Risk factors leading to reduced bone mineral density in hemodialysis patients with metabolic syndrome

Abstract

Although metabolic syndrome (MS) is associated with low bone mineral density (BMD) in the general population, it is unknown whether similar associations exist in patients with chronic kidney disease. We investigated risk factors that can lead to low BMD values in hemodialysis patients with MS according to the diagnostic criteria set by International Diabetes Federation (IDF) in this study. A total of 64 patients with MS undergoing hemodialysis and 60 hemodialysis patients who were matched in terms of age, gender, and hemodialysis duration without MS were enrolled in the study. BMD was measured at lumbar vertebra (LV) and femur neck (FN) by performing dual-energy X-ray absorptiometry (DEXA). LV and/or FN-BMD results revealed that, of the hemodialysis patients with MS, 45% had osteoporosis and 48% had osteopenia. On the other hand, of the hemodialysis patients without MS, 42% had osteoporosis and 52% had osteopenia. Low BMD values were observed to be correlated negatively with age, hemodialysis period, and parathormone (PTH) both in the group with MS and in the group without MS. Height, weight, BMI, calcium, phosphorus, alkaline phosphatase, heparin, and vitamin D therapy and urea reduction ratio were not established to be correlated with BMD.

Keywords:

• end-stage renal failure
• metabolic syndrome
• hemodialysis
• bone mineral density

INTRODUCTION

Osteoporosis is a major public healthcare issue as it leads to increased morbidity and mortality. Factors such as later age, female gender, premature gonadal failure, low body weight, sedentary lifestyle, smoking, alcohol consumption, poor calcium intake, and glucocorticoid therapy accelerate bone mineral loss.¹ Vitamin D metabolism is impaired during calcium and phosphate regulation in end-stage renal failure (ESRF). Renal osteodystrophy is associated with elevated morbidity in patients with ESRF. The most significant problems associated with bone metabolism in hemodialysis patients are secondary hyperparathyroidism, osteomalacia, and adynamic bone disease.² They can each be accountable for low bone mineral density (BMD). Moreover, low BMD is also associated with elevated fracture risk.³

Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. The association of MS with higher BMD was explained by the higher BMI in those with MS.⁴

We aimed to investigate the relationship between BMD and age, gender, body mass index (BMI), duration of dialysis, calcium levels, phosphorus levels, alkaline phosphatase (ALP), heparin dose, urea reduction ratio (URR; %), intact parathormone (PTH), and alpha calcidiol therapy in hemodialysis patients established with metabolic syndrome (MS) according to International Diabetes Federation (IDF) diagnostic criteria in this present study.

MATERIALS AND METHODS

This study was conducted in patients with end-stage renal disease undergoing hemodialysis as renal replacement therapy after obtaining the approval of the local ethics committee. A total of 64 (29 females and 35 males) hemodialysis patients with MS and 60 (28 females and 32 males) age, gender, hemodialysis duration-matched hemodialysis patients without MS were enrolled in the study, bringing the total number of patients to 124 (57 females and 67 males). Patients with liver, thyroid, parathyroid, and adrenal insufficiencies; receiving hormone replacement therapy; and having a history, within the last 3 months, of an acute event (cerebral, coronary, etc.), acute infection, major trauma, or surgery requiring anesthesia were excluded from the study, as well as those who did not provide informed consent. None of the postmenopausal women were undergoing hormone replacement therapy. The patients were not established with compression fracture/hip or long bone anamnesis. None of the patients had a history of renal transplantation.

Participants were instructed to fast for the 12 hours prior to study initiation. Demographic and clinical data such as age, gender, health status, and current medications were recorded.

All hemodialysis patients had a dietary intake of 30–35 kcal/kg/day including protein, 1.2 g/kg/day; calcium, 1000–1500 mg/day; phosphorus, 600–700 mg/day; and magnesium, 200–250 mg/day. Certain patients were also receiving calcium acetate, vitamin-B complex, iron supplements, and erythropoietin as phosphorus-binding agents.

Waist circumferences were measured in a standing position during gentle exhaling at the area located midway between the lower costal margin and the iliac crest in the narrowest section. Hip circumferences were measured at the level of the greater trochanter.

Subjects were asked to remove outer garments, except underwear, prior to measurements. The weight and height measurements were performed with a standard error mean of ±0.5 kg and ±0.5 cm, respectively. The BMI was calculated with the weight (kg)/height² (m²) formula.

Blood pressure was measured from both arms in a sitting position after a 10-min rest by placing a proper cuff attached to a mercury sphygmomanometer. Korotkoff I and IV sounds were taken into account. Two subsequent measurements with at least 3-min intervals were obtained and recorded. In the morning, prior to hemodialysis, blood samples were drawn between 8 am and 10 am to assess plasma glucose, serum urea, albumin, total calcium, phosphorus, ALP, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and intact PTH.

Laboratory methods

Plasma glucose levels were measured by Roche Cobas Integra 800 Analysis Device (Mannheim, Germany) based on enzymatic hexokinase method. Fasting glucose levels ≥7.0 mmol/L or plasma glucose levels in oral glucose tolerance test (OGTT) ≥11.1 mmol/L were considered as DM; fasting glucose levels ≥5.5 and <7.0 mmol/L were considered as impaired fasting glucose; and plasma glucose levels in OGTT ≥7.8–11.0 mmol/L were considered as impaired glucose tolerance.

Serum total cholesterol and triglyceride were measured using standard commercial enzymatic kits (CHOD-PAP and GPO-PAP methods; Roche Diagnostics, Mannheim, Germany). HDL-cholesterol levels were measured through the enzymatic colorimetric assay using a direct method (ADVIA 1650/2400; Bayer, Milano, Italy) after separation of cholesterol from non-HDL particles. LDL-cholesterol concentration was calculated according to the Friedewald formula.⁵

The MS was defined according to the IDF definition of MS: the presentation of central obesity (defined as waist circumference ≥90 cm in men and ≥80 cm in women for Asian populations) plus any two of the following risk factors: triglyceride concentration ≥1.70 mmol/L (150 mg/dL), or specific treatment for this lipid abnormality; HDL-cholesterol concentration <1.04 mmol/L (40 mg/dL) in males or <1.30 mmol/L (50 mg/dL) in females, or specific treatment for this lipid abnormality; BP ≥ 130/85 mmHg, or treatment of previously diagnosed hypertension; or fasting plasma glucose ≥5.55 mmol/L (100 mg/dL), or previously diagnosed type 2 diabetes.⁶

Serum urea, albumin, total calcium, phosphorus, and ALP were analyzed with the Technicon RA-XT chemistry system (Bayer, Leverkusen, Germany) using a calorimetric technique. Calcium levels were corrected with respect to albumin concentrations. Calcium, phosphorus, and ALP levels were taken as the mean value of the data in the preceding year. URR was calculated by considering pre- and post-dialysis values. The intact PTH level was measured with the Immulite kit (LKPH1; Diagnostic Products Corporation, Genova, Italy) using a chemiluminescent enzyme immunometric assay.

BMD was measured at lumbar vertebra (LV) and femur neck (FN) by using dual-energy X-ray absorptiometry (DEXA) with Norland XL densitometer. Standard deviation from the mean value of age and gender-matched controls was expressed as Z-score, while the standard deviation from the mean value of younger healthy ones was expressed as T-score. The results were evaluated according to World Health Organization (WHO) osteoporosis criteria.⁷ Therefore, a T-score of −1 to −2.5 was regarded as osteopenia, while a score of −2.5 or lower was regarded as osteoporosis.

Statistical analysis

The Statistics Package for the Social Sciences (SPSS) software (version 11.5) was used for the statistical procedures; and a p-value of <0.05 was considered as statistically significant. The differences between these groups were evaluated through the χ² McNemar's test and Student's t-test was used. All these parameters were re-analyzed through the backward stepwise logistic regression analysis. Pearson correlation coefficient was used to investigate the correlation between BMD measurements and risk factors.

RESULTS

Of the 29 females with MS, 22 were postmenopausal or established with permanent amenorrhea, whereas of the 28 females in the group without MS, 20 were established to be either postmenopausal or with permanent amenorrhea.

ESRF etiologies of the patients with or without MS are presented in Table 1. There was no significant difference between etiological factors (p > 0.05).

TABLE 1.  Primary diseases of the patients in this study

	MS (n = 64)	No MS (n = 60)
Diabetic nephropathy	19	18
Chronic glomerulonephritis	13	11
Hypertensive nephropathy	9	8
Chronic pyelonephritis	7	7
Obstructive nephropathy	5	4
Polycystic renal disease	4	6
Amyloidosis	2	2
Unknown etiology	5	4
Total	64	60

Note: MS, metabolic syndrome.

Statistical comparisons of the groups consisting of hemodialysis patients with or without MS in terms of mean age, gender, mean weight, height, waist circumference, BMI, dialysis duration, weekly heparin dose, weekly alpha calcidiol dose, serum calcium, phosphorus, ALP, PTH, URR, lumbar spine, and total hip BMD T- and Z-scores are presented in Table 2.

TABLE 2.  Demographical characteristics and biochemical data of the patients

	MS (mean ± SD; n = 64)	No MS (mean ± SD; n = 60)	p-Values
Age (years)	54.36 ± 12.2	48.25 ± 14.76	0.432
Gender (female/male ratio)	29/35	28/32	0.765
Weight (kg)	72.66 ± 12.81	61.39 ± 11.43	0.000
Height (cm)	165.8 ± 8.4	163.4 ± 7.6	0.277
WC (cm)	96.28 ± 6.72	76.84 ± 13.88	0.000
BMI (kg/m^2)	26.2 ± 2.36	22.4 ± 2.6	0.0354
Dialysis duration (months)	39.4 ± 19	37.8 ± 22	0.467
Heparin dose (unite/week)	15600 ± 2400	13800 ± 2500	0.386
α-calcidiol dose (mcg/week)	2.6 ± 1.8	2.4 ± 1.4	0.465
Calcium (mg/dL)	9.2 ± 0.8	9.4 ± 0.9	0.784
Phosphorus (mg/dL)	4.9 ± 1.5	4.3 ± 1.3	0.367
ALP (U/L)	148.8 ± 88.6	146.4 ± 91.5	0.968
PTH (mg/dL)	296.8 ± 340.4	288.95 ± 380.9	0.245
URR (%)	64.2 ± 6.8	65.9 ± 7.2	0.456
Lumbar spine BMD (g/cm^2)
T-score	−2.96 ± 1.98	−2.67 ± 1.64	0.896
Z-score	−1.78 ± 0.6	−1.64 ± 0.5	0.453
Total hip BMD (g/cm^2)
T-score	−1.75 ± 1.45	−1.69 ± 1.84	0.673
Z-score	−0.9 ± 0.3	−0.8 ± 0.4	0.654

Note: MS, metabolic syndrome; WC, waist circumference; BMI, body mass index; ALP, alkaline phosphatase; PTH, parathormone; URR, urea reduction ratio; BMD, bone mineral density.

LV and/or FN-BMD results revealed that of the hemodialysis patients with MS, 45% had osteoporosis and 48% had osteopenia. On the other hand, the incidences for osteoporosis and osteopenia in hemodialysis patients without MS were 42 and 52%, respectively. The groups were not observed to be significantly different with respect to osteoporosis and osteopenia (p > 0.05). Furthermore, intragroup and intergroup comparisons did not reveal any significant differences in terms of gender (p > 0.05).

Age was established to be negatively correlated significantly with FN-BMD (r = −0.42; p < 0.05) and LV-BMD (r = −0.42; p < 0.05) both in the group with and in the group without MS. Negative correlation between age and BMD was present for both genders. However, the groups were not observed to be significantly different (p > 0.05).

Similarly, PTH was established to be negatively correlated with LV-BMD (r = −0.53, p < 0.01) and FN-BMD (r = −0.34, p < 0.01) both in the group with and in the group without MS. A strong correlation was noted between LV-BMD and FN-BMD (r = 0.73, p < 0.01).

Likewise, duration of dialysis was observed to be negatively correlated significantly with FN-BMD (r = −0.42; p < 0.05) and LV-BMD (r = −0.42; p < 0.05) both in the group with and in the group without MS. The negative correlation between age and BMD was valid for both genders. However, no significant differences were observed between the groups (p > 0.05).

On the other hand, BMD was not established to be correlated significantly with height, weight, BMI, calcium, phosphorus, ALP, heparin and vitamin D therapy, and URR in either of the groups. No gender-specific differences were observed in the groups, either.

DISCUSSION

This study revealed that of the hemodialysis patients with MS, 45% had osteoporosis and 48% had osteopenia. On the other hand, of the hemodialysis patients without MS, 42% had osteoporosis and 52% had osteopenia. To the best of our knowledge, no study had reported a correlation between MS and BMD in hemodialysis patients in the literature. Therefore, discussion was carried out on studies performing BMD measurements on hemodialysis patients and patients with MS in the general population. There are few studies demonstrating the association between low BMD and fracture risk in hemodialysis patients.^3,8 In the general population, however, each 1-point drop in standard deviation in BMD corresponds to 1.5–3 times higher fracture risk.⁷

Although many studies have reported severely decreased BMD values in hemodialysis patients,^9–15 there are also studies reporting normal or only slightly lower values.^16,17 We observed significantly low BMD values in hemodialysis patients with or without MS in this study, which demonstrated that the drop in BMD values was more significant in hemodialysis patients when compared with age and gender-matched controls. The mean age of hemodialysis patients has been growing higher in recent years. Low BMD values constitute a risk factor also for the normal population at a later age. However, factors other than age also have an impact on reduced BMD values in hemodialysis patients.

The chief cause of low BMD in patients with ESRF is the decrease in bone cortex.¹⁸ Cortical porosity is elevated in hyperparathyroidism.¹⁹ Consequently, it is not unexpected that PTH is a major parameter with an impact on BMD. We observed a negative correlation between BMD and PTH levels both in the group with and without MS in this study. Secondary hyperparathyroidism is the most common form of renal bone disease in hemodialysis patients.¹² A study involving bone histology in hemodialysis patients established that 66% of all histological findings in the bone were associated with high-turnover bone disease. The same study also reported 2.5 times higher PTH levels in hemodialysis patients when compared with peritoneal dialysis patients.²⁰ A number of studies have reported negative correlation between BMD and PTH levels.^9,11,15,21 On the contrary, there are also studies failing to demonstrate a negative correlation between BMD and PTH.^12,17,22,23 Those inconsistent results may be attributed to inadequate patient population size or to the use of methods that measure C-terminal PTH in certain studies.

We established a negative correlation between BMD and age in both of our groups in this study. Age-related bone loss has a major role in the pathogenesis of osteoporosis and bone loss rate may be 1–2% annually in healthy adults over the age of 40 years. In fact, the figure may be as high as 2–4% in the first 5–8 postmenopausal years.¹ However, while certain studies reported no correlation between age and BMD in patients undergoing dialysis,^9,12 others reported a negative correlation only in female patients but did not establish a similar correlation in their male patients.⁸ Taal et al. established a negative correlation between age and BMD in 88 hemodialysis patients whose mean age was calculated to be 58.2 years.¹⁵ Currently, older patients are increasingly being admitted to dialysis and they have better survival rates. Consequently, age-related bone loss will have greater significance for hemodialysis patients in the coming years.

We did not establish a correlation between gender and BMD in either of our groups in this study. Most studies measuring BMD in patients undergoing dialysis did not report data on gender. However, certain studies investigating the gender effect reported BMD values to be lower in female hemodialysis patients.^9,15 On the other hand, there is another study reporting no significant difference between female and male patients in terms of BMD loss.²⁴ We maintain that the conflicting results can be attributed to sample size, dialysis duration, and etiological factors.

The positive correlation between body weight and BMD in the normal population and in patients with MS in the normal population is widely known.^4,25 However, we did not establish a correlation between BMI and BMD in either of our groups in this study. Certain studies^9,15 demonstrated a positive correlation between BMD and body weight or BMI. Another study established this positive correlation in patients with diabetic nephropathy but failed to observe it in patients with chronic glomerulonephritis.²⁶ We maintain that the absence of correlation in this study can be attributed to the fact that the components of MS in our hemodialysis patients were hypertension and blood lipids.

We established negative correlation between hemodialysis duration and BMD in both of our groups in this study. However, we did not establish a correlation between chronic renal failure (CRF) etiologies and BMD in either group. Certain studies conducted with hemodialysis patients have reported negative correlation between dialysis duration and BMD,^9,10,13,21 but others did not observe correlation.¹⁴ Furthermore, while a negative correlation was observed between BMD and dialysis duration in hemodialysis patients with chronic glomerulonephritis, a similar correlation was not established in diabetic patients with nephropathy.²⁶

The association of osteoporosis with calcium intake and vitamin D therapy is controversial. We did not observe a correlation between BMD and vitamin D therapy in either of our groups in this study. It has been demonstrated that calcium supplement therapy administered to postmenopausal hemodialysis patients is effective in preventing bone loss.²⁷

In conclusion, we confirmed the significance of hemodialysis duration and PTH-related bone disease in hemodialysis patients on BMD both for patients with and without MS. Parameters other than hemodialysis duration, PTH, and age (such as dialysis duration, gender, height, weight, BMI, vitamin D therapy, erythropoietin dose, heparin dose, URR, calcium, phosphorus and ALP) were not established to be correlated with BMD in either of our groups. Inconsistent results obtained in various studies concerning the correlation between similar parameters and BMD may be associated with ESRF etiology, sample size, hemodialysis duration, nutritional and environmental factors, use of different methods in BMD measurement, and biochemical tests.

Acknowledgments

This study is the first original clinical study investigating the effective parameters on BMD in hemodialysis patients with MS. We certify that no support has been provided for this study by any organization or institution.