The Role of Metabolic Syndrome and its Components in Incident Fracture: A 15-Year Follow-Up Among the Iranian Population (original) (raw)

Journal Article

Atieh Amouzegar ,

Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences

,

Tehran

,

Iran

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Samaneh Asgari ,

Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences

,

Tehran

,

Iran

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Fereidoun Azizi ,

Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences

,

Tehran

,

Iran

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Amir Abbas Momenan ,

Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences

,

Tehran

,

Iran

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Mohammadreza Bozorgmanesh ,

Mohammadreza Bozorgmanesh

Department of Orthopedic Surgery, Arak University of Medical Sciences

,

Arak

,

Iran

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Farzad Hadaegh

Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences

,

Tehran

,

Iran

Correspondence: Farzad Hadaegh, MD, Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19395-4763, Tehran 1985717413, Islamic Republic of Iran. Email: [email protected].

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Received:

22 September 2020

Editorial decision:

13 January 2021

Published:

01 February 2021

Corrected and typeset:

20 February 2021

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Atieh Amouzegar, Samaneh Asgari, Fereidoun Azizi, Amir Abbas Momenan, Mohammadreza Bozorgmanesh, Farzad Hadaegh, The Role of Metabolic Syndrome and its Components in Incident Fracture: A 15-Year Follow-Up Among the Iranian Population, The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 5, May 2021, Pages e1968–e1983, https://doi.org/10.1210/clinem/dgab023
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Abstract

Context

The relationship between metabolic syndrome (MetS) and the risk of fracture is a matter of debate.

Objective

This work aimed to determine the impact of MetS and its components on the risk of hospitalized fractures, during a median follow-up of 15.9 years.

Methods

A total of 7,520 participants (4,068 women) 30 years or older entered the study. Multivariable Cox proportional hazards regression were applied for data analysis.

Results

The prevalence of MetS was 40.0% and 40.4% in men and women, respectively. During the follow-up, hospitalized fracture was observed in 305 cases (men = 152). The multivariable hazard ratio (HR) and 95% confidence interval (CI) of MetS for incident fracture for men and women was 0.72 (0.49-1.05, P = .08) and 1.38 (0.96-1.98, P = .08), respectively. In the fully adjusted model, high fasting plasma glucose (FPG) among men tended to be associated with a lower risk of fracture [0.67 (0.44-1.02, P = .06)]; among women, high waist circumference (WC) was associated with a greater risk [2.40 (1.55-3.73)]. Among the population 50 years and older in the pooled sample, MetS was not accompanied by the risk of fracture, but high WC was associated with a higher risk [1.58 (1.07-2.33)]. For incident hip/pelvic fracture, abdominal obesity—but not MetS per se—was also a strong and independent risk factor.

Conclusion

A significant sex difference in the association between MetS and its components with incident fracture was observed. Women with central adiposity were at increased risk of hospitalized fracture, whereas men with high FPG were at decreased risk.

As stated by Reaven in 1988, metabolic syndrome (MetS) is a constellation of metabolic factors including increased visceral adiposity, impaired insulin sensitivity, high blood pressure (BP), and dyslipidemia (1). Several studies have demonstrated that MetS is associated with type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) (2, 3). Based on different diagnostic criteria, 1 out of 3 Iranian adults aged 30 years or older is affected by MetS, which has been reported to be higher in women compared to men (42% vs 24%, respectively) (4). Despite the high burden of CVD risk factors in the Middle East and North Africa (MENA) region (5), limited experience exists regarding the prevalence of MetS in the region, with studies showing prevalence similar to that reported in our previous studies (6, 7). We also showed that more than 5% of Tehranian adults developed MetS per year (8).

Osteoporotic fracture, a debilitating chronic disease affecting mainly postmenopausal women and older men, is an important, potentially preventable public health issue across the world. Iran accounts for about 1% of the hip fracture burden in the world and more than 12% of the burden in the Middle East (9). Owing to its high morbidity and mortality and its significant economic costs, it is more problematic in countries with high life expectancy and an old-age population, who are more susceptible to osteoporotic fractures (10).

MetS, as well as being an individual trait, has some effects on bone metabolism. The association between MetS and bone status has been assessed in some studies, with inconsistent results. A meta-analysis conducted on 3 prospective studies showed that MetS is associated with a 15% reduced risk of fracture in adults (11), whereas another found no association between MetS and prevalent or incident bone fracture (12). Results of a meta-analysis conducted by Yang et al suggested that MetS was associated with a lower risk of fractures in men but not women. (13). Importantly there was significantly high heterogeneity between the studies included in these mentioned meta-analyses, and all of them were conducted in US, European, and East Asian populations (11-13).

Moreover, among the components of MetS, the role of central obesity, glucose tolerance disorders, and high BP in the incidence of fractures has been studied more extensively (11-13). However, these studies differ greatly; and little has been done regarding the role of lipid disorders. Therefore, we conducted the present study on a prospective, long-term, large, community-based cohort from a Middle-Eastern population to determine the risk of hospitalized fracture in individuals with MetS and to evaluate the role of each MetS component in fracture risk among men and women, during more than a decade of follow-up in the oldest cohort of the MENA region.

Materials and Methods

Study Design and Population

The Tehran Lipid and Glucose Study (TLGS) is a population-based longitudinal study conducted on individuals aged 3 years or older living in the urban area of Tehran (the capital of Iran). This study aimed to determine the prevalence and incidence of noncommunicable diseases and their related risk factors. It also looked at developing a healthy lifestyle to counteract these risk factors. The TLGS enrollment was carried out in 2 phases, the first of which was from January 31, 1999, to July 3, 2001, with a second enrollment phase from October 20, 2001, to September 22, 2005. Data collection is planned to continue for at least 20 years at approximately 3-year intervals. The design and registration of the TLGS have been previously described (14).

Among a total of 9,747 participants 30 years or older (8,071 individuals from phase I and 1,676 participants from phase II), we excluded individuals with missing data regarding body mass index (BMI), waist circumference (WC), fasting plasma glucose (FPG), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), smoking status, education level, marital status, and physical activity at baseline (n = 1,548, considering overlaps between numbers). After excluding individuals without any follow-up measurements after baseline recruitment (n = 679), a total of 7,520 participants (women = 4,068) were followed until March 20, 2016, for the present study analyses.

The ethics committee of the Research Institute for Endocrine Sciences of Shahid Beheshti University of Medical Sciences approved the study proposal, and written informed consent was obtained from all participants.

Clinical and Laboratory Measurements

Body measurements of the study participants (weight and height) were recorded with shoes removed and while wearing light clothing. Weight was measured to the nearest 100 g. Height was measured in a standing position, using a tape measure, while shoulders were in normal alignment. WC was measured with light clothing at the level of the umbilicus (14).

A standard questionnaire was used to collect information on demographic data, history of CVD, medication history, smoking habits, education level, physical activity, and marital status.

Based on the TLGS design (14), 2 measurements of SBP and DBP were taken from the right arm after a 15-minute rest in a sitting position. The mean of the 2 measurements was considered as the participant’s BP. A blood sample was taken following a 12- to 14-hour overnight fast from all study participants between 7 am and 9 am. Details regarding laboratory measurements including FPG and creatinine have been reported elsewhere (14). All blood analyses were carried out in the TLGS research laboratory the day of blood collection.

Definition of Terms

Education level was sorted into 3 groups: formal education lasting less than 6 years, 6 to 12 years, and greater than 12 years. Marital status was defined as being either single (including widowed/divorced) or married. Smoking status was categorized into 3 groups: current smokers (who smoke cigarettes or water pipe daily or occasionally), former smokers (those who used to smoke), and never smokers. We defined low physical activity for participants enrolled in phase I as being physically active for fewer than 3 days per week using the Lipid Research Clinic questionnaire. For participants recruited in phase II, the Modifiable Activity Questionnaire was used, and individuals with fewer than 600 metabolic equivalent task minutes per week were categorized as being in the low physical activity group (14, 15). Applying the Joint Interim Statement (16), those who met at least 3 of the following 5 criteria were considered to have MetS: (1) WC greater than or equal to 95 cm for both sexes for Iranian adults, as recommended by The Iranian National Committee of Obesity and based on multiple cross-sectional and prospective studies (16); (2) TGs greater than or equal to 150mg/dL or use of lipid-lowering medications; (3) HDL-C less than 40 mg/dL in men, and less than 50 mg/dL in women, or use of lipid-lowering medications; (4) SBP/DBP greater than or equal to 130/85 mm Hg or use of antihypertensive medication; and (5) FPG greater than or equal to 100 mg/dL or use of antidiabetic medications. T2DM was defined as FPG greater than or equal to 126 mg/dL or use of glucose-lowering medication. Menopausal status was defined based on the World Health Organization’s definition of menopause status, namely the absence of spontaneous menstrual bleeding for more than 12 months, for which no other pathologic or physiologic cause could be determined (17) and for those with missing information, the menopausal age was set at 50 years or older (18).

Outcomes

According to the previously published article on outcomes in the TLGS cohort (19), each participant is followed up for any medical event leading to hospitalization during the previous year by telephone call. They were asked about any medical conditions by a trained nurse and later, a trained physician collected complementary data regarding that event during a home visit and by the acquisition of data from medical files. The collected data were then evaluated by an outcome committee consisting of an internist, endocrinologist, cardiologist, epidemiologist, and other experts, if required, to assign a specific outcome for every event. Importantly, the outcome committee is blinded to the status of baseline risk factors. In the present study, only hospital-confirmed fracture events were included. Following the TLGS protocol, fractures, whether in the upper or lower extremities, requiring at least 24-hour admission to the hospital were recorded and adjudicated by the outcome committee. The diagnosis of fracture was decided based on the patient’s claim and the hospital discharge abstract. Hospitalized fracture, in the present study, was defined as fractures in the upper extremity (ie, clavicle, scapula, upper humorous, elbow, forearm, wrist, and hand), lower extremity (ie, pelvic, hip, femur, patella, and other leg), vertebral, or other fractures.

Statistical Analyses

Baseline characteristics of the study population are described as mean (SD) values for continuous variables, and as frequencies (%) for categorical variables. A comparison of the baseline characteristics between men and women was performed using the t test for normally distributed continuous variables, the chi-square test for categorical variables, and the Mann-Whitney U statistic for skewed and ordered variables.

The association between the baseline status of MetS and its components with incident hospitalized fracture was assessed using Cox proportional hazards regression. These associations were evaluated in 4 models. Model 1: MetS or each component of MetS plus age and sex (for total population); Model 2: Model 1 plus smoking status, education, physical activity, marital status, steroid usage, and menopausal status (only for women); Model 3: Model 2 plus other MetS components (this model was not performed for MetS per se); and Model 4: Model 3 and BMI (for MetS, this model was model 2 and BMI). The event date was defined as the date of the first incident fracture. Those who met the following criteria were censored: leaving the residential area, death, loss to follow-up, or end of follow-up. For individuals with a first-incident fracture, survival time was defined as the time between the entered date and the event date. Additionally, for censored participants, the survival time was defined as the difference between the entered date and the last available follow-up date. Schoenfeld’s global test of residuals was used to test the proportionality assumption of the multivariable Cox regression. We also reported the interaction of sex with MetS and its related components in multivariable models. Because significant interactions were observed between sex and MetS, high WC, and high BP (minimum P value = .001) in multivariable analysis, all analyses were conducted separately in men and women. To be comparable to other studies in this field, we also examined the association between MetS and its components in the pooled sample. Considering multiple testing in examining the interaction of sex with different potential risk factors in multivariable analysis, the level of P value was decreased to .01 and significant interactions were still observed between sexes with high WC.

All analyses were conducted using STATA, version 12 SE (StataCorp). A 2-tailed P value of less than .05 was considered statistically significant, and .05 less than or equal to P less than .07 was considered as tended to be significant.

Results

The baseline characteristics of participants by sex are shown in Table 1. The mean age at baseline was 47.9 years (SD: 13.1) for men and 45.9 years (SD: 11.5) for women. There were significant differences in baseline characteristics between men and women, except for WC, DBP, and the use of steroid medications. Compared to men, women had higher values for BMI and HDL-C but lower levels of FPG, SBP, and TGs. Men were older and more likely to be current smokers, be married, and have higher levels of education. Fig. 1 shows the prevalence of MetS and its components among the study population. The prevalence of MetS was 40.0% and 40.4% in men and women, respectively. Compared to women, male participants had a higher prevalence of high TGs but a lower prevalence of low HDL-C. At baseline, 68.1% of our female population were at postmenopausal status.

Table 1.

Baseline characteristics of the study population stratified by sex: Tehran Lipid and Glucose Study (1999-2016)

Values are shown as mean (SD) and number (%), for continuous and categorical variables, respectively; for TG and menopausal age, values are shown as median (interquartile range).

Abbreviations: 2h-PCPG, 2-hour post-challenge plasma glucose; BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; MetS, metabolic syndrome; SBP, systolic blood pressure; TGs, triglycerides; WC, waist circumference; y, year.

Table 1.

Baseline characteristics of the study population stratified by sex: Tehran Lipid and Glucose Study (1999-2016)

Values are shown as mean (SD) and number (%), for continuous and categorical variables, respectively; for TG and menopausal age, values are shown as median (interquartile range).

Abbreviations: 2h-PCPG, 2-hour post-challenge plasma glucose; BMI, body mass index; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; MetS, metabolic syndrome; SBP, systolic blood pressure; TGs, triglycerides; WC, waist circumference; y, year.

Figure 1.

Prevalence of metabolic syndrome (MetS) and its components among the study population.

During the median follow-up time of 15.9 years (interquartile range, 11.8-16.5 years), fractures were observed in 152 men and 153 women. The crude and age-standardized incidence rates of fracture among the whole population were 289.0 (95% CI, 258.0-323.0) and 277.0 (95% CI, 232.0-331.0) per 100 000 person-years. The crude and age-standardized fracture incidence rates of hip/pelvic fracture were 200.0 (95% CI, 160.0-250.0) and 220 (95% CI, 170.0-270.0) per 100 000 person-years, respectively. The distribution of fractures in each sex is shown in Fig. 2.

Figure 2.

Distribution of hospitalized fractures by sex: Tehran Lipid and Glucose Study (1999-2016).

Table 2 shows the adjusted hazard ratios (HRs) and 95% CIs of MetS and its components for incident hospitalized fractures in the 4 models. Among men, the presence of MetS in all models was associated with a lower but not significant risk for fractures. Among men, the high FPG component was associated with a 34% lower risk of fracture in model 1 (HR, 0.66; 95% CI, 0.44-0.99, P = .05); this risk tended to be significant in model 4 (HR, 0.67; 95% CI, 0.44-1.02, P = .06). Among women, the presence of MetS in all the models was associated with a higher but not significant risk for incidence of fractures. Among women, the high WC component was associated with a 63% higher risk of fracture in model 1 (HR, 1.63; 95% CI, 1.17-2.27, P = .004); this risk remained significant in model 4 (HR, 2.40; 95% CI, 1.55-3.73, P < .001). Among the total population, only the high WC component remained a significant risk factor for incident fracture (HR, 1.67; 95% CI, 1.23-2.27, P = .001) in fully adjusted model.

Table 2.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among men, women, and whole population: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 7,520 (men = 3,452); number of fractures = 305 (men = 152).

Model 1: MetS or each MetS component + age + sex (for total population).

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status + menopausal status (only for women).

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Sex interaction value (MetS = 0.026; high WC = 0.001; high BP = 0.05; high FPG = 0.38; high TGs = 0.54; low HDL-C = 0.23).

Significant P values are shown in bold.

High WC was defined as WC ≥ 95 cm for both sexes (16, 55).

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 2.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among men, women, and whole population: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 7,520 (men = 3,452); number of fractures = 305 (men = 152).

Model 1: MetS or each MetS component + age + sex (for total population).

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status + menopausal status (only for women).

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Sex interaction value (MetS = 0.026; high WC = 0.001; high BP = 0.05; high FPG = 0.38; high TGs = 0.54; low HDL-C = 0.23).

Significant P values are shown in bold.

High WC was defined as WC ≥ 95 cm for both sexes (16, 55).

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

We conducted a series of sensitivity analyses to assess the robustness of our findings. First, we excluded participants with prevalent T2DM (Table 3). The results among the nondiabetic population generally followed our main findings. However, among men, the association between the high FPG component and incident fracture disappeared. Second, to exclude the probability of traumatic fractures, we redid our analysis among the population aged 50 years or older (N = 2870) in the pooled sample (Table 4). The crude and age-standardized fracture incidence rates (95% CI) of incident fracture among those 50 years or older were 500.0 (430.0-570.0) and 520.0 (440.0-600.0) per 100 000 person-years, respectively; these were 200.0 (160.0-250.0) and 220.0 (170.0-270.0) per 100 000 person-years for incident hip/pelvic fracture, respectively. Accordingly, although the presence of MetS was not accompanied by the risk of fracture, the high WC component was associated with a significantly higher risk (HR, 1.58; 95% CI, 1.07-2.33, P = .02) and high TGs also had a trend toward association with a lower risk (HR, 0.74; 95% CI, 0.54-1.02, P = .06) in the fully adjusted model. Third, we examined the association of MetS and its components among postmenopausal women. Accordingly, the high WC component remained a significant risk factor in the fully adjusted model (HR, 2.43; 95% CI, 1.53-3.86, P < .001) (Table 5). Fourth, we redid our analysis using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) cutoffs of WC (men ≥ 102 cm, women ≥ 88 cm) (7). The results remained essentially unchanged. Among men, MetS was significantly associated with lower risk of fracture in the fully adjusted model (HR, 0.62; 95% CI, 0.42-0.93, P = .02). Among women, the presence of a high WC component was associated with a higher risk of fracture in all models. Also, among the total population, the high WC component remained a significant risk factor for incident fracture (Table 6). Fifth, we examined the association of MetS and its components for incident distal upper extremity (including elbow, forearm, wrist, and hand) and pelvic/hip fracture. High WC was associated with a higher risk of pelvic/hip fracture in the fully adjusted model (HR, 2.0; 95% CI, 1.10-3.63, P = .02) (Table 7).

Table 3.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among the nondiabetic population in men, women, and whole population: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 7,194 (men = 3,297); number of fractures = 289 (men = 148).

Model 1: MetS or each MetS component + age + sex (for total population).

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status + menopausal status (only for women).

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 3.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among the nondiabetic population in men, women, and whole population: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 7,194 (men = 3,297); number of fractures = 289 (men = 148).

Model 1: MetS or each MetS component + age + sex (for total population).

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status + menopausal status (only for women).

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 4.

Cox proportional of metabolic syndrome and its components for incident hospitalized fracture among population 50 years or older: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 2,870; number of fractures = 184.

Model 1: MetS or each MetS component + age + sex.

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status.

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 4.

Cox proportional of metabolic syndrome and its components for incident hospitalized fracture among population 50 years or older: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 2,870; number of fractures = 184.

Model 1: MetS or each MetS component + age + sex.

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status.

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 5.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among postmenopausal women: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 2,769; number of fractures = 134.

Model 1: MetS or each MetS component + age.

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status.

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 5.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among postmenopausal women: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 2,769; number of fractures = 134.

Model 1: MetS or each MetS component + age.

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status.

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 6.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among men, women, and whole population, using NCEP ATP III WC cutoff pointsa: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 7,520 (men = 3,452); number of fractures = 305 (men = 152).

Model 1: MetS or each MetS component + age + sex (for total population).

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status + menopausal status (only for women).

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

_a_Sex-specific WCs were considered for MetS calculation. NCEP ATP III WC cutoff points: WC for men ≥ 102 cm, and women ≥ 88 cm.

Table 6.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized fracture among men, women, and whole population, using NCEP ATP III WC cutoff pointsa: Tehran Lipid and Glucose Study (1999-2016)

Sample size = 7,520 (men = 3,452); number of fractures = 305 (men = 152).

Model 1: MetS or each MetS component + age + sex (for total population).

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status + menopausal status (only for women).

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

_a_Sex-specific WCs were considered for MetS calculation. NCEP ATP III WC cutoff points: WC for men ≥ 102 cm, and women ≥ 88 cm.

Table 7.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized distal of the upper extremity and hip/pelvic fracture: Tehran Lipid and Glucose Study (1999-2016)

Distal upper extremity including clavicle, scapula, upper humorous, elbow, forearm, wrist, and hand.

Distal upper extremity Sample size = 7,520; number of fractures = 66.

Hip/Pelvic: Sample size = 7,520; number of fractures = 80.

Model 1: MetS or each MetS component + age + sex.

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status.

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Distal upper extremity fracture was included: elbow, forearm, wrist, and hand fracture.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Table 7.

Cox proportional hazard model of metabolic syndrome and its components for incident hospitalized distal of the upper extremity and hip/pelvic fracture: Tehran Lipid and Glucose Study (1999-2016)

Distal upper extremity including clavicle, scapula, upper humorous, elbow, forearm, wrist, and hand.

Distal upper extremity Sample size = 7,520; number of fractures = 66.

Hip/Pelvic: Sample size = 7,520; number of fractures = 80.

Model 1: MetS or each MetS component + age + sex.

Model 2: Model 1 + smoking status + education + physical activity + steroid usage + marital status.

Model 3: Model 2 + each other MetS component (this model was not performed for MetS per se).

Model 4: Model 3 + body mass index.

Distal upper extremity fracture was included: elbow, forearm, wrist, and hand fracture.

Significant P values are shown in bold.

Significant P value: P less than .05.

Tend to be significant: .05 ≤ P < .07.

Abbreviations: BP, blood pressure; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Discussion

For the first time in the MENA region, with a high burden of CVD risk factors, we examined the sex-stratified association between MetS and its components with the risk of hospitalized fracture during more than a decade follow-up. In a multivariable analysis adjusted for age, smoking, educational level, physical activity, and steroid use, we found that MetS is associated with a higher and lower, but not significant, trend of fracture risk among women and men, respectively. Regarding MetS traits, in a multivariable analysis among men, we found that high FPG in men tended to be associated with a lower risk of fracture, whereas among women, high WC was associated with a significantly higher risk of fractures. Moreover, in a sensitivity analysis, among the nondiabetic population, the results were generally in close agreement with our major findings, except that high FPG among men did not show a lower risk for fracture. Additionally, among participants aged 50 years and older, MetS did not remain a significant risk factor for fracture while abdominal obesity still had a significantly higher risk. We also found that the presence of abdominal obesity was accompanied by a 100% increased risk of pelvic/hip fracture.

It is important to note that the comparison of our findings with other studies in this field is not easy because there are 4 sources of heterogeneity: 1) different definitions of MetS (20-22) and the outcome as bone mineral density (BMD) vs fracture (22, 23); 2) various study designs (cross-sectional vs cohort studies) (12); 3) level of adjustment for confounders (12, 24); and 4) whether the association was examined in each sex or among the whole population (12, 21, 22, 25).

The relationship between MetS and BMD as a surrogate for risk of fracture has been addressed in some studies (22, 26) with conflicting results. Xue et al conducted a meta-analysis in which they found that the presence of MetS was associated with increased BMD of the spine, with no correlation with femoral neck BMD, in a model not adjusted for BMI (27). In another meta-analysis conducted by Esposito et al, there was no difference in the spine, femoral neck, and calcareous BMD values between participants with and without MetS (11). A recent study carried out in the South of Iran among the older population showed that in the fully adjusted regression model (including BMI), the presence of MetS was significantly associated with mean BMD levels in all locations in men, and in the lumbar spine in women. The researchers also found that the prevalence of osteoporosis using BMD criteria was significantly lower in both sexes in the presence of MetS (28).

Some studies stepped beyond to find the association between MetS and a surrogate outcome such as BMD and tried to find the effect of MetS on fractures with inconsistent results. The association between MetS/insulin resistance with incident fracture among prospective studies is shown in Table 8. The meta-analysis by Esposito et al found that MetS is associated with a 15% reduced risk of fractures in adults, and most of the reduced fracture risk was seen in the cohort studies; therefore the results should be interpreted cautiously because of high heterogeneity (11). Sun et al, in another meta-analysis, found no association between MetS and prevalent or incident bone fractures (12). The results of a meta-analysis by Yang et al containing 5 prospective cohort studies suggested that MetS was associated with a 24% reduction in risk of any fractures (moderate heterogeneity) in multivariable analysis; moreover, the reduced risk of fracture was mainly found among men. (13). Similarly, in our study, using the NCEP ATP III WC cutoff, we found that among men the presence of MetS was significantly associated with a lower risk of fracture.

Table 8.

Association of metabolic syndrome/insulin resistance with incident fracture in prospective studies

Abbreviations: BMD, bone mineral density; BMI, body mass index; HR, hazard ratio; M, men; MetS, metabolic syndrome; OR, odds ratio; RR, relative risk; TLGS, Tehran Lipid and Glucose Study; US, United States; W, women.

_a_All fractures.

_b_Mean ± SD.

_c_Range.

Table 8.

Association of metabolic syndrome/insulin resistance with incident fracture in prospective studies

Abbreviations: BMD, bone mineral density; BMI, body mass index; HR, hazard ratio; M, men; MetS, metabolic syndrome; OR, odds ratio; RR, relative risk; TLGS, Tehran Lipid and Glucose Study; US, United States; W, women.

_a_All fractures.

_b_Mean ± SD.

_c_Range.

In the present study, abdominal obesity was a strong and independent risk factor for fractures in women (including postmenopausal women) and the total population even among those free of T2DM; this harmful effect was also shown after adjusting for general adiposity. The unfavorable impact of central adiposity was also shown for hip/pelvic fracture in TLGS participants. In a recent meta-analysis, the authors reported a marginally significant positive association between central obesity and risk of hip fracture (combined relative risk: 1.36; 95% CI, 0.97-1.89, P = .07). Xue et al (27) in another meta-analysis of prospective studies also found that, compared with the lowest WC category, the participants with higher WCs had about a 60% higher risk for hip fracture, considering high heterogeneity between included studies. Recently Paik et al in the Nurses’ Health Study conducted among 54 934 women demonstrated that larger WC was associated with higher incident risk of vertebral fracture over a 12-year follow-up (30). There are several explanations regarding the possible role of abdominal obesity in increasing the incidence of fracture. Inflammatory cytokines released by visceral adipocytes might increase bone resorption or suppress bone formation. Among 72 individuals with MetS, Iacobellis et al found a higher level of adiponectin was negatively correlated with BMD in the femoral neck and lumbar spine, compared with a control group (31). Furthermore, leptin and adiponectin play certain roles in osteoporotic fractures: While leptin increases the outflow of sympathetic impulses on bone (32), it has been suggested that adiponectin may be an actor for fracture (33). It seems that adiponectin indirectly increases osteoclastogenesis by stimulating the receptor-activated nuclear factor–κB ligand (RANKL) pathway to inhibit osteoprotegrin production in human osteoblasts, resulting in decreased biomechanical strength properties, which may enhance susceptibility to fractures (34). Moreover, researchers also found that higher serum adiponectin levels were significantly accompanied by an increased risk of fractures at any site in patients with T2DM, including postmenopausal women (35). Importantly, the effects of adipocytokines are not the same on different bone types and sites. A cohort study conducted among Japanese postmenopausal women showed that lower leptin levels and higher adiponectin levels were significantly associated with a 30% lower and 18% higher risk for incident long-bone and vertebral fractures, respectively (36). In addition, the risk of falling due to mechanical instability and impaired balance may increase, as body size in the abdominal region increases (37-39).

Lipid components of MetS in the present study did not have a significant risk for incident fracture. Among participants aged 50 years or older, the high TGs component of MetS was associated with a 26% lower risk of fracture in the fully adjusted model. The higher TGs levels were associated with higher (40, 41) or lower fracture risk (20, 42) in a few studies. Results of the Tromsø study showed a lower risk of nonfasting high TGs levels on fracture risk for White participants, but the researchers did not consider other MetS components or BMI in their analysis (20). Similar to our study, the results of the MINOS study showed that in men, when all the criteria of MetS were included in one multivariable model, only the presence of high TGs was associated with an approximately 47% lower risk of fracture. The discordant results in this regard could be due to the effect of reverse causality. The high TGs level could be a surrogate for better nutrition, higher calcium intake, access to a high-quality diet, high protein, and sufficient intake of vitamins and mineral-containing foods, and many other factors that lead to a lower rate of fracture (42, 43).

We found that high FPG components, including both prediabetes and T2DM in men, tended to be associated with a lower risk of fracture by 34%; this risk reached null after excluding prevalent cases of T2DM. Previous studies have suggested an effect of glucose intolerance on bone health; however, conflicting results were reported. Recently, a meta-analysis showed a small but significant association between T2DM and increased risk of overall fracture but the results were faced with high heterogeneity (44). The evidence supporting an association between prediabetes and fracture risk is also inconsistent. The Rotterdam study showed that individuals with impaired glucose tolerance had a higher BMD and lower fracture risk (45). Similarly, Gagnon et al in a cohort of middle-aged and older Austrian men and women without T2DM found that prediabetes was inversely associated with low trauma and/or any fractures in women (46). It seems that insulin resistance is associated with higher BMD owing to the anabolic effect of insulin and increases in free sex-hormone levels (47-50). Higher homeostatic model assessment of insulin resistance is also associated with a generally favorable effect on bone microarchitecture that is not dependent on body weight. It has been shown that the presence of insulin resistance may protect, in part, against bone loss due to estrogen deficiency and/or aging in postmenopausal women and may contribute to higher BMD and microarchitecture consistently (51).

Our study has some strengths. First, it is a community-based prospective study with a large number of Iranian men and women, measuring bone fracture as a hard outcome and not BMD as a surrogate outcome. The cohort design of our study has allowed us to examine the issue of causality between MetS and its components and the risk of fracture. In addition, we considered potential important confounders in our data analysis. We acknowledge the limitations of our study. First, because the TLGS protocol considered only hospitalized fracture as the outcome, it was slightly likely to miss patients with milder fractures who were not admitted to the hospital. Second, in the present study, we reported a lower incident rate of vertebral fracture because most vertebral fractures remain asymptomatic and are diagnosed only with appropriate radiographic tools among those with clinical symptoms. Also, the majority of vertebral fractures are not connected with severe trauma, and generally, this type of fracture was underdiagnosed (52). Despite this, the overall incidence of hospitalized fractures (especially fracture of the hip/pelvic region) in TLGS participants was not lower than comparable data from other parts of the country (53). Third, in the present study, we examined the association between prevalent MetS and incident fracture. Despite the high incidence of MetS among the Iranian population, considering a limited number of fracture events, we did not examine the association between incident MetS and fracture events (8). Fourth, although we conducted a sensitivity analysis in those aged 50 years or older to exclude cases with a high probability of traumatic fractures, (40) we did not have precise data on osteoporotic vs traumatic fractures. It is possible that a few individuals younger than 50 years might have osteoporotic fractures in the background of low BMD and those 50 years or older might have traumatic fractures. Fifth, owing to a lack of data, we did not consider other residual confounders such as nutritional status or calcium and vitamin D intake and use of antiosteoporosis medications in our data analysis. It has been shown that the prevalence of vitamin D deficiency is high in the Iranian population and more than half of these individuals are reported to suffer from vitamin D deficiency (54). Hence, considering the lack of variation in this important confounder, the absence of data on vitamin D in this population-based cohort might not affect our data analysis. Last, the study was carried out in the metropolitan city of Tehran, and its results may therefore not be generalizable to rural areas.

Conclusion

In this long-term, population-based study, we showed a significant sex difference in the association between MetS and its components with incident fracture. Iranian men and women with MetS were at lower and higher risk for fracture, respectively. Among the various MetS components, central adiposity was a strong and independent risk predictor for fracture among women, even after controlling for general adiposity, whereas in males, the high FPG component of MetS was associated with a lower risk of fracture.

Abbreviations

Abbreviations

• BMD
• BMI
• BP
• CVD
• DBP
• HDL-C
  high-density lipoprotein cholesterol
• HR
• FPG
• MENA
  Middle East and North Africa
• MetS
• NCEP ATP III
  National Cholesterol Education Program Adult Treatment Panel III
• SBP
• T2DM
• TGs
• TLGS
  Tehran Lipid and Glucose Study
• WC

Acknowledgments

We acknowledge the 378 staff and participants in the TLGS study for their cooperation.

Additional Information

Disclosures: The authors have nothing to disclose.

Data Availability

The data sets generated during the present study are not publicly available but are available from the corresponding author on reasonable request.

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