Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers
.

INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.

Two-year cortical and trabecular bone loss in CKD-5D: biochemical and clinical predictors.

This prospective two-year study of patients on chronic dialysis measured changes in bone mineral density (BMD). Patients with higher baseline BMD and shorter dialysis vintage lost more bone. Treatment with anti-hypertensives acting on the central nervous system was protective against bone loss. Baseline serum levels of sclerostin and bone-specific alkaline phosphatase predicted bone loss. INTRODUCTION: This prospective 2-year study of chronic kidney disease on dialysis (CKD-5D) patients assessed trabecular and cortical bone loss at the hip and spine and examined potential demographic, clinical, and serum biochemical predictors of bone loss. METHODS: Eighty-nine CKD-5D patients had baseline, year 1, and year 2 bone mineral density (BMD) measurements using dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT); concurrent blood samples were drawn and clinical variables recorded. No study treatments occurred. RESULTS: The 2-year total hip BMD change was - 5.9% by QCT and - 3.1% by DXA (p < 0.001). Spinal BMD was unchanged. QCT total hip cortical mass and volume decreased (- 7.3 and - 10.0%); trabecular volume increased by 5.9% (ps < 0.001). BMD changes did not vary with age, BMI, race, diabetes, smoking, or exercise. Patients with higher baseline BMD and shorter dialysis vintage lost more bone (p < 0.05). Vitamin D analogs and phosphate binders were not protective against bone loss; cinacalcet was protective by univariate but not by multivariable analysis. CNS-affecting antihypertensives were protective against loss of BMD, cortical mass, cortical volume (ps < 0.05) and trabecular mass (p = 0.007). These effects remained after adjustment. BSAP correlated with changes in BMD, cortical mass, and volume (p < 0.01) as did sclerostin (inversely). CONCLUSIONS: There was severe cortical bone loss at the hip best recognized by QCT. Patients with shorter dialysis vintage and less pre-existing bone loss lost more bone, while treatment with CNS-acting antihypertensives was protective. BSAP and sclerostin were useful markers of bone loss.

B-cell-activating factor is elevated in serum of patients with myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is a B-cell-mediated autoimmune disease. B-cell-activating factor (BAFF) is a major factor in B-cell development and activation. In this study we investigated serum BAFF levels in MG patients. METHODS: We compared the serum BAFF levels of 20 MG patients with gender-matched healthy controls. We assayed serum concentrations of BAFF and anti-acetylcholine receptor antibody (AChR) titers. RESULTS: Serum BAFF levels of MG patients with AChR antibodies were significantly higher than those of healthy controls. A significant positive correlation was observed between serum BAFF levels and anti-AChR antibody titers. BAFF values did not correlate with disease severity. CONCLUSIONS: BAFF may play a major role in the pathogenesis of MG, and it may provide a potential target for therapy in patients with MG. Muscle Nerve 54: 1030-1033, 2016.

Changes in biomarkers of bone turnover in an aripiprazole add-on or switching study.

BACKGROUND: The association between mental illness and osteoporosis and fractures is particularly pronounced in psychotic disorders. Antipsychotic use has previously been described to affect bone density. METHOD: A 52-week follow-up of patients switched to aripiprazole or with aripiprazole added on, conducting a specific analysis of markers of bone turnover: urinary NTX (a biomarker of bone resorption) and serum BSAP (a biomarker of bone formation). Baseline and serial measurements of bone markers NTX, BSAP and of hormones prolactin, oestrogen and testosterone were done at weeks 0 and 1, 2, 6, 12, 26 and 52, respectively. RESULTS: NTX concentration reduced over time but this did not reach significance in the whole group (log-NTX: ß=-0.0012, p=0.142). For BSAP the addition of or replacement with aripiprazole produced a significant reduction (log-BSAP: ß=-0.00039, p=0.002). Analysis with prolactin similarly showed a significant reduction (log-prolactin: ß=-0.0024, p<0.001); other hormones did not change significantly. Sensitivity analysis to compare the switchers to aripiprazole versus the "add-on" showed that the former group had a significant reduction in NTX. CONCLUSIONS: We found that switching to aripiprazole was associated with changes in molecular biomarkers of bone resorption, indicating a more favourable profile for bone health.

Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women.

Ligands of the transforming growth factor-beta superfamily and activin-receptor signaling play an important role in erythropoiesis. Sotatercept, an activin receptor type IIA (ActRIIA) ligand trap, is a novel, recombinant, fusion protein comprising the extracellular domain of human ActRIIA linked to the Fc portion of human immunoglobulin G1. Sotatercept, originally developed to increase bone mineral density, was noted to have robust effects on erythropoiesis. Here, we evaluated the safety, pharmacokinetic properties, and pharmacodynamic effects of sotatercept in 31 healthy postmenopausal women. Sotatercept was administered at dose level 0.1, 0.3, or 1 mg/kg every 28 days subcutaneously for up to four doses. Sotatercept was generally safe and well tolerated, and elicited clinically significant, dose-dependent increases in hemoglobin, hematocrit, and red blood cell counts that persisted for up to 4 months. The effect of sotatercept on hemoglobin was dose-limiting. Sotatercept also increased bone mineral density and biomarkers of bone formation. The sotatercept serum exposure-dose relationship was linear, with a mean terminal half-life of approximately 23 days. ActRIIA ligands are important regulators of erythrocyte production in healthy individuals. Clinical studies are ongoing to explore the potential of sotatercept to treat anemia and diseases of ineffective erythropoiesis as well as an agent to increase bone mineral density.

Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis.

CONTEXT: Sclerostin is a circulating inhibitor of the Wnt-signaling pathway produced by osteocytes, which acts as a negative regulator of bone formation. Effects of zoledronic acid on sclerostin serum levels in postmenopausal osteoporosis are unknown. OBJECTIVE: The purpose of this study was to evaluate sclerostin serum levels after zoledronic acid administration and correlate variations with bone turnover markers. DESIGN AND SETTING: We conducted a prospective intervention study in an ambulatory care setting. PARTICIPANTS AND INTERVENTION: Forty women (mean age 62.6 ± 4.9 years) with postmenopausal osteoporosis were enrolled in this study and randomized into 2 groups to receive zoledronic acid (5 mg) or placebo. MAIN OUTCOMES MEASURES: At baseline and then at 2, 7, 30, and 360 days after zoledronic acid or placebo administration, serum levels of sclerostin, bone-specific alkaline phosphatase (BSAP), as a bone formation marker, and serum C-telopeptide of type 1 collagen (CTX), as a bone resorption marker, were measured. RESULTS: Sclerostin serum levels increased by day 2, reached a peak at day 7 (3-fold baseline, P < .001), and then decreased at day 30 and returned near to baseline after 360 days in the zoledronic acid group. Both CTX and BSAP were reduced, and a significant negative correlation was observed between the percentage changes of sclerostin and the variation in BSAP and CTX at all time points in the zoledronic acid group (P < .05). No changes were observed in the placebo group. CONCLUSIONS: Our data demonstrate that zoledronic acid increases sclerostin serum levels and that sclerostin could play a role in coupling bone resorption to bone formation.

Lactation and bone turnover: a conundrum of marked bone loss in the setting of coupled bone turnover.

CONTEXT: Mothers who exclusively breastfeed lose up to 10% of their bone mass. This is primarily mediated by PTHrP, in combination with low estrogen levels. The mechanisms underlying this marked bone loss are unknown. Uncoupling of bone turnover, which is seen in other prototypical states of bone loss, would seem the likely explanation. However, the most current markers of bone turnover have not been studied in human lactation. OBJECTIVES: The purpose of this study was to assess bone formation in lactating humans using the most current bone turnover markers. DESIGN AND PARTICIPANTS: We conducted a prospective cohort study with repeated measures of bone metabolism in a volunteer sample of 49 women, recruited into three study groups: lactating, bottle feeding, and healthy controls. The postpartum women were studied at 6-8 and 12-14 wk postpartum, whereas the controls were studied at the follicular phase of their menstrual cycles. OUTCOME MEASURES: Biochemical markers of bone turnover were assessed. RESULTS: Mean serum C-telopeptide of type I collagen, a sensitive marker of bone resorption, was approximately 2-fold higher in lactating women as compared with bottle-feeding and healthy controls (P = 0.037 and P < 0.001, respectively). Surprisingly, amino-terminal telopeptides of procollagen 1, the most current marker of bone formation, bone-specific alkaline phosphatase, and osteocalcin were all significantly higher in the lactating group as compared with controls (P < 0.001, P = 0.002, and P < 0.001, respectively). CONCLUSIONS: In contrast to prototypical states of rapid bone loss (myeloma, cancer, and immobilization) in which markers of bone turnover display marked uncoupling, lactational bone loss, as assessed in this small exploratory study, is distinct, showing comparably rapid bone loss in the face of apparent osteoclast-osteoblast coupling.

Hormonal profiles and biochemical indices of bone turnover in Indian women.

UNLABELLED: The study establishes Indian referent database for bone turnover markers. The levels of markers decreased across the four quartiles of BMD showing a negative correlation with BMD. The study depicts that levels of hormones and bone turnover makers can aid in identifying women at risk for osteoporosis. INTRODUCTION: Biochemical markers of bone turnover reflect changes in bone metabolism earlier and aid in the management of osteoporosis. Since a referent database for Indian women is lacking, the study was initiated to establish the same and suggest that hormonal profiles and markers of bone turnover can aid in identifying women at risk for osteoporosis. METHODS: Osteocalcin (OC), bone specific alkaline phosphatase ((BSAP), C-terminal crosslinking telopeptide of type-I collagen (CTX-I), deoxypyridinoline (DPD), follicle-stimulating hormone (FSH) and estrone glucuronide (E(1)G) were measured in 365 Indian women (20-70 years) and correlated with BMD measurements by dual energy absorptiometry (DXA) using one way analysis of variance (ANOVA). RESULTS: The mean levels of bone resorption markers; CTX-I and DPD increased significantly across the age showing a negative correlation with BMD. The increase in levels of CTX-I and DPD was significantly higher (p < 0.0001) as compared to the femoral and spinal BMD, which dropped only 30-36%. The levels of bone turnover markers and FSH decreased across the four quartiles of spinal and femoral BMD showing a negative correlation whereas E(1)G levels increased across the four quartiles. CONCLUSION: The bone turnover markers were comparatively low in cohort of Indian women studied.