Early-life famine exposure, adulthood obesity patterns, and risk of low-energy fracture

Abstract

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.

Keywords

famine / obesity / body mass index / waist-to-hip ratio / low-energy fracture

1 Introduction

Osteoporosis is a systemic skeletal disease associated with an increased risk of fracture due to loss of bone density and bone mass and increased bone fragility due to the degradation of the microstructure of bone tissue as people age. The incidence of osteoporosis is increasing dramatically as the elderly population grows worldwide. The prevalence of osteoporosis in China has increased remarkably in recent years from 14.94% in 2008 to 27.96% during the period spanning 2012–2015 [1]. Low-energy fracture is an adverse complication of osteoporosis that leads to increased mortality and reduced physical function and quality of life; it places a heavy burden on public health services and accounts for over 12–18 billion dollars of direct medical expenditures per year in the United States [2]. Low-energy fracture is becoming a common, serious, costly health problem.

With the prevalence of the developmental origins of health and diseases, increasing attention is being devoted to malnutrition experienced during fetal development. An increasing body of epidemiological evidence suggests that experiencing malnutrition during fetal life leads to an increased risk of metabolic syndrome [3,4], Type 2 diabetes [5,6], dyslipidemia [7], nonalcoholic fatty liver disease [8], and even cancers [9]. Epidemiological studies have shown that maternal malnutrition during pregnancy leads to reduced bone mineral intake of the fetus in utero and after birth [10]. In addition, low birthweight [11] and childhood dysplasia [12] are directly related to the risk of future hip fracture. Obesity measured by the body mass index (BMI) and waist-to-hip ratio (WHR) is also associated with osteoporosis [13]. Extensive epidemiological evidence indicates that high weight is associated with high bone mass, and weight loss may lead to bone loss [14]. However, a contrasting study reported a negative association between fat mass and bone mass when body weight is adjusted to the mechanical load on bone mass [15]. The famine that struck China between 1959 and 1962 caused chronic malnutrition and massive population losses. The affected populations might experience a considerable nutritional transition and overnutrition in the subsequent rapid economic development of China. A few studies have been conducted on the association between early-life famine exposure and the risk of fracture. A recent study by the China Health and Nutrition Survey reported that increased risk of fracture is associated with famine exposure in Chinese adults [16]. Up to now, little is known about the effects of early-life famine exposure combined with obesity in adulthood on the risk of osteoporosis later in life. Data on the associations of adult obesity and early famine exposure with fracture risk and on the effects of different obesity patterns alone or in combination on famine exposure and fracture risk are scarce.

To fill this knowledge gap, we explored the association of early-life famine exposure with low-energy fracture. We also determined the joint association of early-life famine exposure and obesity with the risk of low-energy fracture.

2 Materials and methods

2.1 Study population

The cross-sectional study population was recruited between August 2014 and May 2015 from Jiading District in Shanghai, China. Previous research that used this community population has already described the design, sampling process, physical examination, and laboratory screening in detail [17]. In brief, 6570 middle-aged elderly residents have completed questionnaire assessments, clinical examinations, and biochemical tests. After excluding participants with high-energy fractures, such as those caused by cancer, motor vehicle accidents, crush injuries, and sharp injuries (n = 539), and participants born before January, 1941 (n = 708), a total of 5323 subjects were included for analysis. The study protocol was approved by the Committee on Human Research at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and informed consent was obtained from all participants.

2.2 Measurements

Demographic data (e.g., age, gender, education, occupation, and marital status), past medical history, and health behavior information (e.g., smoking, drinking, and physical activity) were collected by uniformly trained investigators through standardized questionnaires. All subjects received a routine physical examination that included the measurement of height, weight, waist circumference (WC), hip circumference (HC), and resting blood pressure. The participants were required to take off their shoes and wear light clothes during the measurement. WC was measured at the umbilical level, and HC was measured at the tip of the left and right greater trochanter bone of the hip. The height, WC, and HC measurements were accurate to 0.1 cm, and the weight measurement was accurate to 0.1 kg. BMI was calculated as weight (kg) divided by height (m) squared. Waist-to-hip ratio (WHR) was computed as WC divided by HC. The blood pressure measurement required the subjects to present their nondominant arms after at least 5 min of sitting and resting. An Omron electronic sphygmomanometer (Model HEM-752; Omron, Dalian, China) was used to measure blood pressure three times for at least 1 min each time, and the average value was used for data analysis. Current smokers were defined as subjects who smoked at least one cigarette a day or at least seven cigarettes a week over the past six months, and current drinkers were defined as subjects who had at least once a week of alcohol intake over the past six months. Physical activity information was collected using the International Physical Activity Questionnaire – Short Form [18]. The questionnaire recorded the duration and days of walking and the moderate and vigorous physical activities of the subjects one week before the survey. Moderate to vigorous physical activity was defined as moderate physical activity ≥ 150 min per week, vigorous aerobic exercise for over 75 min per week, or equivalent moderate and severe aerobic activity.

2.3 Assessment of famine exposure

Consistent with existing research [19], the participants were divided into four groups on the basis of their date of birth. Participants born between January 1, 1959, and December 31, 1962, were classified as the fetal famine exposure group. Participants born between January 1, 1949, and December 31, 1958, were classified as the childhood famine exposure group. Those born between January 1, 1941, and December 31, 1948, were classified as the adolescent famine exposure group, and participants born after January 1, 1963, were classified as the nonexposed group.

2.4 Assessment of obesity patterns

General obesity was assessed by BMI and divided into normal (BMI < 24.0 kg/m²), overweight (24.0 ≤ BMI ≤ 27.9 kg/m²), and obesity (BMI ≥ 28.0 kg/m²). Abdominal obesity was assessed by WHR and classified as normal (< 0.90 for men and < 0.85 for women), moderate (0.90–0.94 for men and 0.85–0.89 for women), and high (≥ 0.95 for men and ≥ 0.90 for women).

2.5 Ascertainment of low-energy fracture

The history of fracture since birth, including the fracture site, age at the time of fracture, and cause of the fracture, was recorded through an interviewer-assisted questionnaire. Low-energy fracture was defined as fracture caused by falling from standing height or lower after the age of 40 years.

2.6 Statistical analysis

Categorical variables were reported as frequency (percentage), and continuous variables were reported as the mean ± standard deviation for normally distributed variables and as medians (interquartile range) for skewed distributions.

Logistic regression models were used to evaluate the risk of fracture. Model 1 was unadjusted. Model 2 was adjusted for age, sex (for whole cohort only), education, smoking status, drinking status, and physical activity. Model 3 was further adjusted for BMI and WHR on the basis of Model 2, and Model 4 was further adjusted for menopause status and hormone replacement treatment status for women on the basis of Model 3.

The “age balanced” approach [20] was used to minimize the age differences between individuals in the nonexposed and famine-exposed groups, with specific age-balanced control defined as a combination of those born in 1963–1970 and 1955–1958 for the fetal-exposed group and as a combination of those born in 1959–1968 and 1939–1948 for the childhood-exposed group.

The association between famine exposure and the risk of low-energy fracture was analyzed by stratification in accordance with the BMI categories (BMI < 24.0 kg/m², BMI = 24.0–27.9 kg/m², and BMI ≥ 28.0 kg/m²). To explore the potential interaction between famine exposure and BMI in the development of low-energy fracture, we used the cross-product term of famine exposure and BMI categories as the interaction term. Likelihood ratio tests were conducted to evaluate the potential interaction by comparing the full model containing the interaction term with a simplified model without the interaction term. Similarly, the analysis was stratified based on WHR categories: men < 0.90, women < 0.85; men 0.90–0.94, women 0.85–0.89; men ≥ 0.95, and women ≥ 0.90. The association between famine exposure and the risk of low-energy fracture in each WHR category was examined. Mutual adjustment may effectively eliminate the potential confounding effect resulting from the different effects of general obesity and abdominal obesity on fracture [21,22]. Therefore, in accordance with previous studies [8,23], this study adjusted WHR for the analyses stratified on BMI and BMI for the analyses stratified on WHR to provide a highly accurate estimate of the association between famine exposure and fracture. Odds ratios (ORs) and 95% confidence intervals (CIs) were assessed using multivariable adjusted logistic regression analysis to estimate the association between the different famine exposure groups and combined obesity patterns and low-energy fracture.

All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). P < 0.05 (two-tailed) was considered statistically significant.

3 Results

Overall, the 5323 participants divided into four famine-exposed groups were included in the study. The prevalence of low-energy fracture was 8.32% (443/5323), and this fracture included 38 vertebral, 28 hip, and 377 nonhip, nonvertebral fractures. The characteristics of the study participants in terms of famine exposure are shown in Tab.1. Compared with the nonexposed group, the fetal-famine-exposed group was more likely to be current smokers, had a higher education level, and was less likely to engage in moderate and vigorous physical activities.

The results of the multivariable-adjusted logistic regression analysis conducted to evaluate the association between famine exposure and the risk of low-energy fracture are shown in Tab.2. In the whole cohort, participants who experienced fetal and childhood famine exposure had a significantly increased risk of low-energy fracture compared with the nonexposed participants. The association between early-life famine exposure and low-energy fracture differed between men and women (P for interaction = 0.0019). With the nonexposed group as the reference, the OR and 95% CI for the presence of low-energy fracture in women were 3.52 and 1.56–7.97 for fetal famine exposure, 3.86 and 1.55–9.62 for childhood famine exposure, and 3.48 and 1.04–11.69 for adolescence famine exposure, respectively, after adjusting for age, education, smoking status, drinking status, and physical activity. Further adjustment for BMI and WHR did not change the association of low-energy fracture with fetal (OR = 3.55; 95% CI: 1.57–8.05), childhood (OR = 3.90; 95% CI: 1.57–9.71), or adolescence (OR = 3.53; 95% CI: 1.05–11.88) famine exposure. By contrast, no significant association was detected between famine exposure and low-energy fracture in men. The multivariable-adjusted ORs (95% CIs) of low-energy fracture in the fetal, childhood, and adolescence famine exposure groups were 1.57 (0.64–3.84), 0.93 (0.29–2.98), and 0.58 (0.10–3.34), respectively.

The prevalence of low-energy fracture according to famine exposure and BMI or WHR is shown in Fig.1. The prevalence of fracture in the famine-exposed group was relatively higher than that in the nonexposed and fetal-famine-exposure groups. The prevalence was particularly high in those who were obese. The highest prevalence of fracture was observed in the people who were obese and had fetal famine exposure. Likewise, the highest prevalence of fracture was noted among those with high WHR and had undergone adolescence famine exposure.

Tab.3 presents the association of fetal and childhood famine exposure with the risk of low-energy fracture and compares it with that in the specific age-balanced group. The average age for the age-balanced group was 53.98, and the fetal-exposure group had an average age of 53.88. In the whole cohort, compared with the age-balanced group, the fetal-exposure group was associated with a 55% increased risk of fracture, with the OR of 1.55 (95% CI: 1.06–2.26). In women, after further adjusting for menopause status and hormone replacement treatment status, the fetal-exposure group was significantly associated with an increased risk of fracture compared with the age-balanced group, with an OR of 1.66 (95% CI: 1.03–2.66). The age-balanced group had an average age of 60.46, and the childhood-exposure group had an average age of 60.74. In the whole cohort and among women, after multivariable adjustment, the childhood-exposure group was significantly associated with an increased risk of fracture, with ORs of 1.31 (95% CI: 1.06–1.61) and 1.37 (95% CI: 1.07–1.76), respectively.

Tab.4 presents the interaction of different measures of obesity and famine exposure with low-energy fracture in comparison with that in the specific age-balanced group. Fetal famine exposure and adult obesity had an increased risk of fracture compared with the age-balanced group with BMI < 24 kg/m², with an OR of 3.06 (95% CI: 1.58–5.94) for the fetal exposure group, which is higher than the age-balanced group (OR (95% CI): 1.22 (0.62–2.39)). Similar trends were observed in women. Furthermore, general obesity and famine exposure had a significant multiplicative interaction with the risk of fracture in the whole cohort (P for interaction = 0.0098) and among females (P for interaction = 0.0008). Compared with the age-balanced group with BMI < 24 kg/m², we observed an increased risk of fracture in individuals with childhood famine exposure who had normal weight, but this tendency was not observed in the overweight and obese participants, although famine exposure and BMI had no significant multiplicative interaction with fracture risk in males and females. When the age-balanced group with low WHR was used as the reference group, fetal famine exposure and abdominal obesity had no significant association with fracture risk, with ORs (95% CIs) of 1.19 (0.59–2.38) in the whole cohort, 1.64 (0.46–5.86) in males, and 1.05 (0.45–2.46) in females (Tab.4). A similar pattern was observed when the age-balanced method was not used, that is, when the nonexposed group was combined with the normal-BMI or normal-WHR group as the reference group (Table S1). Additionally, abdominal obesity and fetal or childhood exposure had no significant multiplicative interaction with fracture risk in the whole cohort, among men, and among women.

Overweight/obesity combined with central obesity was further evaluated based on the subgroups of famine exposure and their relation to the risk of low-energy fracture, with the group with low BMI and low WHR as a reference (Tab.5). Compared with the individuals in the reference group, the individuals who had abdominal obesity and were overweight/obese had the highest risk of low-energy fracture in the fetal famine exposure group, in the whole cohort, and among women. Relative to the reference group, the multivariable-adjusted ORs (95% CIs) for the association of overweight/obesity and abdominal obesity with the risk of low-energy fracture were 2.26 (1.04–4.90) and 3.32 (1.17–9.40), respectively, in whole cohort and among females in the fetal-exposed group. In the whole cohort and females, a significant multiplicative interaction was observed between the combined obesity pattern and the famine-exposed group (P for interaction = 0.0468 and 0.0136, respectively). In the childhood famine-exposed group, although a significant interaction existed between obesity patterns and famine in men (P for interaction = 0.0321), no statistically significant difference was observed across all groups. When the nonexposed group with low WHR combined with normal weight was used as the reference group, those with fetal famine exposure combined with high WHR and overweight had a significantly increased risk of fracture (Table S2). The combined obesity pattern and famine exposure had a significant interaction with fracture risk only in women (P for interaction = 0.0145).

4 Discussion

The findings of this large community-based cohort study provide new insights into the association among famine exposure, obesity, and the risk of low-energy fracture. Famine exposure in early life was significantly associated with an increased risk of low-energy fracture in women. Females with fetal famine exposure and general obesity had nearly a fourfold increased risk of low-energy fracture compared with those in the age-balanced control group with normal BMI. In addition, general obesity combined with central obesity significantly increased the risk of fracture in women with fetal famine exposure and had a significant interaction with famine exposure for the risk of fracture.

Previous studies have demonstrated the association of under-nutrition with bone mineral density (BMD) and bone mass [24,25]. Caloric restriction for at least one year in childhood reduces BMD and increases the risk of osteoporosis in women, as measured by dual-energy X-ray absorptiometry [26]. Famine exposure in early life is associated with an increased risk of osteoporosis, as determined by ultrasonography, in adulthood among postmenopausal women but not among men [27]. However, the literature on the association between famine exposure and low-energy fracture remains relatively scarce. Our study aligns with another prospective study, which also identified an association between early-life famine exposure and self-reported fracture [16]. In the subgroup analysis of that study, no significant interaction was found between famine exposure and overweight or obesity, whereas our study further explored the interaction between famine exposure and obesity, focusing on general and abdominal obesity and their combinations, and revealed significant interactions specific to women. This exploration enhances the scope and depth of examining the association between early-life famine exposure and the risk of fracture in adulthood. Moreover, for the first time, our study demonstrated that general obesity exacerbates the association between fetal famine exposure and the risk of low-energy fracture in women, either alone or in combination with abdominal obesity, providing new insights into the role of obesity in the association between early-life famine exposure and the risk of low-energy fracture.

Animal studies and epidemiological investigations have provided insights into the negative effects of prenatal famine exposure and other forms of malnutrition on bone health. For example, maternal low-protein diets are associated with bone mass reduction [28], and low maternal weight, vitamin D deficiency, and inadequate calcium intake are associated with low bone mineral content at birth [29,30]. Insufficient calcium intake during childhood affects bone growth and peak bone mass [31]. Furthermore, numerous studies have confirmed the association between prenatal exposure to famine and low birthweight [32,33]. Low birthweight [31] and childhood stunting [32] lead to restricted bone growth and decreased BMD, thus increasing the risk of osteoporosis. These studies further support our finding that early-life famine exposure is strongly associated with an increased risk of fracture and highlight the importance of ensuring adequate nutrition during pregnancy and childhood for optimal bone development and reducing the risk of fracture later in life.

The fetal programming hypothesis proposed by Professor Barker in 1986 posits that the adaptation of the fetus to cope with the malnutrition environment in utero permanently changes the structure and function of the body after birth. A clinical study [34] found that people born during famines have altered DNA methylation in many genes. An animal experiment also proved that maternal malnutrition alters the DNA methylation of genes important for metabolism in the offspring [35]. In addition, the thrifty gene hypothesis [36] and developmental plasticity [37] suggest that fetuses that suffered from malnutrition in utero are susceptible to various health problems in later life even if conditions improve after birth. Notably, the process of low-energy fracture also involves epigenetic changes. DNA methylation can regulate the level and function of gene expression, causing corresponding pathophysiological changes and responding to environmental changes [38]. In addition, malnutrition in early life not only increases the secretion of stress hormones in the body, which persists in long-term physical conditions [39], but also stimulates the production of pro-inflammatory cytokines [40] that affect osteoblasts and osteoclasts, disrupting the bone conversion balance and resulting in susceptibility to osteoporosis. Malnutrition in early life can lead to immaturity of the gut microbiota, and osteoporosis due to decreased BMD is associated with altered gut microbiota [41].

This study explores the association of different stages of famine exposure (fetal, childhood, and adolescence) and obesity with the risk of low-energy fracture. The results suggest that the specific association between them is complex and varies depending on the specific life stage. Fetal famine exposure, especially when combined with obesity, can lead to developmental adaptations that may have long-lasting effects on bone health, making individuals susceptible to fracture later in life [27]. However, the effect of famine exposure on bone health may differ during childhood and adolescence. Childhood and adolescence are stages when the bones are still growing and developing and may have a great capacity to recover or adapt to nutritional deficiencies, thus reducing the impact on bone health. Moreover, the effects of fetal metabolic programming on bone health may be more pronounced than the effects of nutritional deficiencies during childhood and adolescence. Other factors, such as genetic variations or other environmental influences, may also affect bone health.

With regard to the effect of obesity on the risk of low-energy fracture, this study posits that obesity in adulthood can lead to metabolic changes and chronic inflammation, and an increased inflammatory state further increases the risk of fracture in adults [42]. However, a nonlinear relationship might exist between BMI and the risk of fracture [43]. Meanwhile, the results on the association between abdominal obesity and fracture risk are conflicting. Some studies have concluded that abdominal obesity increases the risk of fracture [21,44], whereas others have shown that WC or WHR is not associated with fracture risk or even negatively related [45,46]. In addition, obesity-related complications increase the risk of various metabolic disorders, and these changes may indirectly affect bone health and increase the risk of low-energy fracture. The current study highlights the interaction between obesity and fetal famine exposure in relation to the risk of low-energy fracture. The long-term effects of famine exposure and obesity on bone health are complex. Understanding of these relationships is still evolving, and additional research is needed to explore the underlying mechanisms.

Our findings also highlight the gender difference in the association between famine exposure and fracture, given that we obtained significant results only among women. The reasons for this gender difference may be explained by the following reasons. First, during times of severe famine, especially among infants and children, men tend to have higher mortality rates than women [47]. Moreover, male fetuses grow faster in the uterus and require more nutrients than female fetuses, so when the mother is malnourished, male fetuses are more vulnerable and have a higher rate of miscarriage than female fetuses. According to the mortality selection hypothesis, male survivors of famine exposure in early life are healthier as adults than female survivors of the same age [48]. Second, in the past, the social phenomenon of “son preference” existed in most parts of China, and when resources were scarce, families tended to prioritize the allocation of scarce resources to boys. “Son preference” also led to more boys being breastfed than girls, and daughters tended to receive less material support from their parents, which in turn led to severe ongoing negative health effects for women who experienced famine. Furthermore, men’s bones are larger than women’s, and their BMD tends to increase as they age. Last, estrogen is an important factor that affects bone maturation, and estrogen declines rapidly as women age, leading to bone loss.

To the best of our knowledge, this study is the first to jointly investigate the association of early-life famine exposure and adulthood obesity patterns with the risk of low-energy fracture. The strengths of our study are its detailed anthropometric measurements rather than self-reports; the former provides more accurate estimates of general and abdominal obesity compared with the latter. However, the study has some potential limitations. First, the use of the birth dates of the study participants for the grouping of famine exposure resulted in the nonexposed group being relatively young, which inevitably led to bias. We utilized an age-balanced method recommended by previous studies [7,49]. However, this method may also have some limitations when it is used to incorporate post-famine individuals in the control group who could have been affected by the famine during the post-fetal period. Moreover, the Great Chinese Famine has no exact start and end dates. Nevertheless, our groupings are consistent with those in previous studies [5,8]. Second, the definition of low-energy fracture was based on self-reported information, which may be subject to recall bias. However, fracture as an important life event is less likely to entail recall bias [16]. Third, we did not have information on vitamin D, calcium intake, estrogen levels, and genetic susceptibility to fracture, which may have affected the association between famine exposure and low-energy fracture. To address this issue, future studies should include these additional covariates to obtain a comprehensive understanding of the association between early-life famine exposure and fracture. Fourth, due to resource and time constraints, we were unable to collect new data in this study. Long-term follow-up is needed and will undoubtably provide additional valuable information. Fifth, due to the limited number of fractures, the statistical power of evaluating the effect of different famine exposure groups on fractures stratified by BMI and WHR was limited. Last, due to the nature of this cross-sectional study, we could not draw a causality inference of the association of famine exposure and obesity with fracture. Future studies can utilize longitudinal or interventional designs to further investigate the causal relationships between famine exposure and the risk of fracture.

In conclusion, early-life famine exposure interacts with adulthood general obesity and considerably increases the risk of low-energy fracture later in life among women. These findings can be used to create preventive strategies for osteoporosis across the entire human lifespan (from prenatal to later life) to mitigate the low-energy fracture risk among Chinese populations.

References

[1] Chen P, Li Z, Hu Y. Prevalence of osteoporosis in China: a meta-analysis and systematic review. BMC Public Health 2016; 16(1): 1039

[2] Li N, Cornelissen D, Silverman S, Pinto D, Si L, Kremer I, Bours S, de Bot R, Boonen A, Evers S, van den Bergh J, Reginster JY, Hiligsmann M. An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. Pharmacoeconomics 2021; 39(2): 181–209

[3] Zhang Y, Qi H, Hu C, Wang S, Zhu Y, Lin H, Lin L, Zhang J, Wang T, Zhao Z, Li M, Xu Y, Xu M, Bi Y, Wang W, Chen Y, Lu J, Ning G. Association between early life famine exposure and risk of metabolic syndrome in later life. J Diabetes 2022; 14(10): 685–694

[4] de Rooij SR, Painter RC, Holleman F, Bossuyt PM, Roseboom TJ. The metabolic syndrome in adults prenatally exposed to the Dutch famine. Am J Clin Nutr 2007; 86(4): 1219–1224

[5] Lu J, Li M, Xu Y, Bi Y, Qin Y, Li Q, Wang T, Hu R, Shi L, Su Q, Xu M, Zhao Z, Chen Y, Yu X, Yan L, Du R, Hu C, Qin G, Wan Q, Chen G, Dai M, Zhang D, Gao Z, Wang G, Shen F, Luo Z, Chen L, Huo Y, Ye Z, Tang X, Zhang Y, Liu C, Wang Y, Wu S, Yang T, Deng H, Li D, Lai S, Bloomgarden ZT, Chen L, Zhao J, Mu Y, Ning G, Wang W; 4C Study Group. 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

[6] Li Y, He Y, Qi L, Jaddoe VW, Feskens EJ, Yang X, Ma G, Hu FB. 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

[7] Hu C, Du R, Lin L, Zheng R, Qi H, Zhu Y, Wei R, Wu X, Zhang Y, Li M, Wang T, Zhao Z, Xu M, Xu Y, Bi Y, Ning G, Wang W, Chen Y, Lu J. The association between early-life famine exposure and adulthood obesity on the risk of dyslipidemia. Nutr Metab Cardiovasc Dis 2022; 32(9): 2177–2186

[8] Qi H, Hu C, Wang S, Zhang Y, Du R, Zhang J, Lin L, Wang T, Zhao Z, Li M, Xu Y, Xu M, Bi Y, Wang W, Chen Y, Lu J. Early life famine exposure, adulthood obesity patterns and the risk of nonalcoholic fatty liver disease. Liver Int 2020; 40(11): 2694–2705

[9] Hughes LA, van den Brandt PA, de Bruïne AP, Wouters KA, Hulsmans S, Spiertz A, Goldbohm RA, de Goeij AF, Herman JG, Weijenberg MP, van Engeland M. Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms. PLoS One 2009; 4(11): e7951

[10] Cooper C, Javaid K, Westlake S, Harvey N, Dennison E. Developmental origins of osteoporotic fracture: the role of maternal vitamin D insufficiency. J Nutr 2005; 135(11): 2728S–2734S

[11] Balasuriya CND, Evensen KAI, Mosti MP, Brubakk AM, Jacobsen GW, Indredavik MS, Schei B, Stunes AK, Syversen U. 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

[12] Mikkola TM, von Bonsdorff MB, Osmond C, Salonen MK, Kajantie E, Eriksson JG. 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

[13] Zhao LJ, Liu YJ, Liu PY, Hamilton J, Recker RR, Deng HW. Relationship of obesity with osteoporosis. J Clin Endocrinol Metab 2007; 92(5): 1640–1646

[14] Radak TL. 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

[15] Zhao LJ, Jiang H, Papasian CJ, Maulik D, Drees B, Hamilton J, Deng HW. Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis. J Bone Miner Res 2008; 23(1): 17–29

[16] Shi Z, Shi X, Yan AF. Exposure to Chinese famine during early life increases the risk of fracture during adulthood. Nutrients 2022; 14(5): 1060

[17] Wang B, Li M, Zhao Z, Wang S, Lu J, Chen Y, Xu M, Wang W, Ning G, Bi Y, Wang T, Xu Y. Glycemic measures and development and resolution of nonalcoholic fatty liver disease in nondiabetic individuals. J Clin Endocrinol Metab 2020; 105(5): 1416–1426

[18] Lee PH, Macfarlane DJ, Lam TH, Stewart SM. Validity of the International Physical Activity Questionnaire Short Form (IPAQ-SF): a systematic review. Int J Behav Nutr Phys Act 2011; 8: 115

[19] Du R, Zheng R, Xu Y, Zhu Y, Yu X, Li M, Tang X, Hu R, Su Q, Wang T, Zhao Z, Xu M, Chen Y, Shi L, Wan Q, Chen G, Dai M, Zhang D, Gao Z, Wang G, Shen F, Luo Z, Qin Y, Chen L, Huo Y, Li Q, Ye Z, Zhang Y, Liu C, Wang Y, Wu S, Yang T, Deng H, Chen L, Zhao J, Mu Y, Li D, Qin G, Wang W, Ning G, Yan L, Bi Y, Lu J. 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

[20] Li C, Tobi EW, Heijmans BT, Lumey LH. The effect of the Chinese famine on type 2 diabetes mellitus epidemics. Nat Rev Endocrinol 2019; 15(6): 313–314

[21] Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Association between abdominal obesity and fracture risk: a prospective study. J Clin Endocrinol Metab 2013; 98(6): 2478–2483

[22] Nielson CM, Srikanth P, Orwoll ES. Obesity and fracture in men and women: an epidemiologic perspective. J Bone Miner Res 2012; 27(1): 1–10

[23] Meng R, Lv J, Yu C, Guo Y, Bian Z, Yang L, Chen Y, Zhang H, Chen X, Chen J, Chen Z, Qi L, Li L; China Kadoorie Biobank Collaborative Group. Prenatal famine exposure, adulthood obesity patterns and risk of type 2 diabetes. Int J Epidemiol 2018; 47(2): 399–408

[24] Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T. 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

[25] Pando R, Masarwi M, Shtaif B, Idelevich A, Monsonego-Ornan E, Shahar R, Phillip M, Gat-Yablonski G. Bone quality is affected by food restriction and by nutrition-induced catch-up growth. J Endocrinol 2014; 223(3): 227–239

[26] Kin CF, Shan WS, Shun LJ, Chung LP, Jean W. Experience of famine and bone health in post-menopausal women. Int J Epidemiol 2007; 36(5): 1143–1150

[27] Zong L, Cai L, Liang J, Lin W, Yao J, Huang H, Tang K, Chen L, Li L, Lin L, Chen H, Li M, Lu J, Bi Y, Wang W, Wen J, Chen G. Exposure to famine in early life and the risk of osteoporosis in adulthood: a prospective study. Endocr Pract 2019; 25(4): 299–305

[28] Mehta G, Roach HI, Langley-Evans S, Taylor P, Reading I, Oreffo RO, Aihie-Sayer A, Clarke NM, Cooper C. 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

[29] Winzenberg T, Jones G. Vitamin D and bone health in childhood and adolescence. Calcif Tissue Int 2013; 92(2): 140–150

[30] Ganpule A, Yajnik CS, Fall CH, Rao S, Fisher DJ, Kanade A, Cooper C, Naik S, Joshi N, Lubree H, Deshpande V, Joglekar C. 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

[31] Chevalley T, Rizzoli R. Acquisition of peak bone mass. Best Pract Res Clin Endocrinol Metab 2022; 36(2): 101616

[32] Yao WY, Li L, Jiang HR, Yu YF, Xu WH. 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

[33] Zhang Y, Ying Y, Zhou L, Fu J, Shen Y, Ke C. Exposure to Chinese famine in early life modifies the association between hyperglycaemia and cardiovascular disease. Nutr Metab Cardiovasc Dis 2019; 29(11): 1230–1236

[34] Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD, Slagboom PE, Heijmans BT. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18(21): 4046–4053

[35] Tanwar VS, Ghosh S, Sati S, Ghose S, Kaur L, Kumar KA, Shamsudheen KV, Patowary A, Singh M, Jyothi V, Kommineni P, Sivasubbu S, Scaria V, Raghunath M, Mishra R, Chandak GR, Sengupta S. 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

[36] Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 1962; 14(4): 353–362

[37] Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE. Developmental plasticity and human health. Nature 2004; 430(6998): 419–421

[38] Delgado-Calle J, Fernández AF, Sainz J, Zarrabeitia MT, Sañudo C, García-Renedo R, Pérez-Núñez MI, García-Ibarbia C, Fraga MF, Riancho JA. Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. Arthritis Rheum 2013; 65(1): 197–205

[39] Slopen N, Non A, Williams DR, Roberts AL, Albert MA. Childhood adversity, adult neighborhood context, and cumulative biological risk for chronic diseases in adulthood. Psychosom Med 2014; 76(7): 481–489

[40] Miller GE, Chen E, Fok AK, Walker H, Lim A, Nicholls EF, Cole S, Kobor MS. 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

[41] Das M, Cronin O, Keohane DM, Cormac EM, Nugent H, Nugent M, Molloy C, O’Toole PW, Shanahan F, Molloy MG, Jeffery IB. Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatology (Oxford) 2019; 58(12): 2295–2304

[42] Caffarelli C, Alessi C, Nuti R, Gonnelli S. Divergent effects of obesity on fragility fractures. Clin Interv Aging 2014; 9: 1629–1636

[43] De Laet C, Kanis JA, Odén A, Johanson H, Johnell O, Delmas P, Eisman JA, Kroger H, Fujiwara S, Garnero P, McCloskey EV, Mellstrom D, Melton LJ 3rd, Meunier PJ, Pols HA, Reeve J, Silman A, Tenenhouse A. Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int 2005; 16(11): 1330–1338

[44] Meyer HE, Willett WC, Flint AJ, Feskanich D. 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

[45] Kauppi M, Stenholm S, Impivaara O, Mäki J, Heliövaara M, Jula A. 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

[46] Benetou V, Orfanos P, Benetos IS, Pala V, Evangelista A, Frasca G, Giurdanella MC, Peeters PH, van der Schouw IT, Rohrmann S, Linseisen J, Boeing H, Weikert C, Pettersson U, Van Guelpen B, Bueno de Mesquita HB, Altzibar J, Boffetta P, Trichopoulou A. Anthropometry, physical activity and hip fractures in the elderly. Injury 2011; 42(2): 188–193

[47] Zarulli V, Barthold Jones JA, Oksuzyan A, Lindahl-Jacobsen R, Christensen K, Vaupel JW. Women live longer than men even during severe famines and epidemics. Proc Natl Acad Sci USA 2018; 115(4): E832–E840

[48] Mu R, Zhang X. 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

[49] Wang Y, Wan H, Chen C, Chen Y, Xia F, Han B, Li Q, Wang N, Lu Y. Association between famine exposure in early life with insulin resistance and beta cell dysfunction in adulthood. Nutr Diabetes 2020; 10(1): 18

RIGHTS & PERMISSIONS

Higher Education Press