Beta CTX Research Articles

THU433 Spontaneous Vertebral Fractures In The Setting Of Prolonged CRRT

Abstract Disclosure: F. Akanbi: None. M. Kutahyalioglu: None. P. Gogineni: None. S. Raja: None. Introduction: Bone resorption and hypercalcemia due to prolonged immobilization are known complications in critically ill patients. This is more pronounced in patients with high bone turnover rates such as in secondary hyperparathyroidism. In this case report, the chelation of calcium by citrate masked the immobilization hypercalcemia, resulting in marked bone loss and spontaneous vertebral fractures in the context of normal calcium levels. Case report: 23 year old man with no past medical history was seen on account of concerns for calcium loss from his bones as he was on CRRT, for 4 months and the amount of calcium in the extracorporeal circuit was more than expected. He had presented with new onset systolic heart failure (EF 10%) secondary to fulminant post-COVID-19 myocarditis, and renal failure due to acute tubular necrosis. CRRT with citrate dextrose anticoagulation was initiated at presentation. He had received pulse dose prednisone for presumed post-viral myocarditis. He was awaiting heart and kidney transplantation. Greater than average calcium clearance during CRRT prompted workup for hypercalcemia. He denied personal or family history of hypercalcemia, renal stones, fractures, dental issues or hyperparathyroidism. He reported eating adequate amounts of dairy products. Labs showed corrected calcium 9.3 (8.6-10.3 mg/dl), elevated PTH 189 (10-65 pg/ml), low serum protein and albumin, and low 25OHVD that was 14 (25-100 ng/mL) on presentation and actively being replaced with ergocalciferol. Phosphorus, magnesium, liver and thyroid function were normal. The patient had complained of back pain after being immobile for 3 months. MRI showed subacute vertebral fractures of T12 and L1. Thereafter, spine X-ray showed multiple vertebral fractures of L2-L5. Beta CTX was 4153 (120-946 pg/ml) and DXA scan revealed low bone density for age with Z score -3.7 in the femoral neck, invalid in the spine due to the fractures, felt to be the source of high extracorporeal calcium concentration. A dose of Denosumab was given for treatment with improvement of calcium clearance during CRRT. Discussion: Acute fractures and infrequently, prolonged immobilization cause hypercalcemia with suppression of PTH. In our patient who was critically ill and immobilized for 4 months, the use of CRRT maintained normocalcemic blood levels, and renal failure with vitamin D deficiency caused secondary hyperparathyroidism. Only the declining requirements for calcium replacement during CRRT prompted workup for hypercalcemia that lead to identification of significant vertebral fractures and treatment. Declining need for calcium replacement during CRRT should prompt investigation and treatment of disorders of hypercalcemia and metabolic bone disorders in this patient population. Presentation: Thursday, June 15, 2023

A Double-Blind Placebo-Controlled Randomized Trial Evaluating the Effect of Polyphenol-Rich Herbal Congee on Bone Turnover Markers of the Perimenopausal and Menopausal Women.

Based on the benefit of polyphenolic compounds on osteoporosis, we hypothesized that the polyphenol-rich herbal congee containing the combined extract of Morus alba and Polygonum odoratum leaves should improve bone turnover markers in menopausal women. To test this hypothesis, a randomized double-blind placebo-controlled study was performed. A total of 45 menopausal participants were recruited in this study. They were randomly divided into placebo, D1, and D2 groups, respectively. The subjects in D1 and D2 groups must consume the congee containing the combined extract of M. alba and P. odoratum leaves at doses of 50 and 1500 mg/day, respectively. At the end of an 8-week consumption period, all subjects were determined serum bone markers including calcium, alkaline phosphatase, osteocalcin, and beta CTX. In addition, the hematological and blood clinical chemistry changes, and total phenolic content in the serum were also determined. The results showed that the menopausal women in D2 group increased serum alkaline phosphatase, osteocalcin, and total phenolic compounds content but decreased CTX level. Clinical safety assessment failed to show toxicity and adverse effects. Therefore, herbal congee containing the combined extract of M. alba and P. odoratum leaves is the potential functional food that can decrease the risk of osteoporosis.

FGF-23, α-Klotho Gene Polymorphism and Their Relationship with the Markers of Bone Metabolism in Chronic Peritoneal Dialysis Patients.

The aim of the present study was to evaluate the variations of some major bone metabolism markers with reference to klotho gene polymorphism (KGP) and bone mineral density (BMD) values in patients on chronic peritoneal dialysis (CPD). In 51 CPD patients and 40 healthy persons, assays for intact parathormone (iPTH), fibroblast growth factor 23 (FGF-23), osteoprotegerin (OPG), osteocalcin (OC), procollagen type-1 N terminal propeptide (PINP), beta- crosslaps (beta CTx), tartrate resistant acid phosphatase (TRAP5b), bone alkaline phosphatase (BAP), 1,25(OH)D3, and 25(OH)D3 and α-klotho gene mutations were performed. In CPD patients, 1,25(OH)D3 and 25(OH)D3 deficiency rates were 96% and 94% respectively. iPTH (249 pg/mL vs 39 pg/mL) and FGF-23 (1089 RU/mL vs 153 RU/mL), OPG, OC, PINP, beta CTx, TRAP5b levels were significantly higher in patients. iPTH levels and whole-body BMD values were negatively correlated in patients. The rate of KGP was similar in all groups. In CPD patients, besides vitamin D deficiency, high levels of OPG, OC, PINP, beta CTx, TRAP5b were evident. Positive correlation between iPTH levels and BAP and PINP levels suggested a diagnostic value for those markers during the management of CKD MBD. On the other hand, high serum TRAP5b concentrations did not seem to be affected by neither calcitriol treatment nor the severity of hyperparathyroidism. iPTH and FGF-23 levels and whole-body BMD values showed a significant negative correlation. We were unable to show any correlation between KGP and any of the CKD-MBD parameters measured in this study.

SAT0476 Vitamin D Supplementation in Liver Transplant Patients

BackgroundLiver transplant patients are at risk of developing osteoporosis and vitamin D deficiency. This deficit can be correlated with an increase in the rate of bone destruction and a decrease...

Grand challenges in bone endocrinology.

Grand challenges in bone endocrinology.

Biomarkers for Osteoporosis Management

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increased risk of fracture. While the level of bone mass can be estimated by measuring bone mineral density (BMD) using dual X-ray absorptiometry (DXA), its measurement does not capture all the risk factors for fracture. Quantitative changes in skeletal turnover can be assessed easily and non-invasively by the measurement of serum and urinary biochemical markers; the most sensitive markers include serum osteocalcin, bone specific alkaline phosphatase, the N-terminal propeptide of type I collagen for bone formation, and the crosslinked C- (CTX) and N- (NTX) telopeptides of type I collagen for bone resorption. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, are likely to lead to the development of new biochemical markers that reflect changes in the material property of bone, an important determinant of bone strength. Among those, the measurement of the urinary ratio of native (alpha) to isomerized (beta) CTX - an index of bone matrix maturation - has been shown to be predictive of fracture risk independently of BMD and bone turnover. In postmenopausal osteoporosis, levels of bone resorption markers above the upper limit of the premenopausal range are associated with an increased risk of hip, vertebral, and nonvertebral fracture, independent of BMD. Therefore, the combined use of BMD measurement and biochemical markers is helpful in risk assessment, especially in those women who are not identified as at risk by BMD measurement alone. Levels of bone markers decrease rapidly with antiresorptive therapies, and the levels reached after 3-6 months of therapy have been shown to be more strongly associated with fracture outcome than changes in BMD. Preliminary studies indicate that monitoring changes of bone formation markers could also be useful to monitor anabolic therapies, including intermittent parathyroid hormone administration and, possibly, to improve adherence to treatment. Thus, repeated measurements of bone markers during therapy may help improve the management of osteoporosis in patients.

Marker of Bone Resorption in Acute Response to Exogenous or Endogenous Parathyroid Hormone

Parathyroid hormone (PTH) changes morphology of osteoclasts within minutes after its systemic administration. The aim of our study was to test in healthy men whether both exogenous and endogenous PTH could change acutely (minutes to hours) the serum cross-linked C-telopeptide of type I collagen (beta CTX), which is released during osteoclastic resorption of bone. Twelve healthy men (age range 24–34 yr) were each studied during 180 min on a control period, after a single subcutaneous injection of teriparatide, and after 30 min EDTA infusion to stimulate endogenous PTH secretion. The tests were started after overnight fast, 3 h after a standard calcium load. The EDTA infusion induced a significant decrease in serum ionized calcium (by 8.5% at 33 min) and a significant increase in plasma PTH (by 305% at 33 min). Both the EDTA and teriparatide resulted in a significant increase in beta CTX (p < 0.001) with maximum increases of 64% and 80%, respectively. A mild, but significant decrease in beta CTX was observed during the control test period. In conclusion, single-dose teriparatide injection as well as a stimulation of endogenous PTH in healthy men results in an acute increase of the bone resorption marker.

Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone

Mechanical behavior of bone depends on its mass and architecture, and on the material properties of the matrix, which is composed of a mineral phase and an organic component mainly constituted of type I collagen. Mineral accounts largely for the stiffness of bone, whereas type I collagen provides bone its ductility and toughness, i.e., its ability to undergo deformation and absorb energy after it begins to yield. The molecular mechanisms underlying the effect of alterations in type I collagen on bone mechanical properties are unclear. We used an in vitro model of fetal bovine cortical bone specimens ( n = 44), where the extent of type I collagen cross-linking was modified by incubation at 37°C for 0, 60, 90 and 120 days, keeping constant the architecture and the mineral content. At each incubation time, the following parameters were determined: (1) the bone concentration of enzymatic (pyridinoline; PYD and deoxypyridinoline, DPD) and non-enzymatic (pentosidine) crosslinks by HPLC, (2) the extent of aspartic acid isomerization of the type I collagen C-telopeptide (CTX) by ELISA of native (alpha CTX) and isomerized (beta CTX) forms, (3) the mineral density by DXA, (4) the porosity by micro-computed tomography and (5) the bending and compressive mechanical properties. Incubation of bone specimens at 37°C for 60 days increased the level (per molecule of collagen) of PYD (+98%, P = 0.005), DPD (+42%, P = 0.013), pentosidine (+55-fold, P = 0.005), and the degree of type I collagen C-telopeptide isomerization (+4.9-fold, P = 0.005). These biochemical changes of collagen were associated with a 30% decrease in bending and compressive yield stress and a 2.5-fold increase in compressive post-yield energy absorption ( P < 0.02 for all), with no significant change of bone stiffness. In multivariate analyses, the level of collagen cross-linking was associated with yield stress and post-yield energy absorption independently of bone mineral density, explaining up to 25% of their variance. We conclude that the extent and nature of collagen cross-linking contribute to the mechanical properties of fetal bovine cortical bone independently of bone mineral density.

858 POSTER Alpha and beta CTX urine levels in patients with prostate cancer

858 POSTER Alpha and beta CTX urine levels in patients with prostate cancer

Markers of bone remodeling predict rate of bone loss in multiple sclerosis patients treated with low dose glucocorticoids

Background: The aim of this study was to evaluate the clinical value of markers of bone remodeling in assessment of rate of bone loss in patients with multiple sclerosis (MS) long term treated with low dose glucocorticoids. Methods: The study involved 70 patients with MS. Motor function of the patients was evaluated using the Kurtzke Expanded Disability Status Scale (KEDSS). Bone mineral density (BMD) was determined at the lumbar spine and proximal femur at baseline and after 1.8±0.8 years. Bone remodeling was assessed using circulating concentrations of type 1 collagen cross-linked C-telopeptide (beta CTX), aminoterminal propeptide of type I procollagen, and N-MID osteocalcin (OC). A control group of 140 age-matched healthy subjects was used to compare bone-turnover markers. Results: The plasma CTX concentration was the most significant parameter of bone remodeling which correlated with the rate of bone loss and with the KEDSS. The rate of bone loss at the proximal femur was not significantly different between tertiles of plasma OC concentrations. Conclusion: In physically active patients with MS treated with low-dose GC, the bone-turnover markers were not different from controls. Patients having plasma CTX but markers of bone formation higher as compared to controls were confirmed 2 years later as bone losers.

CORRELATIONS BETWEEN LEPTIN, BODY COMPOSITION, BONE MINERAL DENSITY AND BONE METABOLISM IN KIDNEY TRANSPLANT RECIPIENTS AND DIALYZED PATIENTS

P301 Aims: In kidney transplant recipients leptin levels are often elevated and BMD decreased, however, so far data about correlations between leptin and BMD in this population is lacking. It has been suggested that leptin is a predictor of BMD in postmenopausal women. Moreover, leptin acts a a marker of fat stores. We examined the relationships between leptinemia, some markers of nutritional status, BMD and bone metabolism in kidney transplant recipients as well as in dialyzed patients (hemodialyzed -HD, peritoneally dialyzed -CAPD). We also assessed whether leptin is significant and independent predictor of BMD in this population. Methods: Methods: BMD and fat content (global, percentage, trunk) was measured using dual energy X-ray absorptiometry (DEXA) in 27 kidney allograft recipients, 25 HD and 23 CAPD patients,. Intact PTH and osteocalcin were studied by radioimmunoassay using commercially available kits from Cis, France. Vitamin 1,25 (OH)2D3 and IGF-1 concentrations were measured RIA using commercially available kits from Biosource, Europe S.A., Belgium. Levels of IGF-BP-1 and 3 were assayed by IRMA (Diagnostic Systems Laboratories, Inc, USA). Levels of PICP (procollagen type I carboxy-terminal extension peptide) and ICTP (procollagen type I cross-linked carboxy-terminal telopeptide) were estimated by radioimmunoassays (Orion Diagnostica, Finland). Bone-specifc alkaline phosphatase-bALP was estimated using ELISA kit from Metra Biosystem, USA. Serum beta2microglobulin was estimated using kits from AlphaDialab, Vienna, Austria. Beta Ctx (degradation products of C-terminal telopeptides of type I collagen), were assayed by ELISA (Osteometer, Denmark). Serum tartrate-resistant acid phosphatase-TRAP was estimated using kit from Suomen Bioanalytiikka Oy, Finland. DPD (deoxypirydynoline) in urine was assayed by immunochemiluminescence (ACS 180 Bayer) and expressed as DPD/creatinine ratios. Serum leptin was assessed by RIA using kits from Linco Research, USA. Results: Leptin correlated with percentage of body fat, trunk fat, lean body mass, serum creatinine and urea. Insulin growth factor binding protein 1 was negatively related to waist-hip ratio, global and trunk fat., whereas BMD of the lumbar spine was related to the dose of prednisone, azathioprine, level of cyclosporine, serum calcium as well as osteoprotegerin level in kidney transplant recipients. In femoral neck BMD was significantly higher in CAPD patients, without significant differences in BMD in lumbar spine. There was a negative correlation between BMD at the femoral neck and time on hemodialysis (r=-0.45, p<0.05). In CAPD patients BMD at the lumbar spine correlated negatively with vitamin D3 (r=-0.54, p<0.05), osteocalcin (r=-0.54, p<0.05), and positively with BMI (r=0.63, p<0.01). BMD at the femoral neck correlated positively with BMI (r=0.59, p<0.01), and negatively with osteocalcin (r=-0.63, p<0.05) and time on CAPD (r=-0.52, p<0.05). Leptin correlate only with cholesterol (r=0.25, p<0.05), TSH (r=0.35, p<0.01), beta2microglobulin (r=0.32, p<0.001) and BMD at the femoral neck (r=-0.23, p<0.05) in all dialyzed (HD and CAPD) patients. Conclusions: Leptin levels are associated with renal function and body fat in kidney allograft recipients. Leptin is not related to nutritional status, BMD and bone metabolism BMD in kidney allograft recipients, but depends on currents dosage of immunosuppressants and serum calcium. Leptin is not a predictor of BMD in dialyzed patients.

Decreased beta-isomerization of the C-terminal telopeptide of type I collagen alpha 1 chain in Paget's disease of bone.

In Paget's disease of bone, the normal lamellar bone is replaced by a woven structure with an irregular arrangement of collagen fibers. In this study, we investigated whether the degree of beta-isomerization within C-telopeptide of alpha 1 chain of type I collagen was altered in Paget's disease compared with other bone diseases with no alteration of bone structure. In Paget's disease (n = 26), but not in patients with primary hyperparathyroidism (n = 6) or hyperthyroidism (n = 17), the urinary excretion of nonisomerized (alpha) fragments derived from degradation of type I collagen C-telopeptide (CTX) was markedly increased compared with beta-isomerized CTX (+ 13-fold vs. + 3.5-fold over controls) resulting in an urinary alpha CTX/beta CTX ratio 3-fold higher than in controls (2.6 +/- 1.0 vs. 0.8 +/- 0.3, p < 0.001). In five pagetic patients in complete remission, as demonstrated by normal total alkaline phosphatase activity, the alpha CTX/beta CTX ratio was normal. The immunohistochemistry of normal and pagetic human bone sections showed a preferential distribution of alpha CTX within woven structure, while lamellar bone was intensely stained with an anti-beta CTX antibody, suggesting a lower degree of beta-isomerization of type I collagen in the woven pagetic bone. In collagenase digest of human bone specimens, we found a lower proportion of beta-isomerized type I collagen molecules in pagetic bone (40% of beta CTX) than in normal bone taken from trabecular (68%) and cortical compartments (71%). In conclusion, we found that in Paget's disease the alpha CTX/beta CTX ratio in bone and in urine is markedly increased. This altered beta isomerization can be accurately detected in vivo by measuring urinary degradation products arising from bone resorption.