Inverse association between bone microarchitecture assessed by HR-pQCT and coronary artery calcification in patients with end-stage renal disease

doi:10.1016/j.bone.2014.03.048

Bone

Volume 64, July 2014, Pages 33-38

https://doi.org/10.1016/j.bone.2014.03.048 Get rights and content

Highlights

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Bone loss and coronary artery calcification (CAC) are common in renal failure.
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Bone microarchitecture and CAC were studied in dialysis patients.
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The methods used were HR-pQCT, DEXA and coronary calcium scores (Agatston).
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Bone microarchitecture associates with CAC independent of patient age and gender.

Abstract

It is a matter of debate whether vascular calcification and bone loss are simultaneously occurring but largely independent processes or whether poor bone health predisposes to vascular calcification, especially in patients with kidney disease. Here we investigated the association between the changes of microarchitecture in weight bearing bone and the extent of coronary artery calcification in patients with chronic renal failure.

The bone microarchitecture of the tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT), bone mineral density using dual X-ray absorptiometry (DXA) of the lumbar spine, femoral neck and distal radius as well as coronary artery calcification using multi-slice CT and reported as Agatston score were measured in 66 patients with end-stage renal disease on chronic hemodialysis. Markers of bone turnover, vitamin D status and intact parathyroid hormone (iPTH) were assessed.

CAC score was found to be < 100 in 39% and ≥ 100 in 61% of patients. The median [95% CI] total CAC score was 282 [315–2587]. By univariate analysis, significant correlations between CAC and age (R = 0.52, p < 0.001), weight (R = 0.3, p < 0.01) and serum cross laps (CTX, R = − 0.39, p < 0.01) were found, and parameters of bone microarchitecture were numerically but not significantly lower in patients with CAC scores ≥ 100. In multivariate analysis stratifying for gender and correcting for age, tibial density (D_tot) and bone volume/total volume (BV/TV) were significantly lower in patients with CAC scores ≥ 100 (p < 0.05 for both).

Low trabecular bone volume and decreased cortical bone density are associated with coronary artery calcification in dialysis patients.

Introduction

Chronic kidney disease is a major cardiovascular risk factor [1]. Mortality is approximately 5-fold increased in patients with end-stage renal disease requiring dialysis treatment compared to the general population, with cardiovascular disease being the most common cause of death [2], [3]. Vascular calcification occurs early and progresses rapidly in patients on dialysis [4], [5], and coronary artery calcification (CAC) is an independent risk factor for mortality in end-stage renal disease patients [6], [7]. Although the excessively high incidence and prevalence of vascular calcification are well known, the pathophysiologic mechanisms leading to accelerated vascular calcification are still incompletely understood. The so-called “non-traditional” vascular risk factors seem to become more important for the development of cardiovascular disease as renal function declines. Disorders in mineral and bone metabolism are thought to contribute significantly to cardiovascular morbidity in renal patients [8]. Currently, data on the relationship between bone health and vascular calcification are controversial. An association between bone mineral density and vascular calcification has been reported in the general population [9], [10], [11] as well as in patients with end-stage renal disease [12], [13]. Additionally, correlations between bone turnover or bone volume and vascular calcification have been reported for iliac bone biopsies taken from dialysis patients [14], [15]. However, other studies did not find a relationship between bone parameters and vascular calcification in the general population [16], [17], [18] or renal patients [19], [20].

So far, studies investigating the relationship between bone and vascular calcification had to rely on rather insensitive methods such as conventional bone mineral density measurements using dual X-ray absorptiometry (DXA) or involved invasive bone biopsies to obtain sufficient information on bone microarchitecture [9], [10], [11], [14], [15]. With high-resolution peripheral quantitative computed tomography (HR-pQCT), detailed information on bone microarchitecture can be obtained non-invasively [21]. Due to its high resolution (approx. 82 μm), HR-pQCT allows for visualization of trabecular and cortical structures. Other methods used so far, such as quantitative computed tomography (qCT), lack the ability to study the trabecular compartment of bone in detail. Similar to histomorphometric analysis of bone biopsy samples, static bone parameters such as bone volume or trabecular number can be obtained with HR-pQCT. Recently, HR-pQCT measurements were reported to be useful in identifying renal patients with a history of low trauma fracture, which underscores the utility of HR-pQCT in this population [22], [23].

The aim of this study was to investigate the association between bone microarchitecture measured by HR-pQCT and coronary artery calcification assessed by computed tomography in end-stage renal disease patients.

Section snippets

Patients

All subjects were recruited from the hemodialysis center of the Medical University Vienna. A chart review was performed for demographic data, dialysis duration, calcium and vitamin D intake, phosphate binder or calcimimetic therapy, previous renal transplantations, intake of oral anticoagulants and other aspects of the patients' medical history. Patients with a history of bisphosphonate use within 5 years prior to study entry were excluded from participation. Dialysis duration was defined as the

Bone mineral density by dual-energy X-ray absorptiometry

Areal bone mineral density measurements (aBMD) were performed with dual-energy X-ray absorptiometry on a QDR-4500 scanner (Hologic, Waltham, MA), using the manufacturer's recommended standard procedures for the postero-anterior lumbar spine at L₁–L₄, the distal radius (total) and the proximal femur at the femoral neck, trochanter, intertrochanteric region, total region and Ward's triangle. Patients underwent conventional lateral x-ray imaging of the lumbar spine to exclude falsely elevated aBMD

Patient characteristics

Of 66 patients studied, 62 were Caucasian, 3 were Indian and 1 was African. Causes of renal failure were glomerulonephritis (17%), diabetic nephropathy (15%), hypertensive/vascular disease (11%), polycystic kidney disease (5%), pyelonephritis/vesico-ureteral reflux (5%) and other known (24%) or unknown (23%) diseases. Twenty patients had undergone previous kidney transplantation. Twelve patients had received one kidney transplant, 5 patients had received 2 transplants and 3 patients had

Discussion

To our knowledge, this is the first study investigating the association between bone microarchitecture measured by HR-pQCT and coronary artery calcification in patients with end stage renal disease. The key finding of this study is that patients with CAC scores ≥ 100 have a lower trabecular bone volume and total density of the tibia compared to patients with lower CAC scores, independent of sex and age.

It is currently a matter of debate whether increased vascular calcification in chronic kidney

Disclosure statement

The authors have nothing to disclose.

Acknowledgments

Preliminary data from this study were presented in abstract form at the ISN Nexus Symposium “Bone and the Kidney” in Copenhagen, Denmark, September 20–23, 2012.

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In a longitudinal study measuring CAC and BMD in older dialysis patients, Malluche et al.8 showed that patients with the highest BMD loss had the greatest increase in CAC. Similar, albeit cross-sectional, studies have shown that both patients with CKD and those on dialysis who have a lower BMD have higher CAC scores10,22-27 and a higher all-cause mortality.22 Importantly, the average age of patients in these studies was above 65 years, when age-related osteoporosis may have contributed to these processes.
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This was a multicenter longitudinal study in children and young people (5–30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores.
One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P = 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P = 0.09). Median cIMTz and PWVz showed nonsignificant increase (P = 0.23 and P = 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R² = 0.48, β = 0.40, P = 0.03). Young people who demonstrated statural growth (n = 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n = 24).
This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.
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Simultaneous assessment of bone and LLAC at the distal tibia in our study revealed that lower cortical BMD and worse cortical bone microstructure were associated with LLAC severity. Our findings are similar to a study by Cejka et al. which found that high CAC was associated with lower BMD and trabecular bone volume at the distal tibia using HRpQCT in 66 dialysis patients [73]. The study and ours found no association between VC and DXA BMD.
Vascular calcification (VC) and renal osteodystrophy are important complications of advanced chronic kidney disease (CKD). High resolution peripheral quantitative computed tomography (HRpQCT) is able to assess bone microstructure in renal osteodystrophy and lower leg arterial calcification (LLAC) is usually seen as an incidental finding. LLAC can be a useful quantitative assessment of VC in CKD but the relationship between LLAC and vascular biomarkers and bone is unknown. We aimed to assess the relationship between LLAC and biomarkers, bone turnover and microstructure.
In this cross-sectional study, fasting blood samples were taken from 69 CKD stages 4-5D patients and 68 healthy controls. HRpQCT of distal tibia and radius were performed. 43 CKD patients had trans-iliac bone biopsy after tetracycline labelling.
LLAC was more severe in CKD than controls (median [IQR] 1.043 [0.05–16.52] vs 0 [0–0.55] mgHA, p < 0.001). CKD patients with diabetes (28%) had significantly higher LLAC compared to non-diabetic CKD (median [IQR] 24.07 [3.42–61.30] vs 0.23 [0–3.78] mgHA, p < 0.001). LLAC mass in CKD correlated with serum phosphate (rho = 0.29, p < 0.05), calcium x phosphate product (rho = 0.31, p < 0.05), intact parathyroid hormone (rho = 0.38, p < 0.01), intact fibroblast growth factor-23 (iFGF23) (rho = 0.40, p = 0.001), total alkaline phosphatase (rho = 0.41, p < 0.001), bone alkaline phosphatase (rho = 0.29, p < 0.05), osteocalcin (rho = 0.32, p < 0.05), osteoprotegerin (rho = 0.40, p = 0.001) and dephosphorylated-uncarboxylated matrix Gla protein (rho = 0.31, p < 0.05). LLAC in CKD also correlated with worse distal tibia cortical bone mineral density, thickness and porosity. No association was found between LLAC and bone turnover, mineralization or volume on biopsy in CKD. In multivariate analysis, only age, diabetes, iPTH and iFGF23 were independently associated with LLAC in CKD.
High levels of PTH and FGF23, along with older age and the presence of diabetes may all play independent roles in the development of LLAC in advanced CKD.
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Peripheral blood samples were drawn from 593 patients undergoing clinically indicated coronary angiography. CAD severity was assessed by the presence of significant coronary artery stenosis (CAS) as well as an ordinal categorical variable. Subjects were followed for all-cause death over a median follow-up of 40 months.
OCN + early CEPC counts (square-root transformed) were independently associated with the presence of significant CAS [odds ratio (OR) per standard deviation (SD) increment: 1.389, 95% confidence interval [CI]: 1.131 to 1.707, p = 0.002). Similar association was observed with an increase in levels of CAS (OR: 1.353, 95% CI: 1.157 to 1.582, p < 0.001). There was a weak tendency between OCN + early CEPC counts and all-cause mortality (p = 0.090), whereas the highest decile of OCN + early CEPC counts had a 2.991-fold increased risk of all-cause death (p = 0.047).
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Kim et al. [28] found no significant association of BMD, determined by DXA, with CAC when adjusting for age and comorbid conditions. Both Malluche et al. [24] and Cejka et al. [23] described independent associations of CAC only with volumetric BMD, whereas no independent associations with DXA were found. In accordance with both studies, we demonstrate here the superiority of volumetric BMD over BMD, determined by DXA, at different skeletal sites for the prediction of CAC score.
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major complication of end-stage renal disease (ESRD). Reduced bone mineral density (BMD) is associated with vascular calcification. Here we investigated associations between vertebral bone density (VBD) and coronary artery calcification (CAC), quantified by cardiac computed tomography (CT), and BMD quantified by dual-energy X-ray absorptiometry (DXA), and their relations with mortality.
In 231 ESRD patients (median age 56 years, 63% males) comprising incident dialysis patients, prevalent peritoneal dialysis patients and recipients of living donor kidney transplant, VBD (Hounsfield units, HUs) and CAC scores (Agatston units, AUs) were quantified by cardiac CT, and, in 143 of the patients, BMD was measured by DXA of total body. Metabolic and inflammation biomarkers potentially linked to CKD-MBD were also analysed.
Patients with low tertile of VBD were older and had more often cardiovascular disease (CVD), and higher HbA1c (non-diabetics), interleukin-6 and CAC score. Low VBD was independently associated with higher CAC score (> 100 AUs) after adjustment for age, gender, diabetes, CVD, inflammation and cohorts. In Cox proportional hazards analysis, low VBD was independently associated with all-cause mortality after adjustment for age, gender, diabetes, CVD, inflammation and subjective global assessment (SGA). The root mean-squared error of prediction (RMSE) showed a good degree of association between VBD and BMD evaluated from DXA. In receiver-operator characteristics curve (ROC) analysis, lower VBD was more strongly associated with higher CAC score and all-cause mortality than BMD evaluated from DXA.
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Original Full Length ArticleInverse association between bone microarchitecture assessed by HR-pQCT and coronary artery calcification in patients with end-stage renal disease

Highlights

Abstract

Introduction

Section snippets

Patients

Bone mineral density by dual-energy X-ray absorptiometry

Patient characteristics

Discussion

Disclosure statement

Acknowledgments

Kidney Int

Bone Miner

Am J Kidney Dis

Kidney Int

J Am Coll Cardiol

J Am Coll Cardiol

Am J Kidney Dis

Kidney Int

Kidney disease as a risk factor for development of cardiovascular disease

Hypertension

Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization

N. Engl. J. Med.

USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis

N Engl J Med

Natural history of vascular calcification in dialysis and transplant patients

Nephrol Dial Transplant

Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis

Clin Exp Nephrol

Review article: getting the balance right: assessing causes and extent of vascular calcification in chronic kidney disease

Nephrology (Carlton)

Bone mineral density and aortic calcification: the study of osteoporotic fractures

J Am Geriatr Soc

Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women

Calcif Tissue Int

Association among serum fetuin-A level, coronary artery calcification, and bone mineral densitometry in maintenance hemodialysis patients

Artif Organs

Original Full Length Article
Inverse association between bone microarchitecture assessed by HR-pQCT and coronary artery calcification in patients with end-stage renal disease