Celebrating 50-years: the history and future of the International Society of Bone Morphometry.

The International Society of Bone Morphometry (ISBM) is dedicated to advancing research, education, and clinical practice for osteoporosis and other bone disorders by developing and improving tools for the quantitative imaging and analysis of bone. Its initial core mission was to promote the proper use of morphometric techniques in bone research and to educate and train clinicians and basic scientists in bone morphometry. This article chronicles the evolution of the ISBM and the history and development of bone morphometric techniques for the past 50-years, starting with workshops on bone morphometry in 1973, to the formal incorporation of the ISBM in 1996, to today. We also provide a framework and vision for the coming decades. This effort was led by ISBM presidents Dr Erica L. Scheller (2022-2024) and Dr Thomas J. Wronski (2009-2012) in collaboration with all other living ISBM presidents. Though the underlying techniques and questions have changed over time, the need for standardization of established tools and discovery of novel approaches for bone morphometry remains a constant. The ISBM fulfills this need by providing a forum for the exchange of ideas, with a philosophy that encourages the open discussion of pitfalls and challenges among clinicians, scientists, and industry partners. This facilitates the rapid development and adaptation of tools to meet emerging demands within the field of bone health at a high level.

FGF-23 and sclerostin in serum and bone of CKD patients.

AIMS: Renal osteodystrophy occurs in the early stages of chronic kidney disease (CKD) and progresses during loss of kidney function. Fibroblast growth factor (FGF)-23 and sclerostin, both produced by osteocytes, are increased in blood of patients with CKD. The aim of this study was to analyze the impact of decline in kidney function on FGF-23 and sclerostin protein expression in bone and to study their relationship with their serum levels and bone histomorphometry. MATERIALS AND METHODS: 108 patients aged 25 - 81 years (mean ± SD: 56 ± 13 years) underwent anterior iliac crest biopsies after double-tetracycline labeling. Eleven patients were CKD-2, 16 were CKD-3, 9 were CKD-4 - 5, and 64 CKD-5D. Patients were on hemodialysis for 49 ± 117 months. 18 age-matched patients without CKD were included as controls. Immunostaining was performed on undecalcified bone sections to quantify FGF-23 and sclerostin expression. Bone sections were also evaluated by histomorphometry for bone turnover, mineralization, and volume. RESULTS: FGF-23 expression in bone correlated positively with CKD stages (p < 0.001) increasing from 5.3- to 7.1-fold starting at CKD-2. No difference in FGF-23 expression was seen between trabecular and cortical bone. Sclerostin expression in bone correlated positively with CKD stages (p < 0.001) with an increase from 3.8- to 5.1-fold starting at CKD-2. This increase was progressive and significantly greater in cortical than cancellous bone. FGF-23 and sclerostin in blood and bone were strongly associated with bone turnover parameters. Expression of FGF-23 in cortical bone correlated positively with activation frequency (Ac.f) and bone formation rate (BFR/BS) (p < 0.05), while sclerostin correlated negatively with Ac.f, BFR/BS, and osteoblast and osteoclast numbers (p < 0.05). FGF-23 trabecular and cortical expressions correlated positively with cortical thickness (p < 0.001). Sclerostin bone expression correlated negatively with parameters of trabecular thickness and osteoid surface (p < 0.05). CONCLUSION: These data show a progressive increase in FGF-23 and sclerostin in blood and bone associated with decrease in kidney function. The observed relationships between bone turnover and sclerostin or FGF-23 should be considered when treatment modalities are developed for management of turnover abnormalities in CKD patients.

Trabecular bone microcrack accumulation in patients treated with bisphosphonates for durations up to 16 years.

This study quantified the length, number, and density of microcracks in bone from patients treated with bisphosphonates as a function of duration. Anterior iliac crest bone samples from 51 osteoporotic Caucasian females continuously treated with oral bisphosphonates for 1-16 years were obtained by bone biopsy. Samples were histologically processed and analyzed for bone area, microcrack number, and microcrack length. The analyses used statistical modeling and considered patient age, bone mineral density, bone volume/total volume, trabecular thickness, and bone turnover as potential covariates. Microcrack density (number of microcracks/total examined bone area) was linearly related (p = 0.018) to bisphosphonate treatment duration. None of the analyzed covariates contributed significantly to the observed relationship between microcrack density and bisphosphonate treatment duration. Observed increases in microcrack density with increasing bisphosphonate treatment duration is important because increasing levels of microcracks may not only affect bone remodeling but also reduce elastic modulus and are suspected to adversely affect other mechanical properties that may influence fracture risk. The present findings add to our prior results showing changes in bone material properties and modulus with bisphosphonate treatment duration and thereby provide a more comprehensive assessment of the relationship between bisphosphonate treatment duration and bone quality. Statement of Clinical Significance: The present findings provide information guiding clinical use of oral bisphosphonates for post-menopausal osteoporosis therapy.

Treatment of bone loss in CKD5D: Better survival in patients with non-high bone turnover.

67% of CKD5D patients have low bone mass and present with high (HTO) or non-high (N-HTO) bone turnover. HTO has excessive resorption calling for anti-resorbers, while in N-HTO, anabolic therapy appears preferable. There are no data on this tailored approach. Adult CKD5D patients with dual energy X-ray absorptiometry (DXA) t-scores ≤ -1.0 were enrolled into this 12-month randomized controlled trial and stratified as HTO or N-HTO using values of parathyroid hormone (PTH), PTH-ratio, and TRAP5b. HTO patients were randomized into treatment with alendronate or controls, and N-HTO patients into teriparatide or controls. Clinical, lab, DXA, quantitative computed tomography bone mineral density (QCT BMD), and coronary artery calcifications (CAC) and aorta calcifications (AoC) MSQCT data were obtained at 0 and 12 months. Primary outcome was change (Δ) in BMD by QCT, secondary outcomes were changes in CAC (ΔCAC), in AoC (ΔAoC), and death. There were 80 HTO and 61 N-HTO patients. Median HTO baseline PTH was 664 and N-HTO 183. Bone loss improved in treated N-HTO (5.7 g/cm3 vs. -10.7) but not in HTO (0.2 g/cm3 vs. -3.5) patients. There were no differences in ΔAoC or ΔCAC between treatment groups in either arm. Across all patients in the study, ΔAoC was lower in Blacks than Whites. (3.6 vs. 8.8) The HTO ΔAoC was 5 Hounsfield Units higher than N-HTO. In N-HTO, there were 0 deaths, but 20% in HTO (p = 0.005). N-HTO patients (PTH range 138 - 337 pg/mL) had better survival and less ΔAoC than those with HTO. Teriparatide treatment significantly improved low bone mass in N-HTO patients. Blacks had less ΔAoC regardless of turnover or treatment.

Prevalence of low bone formation in untreated patients with osteoporosis.

BACKGROUND: Osteoporosis treatment usually starts with an antiresorber and switches to an anabolic agent if it fails. It is known that suppressing bone resorption also results in reduced bone formation. In addition, patients with prior treatment with antiresorbers may have reduced response to subsequent anabolic treatment. This study determined the prevalence of low bone formation in untreated osteoporosis patients to identify patients who may not be optimally treated under the current paradigm. METHODS: This is a cross-sectional study of bone samples stored in the Kentucky Bone Registry. Included samples were from adult patients presenting for workup of osteoporosis. Exclusion criteria were other diseases or treatments affecting bone. Patients underwent iliac crest bone biopsies after tetracycline labeling for identification of bone formation. RESULTS: 107 patients met study criteria, 92 White and 5 Black women and 10 White men. Forty percent of patients (43/107) had low bone formation/bone surface (BFR/BS < 0.56 mm3/cm2/yr). Clinical and serum parameters did not differ between formation groups, except for type II diabetes, which was found exclusively in the low formation group. CONCLUSIONS: Starting treatment of osteoporotic patients with an antiresorber in all patients appears not optimal for a significant portion.

The Role of Alterations in Alpha-Klotho and FGF-23 in Kidney Transplantation and Kidney Donation.

Cardiovascular disease and mineral bone disorders are major contributors to morbidity and mortality among patients with chronic kidney disease and often persist after renal transplantation. Ongoing hormonal imbalances after kidney transplant (KT) are associated with loss of graft function and poor outcomes. Fibroblast growth factor 23 (FGF-23) and its co-receptor, α-Klotho, are key factors in the underlying mechanisms that integrate accelerated atherosclerosis, vascular calcification, mineral disorders, and osteodystrophy. On the other hand, kidney donation is also associated with endocrine and metabolic adaptations that include transient increases in circulating FGF-23 and decreases in α-Klotho levels. However, the long-term impact of these alterations and their clinical relevance have not yet been determined. This manuscript aims to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation, and importantly, underscore specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.

Low Turnover Renal Osteodystrophy With Abnormal Bone Quality and Vascular Calcification in Patients With Mild-to-Moderate CKD.

Introduction: Limited information is available on renal osteodystrophy (ROD) and vascular calcification (VC) during early chronic kidney disease (CKD). This study was designed to evaluate ROD and VC in 32 patients with CKD stages II to IV. Methods: Patients underwent dual-energy X-ray absorptiometry (DXA) for assessment of bone mineral density (BMD) and trabecular bone score (TBS), thoracic computed tomography for VC scoring using the Agatston method, and anterior iliac crest bone biopsy for mineralized bone histology, histomorphometry, and Fourier transform infrared spectroscopy (FTIR). Classical and novel bone markers were determined in the blood. Results: Mean estimated glomerular filtration rate (eGFR) was 44 ± 16 ml/min per 1.73 m2. Of the patients, 84% had low bone turnover. In Whites, eGFR correlated negatively with the turnover parameter activation frequency (Ac.f) (r -0.48, P = 0.019) and with parameters of bone formation. Most patients had VC (>80%) which correlated positively with levels of phosphorus, c-terminal fibroblast growth factor-23, and activin. Aortic calcifications (ACs) correlated negatively with bone formation rate (BFR) and Ac.f (rho -0.62, -0.61, P < 0.001). TBS correlated negatively with coronary calcification (rho -0.42, P = 0.019) and AC (rho -0.57, P = 0.001). These relationships remained after adjustment of age. The mineral-to-matrix ratio, an FTIR metric reflecting bone quality, was negatively related to Ac.f and positively related to AC. Conclusion: Low bone turnover and VC are predominant in early stages of CKD. This is the first study demonstrating mineral abnormalities indicating reduced bone quality in these stages of CKD.

Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years.

Oral bisphosphonates are the primary medication for osteoporosis, but concerns exist regarding potential bone-quality changes or low-energy fractures. This cross-sectional study used artificial intelligence methods to analyze relationships among bisphosphonate treatment duration, a wide variety of bone-quality parameters, and low-energy fractures. Fourier transform infrared spectroscopy and histomorphometry quantified bone-quality parameters in 67 osteoporotic women treated with oral bisphosphonates for 1 to 14 years. Artificial intelligence methods established two models relating bisphosphonate treatment duration to bone-quality changes and to low-energy clinical fractures. The model relating bisphosphonate treatment duration to bone quality demonstrated optimal performance when treatment durations of 1 to 8 years were separated from treatment durations of 9 to 14 years. This may be due to a change in relationship of bone-quality parameters with treatment duration. This model also showed that the effects of bisphosphonate treatment duration were most highly correlated with changes in means and standard deviations of infrared spectroscopically derived mineral and matrix parameters and histomorphometric bone turnover parameters. A second model related treatment duration to bone fracture in all 22 patients who fractured while on treatment with bisphosphonates for more than 8 years. This second model showed that bisphosphonate treatment duration, not hip bone mineral density (BMD), was the most strongly correlated parameter to these low-energy bone fractures. Application of artificial intelligence enabled analysis of large quantities of structural, cellular, mineral, and matrix bone-quality parameters to determine relationships with long-term oral bisphosphonate treatment and fracture. Infrared spectroscopy provides clinically relevant bone-quality information of which bone mineral purity is among the most relevant. Nine or more years of bisphosphonate treatment was associated with abnormal bone mineral purity, matrix abnormalities, and low-energy fractures. These data justify limiting bisphosphonate treatment duration to 8 years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Importance of bone turnover for therapeutic decisions in patients with CKD-MBD.

Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) frequently have low bone formation rates. A recent review suggested that adynamic bone disease is not always associated with negative outcomes and therefore antiresorptive medications could be used more often. However, there is currently no evidence to support an improvement in fracture risk or mortality in patients with CKD-MBD and low bone turnover who are treated with antiresorptive medication. There is reasonable pathophysiological evidence suggesting that it may even be harmful.

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.

Long-term outcomes and management considerations after parathyroidectomy in the dialysis patient.

Parathyroidectomy (PTX) remains an important intervention for dialysis patients with poorly controlled secondary hyperparathyroidism (SHPT), though there are only retrospective and observational data that show a mortality benefit to this procedure. Potential consequences that we seek to avoid after PTX include persistent or recurrent hyperparathyroidism, and parathyroid insufficiency. There is considerable subjectivity in defining and diagnosing these conditions, given that we poorly understand the optimal PTH targets (particularly post PTX) needed to maintain bone and vascular health. While lowering PTH after PTX decreases bone turnover, long-term changes in bone activity have been poorly explored. High turnover bone disease, usually present at the time a PTX is considered, often swings to a state of low turnover in the setting of sufficiently low PTH levels. It remains unclear if all low bone turnover equate with disease. However, such changes in bone turnover appear to predispose to vascular calcification, with positive calcium balance after PTX being a potential contributor. We know little of how the post-PTX state resets calcium balance, how calcium and VDRA requirements change or what kind of adjustments are needed to avoid calcium loading. The current consensus cautions against excessive reduction of PTH although there is insufficient evidence-based guidance regarding the management of chronic kidney disease - mineral bone disease (CKD-MBD) parameters in the post-PTX state. This article aims to compile existing research, provide an overview of current practice with regard to PTX and post-PTX chronic management. It highlights gaps and controversies and aims to re-orient the focus to clinically relevant contemporary priorities in CKD-MBD management after PTX.

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.

A Survey Study of Self-Rated Patients' Knowledge About AKI in a Post-Discharge AKI Clinic.

BACKGROUND: Survivors of acute kidney injury (AKI) are at risk of adverse outcomes. Post-discharge nephrology care may improve patients' AKI knowledge and prevent post-AKI complications. OBJECTIVE: The purpose of this study was to examine patients' awareness about their AKI diagnosis and self-rated knowledge and severity of AKI before and after their first post-discharge AKI Clinic encounter. DESIGN: We conducted a pre- and post-survey study among AKI survivors who attended a post-discharge AKI Clinic. SETTING: AKI Clinic at the University of Kentucky Medical Center (October 2016 to December 2017). Education about AKI was based on transformative learning theory and provided through printed materials and interdisciplinary interactions between patients/caregivers and nurses, pharmacists, and nephrologists. PATIENTS: A total of 104 patients completed the survey and were included in the analysis. MEASUREMENTS: Three survey questions were administered before and after the first AKI Clinic encounter: Question 1 (yes-no) for awareness, and questions 2 and 3 (Likert scale, 1 = lowest to 5 = highest) for self-rated knowledge and severity of AKI. METHODS: Two mixed-model analysis of variance (ANOVA) was used for between-group (AKI severity) and within-group (pre- and post-encounter) comparisons. Logistic regression was used to examine parameters associated with the within-group change in self-perceived knowledge. RESULTS: Twenty-two out of 104 (21%) patients were not aware of their AKI diagnosis before the clinic encounter. Patients' self-ratings of their AKI knowledge significantly increased after the first AKI Clinic encounter (mean ± SEM: pre-visit = 1.94 ± 0.12 to post-visit = 3.88 ± 0.09, P = .001), even after adjustment for age, gender, Kidney Disease Improving Global Outcomes (KDIGO) severity stage, or poverty level. Patients with AKI stage 3 self-rated their AKI as more severe than patients with AKI stage 1 or 2. LIMITATIONS: Our study population may not be representative of the general AKI survivor population. Administered surveys are subject to response-shift bias. CONCLUSIONS: Patients' self-perceived knowledge about AKI significantly increased following the first post-discharge AKI Clinic encounter that included interdisciplinary education. This is the first survey study examining self-perceived AKI knowledge in AKI survivors. Further examination of AKI literacy in survivors of AKI and its effect on post-AKI outcomes is needed. TRIAL REGISTRATION: Not applicable.

CONTEXTE: Les survivants d'un épisode d'insuffisance rénale aiguë (IRA) risquent de souffrir de pathologies associées. Un suivi en néphrologie après la sortie de l'hôpital pourrait accroître les connaissances des patients sur la maladie et prévenir les complications. OBJECTIF: L'étude était bipartite : i) savoir si les patients connaissaient leur diagnostic; ii) mesurer, par auto-évaluation, les connaissances des patients sur l'IRA et sur sa gravité, avant et après une consultation dans une clinique d'IRA. TYPE D'ÉTUDE: Un sondage mené auprès de survivants d'un épisode d'IRA, avant et après une consultation en clinique d'IRA suivant leur congé de l'hôpital. CADRE: La clinique d'IRA du centre médical de l'université du Kentucky (d'octobre 2016 à décembre 2017). L'information fournie suivait la théorie de l'apprentissage transformationnel et était transmise sous forme de documents imprimés et d'interactions interdisciplinaires entre les patients/fournisseurs de soins et les infirmières, les pharmaciens et les néphrologues. PARTICIPANTS: L'étude porte sur 104 patients ayant complété le sondage. MESURES: Trois questions ont été posées aux patients avant et après une première consultation à la clinique. Une question portait sur leur connaissance du diagnostic (oui -non) et deux autres auto-évaluaient leurs connaissances sur l'IRA et sa gravité (échelle de Likert, de 1 [plus faible] à 5 [plus élevé]). MÉTHODOLOGIE: Deux modèles mixtes d'analyse de variance ont été employés pour établir des comparaisons inter-groupes (gravité de l'IRA) et intra-groupes (pré et post-consultation). Une régression logistique a été utilisée pour analyser les paramètres associés aux changements du niveau auto-évalué des connaissances dans un même groupe. RÉSULTATS: Des 104 patients inclus à l'étude, 22 (21 %) ignoraient leur diagnostic d'IRA avant la consultation. L'auto-évaluation des connaissances a augmenté après la première consultation (moyenne ± SEM : 1,94 ± 0,12 [pré-visite]; 3,88 ± 0,09 [post-visite], p=0,001) et ce, même après les ajustements en regard de l'âge et du sexe du patient, du stade de la maladie selon le KDIGO (Kidney Disease Improving Global Outcomes) ou du niveau de revenus. Les patients atteints d'une IRA de stade 3 ont davantage surévalué la gravité de leur maladie que les patients de stades 1 ou 2. LIMITES: La population étudiée pourrait ne pas être représentative de la population générale des survivants d'un épisode d'IRA. Les sondages sont sujets aux biais liés aux changements de réponses. CONCLUSION: L'auto-évaluation des connaissances a augmenté significativement après une première consultation à la clinique d'IRA lorsque celle-ci incluait de l'information interdisciplinaire. Il s'agit de la première étude portant sur l'auto-évaluation des connaissances de survivants d'un épisode d'IRA. Il est nécessaire d'examiner davantage la littératie de l'IRA chez les survivants de la maladie et ses effets sur les pathologies qui en découlent.

Sotatercept Safety and Effects on Hemoglobin, Bone, and Vascular Calcification.

INTRODUCTION: Patients with end-stage kidney disease (ESKD) exhibit anemia, chronic kidney disease‒mineral bone disorder (CKD-MBD), and cardiovascular disease. The REN-001 and REN-002 phase II, multicenter, randomized studies examined safety, tolerability, and effects of sotatercept, an ActRIIA-IgG1 fusion protein trap, on hemoglobin concentration; REN-001 also explored effects on bone mineral density (BMD) and abdominal aortic vascular calcification. METHODS: Forty-three patients were treated in REN-001 (dose range: sotatercept 0.3‒0.7 mg/kg or placebo subcutaneously [s.c.] for 200 days) and 50 in REN-002 (dose range: 0.1‒0.4 mg/kg i.v. and 0.13‒0.5 mg/kg s.c. for 99 days). RESULTS: In REN-001, frequency of achieving target hemoglobin response (>10 g/dl [6.21 mmol/l]) with sotatercept was dose-related and greater than placebo (0.3 mg/kg: 33.3%; 0.5 mg/kg: 62.5%; 0.7 mg/kg: 77.8%; 0.7 mg/kg [doses 1 and 2]/0.4 mg/kg [doses 3‒15]: 33.3%; placebo: 27.3%). REN-002 hemoglobin findings were similar (i.v.: 16.7%-57.1%; s.c.: 11.1%‒42.9%). Dose-related achievement of ≥2% increase in femoral neck cortical BMD was seen among only REN-001 patients receiving sotatercept (0.3‒0.7 mg/kg: 20.0%‒57.1%; placebo: 0.0%). Abdominal aortic vascular calcification was slowed in a dose-related manner, with a ≤15% increase in Agatston score achieved by more REN-001 sotatercept versus placebo patients (60%‒100% vs. 16.7%). The most common adverse events during treatment were hypertension, muscle spasm, headache, arteriovenous fistula site complication, and influenza observed in both treatment and placebo groups. CONCLUSION: In patients with ESKD, sotatercept exhibited a favorable safety profile and was associated with trends in dose-related slowing of vascular calcification. Less-consistent trends in improved hemoglobin concentration and BMD were observed.

The activin receptor is stimulated in the skeleton, vasculature, heart, and kidney during chronic kidney disease.

We examined activin receptor type IIA (ActRIIA) activation in chronic kidney disease (CKD) by signal analysis and inhibition in mice with Alport syndrome using the ActRIIA ligand trap RAP-011 initiated in 75-day-old Alport mice. At 200 days of age, there was severe CKD and associated Mineral and Bone Disorder (CKD-MBD), consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, elevated FGF23, and reduced klotho. The CKD-induced bone resorption and osteoblast dysfunction was reversed, and bone formation was increased by RAP-011. ActRIIA inhibition prevented the formation of calcium apatite deposits in the aortic adventitia and tunica media and significantly decreased the mean aortic calcium concentration from 0.59 in untreated to 0.36 mg/g in treated Alport mice. Aortic ActRIIA stimulation in untreated mice increased p-Smad2 levels and the transcription of sm22α and αSMA. ActRIIA inhibition reversed aortic expression of the osteoblast transition markers Runx2 and osterix. Heart weight was significantly increased by 26% in untreated mice but remained normal during RAP-011 treatment. In 150-day-old mice, GFR was significantly reduced by 55%, but only by 30% in the RAP-011-treated group. In 200-day-old mice, the mean BUN was 100 mg/dl in untreated mice compared to 60 mg/dl in the treated group. In the kidneys of 200-day-old mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin, and interstitial fibrosis were stimulated; all were attenuated by RAP-011 treatment. Hence, the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy and cardiovascular disease and to renal fibrosis. Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome.

Higher mineralized bone volume is associated with a lower plain X-Ray vascular calcification score in hemodialysis patients.

BACKGROUND AND OBJECTIVES: In dialysis patients, there is an increasing evidence that altered bone metabolism is associated with cardiovascular calcifications. The main objective of this study was to analyse, in hemodialysis patients, the relationships between bone turnover, mineralization and volume, evaluated in bone biopsies, with a plain X-ray vascular calcification score. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In a cross-sectional study, bone biopsies and evaluation of vascular calcifications were performed in fifty hemodialysis patients. Cancellous bone volume, mineralized bone volume, osteoid volume, activation frequency, bone formation rate/bone surface, osteoid thickness and mineralization lag time were determined by histomorphometry. Vascular calcifications were assessed by the simple vascular calcification score (SVCS) in plain X-Ray of pelvis and hands and, for comparison, by the Agatston score in Multi-Slice Computed Tomography (MSCT). RESULTS: SVCS≥3 was present in 20 patients (40%). Low and high bone turnover were present in 54% and 38% of patients, respectively. Low bone volume was present in 20% of patients. In multivariable analysis, higher age (p = 0.015) and longer hemodialysis duration (p = 0.017) were associated with SVCS≥3. Contrary to cancellous bone volume, the addition to this model of mineralized bone volume (OR = 0.863; 95%CI: 0.766, 0.971; p = 0.015), improved the performance of the model. For each increase of 1% in mineralized bone volume there was a 13.7% decrease in the odds of having SVCS≥3 (p = 0.015). An Agatston score>400 was observed in 80% of the patients with a SVCS≥3 versus 4% of patients with a SVCS<3, (p<0.001). CONCLUSION: Higher mineralized bone volume was associated with a lower plain X-ray vascular calcification. This study corroborates the hypothesis of the existence of a link between bone and vessel and reinforces the clinical utility of this simple and inexpensive vascular calcification score in dialysis patients.

Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease.

Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr-/- high fat-fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr-/- high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin-A induced osteoclastogenesis.

Coronary artery calcification in CKD-5D patients is tied to adverse cardiac function and increased mortality
.

BACKGROUND: Coronary artery calcification (CAC) is common in patients with chronic kidney disease on hemodialysis (CKD-5D) and is an important predictor of mortality. However, cardiac functional links between CAC and mortality have not been well established. This study tested the hypothesis that CAC increases mortality by adversely affecting cardiac function. METHODS: Patients were recruited from 37 regional dialysis centers. 2-D and Doppler echocardiographic analyses were performed, and CAC was measured using 64-slice computed tomography. Relationships between CAC and echocardiographic measures of left ventricular (LV) function were analyzed. Survival was assessed with median follow-up of 37 months. RESULTS: There were 157 patients: 59% male, 46% Caucasian, 48% diabetic. Median age was 55 years, and median duration of CKD-5D was 45 months. Agatston CAC scores 100 were found in 69% of patients, with 51% having a score  400. CAC was associated with measures of LV systolic and diastolic function (global longitudinal strain (GLS; rho = 0.270, p = 0.004)), peak LV systolic velocity (rho = -0.259, p = 0.004), and estimate of LV filling pressure (E:E'; rho = 0.286, p = 0.001). Multivariate regression confirmed these relationships after adjustment for age, gender, LV ejection fraction, and coronary artery disease. Valvular calcification varied linearly with CAC (p < 0.05). Both LV diastolic and systolic functional measures were significant predictors of mortality, the strongest of which was LV diastolic dysfunction. CONCLUSIONS: These findings show a link between CAC, cardiac function, and mortality in CKD-5D. LV diastolic function (E:E'), peak LV systolic velocity, and GLS are independent predictors of mortality. Valvular calcification may be an important marker of CAC in CKD-5D. These effects on cardiac function likely explain the high mortality with CKD-5D and describe a potentially-valuable role for echocardiography in the routine management of these patients.
.

Only minor differences in renal osteodystrophy features between wild-type and sclerostin knockout mice with chronic kidney disease.

Renal osteodystrophy affects the majority of patients with advanced chronic kidney disease (CKD) and is characterized by progressive bone loss. This study evaluated the effects of sclerostin knockout on bone in a murine model of severe, surgically induced CKD in both sclerostin knockout and wild-type mice. Mice of both genotypes with normal kidney function served as controls. Tibiae were analyzed using micro-computed tomography, and lumbar vertebrae were analyzed by histomorphometry. Results were tested for statistical significance by 2-way ANOVA to investigate whether bone of the knockout mice reacted differently to CKD compared with bone of wild-type mice. In the tibiae, there was no difference after creation of CKD between wild-type and knockout animals for cortical thickness or cross-sectional moment of inertia. Increases in cortical porosity induced by CKD differed significantly between genotypes in the tibial metaphysis but not in the diaphysis. In the trabecular compartment, no difference in reaction to CKD between genotypes was found for bone volume, trabecular number, trabecular thickness, and trabecular separation. In the lumbar vertebrae, significant differences in response to CKD between wild-type and knockout mice were seen for both bone volume and trabecular thickness. Osteoblast parameters did not differ significantly, whereas osteoclast numbers significantly increased in the wild-type but significantly decreased in knockout mice with CKD. No differences in response to CKD between genotypes were found for bone formation rate or mineral apposition rate. Thus, complete absence of sclerostin has only minor effects on CKD-induced bone loss in mice.