Elsevier

Bone

Volume 120, March 2019, Pages 452-458
Bone

Full Length Article
Relationship of cardiometabolic risk biomarkers with DXA and pQCT bone health outcomes in young girls

https://doi.org/10.1016/j.bone.2018.12.013Get rights and content

Highlights

  • CMR is negatively related with total body bone and bone of metaphyseal tibia.

  • HOMA-IR and CRP are main negative predictors of total body bone area and mass.

  • HOMA-IR is adversely related to regional bone sites, particularly metaphyseal.

Abstract

Background

Excess weight exerts the positive effect of mechanical loading on bone during development whereas obesity-related metabolic dysfunction may have a detrimental impact. In adults, the presence of metabolic syndrome and type 2 diabetes has been associated with compromised bone density, quality, and strength, and an increased incidence of fractures. The few studies that have investigated the role of cardio-metabolic disease risk biomarkers (CMR) on bone strength in children have given conflicting results. The aim of this study was to assess the combined and independent relationships of cardio-metabolic biomarkers with total body and regional bone parameters in young girls.

Methods

In 306, 9–12 year old girls, measures of whole body fat and lean mass, areal bone mineral density (aBMD), bone mineral content (BMC), and bone area (BA) were obtained by dual-energy x-ray absorptiometry (DXA). Bone mineral density (vBMD), geometry, and strength of metaphyseal and diaphyseal regions of the femur and tibia and a diaphyseal region of the radius were measured using peripheral quantitative computed tomography (pQCT). Fasting serum measures of CMRs included, fasting glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), systolic and diastolic blood pressure (SBP and DBP), and C-reactive protein (CRP). Multiple linear regression was used to assess the independent associations of a single CMR with total body and peripheral measures of bone strength after controlling for the other CMRs, plus total body soft tissue, and other relevant covariates. Also, a standardized total CMR composite score, calculated by standardizing to z-scores and then summing z-scores of each CMR biomarker, was regressed with total body and regional bone measures to assess the relationship of a cluster of risk factors with bone health.

Results

Total CMR composite score had inverse associations (p < 0.001) with DXA total BMC and BA. Inverse associations (p < 0.05) of CMR risk score with pQCT regional bone measures occurred with total and trabecular BA at the 4% tibia. Of the individual CMRs, HOMA-IR and CRP were significant predictors of total body bone measures by DXA accounting for ~1–5% of the variance in BMC, BA, and/or aBMD. HOMA-IR was the main predictor of regional pQCT bone outcomes, accounting for the most variance in trabecular vBMD (2.6%) and BSI (3.8%) at the 4% tibia. Most markers of dyslipidemia (TG, HDL-C, LDL-C) and hypertension (SBP, DBP) were not associated (p > 0.05) with any total body or regional bone outcomes with the exception of the inverse relationship of LDL-C with total and trabecular BA and the positive relationship of DBP with cortical vBMD at the radius.

Conclusion

Of the obesity-related metabolic impairments, insulin resistance and chronic inflammation may compromise whole body bone development in young girls. In particular, trabecular bone, such as that found at the metaphysis of long bones, may be more susceptible to the detrimental effects associated with obesity-related metabolic dysfunction.

Introduction

Excess adiposity has been linked to the development of insulin resistance, chronic inflammation, and the ensuing metabolic syndrome (MetS) components (i.e. glucose intolerance, dyslipidemia, and hypertension) [1]. These metabolic alterations are known risk factors for cardiovascular disease [1], type 2 diabetes [2], non-alcoholic fatty liver disease [3] and certain cancers [4]. Recent evidence in animal [5,6] and human studies [[6], [7], [8], [9], [10]] has suggested that these obesity-derived metabolic alterations may also be risk factors for compromised bone strength. For example, von Muhlen et al. reported that fracture incidence was 2.6 times more likely to occur in older adults with MetS compared to older adults without MetS [8]. Moreover, the number of MetS components was negatively associated with femoral neck and total hip areal bone mineral density (aBMD) after adjustment for BMI [8]. Kim et al., also observed significantly lower femoral neck aBMD in participants with MetS after adjusting for body weight; however, when assessing associations of the individual MetS components with femoral neck BMD, waist circumference in both men and women and fasting triglycerides in women were the only MetS components having significant inverse relationships with aBMD [10]. Hence, not all components of MetS have similar associations with skeletal outcomes.

Despite evidence in adults of an association between cardiometabolic risk (CMR) factors and compromised bone health, less research has been focused around the effect of obesity-induced metabolic dysfunction on bone development in children. Recently, in a cohort of 9-to-12 year-old girls participating in the Soft Tissue and Bone Development (STAR) study, we have shown that the positive relationship between total body adiposity and whole body bone mineral content (BMC) was attenuated by the presence of 2 or more CMRs defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition of MetS modified for age [11]. In that analysis, the relationship of individual CMRs representative of inflammation, insulin resistance, dyslipidemia, and hypertension with bone outcomes independent of each other was not assessed. It is possible that the relationship of dyslipidemia with bone may be explained by insulin resistance, which underlies many of the MetS components [12]. Currently, few studies have evaluated single CMR biomarkers with bone in children, with inconsistent results [[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]]. In addition, most previous studies in children have focused on the relationship of CMRs with dual-energy x-ray absorptiometry (DXA) measured total body BMC and aBMD. However, BMC and BMD are just two among several indicators of bone health. Bone strength is also comprised of other bone properties such as the microarchitecture at the bone tissue level [24]. With newer 3-dimentional imaging techniques, such as peripheral quantitative computed tomography (pQCT), both the material properties (i.e. density and mass) and the geometric properties (i.e. size and shape) of bone can be measured [25]. Obesity-related CMRs may have differential relationships with these different components of bone strength. For instance, Viljakainen et al. found that C-reactive protein (CRP), a biomarker of inflammation, was not significantly associated with whole body aBMD, but did have a significant inverse relationship with cortical density, periosteal circumference, and overall bone strength at the tibia in young male adults [26]. No study to our knowledge has assessed the associations of obesity-related CMR biomarkers of inflammation, insulin resistance, dyslipidemia, and hypertension together with measures of bone geometry and strength in children. Given the paucity of research assessing the effects of CMR biomarkers with bone indices in children, which is an important age for bone development, and an estimated prevalence of up to 7% of overweight children and 30% of obese adolescents having MetS [27], the aim of this study was to assess the combined and independent relationships of CMR biomarkers with total body and regional bone parameters in young girls.

Section snippets

Study population

The study participants consisted of 344 girls aged 9-to-12 years-old who participated in the cross-sectional arm of the Soft Tissue And Bone Development in Young Girls (“STAR”) study, a study designed to assess the effects of adiposity and related metabolic risk factors on bone development in girls (Clinical trials #NCT02654262). Detailed descriptions of the study protocol with inclusion and exclusion criteria have been published previously [11,[28], [29], [30]]. The study protocol was approved

Results

Descriptive characteristics of the sample are presented in Table 1. Based on U.S. age and gender-specific established cut-points for percentiles of body mass index (kg/m2) [44], the majority of girls had a healthy weight (59%). Only 2% of girls were underweight, while 15% were overweight, and 24% were obese. The majority of girls identified as Hispanic (74%). On average girls were 11 years-old and had just reached their estimated peak height velocity (maturity offset = 0.3 year). Self-reported

Discussion

The aim of this study was to assess the combined and independent relationships of CMR biomarkers with total body bone mass and density and regional bone parameters of geometry and strength in young girls. Our results showed that greater metabolic dysfunction as indicated by a higher CMR z-score was associated with decreases in total body BMC and BA. These findings are similar to those of Pollock et al., who observed that overweight adolescents with a clustering of 2 or more cardio-metabolic

Conclusion

In conclusion, greater cardio-metabolic dysfunction is associated with impaired total body bone strength and regional bone strength, especially that of trabecular bone in young girls. In particular, inflammation and insulin resistance are likely the CMR biomarkers underlying the negative associations observed between obesity-related cardio-metabolic dysfunction and negative bone health outcomes. Whether biomarkers of inflammation and insulin resistance can be used for not only assessing CVD

Declaration of interest

None.

Funding

This work was supported by the National Institute of Child Health and Human Development. [HD074565].

Acknowledgements

This study was executed at the University of Arizona Collaboratory for Metabolic Disease Prevention and Treatment Center. The study was supported by National Institute of Child Health and Human Development.

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    Present address: University of Lisbon, Faculty of Human Kinetics, Exercise and Health Laboratory, CIPER, Estrada da Costa, 1499-002, Cruz Quebrada, Lisbon, Portugal.

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