Abstract
Summary
The association between serum uric acid (SUA) levels and bone mineral density (BMD) is controversial. Fat accumulation is linked to SUA and BMD, thus possibly explaining the mixed results. We found that adiposity drives part of the association between SUA and BMD in women with postmenopausal osteoporosis.
Introduction
Both positive and negative associations between SUA and BMD have been reported. SUA levels and BMD increase with higher body weight and other indices of adiposity; hence, the association between SUA and BMD might be a consequence of the confounding effect of adiposity. We investigated in this cross-sectional study whether the association between SUA and BMD is independent of measures of fat accumulation and other potential confounders.
Methods
SUA levels, femur BMD, markers of bone metabolism, body mass index (BMI), fat mass (FM), waist circumference (WC), and abdominal visceral fat area were measured in 180 treatment-naive postmenopausal osteoporotic women (mean age 66.3 ± 8.5 years, age range 48–81 years).
Results
Women with higher SUA levels (third tertile) had significantly higher femur BMD and lower cross-linked C-terminal telopeptide of type I collagen (CTX) and bone alkaline phosphatase (bALP) levels. SUA levels were positively associated with all indices of adiposity. In multivariable analysis with femur BMD as dependent variable, the association between logarithmic (LG)-transformed SUA levels and BMD (beta = 0.42, p < 0.001) was lessened progressively by the different indices of adiposity, like LG-BMI (beta = 0.22, p = 0.007), LG-WC (beta = 0.21, p = 0.01), LG-FM (beta = 0.18, p = 0.01), and LG-abdominal visceral fat area (beta = 0.12, p = 0.05). The association between SUA levels and markers of bone metabolism was dependent on the effect of confounders.
Conclusion
In postmenopausal osteoporotic women, the strong univariable association between SUA levels and femur BMD is partly explained by the confounding effect of indices of adiposity.
Similar content being viewed by others
References
Edwards NL (2008) The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med 75(Suppl 5):S13–S16
Sautin YY, Johnson RJ (2008) Uric acid: the oxidant–antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 27(6):608–619
Basu S, Michaëlsson K, Olofsson H, Johansson S, Melhus H (2001) Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun 288(1):275–279
Hardy R, Cooper MS (2009) Bone loss in inflammatory disorders. J Endocrinol 201(3):309–320
Lean JM, Davies JT, Fuller K, Jagger CJ, Kirstein B, Partington GA, Urry ZL, Chambers TJ (2003) A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 112(6):915–923
Nabipour I, Sambrook PN, Blyth FM, Janu MR, Waite LM, Naganathan V, Handelsman DJ, Le Couteur DG, Cumming RG, Seibel MJ (2011) Serum uric acid is associated with bone health in older men: a cross-sectional population-based study. J Bone Miner Res 26(5):955–964
Kuyumcu ME, Yesil Y, Oztürk ZA, Cınar E, Kızılarslanoglu C, Halil M, Ulger Z, Yesil NK, Cankurtaran M, Arıoğul S (2012) The association between homocysteine (hcy) and serum natural antioxidants in elderly bone mineral densitometry (BMD. Arch Gerontol Geriatr 55(3):739–743
Lane NE, Parimi N, Lui LY, Wise BL, Yao W, Lay YA, Cawthon PM, Orwoll E, Osteoporotic Fractures in Men Study Group (2014) Association of serum uric acid and incident nonspine fractures in elderly men: the Osteoporotic Fractures in Men (MrOS) study. J Bone Miner Res 29(7):1701–1707
Zhao DD, Jiao PL, Yu JJ, Wang XJ, Zhao L, Xuan Y, Sun LH, Tao B, Wang WQ, Ning G, Liu JM, Zhao HY (2016) Higher serum uric acid is associated with higher bone mineral density in Chinese men with type 2 diabetes mellitus. Int J Endocrinol. doi:10.1155/2016/2528956
Ahn SH, Lee SH, Kim BJ, Lim KH, Bae SJ, Kim EH, Kim HK, Choe JW, Koh JM, Kim GS (2013) Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women. Osteoporos Int 24(12):2961–2970
Makovey J, Macara M, Chen JS, Hayward CS, March L, Seibel MJ, Sambrook PN (2013) Serum uric acid plays a protective role for bone loss in peri- and postmenopausal women: a longitudinal study. Bone 52(1):400–406
Ishii S, Miyao M, Mizuno Y, Tanaka-Ishikawa M, Akishita M, Ouchi Y (2014) Association between serum uric acid and lumbar spine bone mineral density in peri- and postmenopausal Japanese women. Osteoporos Int 25(3):1099–1105
Kang KY, Hong YS, Park SH, JH J (2015) Low levels of serum uric acid increase the risk of low bone mineral density in young male patients with ankylosing spondylitis. J Rheumatol 42(6):968–974
Kim S, Jung J, Jung JH, Kim SK, Kim RB, Hahm JR (2015) Risk factors of bone mass loss at the lumbar spine: a longitudinal study in healthy Korean pre- and perimenopausal women older than 40 years. PLoS One 10(8):e0136283. doi:10.1371/journal.pone.0136283
Lee YJ, Hong JY, Kim SC, Joo JK, Na YJ, Lee KS (2015) The association between oxidative stress and bone mineral density according to menopausal status of Korean women. Obstet Gynecol Sci 58(1):46–52
Muka T, de Jonge EA, de Jong JC, Uitterlinden AG, Hofman A, Dehghan A, Zillikens MC, Franco OH, Rivadeneira F (2016) The influence of serum uric acid on bone mineral density, hip geometry, and fracture risk: the Rotterdam Study. J Clin Endocrinol Metab 101(3):1113–1122
Lin X, Zhao C, Qin A, Hong D, Liu W, Huang K, Mo J, Yu H, Wu S, Fan S (2015) Association between serum uric acid and bone health in general population: a large and multicentre study. Oncotarget 6(34):35395–35403
Chen L, Peng Y, Fang F, Chen J, Pan L, You L (2015) Correlation of serum uric acid with bone mineral density and fragility fracture in patients with primary osteoporosis: a single-center retrospective study of 253 cases. Int J Clin Exp Med 8(4):6291–6294
Zhang D, Bobulescu IA, Maalouf NM, Adams-Huet B, Poindexter J, Park S, Wei F, Chen C, Moe OW, Sakhaee K (2015) Relationship between serum uric acid and bone mineral density in the general population and in rats with experimental hyperuricemia. J Bone Miner Res 30(6):992–999
Sritara C, Ongphiphadhanakul B, Chailurkit L, Yamwong S, Ratanachaiwong W, Sritara P (2013) Serum uric acid levels in relation to bone-related phenotypes in men and women. J Clin Densitom 16(3):336–340
Bhupathiraju SN, Alekel DL, Stewart JW, Hanson LN, Shedd KM, Reddy MB, Hanson KB, Van Loan MD, Genschel U, Koehler KJ (2007) Relationship of circulating total homocysteine and C-reactive protein to trabecular bone in postmenopausal women. J Clin Densitom 10(4):395–403
Morin S, Tsang JF, Leslie WD (2009) Weight and body mass index predict bone mineral density and fractures in women aged 40 to 59 years. Osteoporos Int 20(3):363–370
Dytfeld J, Ignaszak-Szczepaniak M, Gowin E, Michalak M, Horst-Sikorska W (2011) Influence of lean and fat mass on bone mineral density (BMD) in postmenopausal women with osteoporosis. Arch Gerontol Geriatr 53(2):e237–e242
Kim KC, Shin DH, Lee SY, Im JA, Lee DC (2010) Relation between obesity and bone mineral density and vertebral fractures in Korean postmenopausal women. Yonsei Med J 51(6):857–863
Schorr M, Dichtel LE, Gerweck AV, Torriani M, Miller KK, Bredella MA (2016) Body composition predictors of skeletal integrity in obesity. Skelet Radiol 45(6):813–819
Hikita M, Ohno I, Mori Y, Ichida K, Yokose T, Hosoya T (2007) Relationship between hyperuricemia and body fat distribution. Intern Med 46(17):1353–1358
Wang H, Wang L, Xie R, Dai W, Gao C, Shen P, Huang X, Zhang F, Yang X, Ji G (2014) Association of serum uric acid with body mass index: a cross-sectional study from Jiangsu province, China. Iran J Public Health 43(11):1503–1509
Takahashi S, Yamamoto T, Tsutsumi Z, Moriwaki Y, Yamakita J, Higashino K (1997) Close correlation between visceral fat accumulation and uric acid metabolism in healthy men. Metabolism 46(10):1162–1165
Matsuura F, Yamashita S, Nakamura T, Nishida M, Nozaki S, Funahashi T, Matsuzawa Y (1998) Effect of visceral fat accumulation on uric acid metabolism in male obese subjects: visceral fat obesity is linked more closely to overproduction of uric acid than subcutaneous fat obesity. Metabolism 47(8):929–933
Henriksen K, Christiansen C, Karsdal MA (2015) Role of biochemical markers in the management of osteoporosis. Climacteric 18(Suppl 2):10–18
Peng H, Li H, Li C, Chao X, Zhang Q, Zhang Y (2013) Association between vitamin D insufficiency and elevated serum uric acid among middle-aged and elderly Chinese Han women. PLoS One 8(4):e61159. doi:10.1371/journal.pone.0061159
Hui JY, Choi JW, Mount DB, Zhu Y, Zhang Y, Choi HK (2012) The independent association between parathyroid hormone levels and hyperuricemia: a national population study. Arthritis Res Ther 14(2):R56
Hirooka M, Kumagi T, Kurose K, Nakanishi S, Michitaka K, Matsuura B, Horiike N, Onji M (2005) A technique for the measurement of visceral fat by ultrasonography: comparison of measurements by ultrasonography and computed tomography. Intern Med 44(8):794–799
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470
Orriss IR, Arnett TR, George J, Witham MD (2016) Allopurinol and oxypurinol promote osteoblast differentiation and increase bone formation. Exp Cell Res 342(2):166–174
Dalbeth N, Smith T, Nicolson B, Clark B, Callon K, Naot D, Haskard DO, McQueen FM, Reid IR, Cornish J (2008) Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells. Arthritis Rheum 58(6):1854–1865
Chen W, Roncal-Jimenez C, Lanaspa M, Gerard S, Chonchol M, Johnson RJ, Jalal D (2014) Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo. Metabolism 63(1):150–160
Dalbeth N, Topless R, Flynn T, Cadzow M, Bolland MJ, Merriman TR (2015) Mendelian randomization analysis to examine for a causal effect of urate on bone mineral density. J Bone Miner Res 30(6):985–991
Xiong A, Yao Q, He J, Fu W, Yu J, Zhang Z (2016) No causal effect of serum urate on bone-related outcomes among a population of postmenopausal women and elderly men of Chinese Han ethnicity—a Mendelian randomization study. Osteoporos Int 27(3):1031–1039
Zhao LJ, Jiang H, Papasian CJ, Maulik D, Drees B, Hamilton J, Deng HW (2008) Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis. J Bone Miner Res 23(1):17–29
Lyngdoh T, Vuistiner P, Marques-Vidal P, Rousson V, Waeber G, Vollenweider P, Bochud M (2012) Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. PLoS One 7(6):e39321. doi:10.1371/journal.pone.0039321
Burgess S, Daniel RM, Butterworth AS, Thompson SG, EPIC-InterAct Consortium (2015) Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol 44(2):484–495
Oikonen M, Wendelin-Saarenhovi M, Lyytikäinen LP, Siitonen N, Loo BM, Jula A, Seppälä I, Saarikoski L, Lehtimäki T, Hutri-Kähönen N, Juonala M, Kähönen M, Huupponen R, Viikari JS, Raitakari OT (2012) Associations between serum uric acid and markers of subclinical atherosclerosis in young adults. The cardiovascular risk in Young Finns study. Atherosclerosis 223(2):497–503
Palmer TM, Nordestgaard BG, Benn M, Tybjærg-Hansen A, Davey Smith G, Lawlor DA, Timpson NJ (2013) Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. BMJ 347:f4262. doi:10.1136/bmj.f4262
Warodomwichit D, Sritara C, Thakkinstian A, Chailurkit LO, Yamwong S, Ratanachaiwong W, Ongphiphadhanakul B, Sritara P (2013) Causal inference of the effect of adiposity on bone mineral density in adults. Clin Endocrinol 78(5):694–699
Hernández JL, Nan D, Martínez J, Pariente E, Sierra I, González-Macías J, Olmos JM (2015) Serum uric acid is associated with quantitative ultrasound parameters in men: data from the Camargo cohort. Osteoporos Int 26(7):1989–1995
Hordon LD, Peacock M (1987) Vitamin D metabolism in women with femoral neck fracture. Bone Miner 2(5):413–426
Mutt SJ, Hyppönen E, Saarnio J, Järvelin MR, Herzig KH (2014) Vitamin D and adipose tissue-more than storage. Front Physiol 24(5):228
Thomas SD, Morris HA, Nordin BE (2015) Acute effect of a supplemented milk drink on bone metabolism in healthy postmenopausal women is influenced by the metabolic syndrome. Nutr J 14:99
Dong XW, Tian HY, He J, Wang C, Qiu R, Chen YM (2016) Elevated serum uric acid is associated with greater bone mineral density and skeletal muscle mass in middle-aged and older adults. PLoS One 11(5):e0154692. doi:10.1371/journal.pone.0154692
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The study was approved by the local Ethics Committee, and all participants gave their informed consent.
Conflicts of interest
None.
Rights and permissions
About this article
Cite this article
Pirro, M., Mannarino, M.R., Bianconi, V. et al. Uric acid and bone mineral density in postmenopausal osteoporotic women: the link lies within the fat. Osteoporos Int 28, 973–981 (2017). https://doi.org/10.1007/s00198-016-3792-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-016-3792-3