Relationships Among the Metabolic Syndrome,Bone Mineral Density,Bone Turnover Markers,and Hyperglycemia

Abstract

Background:

This study investigated the possible effects of metabolic syndrome on bone mineral density (BMD) and bone turnover markers in Turkish postmenopausal women.

Method:

This prospective case–control study included a total of 230 postmenopausal women, between 45 and 65 years old, including 63 with metabolic syndrome and 167 without metabolic syndrome on the basis of the International Diabetes Federation criteria. The height, weight, body mass index (BMI), waist circumference, hip circumference, and waist-to-hip ratio of each subject were measured. Fasting and nonfasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), calcium, phosphorus, glycated hemoglobin (HbA1c), bone-specific alkaline phosphatase (ALP), 25-hydroxyvitamin D3 [25(OH) D], osteocalcin, and the β-isomerized form carboxy-terminal telopeptide of type I collagen (β-CTx) were measured. Bone mineral densities in the lumbar spine and femoral neck were measured by dual energy X-ray absorptiometry.

Results:

The mean age was 58.49±5.7 years in metabolic syndrome patients and 56.13±5.0 years in patients without metabolic syndrome. There was a statistically significant difference in the age of the patients. The mean BMI was 33.96±5.3 and 30.867±3.8 kg/m² in metabolic syndrome patients and patients without metabolic syndrome, respectively, indicating a statistically significant difference. Serum calcium, osteocalcin, and β-CTx were statistically significantly lower in metabolic syndrome patients. There was no significant difference in the levels of phosphorus, 25-hydroxyvitamin D3, and bone-specific ALP, TSH, and PTH among the patients with metabolic syndrome and without metabolic syndrome. The statistical analysis, after adjusting for age and BMI, revealed no significant difference between the two groups in terms of lumbar and femoral BMD. When the patients in the metabolic syndrome group were split into two groups on the basis of those with a T score −2.5 or less and those with a normal score, a statistically significant difference was identified between the two groups in terms of the fasting blood glucose (FBG) and HbA1c values (P<0.05). Furthermore, a negative correlation was identified between the lumbar T score and the FBG and HbA1c values (P<0.05).

Conclusion:

After adjusting for age and BMI in a comparison of BMD between postmenopausal women with and without metabolic syndrome, it was revealed that metabolic syndrome has no positive or negative effect on BMD. In contrast, a negative correlation was identified between FBG and HbA1c levels and lumbar BMD, suggesting that poor glycemic control may have a negative effect on lumbar BMD in this group of patients.

Introduction

Metabolic syndrome and osteoporosis are medical conditions that cannot be overlooked because both may pose serious problems in advanced age. Metabolic syndrome is a health problem, and its incidence increases with age. It is characterized by abdominal obesity, impaired glucose tolerance, hypertension, and dyslipidemia.¹ A total of 27% of Turkish men and 38.6% Turkish women have been reported to suffer from metabolic syndrome.² In addition, osteoporosis is a condition that is mostly seen in postmenopausal women and at advanced age, with a high morbidity rate as well as mortality.³ Although numerous studies investigating the possible relationship between these diseases have been conducted thus far, controversy still remains.^4,5

In several studies showing that metabolic syndrome may be protective against osteoporosis, positive mechanical and hormonal effects of increased body mass index (BMI) primarily have been emphasized. The main subjects that have been addressed in such studies include extraovarian aromatization-induced increased serum estrogen levels, along with overweight-related mechanical stress on the skeleton, several mediators such as resistin, leptin, adiponectin, and interleukin-6 (IL-6) in the adipose tissue, and increased insulin associated with insulin resistance.^6
–8

On the other hand, there are various studies reporting that metabolic syndrome may be a risk factor for osteoporosis. In one study, the authors suggested that insulin resistance in patients with metabolic syndrome increased the osteolysis of the inflammatory cytokines, which might trigger osteoporosis.⁹ Some have reported that an elevated C-reactive protein (CRP) level was associated with osteoporosis and nontraumatic fracture.¹⁰ Moreover, increased serum lipid levels were reported to play a key role in the pathogenesis of osteoporosis.¹¹ These studies demonstrated that patients with hyperlipidemia, a component of metabolic syndrome, were at higher risk for osteoporosis.

Although there are various studies investigating the effects of metabolic syndrome on bone mineral density (BMD) in the literature, a limited number of studies are available that assess the bone turnover markers in this patient population. To the best of our knowledge, no study investigating the effects of metabolic syndrome on BMD in the Turkish population has been reported. In this study, we investigated the possible effects of metabolic syndrome on BMD and bone turnover markers in Turkish postmenopausal women.

Methods

Study design

This prospective case–control study included a total of 230 postmenopausal women who were randomly admitted to our clinic with ages ranging from 45 to 65 years and outpatients. Patients who were on or received medications affecting the bone metabolism for 6 months, including glucocorticoids, vitamin D supplements, and bisphosphonate hormone replacement therapy; patients with medical conditions affecting bone metabolism, including malignancy, inflammatory diseases, and thyroid disorders; those with diseases restricting physical activity such as stroke or dementia; and those with surgical menopause were excluded. Of the patients, 63 presented with metabolic syndrome and 167 presented without metabolic syndrome, on the basis of the International Diabetes Federation (IDF) criteria. A thorough inspection and systemic examinations were performed in all patients. Chronic diseases and concomitant medications were noted. Smoking status and alcohol intake, regular physical exercise (more than 30 min at one session three times per week on a regular basis), and the amount of daily sunlight exposure were recorded. Postmenopause was defined as the absence of a menstrual cycle for ≥12 months with follicle-stimulating hormone (FSH) levels above 30 mIU/mL.

The study protocol was approved by the ethics committee. The study was conducted in accordance with the principles of the Helsinki Declaration. Informed consent was obtained from all patients.

Diagnosis of metabolic syndrome

The metabolic syndrome diagnosis was made according to the IDF criteria, which state that patients with metabolic syndrome must meet three criteria—central obesity defined with ethnicity-specific values (≥90 cm in men and ≥80 cm in women) plus any two of the following four factors—hypertriglyceridemia (150 mg/dL or specific treatment of lipid abnormality), low high-density lipoprotein cholesterol (HDL-C) (<40 mg/dL for men and <50 mg/dL for women), hypertension (≥135/85 mmHg or previous treatments), and fasting hyperglycemia (≥100 mg/dL) or treated diabetes.¹²

Anthropometric measure

The height and weight of each subject were measured. BMI was calculated as weight (kg) divided by height squared (m²). Waist circumference (WC) was measured midway between the lower rib margin and the iliac crest at the end of a gentle expiration. The hip circumference was measured at the level of the widest circumference over the trochanter major. The waist-to-hip ratio was calculated as the WC divided by the hip circumference. Blood pressure was measured in a sitting position at least two times after 10 min resting.

Bone marker measurements and laboratory testing

A fasting blood specimen was drawn from each subject. Blood samples were collected between 8:00 AM. and 10:30 AM. Fasting blood glucose (FBG), triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), calcium, and phosphorus levels were measured by automated standard methods. Plasma osteocalcin and the β-isomerized form carboxy-terminal telopeptide of type I collagen (β-CTx) were measured via the electrochemiluminescence method using the Cobas^® (Roche, Germany) kit in the Cobas e601^® Analyzer (Roche, Germany). The IDS^® bone-specific alkaline phosphatase (Immunodiagnostic Systems Ltd., United Kingdom) was studied using the enzyme-linked immunosorbent assay (ELISA) kit in the BioTek^® ELISA reader (BioTek Inc., USA). Additionally, 25(OH)D was measured chromatographically using the D3 Waters^® UPLC/MS/MS device (Roche, UK). Glycated hemoglobin (HbA1c) levels were measured by high-performance liquid chromatography (HPLC).

BMD measurement

BMD at the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry. Lumbar spine BMD was defined as the mean of lumbar vertebrae 1–4 (Lunar Dpx-Pro).

Statistical analysis

The statistical analysis was performed using SPSS v.16 software (SPSS Inc., Chicago, IL). Descriptive statistics were expressed in the mean±standard deviation. The chi-squared test was carried out to compare clinical characteristics and qualitative data among the patients. The Student t-test was used to compare normally distributed data and quantitative data among the patients. A Pearson correlation analysis was used in the analysis of correlation, and analysis of covariance (ANCOVA) and logistic regression analyses were performed, adjusting for age and BMI. A P value of <0.05 was considered statistically significant.

Results

Table 1.

Overall Characteristics of Patients on the Basis of Metabolic Syndrome Status

	Metabolic syndrome with n=63	Metabolic syndrome without n=167	P value
Age (year)	58.4±5.7	56.13±5.0	0.02^*
Height (meters)	1.5±0.0	1.5±04	0.127
Weight (kg)	84.1±13.2	78.7±9.0	0.014^*
Body mass index (kg/m²)	33.9±5.3	30.8±3.8	0.001^*
Waist-to-femur ratio (cm)	0.8±0.0	0.8±0.0	0.059
Menopause duration (year)	11.2±6.1	12.0±6.7	0.62
Systolic blood pressure (mmHg)	140.8±18.4	120.6±15.0	0.001^*
Diastolic blood pressure (mmHg)	81.5±7.4	69.7±9.8	0.001^*
Curent smoking	10 (15.9%)	44 (26.4%)	0.163
Regular physical activity	41 (65.1%)	110 (66.0%)	0.914
Daily sunlight exposure (20 min above)	49 (79.2%)	135 (81.1%)	0.492

Values are presented in mean±standard deviation (SD).

P<0.05.

In addition, there was a statistically significant difference in FBG, TGs, and LDL-C and HDL-C levels between metabolic syndrome and patients without metabolic syndrome. Furthermore, serum calcium, osteocalcin, and β-CTx were statistically significantly lower in metabolic syndrome patients. There was no significant difference in the levels of phosphorus, 25-hydroxyvitamin D3, and bone-specific alkaline phosphatase (ALP), TSH, and PTH among the patients with metabolic syndrome and without metabolic syndrome (Table 2).

Table 2.

Laboratory Test Results in Patients With Metabolic Syndrome and Without Metabolic Syndrome

	With metabolic syndrome n=63	Without metabolic syndrome n=167	P value
FBG (mg/dL)	169.7±86.7	87.4±9.1	0.0^*
Total cholesterol (mg/dL)	227.7±37.9	193.9±40.7	0.0^*
HDL (mg/dL)	43.0±8.4	55.1±22.5	0.01^*
LDL (mg/dL)	146.1±33.7	127.5±32.2	0.04^*
Triglycerides (mg/dL)	200.1±72.0	99.3±52.6	0.0^*
25-Hydroxyvitamin D3 (ng/mL)	11.6±6.1	12.4±5.2	0.51
Calcium (mg/dL)	9.4±0.4	9.7±0.4	0.03^*
Phosphorus (mg/dL)	3.6±0.4	3.7±0.6	0.1
Bone-specific ALP (U/L)	18.7±8.9	18.5±8.5	0.9
PTH (pg/mL)	70.4±29.1	65.0±24.2	0.31
TSH (μU/mL)	2.5±8.2	1.4±0.9	0.34
Osteocalcin (ng/mL)	17.6±7.0	21.2±5.8	0.005^*
β-CTx (pg/mL)	327.7±181.7	402.8±46.1	0.022^*

Values are presented in mean±standard deviation (SD).

P<0.05.

FBG, fasting blood glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ALP, alkaline phosphatase; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone; β-CTX, β-isomerized form carboxy-terminal telopeptide of type I collagen.

The mean lumbar (L1–L4) BMD values were 1.053±0.168 and 1.016±0.130 in metabolic syndrome patients and patients without metabolic syndrome, respectively. The mean femoral neck BMD values were 0.935±0,13 and 0.903±0.12 in metabolic syndrome patients and patients without metabolic syndrome, respectively. The lumbar (L1–L4) BMD was found to be significantly higher in the metabolic syndrome group, although the femoral BMD did not differ to any significant level. After adjusting for the effects of age and BMI, the difference between the two groups was eradicated in terms of lumbar BMD (Table 3).

Table 3.

Bone Mineral Density in Patients With Metabolic Syndrome and Without Metabolic Syndrome

	With metabolic syndrome n=63	Without metabolic syndrome n=167	P value
BMD L1 (g/cm²)	1.04±0.12	0.95±0.12	0.11
BMD L2 (g/cm²)	1.10±0.15	1.03±0.15	0.24
BMD L3 (g/cm²)	1.12±0.14	1.04±0.13	0.27
BMD L4 (g/cm²)	1.12±0.17	1.04±0.15	0.31
BMD L1–L4 (g/cm²)	1.05±0.16	1.01±0.13	0.22
BMD femur (g/cm²)	0.93±0.13	0.90±0.12	0.14

Values are presented as mean±standard deviation (SD).

BMD, bone mineral density.

When metabolic syndrome patients were divided into two subgroups including those having normal T scores and those with T scores −2.5 or less, there was no statistically significant difference in the BMI, waist-to-hip ratio, regular physical activity, daily sunlight exposure, smoking status, duration of menopause, HDL-C, LDL-C, TGs, calcium, phosphorus, PTH, TSH, 25-hydroxyvitamin D3, β-CTx, bone-specific ALP, nonfasting blood glucose, and osteocalcin among metabolic syndrome patients and patients without metabolic syndrome (Table 4).

Table 4.

Relationship of Metabolic Syndrome with T Scores and Other Variables: Metabolic Syndrome Patients n=63

	T L1–L4≤–2.5 n=16	T L1–L4>–2.5 n=47	P value	T femur≤–2.5 n=13	T femur>–2.5 n=50	P value
Age	57.8	58.7	0.2	58.5	58.7	0.2
BMI (kg/m²)	33.7	34.1	0.3	33.6	34.3	0.3
Waist-to-neck ratio	0.9	0.8	0.2	0.9	0.8	0.3
Menapouse duration (year)	11.4	11.9	0.7	13.4	11.2	0.1
Total cholesterol (mg/dL)	224.4	228.2	0.7	228.4	227.3	0.8
HDL (mg/dL)	43.1	43.0	0.9	43.0	43.0	0.4
LDL (mg/dl)	141.7	148.6	0.7	143.6	148.3	0.6
Triglycerides (mg/dL)	199.4	200.5	0.9	200.2	200.1	0.5
Calcium (mg/dL)	9.4	9.4	0.9	9.4	9.4	0.6
Phosphorus (mg/dlL)	3.5	3.6	0.1	3.5	3.6	0.2
PTH (pg/mL)	72.4	69.1	0.8	72.0	69.0	0.5
TSH (μU/mL)	2.5	2.5	0.7	2.4	2.5	0.4
25-Hydroxyvitamin D3	11.4	11.8	0.4	10.5	11.9	0.3
β-CTx (pg/mL)	316.3	340.2	0.4	331.1	320.3	0.4
FBG (mg/dL)	200.9	140.8	0.003^*	162.4	170.4	0.5
Bone-specific ALP (U/L)	20.6	16.7	0.1	19.4	17.6	0.4
Osteocalcin (ng/mL)	16.8	18.7	0.2	18.3	16.2	0.3
HbA1c (%)	9.0	7.4	0.005^*	7.8	8.3	0.7

P<0.05.

BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone; β-CTX, β-isomerized form carboxy-terminal telopeptide of type I collagen; FBG, fasting blood glucose; ALP, alkaline phosphatase; HbA1c, glycated hemoglobin.

In the metabolic syndrome group, the mean FBG level was 200.9±42.9 in patients with a lumbar T score at or below −2.5 and 140.8±28.2 in patients with normal lumbar T scores; the difference between the groups was statistically significant (P=0.003). The mean HbA1c level in the metabolic syndrome group was 9.0±2.4 in patients with a lumbar T score at or below −2.5 and 7.4±1.8 in patients with a normal lumbar T score; the difference between the groups was statistically significant (P=0.05). The lumbar BMD values were negatively correlated with the HbA1c values and FBG in patients with metabolic syndrome (P=0.003, r=−0.587, and P=0.008, r=−0.412, respectively).

In the metabolic syndrome group, the mean FBG level was 162.4±2.8 in patients with a femoral T score at or below −2.5 and 170.4±1.4 in patients with normal femoral T scores; the difference between the groups was not statistically significant (P=0.5). The mean HbA1c level was 7.8±2.1 in patients with a femoral T score at or below −2.5 and 8.3±2.3 in patients with normal femoral T scores; the difference was statistically insignificant (P=0.7).

Discussion

In the present study, although the lumbar and femoral BMD values were found to be higher in patients with metabolic syndrome, the statistical analysis performed after adjusting for age and BMI revealed no significant difference between the groups in terms of lumbar and femoral BMD values. There are contrasting opinions in literature related to the effects of metabolic syndrome on BMD.^13

–16 Von Muhlen et al.¹³ reported higher BMD values of the lumbar spine, femoral neck, and total hip in both women and men with metabolic syndrome. In another study including 1013 postmenopausal women and 495 men with metabolic syndrome, Hernandez et al.¹⁴ found higher BMD values of the lumbar spine and femoral neck in women. However, the majority of studies reporting higher BMD values in metabolic syndrome showed that the difference between men and women could be excluded with adjusted BMI ratios.¹⁵ In the present study, the difference was eradicated after adjusting for age and BMI. On the other hand, several studies suggested that there was no difference in BMD values among metabolic syndrome patients and patients without metabolic syndrome. In a study including 2475 women, Hwang et al.¹⁶ reported that lumbar BMD values were lower in women with metabolic syndrome. However, a wide age range, varying between 21 and 94 years, was a major limitation to this study. In addition, Kim et al.¹⁷ found similar femoral neck BMD values among age-matched metabolic syndrome men and women who were diagnosed on the basis of American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) criteria. According to the adjusted BMI ratio, femoral neck BMD values were higher in metabolic syndrome patients diagnosed on the basis of the IDF criteria, compared to individuals without metabolic syndrome. In a meta-analysis, Zhou et al.¹⁸ showed that metabolic syndrome was a risk factor for osteoporosis in men, but not in women.

There are a limited number of studies reporting reduced bone turnover markers in obesity and diabetes, two components of metabolic syndrome.^19,20 In addition, a few studies suggesting an association between bone turnover markers and metabolic syndrome are available in the literature.^21,22 In particular, some authors have shown that male patients with metabolic syndrome had lower osteocalcin.²¹ The majority of the studies demonstrated that most metabolic syndrome patients had reduced osteocalcin values, irrespective of sex.^20,22 One study showed that osteocalcin played a major role in the lipid and glucose metabolism, and patients suffering from obesity and impaired glucose tolerance had lower osteocalcin.²³ In another study, the authors found that osteocalcin was associated with BMI, WC, FBG, and systolic blood pressure and played a key role in the pathogenesis of metabolic syndrome.²⁴ Consistent with these findings, we also observed significantly lower osteocalcin levels in metabolic syndrome patients.

As in many studies, we also suggest a possible relationship between osteocalcin and metabolic syndrome. Induction of reduced bone turnover due to the disease is one of the possible explanations. However, at least for osteocalcin, the relationship can be converse: Bone-synthesized osteocalcin may influence glucose metabolism. Similarly, osteocalcin levels were found to be significantly lower in patients with metabolic syndrome in the present study.

Furthermore, there are a limited number of studies investigating the β-CTx levels in metabolic syndrome in the literature. Bezerra et al.²² found no significant difference in β-CTx levels among metabolic syndrome patients and individuals without metabolic syndrome. In addition, these levels were also lower in this patient population, as evidenced by the MINOS study. However, necessary adjustments were performed in terms of age, BMI, height, leisure physical activity, physical activity at work, physical performance, education status, smoking status, alcohol intake, serum concentrations of 17β-estradiol, and 25(OH)D, β-CTx levels returned to normal.²¹ In our study, we found lower serum β-CTx levels in women with metabolic syndrome than patients without metabolic syndrome. This can be attributed to the fact that the study population consisted of postmenopausal women, compared to most studies including predominantly male patients.

In our study, there was no significant difference in the 25-hydroxyvitamin D3 levels of patients with metabolic syndrome. A review of the literature revealed that vitamin D deficiency increased the risk for metabolic syndrome; therefore, risk was reduced by using vitamin D supplements.²⁵ Furthermore, there is growing evidence that vitamin D may play a key role in maintaining glucose balance. 1,25-Dihydroxy vitamin D3 was reported to increase insulin production and secretion by reducing insulin resistance.²⁶ Vitamin D also accelerates proinsulin–insulin conversion. Studies have revealed the presence of calbindin, a regular vitamin D protein, in the β-cells of the pancreas.²⁷ Therefore, vitamin D deficiency is believed to be a risk factor for metabolic syndrome and type 2 diabetes mellitus. In our study, we observed lower 25-hydroxyvitamin D3 levels in patients with metabolic syndrome; however, these levels did not reach statistical significance. Because this was a cross-sectional study, the patients' 25-hydroxyvitamin D3 levels before the diagnosis of metabolic syndrome were not available. However, the lower 25-hydroxyvitamin D3 levels in this group of patients when compared to the other group suggest that 25-hydroxyvitamin D3 may be playing a role in the etiology of metabolic syndrome, although further studies are required in this regard.

Moreover, we found statistically significantly higher FBG and HbA1c values in patients with lumbar T scores −2.5 or less. The literature data demonstrated that lumbar BMD values were positively correlated with FBG in women, whereas there was a negative correlation between these values and FBG in men.¹³ A negative correlation was found between the FBG and BMD values of patients with metabolic syndrome. Another study showed a correlation between both hip and lumbar BMD values and FBG.²⁸ In another study including diabetic women, bone loss was more common in those with HbA1c ≥7 compared to those with HbA1C<7.²⁹ The authors suggested that reduced BMD values in patients with increased HbA1c and blood glucose might contribute to the impaired blood glucose, and thereby, bone mineral loss. As shown in our study, FBG and HbA1c were significantly associated with the amount of lumbar bone loss. Therefore, we believe that prolonged impaired glucose regulation may have a more significant effect on BMD than mechanical and hormonal effects of obesity in patients with metabolic syndrome.

Limitations of the study include the lack of assessment of diet composition and lack of information about urinary calcium excretion.

In conclusion, significant differences were not identified between patients with and without metabolic syndrome in terms of lumbar and femoral BMD after adjusting for age and BMI. The bone turnover markers osteocalcin and β-CTx were found to be lower in patients with metabolic syndrome. The presence of a negative correlation between fasting blood glucose, HbA1c values, and lumbar BMD suggests that poor glycemic control may have a negative effect on lumbar BMD, but further studies are needed to verify this possibility.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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