Early-life famine exposure, adulthood obesity patterns, and risk of low-energy fracture
Hongyan Qi, Chunyan Hu, Jie Zhang, Lin Lin, Shuangyuan Wang, Hong Lin, Xiaojing Jia, Yuanyue Zhu, Yi Zhang, Xueyan Wu, Mian Li, Min Xu, Yu Xu, Tiange Wang, Zhiyun Zhao, Weiqing Wang, Yufang Bi, Meng Dai(), Yuhong Chen(), Jieli Lu()
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People’s Republic of China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Malnutrition in early life increases the risk of osteoporosis, but the association of early-life undernutrition combined with adulthood obesity patterns with low-energy fracture remains unknown. This study included 5323 community-dwelling subjects aged ≥40 years from China. Early-life famine exposure was identified based on the participants’ birth dates. General obesity was assessed using the body mass index (BMI), and abdominal obesity was evaluated with the waist-to-hip ratio (WHR). Low-energy fracture was defined as fracture occurring after the age of 40 typically caused by falls from standing height or lower. Compared to the nonexposed group, the group with fetal, childhood, and adolescence famine exposure was associated with an increased risk of fracture in women with odds ratios (ORs) and 95% confidence intervals (CIs) of 3.55 (1.57–8.05), 3.90 (1.57–9.71), and 3.53 (1.05–11.88), respectively, but not in men. Significant interactions were observed between fetal famine exposure and general obesity with fracture among women (P for interaction = 0.0008). Furthermore, compared with the groups with normal BMI and WHR, the group of women who underwent fetal famine exposure and had both general and abdominal obesity had the highest risk of fracture (OR, 95% CI: 3.32, 1.17–9.40). These results indicate that early-life famine exposure interacts with adulthood general obesity and significantly increases the risk of low-energy fracture later in life in women.
P Chen, Z Li, Y Hu. Prevalence of osteoporosis in China: a meta-analysis and systematic review. BMC Public Health 2016; 16(1): 1039 https://doi.org/10.1186/s12889-016-3712-7
2
N Li, D Cornelissen, S Silverman, D Pinto, L Si, I Kremer, S Bours, R de Bot, A Boonen, S Evers, J van den Bergh, JY Reginster, M Hiligsmann. An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. Pharmacoeconomics 2021; 39(2): 181–209 https://doi.org/10.1007/s40273-020-00965-9
3
Y Zhang, H Qi, C Hu, S Wang, Y Zhu, H Lin, L Lin, J Zhang, T Wang, Z Zhao, M Li, Y Xu, M Xu, Y Bi, W Wang, Y Chen, J Lu, G Ning. Association between early life famine exposure and risk of metabolic syndrome in later life. J Diabetes 2022; 14(10): 685–694 https://doi.org/10.1111/1753-0407.13319
4
SR de Rooij, RC Painter, F Holleman, PM Bossuyt, TJ Roseboom. The metabolic syndrome in adults prenatally exposed to the Dutch famine. Am J Clin Nutr 2007; 86(4): 1219–1224 https://doi.org/10.1093/ajcn/86.4.1219
5
J Lu, M Li, Y Xu, Y Bi, Y Qin, Q Li, T Wang, R Hu, L Shi, Q Su, M Xu, Z Zhao, Y Chen, X Yu, L Yan, R Du, C Hu, G Qin, Q Wan, G Chen, M Dai, D Zhang, Z Gao, G Wang, F Shen, Z Luo, L Chen, Y Huo, Z Ye, X Tang, Y Zhang, C Liu, Y Wang, S Wu, T Yang, H Deng, D Li, S Lai, ZT Bloomgarden, L Chen, J Zhao, Y Mu, G Ning, W; 4C Study Group Wang. Early life famine exposure, ideal cardiovascular health metrics, and risk of incident diabetes: findings from the 4C Study. Diabetes Care 2020; 43(8): 1902–1909 https://doi.org/10.2337/dc19-2325
6
Y Li, Y He, L Qi, VW Jaddoe, EJ Feskens, X Yang, G Ma, FB Hu. Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood. Diabetes 2010; 59(10): 2400–2406 https://doi.org/10.2337/db10-0385
7
C Hu, R Du, L Lin, R Zheng, H Qi, Y Zhu, R Wei, X Wu, Y Zhang, M Li, T Wang, Z Zhao, M Xu, Y Xu, Y Bi, G Ning, W Wang, Y Chen, J Lu. The association between early-life famine exposure and adulthood obesity on the risk of dyslipidemia. Nutr Metab Cardiovasc Dis 2022; 32(9): 2177–2186 https://doi.org/10.1016/j.numecd.2022.06.005
8
H Qi, C Hu, S Wang, Y Zhang, R Du, J Zhang, L Lin, T Wang, Z Zhao, M Li, Y Xu, M Xu, Y Bi, W Wang, Y Chen, J Lu. Early life famine exposure, adulthood obesity patterns and the risk of nonalcoholic fatty liver disease. Liver Int 2020; 40(11): 2694–2705 https://doi.org/10.1111/liv.14572
9
LA Hughes, den Brandt PA van, Bruïne AP de, KA Wouters, S Hulsmans, A Spiertz, RA Goldbohm, Goeij AF de, JG Herman, MP Weijenberg, Engeland M van. Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms. PLoS One 2009; 4(11): e7951 https://doi.org/10.1371/journal.pone.0007951
10
C Cooper, K Javaid, S Westlake, N Harvey, E Dennison. Developmental origins of osteoporotic fracture: the role of maternal vitamin D insufficiency. J Nutr 2005; 135(11): 2728S–2734S https://doi.org/10.1093/jn/135.11.2728S
11
CND Balasuriya, KAI Evensen, MP Mosti, AM Brubakk, GW Jacobsen, MS Indredavik, B Schei, AK Stunes, U Syversen. Peak bone mass and bone microarchitecture in adults born with low birth weight preterm or at term: a cohort study. J Clin Endocrinol Metab 2017; 102(7): 2491–2500 https://doi.org/10.1210/jc.2016-3827
12
TM Mikkola, MB von Bonsdorff, C Osmond, MK Salonen, E Kajantie, JG Eriksson. Association of body size at birth and childhood growth with hip fractures in older age: an exploratory follow-up of the Helsinki Birth Cohort Study. J Bone Miner Res 2017; 32(6): 1194–1200 https://doi.org/10.1002/jbmr.3100
TL Radak. Caloric restriction and calcium’s effect on bone metabolism and body composition in overweight and obese premenopausal women. Nutr Rev 2004; 62(12): 468–481 https://doi.org/10.1111/j.1753-4887.2004.tb00019.x
15
LJ Zhao, H Jiang, CJ Papasian, D Maulik, B Drees, J Hamilton, HW Deng. Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis. J Bone Miner Res 2008; 23(1): 17–29 https://doi.org/10.1359/jbmr.070813
16
Z Shi, X Shi, AF Yan. Exposure to Chinese famine during early life increases the risk of fracture during adulthood. Nutrients 2022; 14(5): 1060 https://doi.org/10.3390/nu14051060
17
B Wang, M Li, Z Zhao, S Wang, J Lu, Y Chen, M Xu, W Wang, G Ning, Y Bi, T Wang, Y Xu. Glycemic measures and development and resolution of nonalcoholic fatty liver disease in nondiabetic individuals. J Clin Endocrinol Metab 2020; 105(5): 1416–1426 https://doi.org/10.1210/clinem/dgaa112
18
PH Lee, DJ Macfarlane, TH Lam, SM Stewart. Validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF): a systematic review. Int J Behav Nutr Phys Act 2011; 8: 115 https://doi.org/10.1186/1479-5868-8-115
19
R Du, R Zheng, Y Xu, Y Zhu, X Yu, M Li, X Tang, R Hu, Q Su, T Wang, Z Zhao, M Xu, Y Chen, L Shi, Q Wan, G Chen, M Dai, D Zhang, Z Gao, G Wang, F Shen, Z Luo, Y Qin, L Chen, Y Huo, Q Li, Z Ye, Y Zhang, C Liu, Y Wang, S Wu, T Yang, H Deng, L Chen, J Zhao, Y Mu, D Li, G Qin, W Wang, G Ning, L Yan, Y Bi, J Lu. Early-life famine exposure and risk of cardiovascular diseases in later life: findings from the REACTION Study. J Am Heart Assoc 2020; 9(7): e014175 https://doi.org/10.1161/JAHA.119.014175
20
C Li, EW Tobi, BT Heijmans, LH Lumey. The effect of the Chinese famine on type 2 diabetes mellitus epidemics. Nat Rev Endocrinol 2019; 15(6): 313–314 https://doi.org/10.1038/s41574-019-0195-5
21
S Yang, ND Nguyen, JR Center, JA Eisman, TV Nguyen. Association between abdominal obesity and fracture risk: a prospective study. J Clin Endocrinol Metab 2013; 98(6): 2478–2483 https://doi.org/10.1210/jc.2012-2958
22
CM Nielson, P Srikanth, ES Orwoll. Obesity and fracture in men and women: an epidemiologic perspective. J Bone Miner Res 2012; 27(1): 1–10 https://doi.org/10.1002/jbmr.1486
23
R Meng, J Lv, C Yu, Y Guo, Z Bian, L Yang, Y Chen, H Zhang, X Chen, J Chen, Z Chen, L Qi, L; China Kadoorie Biobank Collaborative Group Li. Prenatal famine exposure, adulthood obesity patterns and risk of type 2 diabetes. Int J Epidemiol 2018; 47(2): 399–408 https://doi.org/10.1093/ije/dyx228
24
E Ito, Y Sato, T Kobayashi, S Nakamura, Y Kaneko, T Soma, T Matsumoto, A Kimura, K Miyamoto, H Matsumoto, M Matsumoto, M Nakamura, K Sato, T Miyamoto. Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice. Biochem Biophys Res Commun 2021; 534: 165–171 https://doi.org/10.1016/j.bbrc.2020.11.122
25
R Pando, M Masarwi, B Shtaif, A Idelevich, E Monsonego-Ornan, R Shahar, M Phillip, G Gat-Yablonski. Bone quality is affected by food restriction and by nutrition-induced catch-up growth. J Endocrinol 2014; 223(3): 227–239 https://doi.org/10.1530/JOE-14-0486
26
CF Kin, WS Shan, LJ Shun, LP Chung, W Jean. Experience of famine and bone health in post-menopausal women. Int J Epidemiol 2007; 36(5): 1143–1150 https://doi.org/10.1093/ije/dym149
27
L Zong, L Cai, J Liang, W Lin, J Yao, H Huang, K Tang, L Chen, L Li, L Lin, H Chen, M Li, J Lu, Y Bi, W Wang, J Wen, G Chen. Exposure to famine in early life and the risk of osteoporosis in adulthood: a prospective study. Endocr Pract 2019; 25(4): 299–305 https://doi.org/10.4158/EP-2018-0419
28
G Mehta, HI Roach, S Langley-Evans, P Taylor, I Reading, RO Oreffo, A Aihie-Sayer, NM Clarke, C Cooper. Intrauterine exposure to a maternal low protein diet reduces adult bone mass and alters growth plate morphology in rats. Calcif Tissue Int 2002; 71(6): 493–498 https://doi.org/10.1007/s00223-001-2104-9
A Ganpule, CS Yajnik, CH Fall, S Rao, DJ Fisher, A Kanade, C Cooper, S Naik, N Joshi, H Lubree, V Deshpande, C Joglekar. Bone mass in Indian children—relationships to maternal nutritional status and diet during pregnancy: the Pune Maternal Nutrition Study. J Clin Endocrinol Metab 2006; 91(8): 2994–3001 https://doi.org/10.1210/jc.2005-2431
WY Yao, L Li, HR Jiang, YF Yu, WH Xu. Transgenerational associations of parental famine exposure in early life with offspring risk of adult obesity in China. Obesity (Silver Spring) 2023; 31(1): 279–289 https://doi.org/10.1002/oby.23593
33
Y Zhang, Y Ying, L Zhou, J Fu, Y Shen, C Ke. Exposure to Chinese famine in early life modifies the association between hyperglycaemia and cardiovascular disease. Nutr Metab Cardiovasc Dis 2019; 29(11): 1230–1236 https://doi.org/10.1016/j.numecd.2019.07.004
34
EW Tobi, LH Lumey, RP Talens, D Kremer, H Putter, AD Stein, PE Slagboom, BT Heijmans. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18(21): 4046–4053 https://doi.org/10.1093/hmg/ddp353
35
VS Tanwar, S Ghosh, S Sati, S Ghose, L Kaur, KA Kumar, KV Shamsudheen, A Patowary, M Singh, V Jyothi, P Kommineni, S Sivasubbu, V Scaria, M Raghunath, R Mishra, GR Chandak, S Sengupta. Maternal vitamin B12 deficiency in rats alters DNA methylation in metabolically important genes in their offspring. Mol Cell Biochem 2020; 468(1–2): 83–96 https://doi.org/10.1007/s11010-020-03713-x
36
Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 1962; 14(4): 353–362
pmid: 13937884
37
P Bateson, D Barker, T Clutton-Brock, D Deb, B D’Udine, RA Foley, P Gluckman, K Godfrey, T Kirkwood, MM Lahr, J McNamara, NB Metcalfe, P Monaghan, HG Spencer, SE Sultan. Developmental plasticity and human health. Nature 2004; 430(6998): 419–421 https://doi.org/10.1038/nature02725
38
J Delgado-Calle, AF Fernández, J Sainz, MT Zarrabeitia, C Sañudo, R García-Renedo, MI Pérez-Núñez, C García-Ibarbia, MF Fraga, JA Riancho. Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum 2013; 65(1): 197–205 https://doi.org/10.1002/art.37753
39
N Slopen, A Non, DR Williams, AL Roberts, MA Albert. Childhood adversity, adult neighborhood context, and cumulative biological risk for chronic diseases in adulthood. Psychosom Med 2014; 76(7): 481–489 https://doi.org/10.1097/PSY.0000000000000081
40
GE Miller, E Chen, AK Fok, H Walker, A Lim, EF Nicholls, S Cole, MS Kobor. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc Natl Acad Sci USA 2009; 106(34): 14716–14721 https://doi.org/10.1073/pnas.0902971106
41
M Das, O Cronin, DM Keohane, EM Cormac, H Nugent, M Nugent, C Molloy, PW O’Toole, F Shanahan, MG Molloy, IB Jeffery. Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatology (Oxford) 2019; 58(12): 2295–2304 https://doi.org/10.1093/rheumatology/kez302
42
C Caffarelli, C Alessi, R Nuti, S Gonnelli. Divergent effects of obesity on fragility fractures. Clin Interv Aging 2014; 9: 1629–1636
43
Laet C De, JA Kanis, A Odén, H Johanson, O Johnell, P Delmas, JA Eisman, H Kroger, S Fujiwara, P Garnero, EV McCloskey, D Mellstrom, LJ 3rd Melton, PJ Meunier, HA Pols, J Reeve, A Silman, A Tenenhouse. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int 2005; 16(11): 1330–1338 https://doi.org/10.1007/s00198-005-1863-y
44
HE Meyer, WC Willett, AJ Flint, D Feskanich. Abdominal obesity and hip fracture: results from the Nurses’ Health Study and the Health Professionals Follow-up Study. Osteoporos Int 2016; 27(6): 2127–2136 https://doi.org/10.1007/s00198-016-3508-8
45
M Kauppi, S Stenholm, O Impivaara, J Mäki, M Heliövaara, A Jula. Fall-related risk factors and heel quantitative ultrasound in the assessment of hip fracture risk: a 10-year follow-up of a nationally representative adult population sample. Osteoporos Int 2014; 25(6): 1685–1695 https://doi.org/10.1007/s00198-014-2674-9
46
V Benetou, P Orfanos, IS Benetos, V Pala, A Evangelista, G Frasca, MC Giurdanella, PH Peeters, IT van der Schouw, S Rohrmann, J Linseisen, H Boeing, C Weikert, U Pettersson, B Van Guelpen, HB Bueno de Mesquita, J Altzibar, P Boffetta, A Trichopoulou. Anthropometry, physical activity and hip fractures in the elderly. Injury 2011; 42(2): 188–193 https://doi.org/10.1016/j.injury.2010.08.022
47
V Zarulli, JA Barthold Jones, A Oksuzyan, R Lindahl-Jacobsen, K Christensen, JW Vaupel. Women live longer than men even during severe famines and epidemics. Proc Natl Acad Sci USA 2018; 115(4): E832–E840 https://doi.org/10.1073/pnas.1701535115
48
R Mu, X Zhang. Why does the great Chinese famine affect the male and female survivors differently? Mortality selection versus son preference. Econ Hum Biol 2011; 9(1): 92–105 https://doi.org/10.1016/j.ehb.2010.07.003
49
Y Wang, H Wan, C Chen, Y Chen, F Xia, B Han, Q Li, N Wang, Y Lu. Association between famine exposure in early life with insulin resistance and beta cell dysfunction in adulthood. Nutr Diabetes 2020; 10(1): 18 https://doi.org/10.1038/s41387-020-0121-x