Skeletal fragility has long been overlooked by the nephrology community despite patients with chronic kidney disease (CKD) facing double the risk of hip fracture compared with the general population. Consequently, the term CKD-associated osteoporosis was recently coined to increase awareness. In this context, vertebral fractures are even less studied. Vertebral fractures predict increased fracture risk, and especially in advanced CKD, show a strong association with aortic and iliac vascular calcifications and cardiovascular events such as myocardial infarction. The scope of the present consensus paper is to comprehensively discuss the management of skeletal fragility in CKD patients, from diagnosis to treatment, with a particular focus on vertebral fractures in CKD G4-G5D.

Chronic kidney disease (CKD)-associated osteoporosis increases fracture risk, yet clinical guidance remains unclear. A survey of 89 Italian nephrologists revealed heterogeneous biomarker availability and varied treatment approaches. Denosumab was the preferred antiresorptive agent, while anabolic drugs were rarely used. Findings highlight progress in CKD-related bone health management despite existing uncertainties. CKD-associated osteoporosis comprises the skeletal effects of a complex mineral and bone disorder causing increased risks of fragility fractures (FF), cardiovascular events, and mortality. Existing clinical guidance about CKD-associated osteoporosis is vague, leading us to hypothesize that a treatment gap exists and that clinical practice is dependent on local availability of diagnostic tools. The aim of the current survey was to determine current attitudes and practices among Italian nephrologists regarding the evaluation and management of CKD-associated osteoporosis. An online survey was designed, consisting of 9 thematic groups with a set of 16 closed questions regarding the availability of biomarkers and BTMs at reference laboratories and their use for the diagnosis and treatment of CKD-associated osteoporosis in patients with different stages of CKD, including CKD stages G4-5 and dialysis patients. Results were compared to a previous survey on the use of BTMs from 2022. Eighty-nine Italian nephrologists participated in the survey, reporting that parathyroid hormone (PTH), alkaline phosphatase, and 25-hydroxy-vitamin D measurements were available in 92–100

In 2017, Kidney Disease: Improving Global Outcomes (KDIGO) published a Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Since then, new lines of evidence have been published related to evaluating disordered mineral metabolism and bone quality and turnover, identifying and inhibiting vascular calcification, targeting vitamin D levels, and regulating parathyroid hormone. For an in-depth consideration of the new insights, in October 2023, KDIGO held a Controversies Conference on CKD-MBD: Progress and Knowledge Gaps Toward Personalizing Care. Participants concluded that the recommendations in the 2017 CKD-MBD guideline remained largely consistent with the available evidence. However, the framework of the 2017 Guideline, with 3 major sections-biochemical abnormalities in mineral metabolism; bone disease; and vascular calcification-may no longer best reflect currently available evidence related to diagnosis and treatment. Instead, future guideline efforts could consider mineral homeostasis and deranged endocrine systems in adults within a context of 2 clinical syndromes: CKD-associated osteoporosis, encompassing increased fracture risk in patients with CKD; and CKD-associated cardiovascular disease, including vascular calcification and structural abnormalities, such as valvular calcification and left ventricular hypertrophy. Participants emphasized that the complexity of bone and cardiovascular manifestations of CKD-MBD necessitates personalized approaches to management.

BACKGROUND:Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease (CKD). Many recommendations in the Kidney Disease Improving Global Outcomes (KDIGO) CKD-mineral and bone disorder guidelines are supported by modest evidence and predate the approval of newer agents. Therefore, an expert panel defined consensus SHPT practice patterns in the United States with real-world context from the nephrology community. METHODS:Ten US healthcare providers and one patient participated in a modified Delphi method comprising three phases. Consensus was determined via iterative responses to a questionnaire based on the 2009 and 2017 KDIGO guidelines and published literature on the identification, evaluation, monitoring, and interventional strategies for patients with SHPT. The threshold for consensus was 66% agreement. RESULTS:Panelists generally agreed with KDIGO recommendations, with some differences. Consensus was reached on 42/105 (40%), 95/105 (90.5%), and 105/105 (100%) questions after phases 1, 2, and 3, respectively. Panelists unanimously agreed that SHPT treatment is often started late. There was a preference for serum phosphate level <4.6 mg/dL, and consensus to maintain serum calcium levels <9.5 mg/dL. There was unanimous agreement for vitamin D analogues as first-line options in patients not on dialysis with severe, progressive SHPT and unanimous preference for intravenous calcimimetic, etelcalcetide, in appropriate in-center dialysis patients. Factors such as formularies, dialysis center protocols, and insurance were recognized to influence therapeutic strategies. CONCLUSIONS:Expert consensus was reached on SHPT management, further defining therapeutic strategies and medication use and emphasizing need for treatment early. Despite evidence-based treatment preferences supported by clinical experience, factors other than scientific evidence influence decision making, particularly with medications.

Bone turnover assessment and monitoring are essential for chronic kidney disease (CKD)-associated bone care. Patients with CKD suffer from significantly elevated fracture risk due to abnormally high or low bone turnover, which benefits from diametrically opposite treatments informed by patient-specific bone turnover data. However, a reliable, accessible, noninvasive bone turnover assessment and monitoring tool remains an unmet clinical need. Combining time-lapse (TL) analysis with high-resolution peripheral quantitative computed tomography (HR-pQCT) scans obtained over time allows for in vivo temporospatial bone remodeling assessment. This study aimed to evaluate the feasibility of applying TL HR-pQCT to assess and monitor local bone formation and resorption in patients with CKD. A customized TL HR-pQCT pipeline was developed on a second-generation HR-pQCT platform and optimized using both ex vivo cadaveric phantom and in vivo scan-rescan HR-pQCT images. The annualized least significant changes in bone formation and resorption were evaluated using in vivo longitudinal reproducibility images. Finally, the feasibility of the TL HR-pQCT pipeline in assessing and monitoring bone turnover was evaluated in patients with end-stage kidney disease (ESKD; n = 9). We found that a 2-month TL period was sufficient for the TL HR-pQCT pipeline to reliably assess and monitor local bone turnover in a cohort of patients with ESKD. We also demonstrated the importance of characterizing TL HR-pQCT precision metrics using longitudinal baseline/follow-up rather than short-term scan-rescan datasets. The TL HR-pQCT pipeline assessed a range of bone formation metrics agreeing with the gold-standard histomorphometry bone formation reported in the literature for patients with CKD and ESKD. Our findings highlight that TL HR-pQCT holds promise as a "virtual bone biopsy" that reliably assesses and monitors local bone turnover for CKD bone care. Subsequent work will focus on validating this TL HR-pQCT pipeline against the gold-standard bone biopsy with quantitative histomorphometry.

BackgroundManaging osteoporosis (OP) in chronic kidney disease (CKD) presents significant challenges due to altered bone metabolism. Given the lack of robust clinical trial data and a notable knowledge gap exists among nephrologists regarding an optimal management in this population, an expert consensus is crucial for developing tailored management strategies. This study aimed to gather an expert opinion to bridge this gap and establish consensus recommendations on the diagnosis and management of osteoporosis in CKD patients.MethodsA panel of 13 Indian and 1 international experts, including nephrologists and endocrinologists, participated in a structured survey and discussion process. Thirteen Indian experts provided their opinion on key clinical issues, including screening, diagnosis, and treatment strategies for osteoporosis in CKD. Consensus was achieved in a single round of voting, and recommendations were formulated based on the level of agreement among the panelists.ResultsThe expert panel reached a strong consensus (80-100% agreement) on several critical recommendations. It was agreed that osteoporosis in CKD is often asymptomatic, with fragility fractures being less common, and thus, early screening using dual-energy X-ray absorptiometry (DXA) is essential. The panel emphasized the importance of evaluating bone turnover status using serum biomarkers such as bone-specific alkaline phosphatase (BSAP) and intact parathyroid hormone (iPTH) to guide treatment decisions. Tailored treatment strategies were recommended, with a judicious use of bisphosphonates and denosumab, depending on the patient’s estimated glomerular filtration rate (eGFR) and bone turnover state. The management of renal osteodystrophy (ROD) was deemed necessary before addressing CKD-induced osteoporosis.ConclusionThis expert consensus provides critical insights and guidance for the management of osteoporosis in CKD. The recommendations emphasize individualized treatment approaches, the importance of early screening, and the integration of multidisciplinary care. These findings aim to fill existing knowledge gaps and improve clinical outcomes for CKD patients with osteoporosis.

Chronic kidney disease (CKD) often leads to mineral and bone disorders (CKD-MBD), which compromise bone quality and increase fracture risk. These bone complications frequently persist after kidney transplantation (K-Tx), primarily due to the lingering effects of pre-existing CKD-MBD. Our aim was to evaluate CKD-MBD biomarkers, bone turnover markers, vitamin K-dependent protein (VKDP) levels, and bone microarchitecture using HR-pQCT at the time of K-Tx (T0) and 12 months post-transplant (T2). The main objective was to establish the association between VKDPs and HR-pQCT-derived bone quality parameters. We analyzed data from a cohort of 61 K-Tx patients: mean age 50.9 ± 13.3 years, 67% male, 25 patients (41%) underwent pre-emptive K-Tx, median dialysis duration 12 months (36 patients, 59%), diabetes prevalence 25%, fracture history 32%. The median cumulative total steroid dose was 1194 mg of prednisone equivalent. The following CKD-MBD serum biomarkers and bone turnover markers were measured: 25(OH)D, 1,25(OH)2D, PTH, Bone ALP, P1NP, CTX, cFGF23, Klotho, IGF1, phosphate, calcium. Vitamin K-related proteins included Bone Gla Protein (BGP), undercarboxylated BGP (ucBGP), Matrix Gla Protein, and dephosphorylated-uc MGP (dp-ucMGP). In addition to HR-pQCT of the tibia and radius, DEXA scans of the lumbar spine, hip, and radius were performed at baseline and 12 months post-K-Tx. Spearman correlation (ρ, rho) was assessed between the percentage change in VKDPs, bone biomarkers (PTH, cFGF23), bone turnover markers (P1NP, CTX, Bone ALP), and the percentage change in HR-pQCT parameters of the tibia and radius. Significant improvements were observed in all CKD-MBD biomarkers and bone turnover markers 12 months post-transplant, except for Bone ALP and Klotho levels. PTH decreased from 100 to 27 ng/L, and CTX from 1524 to 246 pg/ml (Fig. 1). VKDP levels also showed significant improvement. The prevalence of vitamin K deficiency, based on a cut-off level of uc-BGP ≥4.5 ng/ml, decreased from 77% to 32% (P < 0.01, Delta % [median and IQR]: −55.22 [−69.50, −24.33]). Using a cut-off level of dp-uc MGP >500 pmol/L, the prevalence of vitamin K deficiency decreased non-significantly from 97% to 79% (P = 0.06). Our findings indicate significant inverse correlations between % Δ uc-BGP and Radius Total Volumetric BMD (r = −0.37, P < 0.05), Failure Load (r = −0.51, P < 0.05), and Stiffness (r = −0.49, P < 0.05). However, correlations between % Δ uc-BGP and Tibial parameters, including Tibial Total Volumetric BMD (r = −0.08), Failure Load (r = −0.11), and Stiffness (r = −0.11), did not reach statistical significance (P > 0.05) (Fig. 2). Our data confirm an improvement in vitamin K status one year after K-Tx. Additionally, the inverse correlation between ucBGP and bone quality parameters assessed by HR-pQCT underscores the crucial role of BGP in bone health. To our knowledge, these are the first reported data in the literature.

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Background/Objectives: Chronic kidney disease and mineral bone disorders (CKD-MBD) are frequently associated with an increased risk of both vascular calcifications (VCs) and bone fractures (BFs). The complex pathogenesis of VCs and BFs involves various factors such as calcium overload, phosphate imbalance, and secondary hyperparathyroidism. Key players, such as the vitamin K-dependent proteins (VKDPs) matrix Gla protein (MGP) and bone Gla protein (BGP), have pivotal roles both for VCs and BFs. The VIKI study highlighted that hemodialysis patients treated with calcimimetics had higher levels of total BGP and MGP compared to those untreated, suggesting a potential protective effect of these drugs on BFs and VCs beyond the beneficial effect of reducing PTH levels. Methods: ETERNITY-ITA is a multi-center, comparative effectiveness, observational, longitudinal study that will enroll 160 hemodialysis patients (80 patients treated with Etelcalcetide and 80 age- and sex-matched patients treated with calcitriol or vitamin D analogs). Nephrologists will tailor the target dose of Etelcalcetide on an individual level to achieve the KDIGO PTH target. In the Etelcalcetide-treated group, the addition of calcitriol will be allowed when required by clinical practice (for correction of hypocalcemia). Conclusions: This study will evaluate the real-world effect of Etelcalcetide on VKDP levels, such as BGP and MGP, at 3, 9, and 18 months from baseline. The resulting preservation of vascular and bone health will be assessed for the first time by examining aortic and iliac artery calcifications and vertebral fractures, respectively.

A 63-yr-old woman with end-stage CKD secondary to glomerulonephritis, on hemodialysis therapy, presented with scoliosis, back pain, and progressive loss of physical function for which corrective surgery was planned. Optimization of bone health was requested by the surgeon as a DXA scan had revealed osteoporosis at spine, hip, and forearm. Due to previous subtotal parathyroidectomy and normal parathyroid hormone and bone-specific alkaline phosphatase levels, a low bone turnover state was suspected. An iliac bone biopsy was performed and revealed low bone turnover, a mineralization defect, and severe osteoporosis. The patient was treated with calcium and intensified vitamin D supplementation, followed by a 2-yr course of teriparatide. Monitoring of bone turnover markers indicated a bone anabolic response to therapy, and a repeat DXA showed increases in BMD at spine and hip. A repeat biopsy at end of treatment showed normal bone turnover and mineralization. This case demonstrates the complicated bone health of patients with advanced CKD. As there are no randomized trials for fracture pretention in patients with CKD, care must be individualized and is often based on expert opinion. The use of bone biopsy is safe and informative in guiding therapy.

Patients with end-stage kidney disease (ESKD) constitute a high-morbidity population.1 In addition to contending with high cardiovascular disease burden, the ESKD population experiences fractures at much higher rates and with worse outcomes compared to the general population.2,3 Because extremely high parathyroid hormone (PTH) levels contribute to hyperparathyroid bone disease and are associated with increased fracture rates,4 reduction of elevated PTH levels through medications or parathyroidectomy has been the mainstay of treatment to protect bone strength in patients with ESKD.

Context Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown.Methods We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics.Results In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median similar to 7 years of pegvisomant. In the cross-sectional study, patients on a median similar to 9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time.Conclusion In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Purpose of review Renal osteodystrophy (ROD) is a complex disorder of bone metabolism that affects virtually all adults and children with chronic kidney disease (CKD). ROD is associated with adverse clinical outcomes including bone loss, mineralization and turnover abnormalities, skeletal deformities, fractures, cardiovascular events, and death. Despite current therapies, fracture incidence is 2-fold to 100-fold higher in adults and 2-fold to 3-fold higher in children when compared to without CKD. Limited knowledge of ROD pathogenesis, due to the lack of patient-derived large-scale multimodal datasets, impedes development of therapeutics aimed at reducing morbidity and mortality of CKD patients. The purpose of the review is to define the much needed infrastructure for the advancement of RDO treatment. Recent findings Recently, we created a large-scale data and tissue biorepository integrating clinical, bone quality, transcriptomic, and epigenomic data along with stored urine, blood, and bone samples. This database will provide the underpinnings for future research endeavors leading to the elucidation and characterization of the pathogenesis of ROD in CKD patients with and without dialysis. Summary The availability of an open-access NIH-funded resource that shares bone-tissue-based information obtained from patients with ROD with the broad scientific community represents a critical step in the process of discovering new information regarding unrecognized bone changes that have severe clinical complications. This will facilitate future high-impact hypothesis-driven research to redefine our understanding of ROD pathogenesis and pathophysiology and inform the development of disease-modifying and prevention strategies

Columbia University Irving Medical Center, New York, New York Correspondence: Dr. Thomas L. Nickolas, Columbia University Irving Medical Center, 622 West 168th Street, PH4-124, New York, NY 10032. Email: [email protected] See related article, “Long-Term Effect of Denosumab on Bone Disease in Patients with CKD,” on pages 1195–1203.