Do metabolic syndrome and its components have an impact on bone mineral density in adolescents?

A literature review was performed. The following electronic databases were searched for articles published over a period of 10 years (January 2004 to June 2015), without language restrictions: Scientific Electronic Library Online (SciELO), Latin American and Caribbean Health (LILACS), Medline, PubMed, Scopus, and Cochrane Library.

The following MeSH terms were used alone or in combination: “metabolic syndrome or metabolic syndrome X or plurimetabolic syndrome or MetS or cardiometabolic risk factors or cardiovascular disease or cardiovascular disease risk factors” or “abdominal obesity or waist circumference” or “hypertriglyceridemia” or “HDL cholesterol” or “diastolic blood pressure or systolic blood pressure” or “fasting glucose” and “bone densities or bone mineral density or bone mineral densities or density, bone mineral or bone mineral content or bone mineral contents or bone density or physiological calcification or bone mineralization”, and “adolescents or adolescence or teens or teen or teenagers or teenager or youth or youths”.

Human studies on the association between MetS and bone mass, regardless of sample size, were included if they met the following criteria: overweight adolescents with cardiometabolic risk factors (waist circumference, HDL cholesterol, triglycerides, diastolic blood pressure, systolic blood pressure, fasting glucose) and aged ≥ 10 years. We considered cohort studies as well as cross-sectional studies. The latter is an anticipation of not finding many prospective studies with a control group. BMD or bone mineral content (BMC) or bone area was measured by dual-energy X-ray absorptiometry (DXA). Comments, letters, and articles containing only the abstracts without the full text were excluded.

At the time of the initial database search twenty studies were identified and selected to be included in the review based on the predefined inclusion criteria. After reading the titles and abstracts, 14 studies that did not meet the inclusion criteria for the review were excluded: age of the study population < 10 years, absence of groups of adolescents with excess weight, lack of comparison between eutrophic and overweight adolescents, absence of cardiometabolic risk factors, use of other methods for the evaluation of BMD, BMC or bone area, and presence of other diseases or syndromes associated with MetS.

Literature reviews on the relationship between a diagnosis of MetS and risk factors during puberty and BMD in adolescents are sparse [4, 5, 7, 14‐16]. Table 1 shows the results of some studies on the topic found in the scientific literature according to date of publication and interest in investigating the risk factors of metabolic syndrome, with bone mass evaluated through densitometry in adolescents.

Afghani et al. [15] studied a cohort of overweight Latin American children and adolescents with a family history of type 2 diabetes mellitus. The authors observed that total body BMC was negatively correlated with the presence of markers of insulin resistance; however, they did not evaluate the effects of other MetS components on bone mass. Similar findings have been reported by Pollock et al. [16] who evaluated total body BMC and BMD in overweight prepubertal children with and without pre-diabetes. These authors observed a significant reduction in both BMC and BMD in the group with pre-diabetes and hyperinsulinemia. In a subsequent study, Pollock et al. [4] compared bone mass between overweight adolescents (14 to 18 years) with and without cardiometabolic risk factors. In that study, BMC was reduced by 5.4% in adolescents that had at least one component of MetS compared to those without any risk factor, and by 6.3% when two or more risk factors were present. The authors found no correlation between elevated triglyceride levels and BMC; however, increased waist circumference, increased visceral fat tissue, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) showed significant negative correlations with total body BMC. In contrast, HDL-cholesterol and total energy intake were positively associated with BMC. In a comment on the study of Pollock et al. [4], Kalkwarf [17] emphasized that these findings were only detected after adjusting total body BMC for fat-free soft tissue mass, assuming that, if the crude BMC values were not adjusted, they would misleadingly indicate that bone mass increases with increasing body weight, a situation previously reported in the literature.

The results published by Mosca et al. [18] corroborate these findings by demonstrating a negative correlation between BMD of overweight, obese or extremely obese adolescents and the percentage of fat mass determined by DXA. The authors concluded that the higher the body fat percentage of adolescents, the lower the BMD and BMC [18]. Complementing these considerations, it should be emphasized that the prevalence of MetS is higher among extremely obese adolescents [19].

Lawlor et al. [5] conducted a cross-sectional study involving a sample of 2305 adolescents in an attempt to demonstrate associations of markers related to insulin resistance (fasting glucose and insulin), triglycerides and HDL-cholesterol with BMD. Controlling for the covariates age, height and pubertal stage in multivariate analysis, the authors found no significant correlation between fasting glucose and BMD. Triglycerides were positively correlated with BMD, BMC and bone area in boys. HDL-cholesterol showed an inverse correlation with BMD, BMC and bone area in both genders. After adjusting for fat mass, fasting insulin in boys was inversely correlated with bone mass. According to these authors, this finding after adjustment for fat mass should be treated with caution and further prospective studies are needed to replicate and explore the results.

A recent study published by Brazilian researchers found a reduction in BMD at different sites in overweight adolescents with MetS when compared to adolescents in the same nutritional condition, but without MetS. Furthermore, adolescents with two or more risk factors for MetS exhibited a significant reduction in bone mass compared to those with no or only one risk factor. Among the MetS components, waist circumference was the determinant factor for BMD reduction [7].

It can be observed that the majority of the studies found were transversal with evaluation of bone densitometry through DXA. In relation to bone histomorphometry, quantitative histological evaluation of calcified bone biopsy performed to obtain information on remodeling and bone structure, a recent experimental study was detected, being constructed to evaluate, among other parameters, the bone histomorphometry of the tibia and vertebra of experimental animals, in the growth phase and mature, who received a diet rich in saturated fat and sucrose (HFS), against animals considered controls, who received diet chow. The authors concluded that the animals submitted to HFS developed a phenotype characterized by excess visceral fat, which presented through increased abdominal circumference and body weight, non-alcoholic hepatic steatosis, and a 334% increase in basal insulinemia in those in the growth phase and 86% in mature rats, indicating insulin resistance, alterations that resembled metabolic syndrome comorbidities. The mature rats maintained in this scheme also developed pressure alterations and a reduction in HDL cholesterol. In addition, after 27 weeks of follow-up, the animals presented a reduction in active osteocalcin (OC). These animals also presented reduced calcemia and increased phosphataemia, in addition to a reduction in the bone surface, thickness of the osteoid, with more important alterations in the vertebral bones than in the tibia, since these suffered the impact of the load. The authors proposed that metabolic syndrome caused by dietary HFS intake increased the porosity of the cortex of the tibia [20].

The period of puberty is characterized by the occurrence of a fundamental process, i.e., the maximum acquisition of BMC [12, 21‐24]. Bone tissue is composed of cells, called osteoblasts and osteoclasts, minerals (calcium and phosphorus), and an organic matrix consisting of collagen and non-collagen proteins. Osteoblasts synthesize and mineralize the protein matrix, while osteoclasts promote bone resorption, maintaining the bone tissue in a constant process of remodeling. During childhood and adolescence, the rate of bone formation exceeds that of bone resorption, favoring bone acquisition [22, 25]. Approximately 40 to 45% of adult bone mass is acquired during adolescence [26]. In this respect, periods of skeletal growth, especially during adolescence, are fundamental for peak bone mass acquisition and to reduce the risk of developing skeletal morbidities such as osteopenia/osteoporosis and fragility fractures in old age [13, 14, 21, 27]. In both genders, peak bone mass acquisition occurs around seven or eight months after maximum longitudinal bone growth (growth spurt) as a result of high concentrations of hormones [22, 24, 25, 28, 29].

The occurrence of low bone mass in children and adolescents has been identified in recent years and has raised the interest of the scientific community [4, 30]. On the one hand, there is growing awareness that bone mineral mass acquired at the end of growth and its development are crucial for reducing the risk of osteoporosis in the future. On the other hand, osteoporosis is increasingly more prevalent and also occurs in young patients, since BMD in these age groups depends on peak bone mass acquired by the end of the second decade of life [31].

The increase in recent decades in the frequency of fractures in childhood from 35% to 65% has raised concerns that the current lifestyle is compromising early bone health [30]. Bone densitometry detects bone mass losses of less than 5%. The interpretation of DXA results in the pediatric population is a challenge because of the changes in bone size and geometry that occur during growth and child development. Adequate interpretation of the results should take into consideration skeletal maturity, pubertal development, ethnic background, weight, and height of the patient [25].

The presence of central obesity, defined by increased waist circumference, and at least two of the following four criteria are necessary for the diagnosis of MetS: triglyceride elevation (≥150 mg/dL); reduction in HDL-cholesterol (<40 mg/dL); arterial hypertension (SBP ≥ 130/DBP ≥ 85 mmHg); and fasting hyperglycemia (blood glucose ≥100 mg/dL), or previously diagnosed type 2 diabetes. [1].

According to Nóbrega et al. [7], the prevalence of MetS was 14% among 271 adolescents, being 13.29% and 15.93% for female and male adolescents respectively. In relation to the components of MetS, there was a higher prevalence in the increase in waist circumference (67.82%), reduction in HDLc (32.09%), Hypertension (22.62%), Hypertriglyceridemia (19.78%), and Hyperglycemia (3.37%).

Within the global context of an increasing prevalence of obesity and other cardiovascular risk factors in children and adolescents, the role of MetS is particularly important, however, despite this, it has been little investigated in the literature. In addition to the health problems already documented in the scientific literature, previous studies have provided indicators of a relationship between MetS and bone mass in the young and adult population, but the results are still inconsistent [3, 4, 6, 7].