couillard C, Mauriege P, Prud’homme D, Nadeau A, Tremblay A, Bouchard C et al (1997) Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia 40(10):1178–1184
Hellstrom L, Wahrenberg H, Hruska K, Reynisdottir S, Arner P (2000) Mechanisms behind gender differences in circulating leptin levels. J Intern Med 247(4):457–462
Acknowledgments
This research is funded by Foundation for Science and Technology Development of Ton Duc Thang University (FOSTECT, http://fostect.tdt.edu.vn), Grant number FOSTECT.2014.BR.09, and a grant from the Department of Science and Technology of Ho Chi Minh City. We sincerely thank Ms Tran Thi Ngoc Trang and Fr Pham Ba Lam for coordinating the recruitment of participants. We also thank doctors and medical students of the Pham Ngoc Thach University of Medicine for the data collection and clinical measurements.
Author Contributions
Lan T. Ho-Pham and Tuan V. Nguyen conceived the idea and designed the study; Lan T. Ho-Pham, Thai Q. Lai, Uyen D. T. Nguyen and Quoc V. Bui made acquisition of data. Lan T. Ho-Pham and Tuan V. Nguyen carried out analysis and interpretation of data; Lan T. Ho-Pham and Tuan V. Nguyen drafted the manuscript; Thai Q. Lai and Tuan V. Nguyen analyzed the data; Lan T. Ho-Pham and Tuan V. Nguyen revised the final manuscript. All authors read and approved the final manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Dr Lan T. Ho-Pham, Dr Thai Q. Lai, Dr Uyen D. T. Nguyen, Dr Quoc V. Bui, Prof. Tuan V. Nguyen declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
The study was approved by the Scientific Committee of the People’s Hospital 115 and Pham Ngoc Thach University of Medicine. All individuals gave written informed consent.
Rights and permissions
About this article
Cite this article
Ho-Pham, L.T., Lai, T.Q., Nguyen, U.D.T. et al. Delineating the Relationship Between Leptin, Fat Mass, and Bone Mineral Density: A Mediation Analysis. Calcif Tissue Int 100, 13–19 (2017). https://doi.org/10.1007/s00223-016-0196-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-016-0196-5