Obesity and risk of fracture in postmenopausal women: a meta-analysis of cohort studies

Abstract

Background

Obesity is associated with an increased risk of fracture in adults, but is unclear in postmenopausal women. We aim to determine the association of obesity with the risk of fracture in postmenopausal women.

Methods

PubMed, EMBASE, Cochrane Library and Web of Science were searched up to 11 April 2022 for cohort studies. And the included studies regarding the relationship between obesity with all cause of fracture in postmenopausal women were included in our meta-analysis. Data were screened and extracted independently by two reviewers. The relative risks (RR) were estimated using a random-effects model. Between-study heterogeneity was assessed using Cochran’s Q and I² statistics.

Results

Eight cohort studies comprising 671,532 postmenopausal women and 40,172 fractures were included. Overall, the pooling analysis shows that obesity in postmenopausal women is associated with an increased risk of all-cause fracture (relative ratio (RR) = 1.18; 95% confidence interval (CI):1.09–1.28, I² = 86.3%, p = .000). Sub-analyses for each site of fracture indicate that obesity was associated with an increased risk of vertebral fracture in postmenopausal women (RR = 1.154, 95% CI: 1.020–1.305, I² = 94.5%, p = .023), but reduced the risk of pelvic fracture (RR = 0.575, 95% CI:0.470–0.702, I² = 0.0%, p = .000). There is no statistically significant difference in the risk of hip and humerus fractures associated with obesity in postmenopausal women.

Conclusion

Obesity is associated with an increased risk of all-cause and vertebral fractures in postmenopausal women, but is a protective factor for pelvic fractures. Our findings suggest that postmenopausal women who regulate their weight might lower their risk of fractures.Registration: (PROSPERO: CRD42022324973)

KEY MESSAGES

• Obesity is associated with an increased risk of all-cause and vertebral fractures in postmenopausal women.

• Obesity maybe a protective factor for pelvic fractures in postmenopausal women.

• Postmenopausal women should regulate their weight to prevent fractures.

Keywords:

• Obesity
• fracture
• postmenopausal women
• meta-analysis
• cohort study

Introduction

Obesity is a complex chronic condition that increases the risk of long-term medical complications and shortens life expectancy [1]. Over the past 30 years, the worldwide prevalence of obesity has steadily increased [2], becoming a major public health problem, increasing health care costs, negatively affecting physical and mental health, and being an independent risk factor for other diseases [3–7]. Obesity is a risk factor for fractures at different sites in both children and adults [8–12]. Overall, the relationship between obesity, bone mass, and fracture risk in different populations is a complex and rather contradictory topic, depending on many factors such as the type of fracture suffered, population, age, and obesity level [13]. Especially in postmenopausal women, both obesity and weight loss are at risk of fractures, which have been reported in different observational studies, but with certain contradictions [14,15]. Studies have shown that obese women have higher rates of certain fracture types, such as ankle and thigh fractures, and lower rates of wrist and hip fractures, than normal-weight postmenopausal women [16]. Other studies have shown that factors such as body composition, bone quality, lifestyle, daily activities and comorbidities all influence the risk of fracture in postmenopausal women [17]. Obese postmenopausal women may have the higher bone density to some extent, which indicates that the association between obesity and fracture risk is more complex [18]. Recently, a meta-analysis including observational studies of fracture risk for an adult with obesity was done by Turcotte et al. and published in 2021 [19]. However, it is a pity that only 2 literatures were included in this meta-analysis to explore the risk of ankle fracture in obese postmenopausal women, which failed to comprehensively analyze the association of fracture in obese postmenopausal women and failed to distinguish the risk of different fracture sites. Moreover, several large prospective cohort studies [20–27] have explored the risk of fracture in obese postmenopausal women, and new findings may be forthcoming. Therefore, we conducted a cohort-based meta-analysis to clarify the risk of fracture in obese postmenopausal women and subgroup the risk at different fracture sites, so as to provide prevention suggestions for clinical practice.

Methods

This study was conducted in accordance with the guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) [28]. The protocol was registered in PROSPERO (No. CRD42022324973; available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022324973, April 20, 2022).

Search strategy

PubMed, EMBASE, Web of science, and Cochrane Library were searched without any restrictions from the databases inception to April 11, 2022. We combined the Medical Subject Headings (MESH) terms and key words in the search strategy. The brief search strategy is as follows: (‘Obesity’ OR ‘Obese’) AND (‘Fractures, Bone’ OR ‘Broken*’ OR ‘Fracture*’) AND (‘Postmenopause’ OR ‘Postmenopausal*’ OR ‘Post-Menopause’ OR ‘Post Menopause’). References of included studies and existing meta-analyses were hand-searched to avoid missing relevant studies. The detail of the search strategy is included in Appendix A.

Eligibility criteria

Included studies were required to meet the following criteria: (1) cohort studies, whether prospective or retrospective; (2) the exposed group could be patients with any type of obesity, and the control group consisted of patients without obesity. Body mass index (BMI) is the most commonly used measure of overweight and obesity in adults. World Health Organization (WHO) defines ‘overweight’ as having a BMI equal to or greater than 25, and ‘obesity’ as having a BMI equal to or greater than 30. According to the standards formulated by the WHO, patients with BMI ≥ 30 are defined as obesity in this review. (3) the risk of fractures as the outcome that expressed as an adjusted odds ratio (OR), relative risk (RR), or hazard ratio (HR). Because the adjusted RR, OR, HR can reduce the influence of confounders and the observation bias. In addition, the inclusion criteria for postmenopausal women are based on the International Classification of Diseases − 10 and are based on age and participant claims. (4) fractures should be a risk occurring naturally under observation.

Exclusion criteria

(1) conference abstracts or erratum; (2) duplicate published studies based on the same observation population; (3) incomplete data or no interested outcome.

Research selection

First, we excluded repetitive and irrelevant studies according to the title and abstract, and then read each potentially eligible full text independently to determine the study that meets the inclusion criteria. And give sufficient reasons for the excluded studies. Two reviewers (Dong-fang Meng and Peng Yu) independently screened these studies. If there is any objection, discuss with the third reviewer (Hui-ying Li) until a consensus is reached.

Data extraction

Two reviewers (Hong-fei Liu and Ji-cao De) independently performed data extraction using predesigned forms based on the guideline for data extraction for systematic reviews and meta-analysis [29] and the content of the extracted data drew on previous high-quality meta-analyses [30,31], including the following information: first author, publication year, country, sample size, fracture number, mean follow-up years, diagnostic criteria, baseline BMI, age, obesity type, fracture type, and confounders adjusted.

Risk-of-bias assessment

We used the Newcastle Ottawa Quality Assessment Scale (NOS) to evaluate the methodological quality of the included cohort studies. NOS assessed the quality of the included studies from three dimensions: selection, comparison and results. The score ranges from 0 to 9, and the higher the score, the higher the quality. NOS score equals or higher than 7, 4–6 and 0–3 represent high, medium and low quality respectively.

Statistical analysis

The Stata 14.0 software was used to conduct the data analysis. We expressed results as RRs with 95% confidence intervals (CIs) and we chose each study’s most fully adjusted results for analysis. If a study provided HR instead of RR, we used the formula (RR = (1 – eHR * ln (1 − r))/r; r: the fracture rate) to covert HR to RR [32]. If the included studies provided OR instead of RR, if the risk of fracture was less than 20%, we interpreted the OR as RR; otherwise, we used generic inverse variance to calculate pooled RR [33]. The incidence of fracture in the original trial included in this study is less than 20%, so these data are not converted. We assessed heterogeneity using the chi-square test and the I² value, p < .1 or I²>50% was considered that heterogeneity was great and a random-effects model was adopted. Otherwise, a fixed-effect model was employed. The sensitivity analysis was performed to verify the robustness of the overall results and to explore sources of heterogeneity. Subgroup analysis was conducted for the location of fractures in obesity. Finally, funnel plots and egger’s regression test were used to assess the publication bias.

Results

Literature search

A total of 1338 records were found through electronic search, and 1155 records remained after adjusting duplicates. After that, 1131 records were discarded because, after reviewing the title and abstract, these studies clearly did not meet the inclusion criteria. The full texts of the remaining 24 records were reviewed in more detail. Finally, eight cohort studies were included in this meta-analysis [20–27]. The detail of the selection process is presented in Figure 1.

Figure 1. Studies screening process.

Study characteristics

The included cohort studies [20–27] were published between 2009 and 2022 from 7 countries, involving Europe, and Asia, with the largest number of studies from Asia. A total of 671,532 postmenopausal women were enrolled, with a maximum sample size of 383,498 [22] and a minimum sample size of 362 [26], and a total of 40,172 fractures were diagnosed. The mean follow-up time ranged from 2.7 to 25 years. The diagnosis of obesity mainly refers to WHO BMI categories, and the diagnosis of fracture site mainly refers to the International Classification of Diseases (ICD) and confounding factors such as age, bone mineral density, and type of treatment were well controlled. The main characteristics of the included trials are shown in Table 1.

Table 1. Basic characteristics of the included cohorts.

Author	Year	Country	History of fracture	Sample size	Fracture Number	Mean follow-up years	Diagnostic criteria	Baseline BMI	Age	Fracture type	Effect size	Confounders adjusted	NOS scores
Charles	2022	Belgium	None	3560	/	9.1	WHO standards	26.4 ± 4.4	60–85	Ankle and pelvic fractures	OR	Intake of calcium/vitamin D supplements and pharmacological treatment for osteoporosis.	8
Rikkonen	2021	Finland	None	12,715	427	25	WHO standards/ICD-10	26.7 ± 4.4	58–83	Hip fracture	HR	Age, bone density.	6
Kim	2021	Korea	None	383,498	38,006	8.35	ICD-10	24.19 ± 3.16	57.06 ± 8.29	Vertebral fracture	HR	Age, smoking status, alcohol intake, income, regular exercise, and so on.	8
Li	2020	China	None	3985	200	5	WHO standards	27.7 ± 5.7	69.4 ± 8.9	Osteoporotic fracture	HR	Age, smoking, drinking, education, prior falls and fractures, and so on.	7
Tanaka	2013	Japan	None	1614	254	6.7	WHO standards	27.2 ± 2.4	63.2 ± 10.1	Osteoporotic fracture	RR	Age, diabetes mellitus, prior fracture, bone mineral density, back pain, and treatment	6
Alhambra	2012	Spain	None	263,563	/	2.7	WHO BMI categories/ICD-10	/	66.9 ± 12.1	Different skeletal sites fracture	RR	Age	5
Pirro	2010	Italy	None	362	112	/	WHO BMI categories	26.5 ± 4.6	68 ± 8	Vertebral fracture	OR	Age, weight, height or BMI, smoking, early menopause, family history of fragility fractures, and BMD.	6
Gnudi	2009	Italy	None	2235	209	3	/	25.4 ± 4.0	67.9 ± 9.3	Humerus fractures	OR	Age, age at menopause and FN BMD	6

ICD: International Classification of Diseases; /: no report; OR: odds ratio; RR: relative risk; HR: hazard ratio.

Quality assessment

The NOS scale was used to assess the quality of the included studies, and the scores are shown in Table 1. 3 cohorts had a score of ≥ 7 and were classified as high quality, 4 cohorts had a score of 6 and 1 cohort had a score of 5 were classified as moderate quality.

Obesity and risk of all-cause fracture in postmenopausal women

All included studies [20–27] explored the relationship between obesity and the risk of all-cause fracture. The pooling analysis shows that obesity disorder in postmenopausal women is associated with an increased risk of all-cause fracture (RR = 1.18; 95% CI:1.09–1.28; I² = 86.3%, Z = 3.89, p = .000). Since I² was greater than 50%, the random effect model was used for meta-analysis, and sensitivity analysis was conducted to explore the source of heterogeneity. The result of the sensitivity analysis showed that none of the included cohort studies had reversed the pooled-effect size, which means that the results of this meta-analysis is robust (Figures 2 and 3).

Figure 2. Meta-analysis of the risk of all-cause fracture caused by obesity.

Figure 3. Sensitivity analysis of the risk of fracture caused by obesity.

Subgroup analysis

Subgroup analysis was performed according to different fracture sites, the most clinically concerned fracture sites included hip fracture, vertebral fracture, pelvic fractures, humerus fracture. Three cohort studies reported the risk of hip fractures due to obesity in postmenopausal women (RR = 1.031; 95% CI:0.780–1.363; I² = 91.0%, p = .830), but the differences were not statistically significant. Three cohort studies have reported the risk of vertebral fracture caused by obesity in postmenopausal women (RR = 1.154; 95% CI:1.020–1.305; I² = 94.5%, p = .023), suggesting that obesity is an important risk factor of vertebral fracture in postmenopausal women. The risk of pelvic fractures for postmenopausal women was reported in two cohort studies (RR = 0.575; 95% CI:0.470–0.702; I² = 0.0%, p = .000), suggesting that obesity was an important protective factor for pelvic fractures in postmenopausal women. Two cohort studies reported the risk of humerus fracture due to obesity in postmenopausal women (RR = 1.139; 95% CI:0.972–1.334; I² = 58.9%, p = .107), but the differences were not statistically significant. The details and the included trials are shown in Table 2.

Table 2. Subgroup analysis for the risk of fracture caused by obesity.

Fracture sites	Included studies	RR (95% CI)	Heterogeneity
			I^2	p-value
Hip fracture	3[21,25,27]	1.031 (0.780–1.363)	91.0%	.830
Vertebral fracture	3[22,24,26]	1.154 (1.020–1.305)	94.5%	.023
Pelvic fractures	2[20,25]	0.575 (0.470–0.702)	0.0%	.000
Humerus fracture	2[25,27]	1.139 (0.972–1.334)	58.9%	.107

Publication bias

A visual inspection of the funnel plot showed no evidence of a significant publication bias in Figure 4. The result of Egger’s regression tests (p = .173 ≥ .05), showed that no publication bias was detected.

Figure 4. Publication bias of the risk of fracture caused by obesity.

Discussion

This meta-analysis comprehensively reviewed the risk fracture in postmenopausal women with obesity compared with non-obesity from cohort studies. We found that obesity is associated with an increased risk of all-cause and vertebral fractures in postmenopausal women, but is a protective factor for pelvic fractures. There is no statistically significant difference in the risk of hip and humerus fractures associated with obesity in postmenopausal women.

Several previous meta-analyses on a similar topic have been published since 2013 to 2021 [12,19,34,35]. Two of them evaluated the association between obesity and the risk of fracture in adults [19,34]. These meta-analyses consistently found adults with obesity compared with the reference group had a significantly decreased risk of hip fracture. In particular, obese women had a 25%–30% lower risk of hip fracture, but our meta-analysis, which included three high-quality cohort studies [21,25,27], found no statistical difference in the risk of hip fracture in obese postmenopausal women compared with normal-weight women. This may be related to the fact that our meta-analysis only focused on postmenopausal women, a special population. In addition, two meta-analyses [12,34] explored the relationship between abdominal obesity (defined by various waist-to-hip ratios) and the risk of hip fracture in patients over 40 years old and found that abdominal obesity was positively correlated with the risk of hip fracture. However, it is a small pity that the risk of hip fracture in obese postmenopausal women was not investigated separately. Previous reviews have focused on the relationship between adult obesity and the risk of hip fracture, but there are few studies on the risk of all-cause fracture in obese postmenopausal women. The meta-analysis conducted by Turcotte et al. summarized the results of two observational studies and found that postmenopausal obese women had a 60% higher risk of ankle fracture than non-obese women. This is consistent with our findings that obese postmenopausal women are associated with an increased risk of all-cause fractures. A recent cross-sectional study [36] investigated the relationship between body mass index and fracture in postmenopausal women. After adjusting for many confounding factors, it was found that the risk of all-cause fracture in obese postmenopausal women was 3.33 times higher than that in normal controls, which was consistent with our findings. In summary, our meta-analysis further confirmed that obesity is the risk of all-cause fractures in postmenopausal women, but some differences should also be noted. Firstly, our meta-analysis also focused on several fracture types most concerned in the clinic, including hip fracture, vertebral fracture, pelvic fracture and humerus fracture. In addition to hip fracture, previous studies paid little attention to the risk of vertebral fracture, pelvic fracture and humerus fracture. However, our results suggest that obese postmenopausal women will increase the risk of vertebral fractures and reduce the risk of pelvic fractures, which may provide a new perspective for clinical prevention and treatment. Secondly, in order to reduce heterogeneity and provide more reliable conclusions, we analyzed the results of prospective cohort studies. Through the summary analysis of 671,532 postmenopausal women and 40,172 fracture cases in 8 cohorts, the results of large samples and high-quality evidence further confirmed the conclusion of previous studies that obesity is the risk of fracture in postmenopausal women.

The advantage of this meta-analysis is that it conforms to the latest PRISMA 2020 statement, carries out prospective protocol registration on PROSPERO, and includes the largest sample size focusing on the risk of fracture in obese postmenopausal women. These scientific steps and feasible programs provide a reliable basis for clinical prevention to a certain extent. Our meta-analysis also has some limitations that may affect the generalization of the results. Firstly, it is difficult to rule out publication bias because our meta-analysis included only eight cohort studies. But fortunately, it passed egger’s test and there was no statistical bias. Secondly, due to the diversity of fracture sites, the number of all caused fractures and the number of specify types fracture in postmenopausal women clinically, it is difficult to completely and comprehensively summarize all fracture types and location characteristics only through the summary and analysis of cohort studies, which needs further observation and exploration.

Conclusion

The findings of this systematic review and meta-analysis suggest that obesity is associated with an increased risk of all-cause and vertebral fractures in postmenopausal women, and is a protective factor for pelvic fractures. Further studies are needed to assess the risk of other fracture sites in menopausal women with obesity.

Author contributions

Hong-fei Liu and Hui-ying Li are responsible for the study concept and design. Literature searching: Dong-fang Meng. Selection of studies: Hong-fei Liu, Peng Yu, Ji-cao De. Extraction of data: Hong-fei Liu, Dong-fang Meng, Hui-ying Li. Quality assessment: Peng Yu, Ji-cao De, Hui-ying Li. Analysed the data: Hong-fei Liu, Dong-fang Meng. Wrote the first draft of the manuscript: Hong-fei Liu, Dong-fang Meng. All authors read and approved the final manuscript.

Acknowledgments

We would like to thank the associate editor and the reviewers for their useful feedback that improved this paper.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during the present study are included in this published article.

Additional information

Funding

This work was supported by the Special Project of Traditional Chinese Medicine Scientific Research in Henan Province (2022JDZX123). This funding source had no role in the design, execution, analyses, interpretation of the data, or decision to submit results.

Appendix A:

The retrieval strategies and retrieval results of each database are shown in Tables A1–A4

Table A1. PubMed.

No.	Content	Result
#1	Search: ‘Obesity’[Mesh] Sort by: Most Recent	241,777
#2	Search: (Obesity[Title/Abstract]) OR (Obese[Title/Abstract]) Sort by: Most Recent	350,295
#3	Search: (‘Obesity’[Mesh]) OR ((Obesity[Title/Abstract]) OR (Obese[Title/Abstract])) Sort by: Most Recent	401,510
#4	Search: ‘Fractures, Bone’[Mesh] Sort by: Most Recent	199,228
#5	Search: (Broken*[Title/Abstract]) OR (Fracture*[Title/Abstract]) Sort by: Most Recent	315,608
#6	Search: (‘Fractures, Bone’[Mesh]) OR ((Broken*[Title/Abstract]) OR (Fracture*[Title/Abstract])) Sort by: Most Recent	357,369
#7	Search: ‘Postmenopause’[Mesh] Sort by: Most Recent	26,697
#8	Search: ((Postmenopausal*[Title/Abstract]) OR (Post-Menopause[Title/Abstract])) OR (Post Menopause[Title/Abstract]) Sort by: Most Recent	64,984
#9	Search: (‘Postmenopause’[Mesh]) OR (((Postmenopausal*[Title/Abstract]) OR (Post-Menopause[Title/Abstract])) OR (Post Menopause[Title/Abstract])) Sort by: Most Recent	69,014
#10	Search: (((‘Obesity’[Mesh]) OR ((Obesity[Title/Abstract]) OR (Obese[Title/Abstract]))) AND ((‘Fractures, Bone’[Mesh]) OR ((Broken*[Title/Abstract]) OR (Fracture*[Title/Abstract])))) AND ((‘Postmenopause’[Mesh]) OR (((Postmenopausal*[Title/Abstract]) OR (Post-Menopause[Title/Abstract])) OR (Post Menopause[Title/Abstract]))) Sort by: Most Recent	191

Table A2. Embase.

No.	Content	Result
#1	‘obesity’/mj	202,309
#2	‘obesity’/exp OR obesity OR obese:ab,ti	741,908
#3	#1 OR #2	741,908
#4	‘fracture’/mj	42,789
#5	broken* OR fracture*:ab,ti	382,550
#6	#4 OR #5	389,884
#7	‘postmenopause’/exp/mj	24,921
#8	postmenopausal* OR ‘post menopause’:ab,ti	94,895
#9	#7 OR #8	96,840
#10	#3 AND #6 AND #9	450

Table A3. Cochran Library.

No.	Content	Result
#1	MeSH descriptor: [Obesity] this term only	12,746
#2	(Obesity):ti,ab,kw OR (Obese):ti,ab,kw	47,170
#3	#1 or #2	47,170
#4	MeSH descriptor: [Fractures, Bone] this term only	2411
#5	MeSH descriptor: [Fractures, Bone] this term only	26,316
#6	#4 or #5	26,316
#7	MeSH descriptor: [Postmenopause] this term only	4924
#8	(Postmenopausal*):ti,ab,kw OR (Post-Menopause):ti,ab,kw OR (Post Menopause):ti,ab,kw	22,064
#9	#7 or #8	22,317
#10	#3 and #6 and #9	32

Table A4. Web of science.

No.	Content	Result
#1	(TS = (Obesity)) OR TS = (Obese)	478,833
#2	((TS = (Bone Fractures)) OR TS = (Broken*)) OR TS = (Fracture*)	664,841
#3	(((TS = (Postmenopause)) OR TS = (Postmenopausal*)) OR TS = (Post-Menopause)) OR TS = (Post Menopause)	98,744
#4	#1 AND #2 AND #3	665