Characteristics and prediction of subclinical hypocalcemia in dairy cows during the transition period using blood analytes

This study aimed to present the characteristics of and to predict subclinical hypocalcemia in dairy cows during the transition period using blood analytes. We examined fluctuations in plasma calcium (Ca), phosphorus (P), bone metabolic markers carboxy-terminal telopeptide of type I collagen (CTX), fibroblast growth factor (FGF23), 1,25(OH)2D3, parathyroid hormone, and other blood biochemical analytes from prepartum week 2 to postpartum day 14 in 116 multiparous high-producing Holstein cows from a free-stall barn dairy farm. With a plasma concentration of Ca <2.0 mmol/L as a criterion for the diagnosis of subclinical hypocalcemia, 64 cows were classified as normocalcemic, and 52 cows as subclinically hypocalcemic. Among the 52 hypocalcemic cows, 50 were detected on postpartum days 1 or 3, and 2 on postpartum day. The subclinically hypocalcemic cows were in a state of low bone turnover in the prepartum period, with low plasma concentrations of Ca and CTX. The subclinically hypocalcemic cows showed signs of a P regulation disorder in the prepartum period. This was marked by high plasma concentrations of P and low concentrations of 1,25(OH)2D3 and FGF23, which is also considered to be the cause of the low bone turnover. The results of a multiple logistic regression model showed that prepartum plasma concentrations of FGF23, CTX, and Ca were ideal predictors of postpartum subclinical hypocalcemia in dairy cows, using the model equation 38.8-0.052*FGF23-0.492*CTX-10.645*Ca, with a score of > 0 considered as an indication of increased risk of subclinical hypocalcemia after calving. The scoring rule had an accuracy of 79.3%, sensitivity of 76.9%, and specificity of 81.3%. The plasma concentrations of FGF23, CTX, and Ca were ideal predictors of postpartum subclinical hypocalcemia in dairy cows.

The Novel Bone Alkaline Phosphatase Isoform B1x Is Associated with Improved 5-Year Survival in Chronic Kidney Disease

Circulating alkaline phosphatase (ALP) is an independent cardiovascular risk marker. Serum bone ALP (BALP) isoforms indicate bone turnover and comprise approximately 50% of total circulating ALP. In chronic kidney disease (CKD), mortality is highest in patients with increased ALP and BALP and low bone turnover. However, not all low bone turnover states are associated with increased mortality. Chronic inflammation and oxidative stress, features of protein energy wasting syndrome, induce cardiovascular BALP activity and fibro-calcification, while bone turnover is suppressed. Circulating BALP isoform B1x is associated with low ALP and low bone turnover and has been exclusively detected in CKD. We investigated the association of serum B1x with survival, abdominal aortic calcification (AAC) score, and aortic pulse wave velocity (PWV) in CKD. Serum ALP, BALP isoforms, parathyroid hormone (PTH), PWV, and AAC were measured repeatedly over 2 years in 68 prevalent dialysis patients. Mortality was assessed after 5 years. B1x was detected in 53 patients. A competing risk analysis revealed an association of B1x with improved 5-year survival; whereas, baseline PWV, but not AAC score, predicted mortality. However, PWV improved in 26 patients (53%), and B1x was associated with variation of PWV over time (p = 0.03). Patients with B1x had lower PTH and total ALP, suggesting an association with lower bone turnover. In conclusion, B1x is associated with time-varying PWV, lower circulating ALP, and improved survival in CKD, and thus may be an indicator of a reduced cardiovascular risk profile among patients with low bone turnover.

Low bone turnover is associated with plain X-ray vascular calcification in predialysis patients

Background Vascular calcification (VC) is a common finding in chronic kidney disease (CKD) patients and predicts subsequent cardiovascular morbidity and mortality in this population. Vascular calcification is linked to disordered mineral metabolism and has been associated with bone histomorphometry changes in CKD. However, data on predialysis patients is scarce. Methods A cross-sectional study was conducted on a cohort of 56 CKD patients not yet on dialysis, who underwent a transiliac bone biopsy for histomorphometric evaluation after double tetracycline labeling. Patients had no previous exposure to calcium salts, vitamin D agents, steroids or bisphosphonates. Vascular calcification was assessed at the time of biopsy, using Kauppila (plain X-ray of the lateral lumbar spine) and Adragão (plain X-ray of the pelvis and hands) scores. Results Vascular calcification was seen in two-thirds of the cohort. Subjects with VC were more likely to be male and have diabetes, and had significantly higher sclerostin and osteoprotegerin circulating levels than those without VC. The histomorphometric analysis showed that bone formation rate was significantly lower in VC compared to non-VC patients. In the multivariable logistic regression analysis, bone formation rate was independently associated with the presence of VC. Conclusions Vascular calcification is highly prevalent in predialysis patients, especially in those with diabetes. The independent association between bone formation rate and VC provides evidence of an important interaction between bone and vessel in CKD. Our results suggest that low bone turnover is a non-traditional risk factor for cardiovascular disease in predialysis patients.

MO568STATIC PARAMETERS OF HISTOMORPHOMETRY FOR THE EVALUATION OF BONE TURNOVER IN RENAL OSTEODYSTROPHY

Background and Aims A full histomorphometric analysis of a transiliac bone biopsy with prior tetracycline labeling remains the gold standard to diagnose renal osteodystrophy. Bone turnover is primarly evaluated by the dynamic parameter bone formation rate, calculated from the incorporation of tetracycline in bone. In cases of failed tetracycline labels, however, an evaluation of bone turnover based on static parameters is warranted. This study investigates the diagnostic accuracy of static histomorphometric parameters for the diagnosis of high and low bone turnover. Method Bone biopsies with prior tetracycline labeling of sufficient quality for a full histomorpometric analysis were included (n = 205). Mean age of participants was 56±13 years, 67% were men, and 22% had diabetes mellitus. Diagnostic accuracy of static histomorphometric parameters for bone turnover was evaluated by area under the receiver operator characteristics curve (AUC) statistics, against the full set of static and dynamic histomorphometric parameters. The cohort was randomly split to allow calculation of optimal diagnostic cutoffs in an exploration cohort (n=105), with subsequent validation in a separate subset of patients (n=100). Results All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover (p &lt; 0.01), and all were significant predictors of both high and low bone turnover (Figure 1). Calculated optimal cutoffs and their sensitivities and specificities in the validation cohort are shown in Table 1. Diagnostic accuracy was very good for high turnover, as the combination of presence of fibrosis with ObPm&gt;5.4%, OcPm&gt;1.5%, and OAr&gt;2.4% provided a correct diagnosis in 94% of patients, with positive (PPV) and negative (NPV) predictive values of 80% and 96%, respectively. Using the same predefined combination, an accuracy of 80% was achieved for low turnover (no fibrosis, ObPm≤1.9% OcPm≤0.9% and OAr≤1.6%), with a PPV of 71% and a NPV of 82%. Conclusion Static histomorphometric parameters provide an acceptable alternative for the diagnosis of high and low bone turnover. In the absence of successful tetracycline labeling, the proposed cutoffs may provide a suitable alternative for the evaluation of bone turnover in renal osteodystrophy.

Prevalence of Mineral Bone Disease in Dialysis Patients

Progressive loss of kidney function in chronic kidney disease (CKD) leads to reduced production of 1-α-(OH)2-D3 (1,25-dihydroxyvitamin D; calcitriol) and abnormal mineral homeostasis leading to bone mineral disorders. The disorder starts with stage 2 CKD but manifests itself as the disease progresses until stage 3 CKD. Material and methods This study was carried out on 61 patients with end-stage renal disease on regular HD at our Centre. After obtaining informed consent, complete blood count, blood urea level, serum creatinine level, albumin level, uric acid level, Ca level, phosphate level, alkaline phosphatase level, and PTH level were done. Results Out of 60 patients 41 (68.33%) were high bone turnover,10 (16.6%) were normal bone turnover whereas 9(15%) were low bone turnover. Conclusion The prevalence of CKD-MBD among dialysis patients is 83.33% at our center and needs proper monitoring by routine investigations including serum phosphate, calcium, vitamin D levels and most importantly i-PTH levels according to guidelines.

Biomarkers of Bone Turnover Identify Subsets of Chronic Kidney Disease Patients at Higher Risk for Fracture

Background We sought to identify biomarkers that indicate low turnover on bone histomorphometry in chronic kidney disease (CKD) patients, and subsequently determined whether this panel identified differential risk for fractures in community-dwelling older adults. Methods Among CKD patients who underwent iliac crest bone biopsies and histomorphometry, we evaluated candidate biomarkers to differentiate low turnover from other bone disease. We applied this biomarker panel to 641 participants in the Health Aging and Body Composition Study (Health ABC) study with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 who were followed for fracture. Cox proportional hazards models evaluated the association of bone mineral density (BMD) with fracture risk and determined whether biomarker-defined low bone turnover modified fracture risk at any level of BMD. Results In 39 CKD patients age 64 ± 13 years, 85% female, with mean eGFR 37 ± 14 mL/min/1.73 m2 who underwent bone biopsy, lower fibroblast growth factor (FGF)-23, higher ɑ-Klotho, and lower parathyroid hormone (PTH) indicated low bone turnover in accordance with bone histomorphometry parameters (individual area under the curve = 0.62, 0.73, and 0.55 respectively; sensitivity = 22%, specificity = 100%). In Health ABC, 641 participants with CKD were age 75 ± 3 years , 49% female, with mean eGFR 48 ± 10 mL/min/1.73 m2. For every SD lower hip BMD at baseline, there was an 8-fold higher fracture risk in individuals with biomarker-defined low turnover (hazard ratio 8.10 [95% CI, 3.40-19.30]) vs a 2-fold higher risk in the remaining individuals (hazard ratio 2.28 [95% CI, 1.69-3.08]) (Pinteraction = .082). Conclusions In CKD patients who underwent bone biopsy, lower FGF-23, higher ɑ-Klotho, and lower PTH together had high specificity for identifying low bone turnover. When applied to older individuals with CKD, BMD was more strongly associated with fracture risk in those with biomarker-defined low turnover.