Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Retrospective Characterization of Bone Histomorphometric Findings in Clinical Patient Specimens.

BACKGROUND: Bone histomorphometry provides comprehensive information on bone metabolism and microstructure. In this retrospective study, we aimed to obtain an overview of the typical indications, referring hospitals, and histomorphometric quantification-based diagnoses of the bone tissue in our histomorphometry laboratory, the only laboratory in Finland carrying out histomorphometric examination of clinical bone biopsies. METHODS: Between January 1, 2005 and December 31, 2020, 553 clinical bone biopsies were sent to our histomorphometry laboratory for histomorphometric examination. The median age of the patients was 55 years (range, 0.2-89.9 years), 51% of them were males, and 18% comprised pediatric patients. We received bone biopsy specimens from 23 hospitals or healthcare units. The majority of the samples we sent by nephrologists. RESULTS: The most common bone biopsy indications were suspicion of renal osteodystrophy (ROD), unknown bone turnover status in osteoporosis, and several or untypical fractures. The most common quantitative bone histomorphometry-based diagnosis was ROD. CONCLUSIONS: This study provides information on the clinical application of bone histomorphometry in Finland. Precise and quantitative ROD evaluation is the most common indication for bone histomorphometry, being crucial in clinical decision-making and targeted treatment of this patient group.

Current therapeutic approach of chronic kidney disease-mineral and bone disorder.

Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD-mineral and bone disorder (CKD-MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD-MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD-MBD, anti-osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD-MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD-MBD based on the current literature with special attention to recent advances.

Renal osteodystrophy and clinical outcomes: a prospective cohort study / Osteodistrofia renal e desfechos clínicos: um estudo de coorte prospectivo

Abstract Introduction: Renal osteodystrophy (ROD) refers to a group of bone morphological patterns that derive from distinct pathophysiological mechanisms. Whether the ROD subtypes influence long-term outcomes is unknown. Our objective was to explore the relationship between ROD and clinical outcomes. Methods: This study is a subanalysis of the Brazilian Registry of Bone Biopsies (REBRABO). Samples from individual patients were classified as having osteitis fibrosa (OF), mixed uremic osteodystrophy (MUO), adynamic bone disease (ABD), osteomalacia (OM), normal/minor alterations, and according to turnover/mineralization/volume (TMV) system. Patients were followed for 3.4 yrs. Clinical outcomes were: bone fractures, hospitalization, major adverse cardiovascular events (MACE), and death. Results: We enrolled 275 participants, of which 248 (90%) were on dialysis. At follow-up, 28 bone fractures, 97 hospitalizations, 44 MACE, and 70 deaths were recorded. ROD subtypes were not related to outcomes. Conclusion: The incidence of clinical outcomes did not differ between the types of ROD.

Resumo Introdução: Osteodistrofia renal (OR) refere-se a um grupo de padrões morfológicos ósseos que decorrem de mecanismos fisiopatológicos distintos. É desconhecido se os subtipos de OR influenciam desfechos em longo prazo. Nosso objetivo foi explorar as relações entre OR e desfechos. Métodos: Este estudo é uma subanálise do Registro Brasileiro de Biópsias Ósseas (REBRABO). As amostras de cada paciente foram classificadas em osteíte fibrosa (OF), osteodistrofia urêmica mista (MUO), doença óssea adinâmica (ABD), osteomalácia (OM), alterações normais/menores, e pelo sistema Remodelação / Mineralização / Volume (RMV). Os pacientes foram acompanhados por 3,4 anos. Os eventos clínicos foram: fraturas ósseas, hospitalizações, eventos cardiovasculares adversos maiores (MACE), e óbito. Resultados: Analisamos 275 indivíduos, 248 (90%) deles estavam em diálise. No acompanhamento, 28 fraturas ósseas, 97 hospitalizações, 44 MACE e 70 óbitos foram registrados. Os subtipos de OR não foram relacionados aos desfechos clínicos. Conclusão: A incidência de desfechos clínicos não diferiu entre os tipos de OR.

Bone turnover prediction in patients with chronic kidney disease (CKD) undergoing hemodialysis using shortened dynamic 18F-NaF PET/CT Ki-Patlak.

This study investigated whether Ki-Patlak derived from a shortened scan time for dynamic 18F-NaF PET/CT in chronic kidney disease (CKD) patients undergoing hemodialysis can provide predictive accuracy comparable to that obtained from a longer scan. Twenty-seven patients on chronic hemodialysis, involving a total of 42 scans between December 2021 and August 2023 were recruited. Dynamic 18F-NaF PET/CT scans, lasting 60-90 min, were immediately acquired post-injection, covering the mid-twelfth thoracic vertebra to the pelvis region. Ki-Patlak analysis was performed on bone time-activity curves at 15, 30, 45, 60, and 90 min in the lumbar spine (L1-L4) and both anterior iliac crests. Spearman's rank correlation (rs) and interclass correlation coefficient were used to assess the correlation and agreement of Ki-Patlak between shortened and standard scan times. Bone-specific alkaline phosphatase (BsAP) and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) were tested for their correlation with individual Ki-Patlak. Strong correlations and good agreement were observed between Ki-Patlak values from shortened 30-min scans and longer 60-90-min scans in both lumbar spine (rs = 0.858, p < 0.001) and anterior iliac crest regions (rs = 0.850, p < 0.001). The correlation between BsAP and Ki-Patlak in the anterior iliac crests was weak and statistically insignificant. This finding suggests that a proposed shortened dynamic 18F-NaF PET/CT scan is effective in assessing bone metabolic flux in CKD patients undergoing hemodialysis, offering a non-invasive alternative approach for bone turnover prediction.

Non-traumatic Simultaneous Bilateral Femur Neck Fracture in a Young Female Unraveling End-Stage Renal Disease: A Case Report and Literature Review.

Introduction: Spontaneous femur neck fracture is rare, especially when they occur bilaterally. Renal osteodystrophy is among the causes of these fractures that should be kept in mind. We report a case of a young female who presented with bilateral hip pain and was found to have bilateral femur neck fracture due to renal osteodystrophy. This was the first presentation of an undiagnosed end-stage kidney disease. This case report aims to highlight the importance of investigating the cause of these rare fractures in young patients and discuss available surgical options. Case Report: A 19-year-old female presented complaining of bilateral hip pain. On physical examination, there was tenderness on palpation of both thighs. Her workup was significant for anemia, a high level of creatinine, hypocalcemia, elevated alkaline phosphatase, and parathyroid hormone. A pelvis radiograph showed bilateral femur neck fracture. Considering her very young age, the metabolic derangements she had and to avoid exposing her to a major surgery, we treated her fractures by fixation using three cannulated screws on each side. We aimed to report this case as it is an unusual presentation of a previously undetected stage 5 chronic kidney disease (CKD) in a very young patient. Conclusion: Renal osteodystrophy due to CKD can present with spontaneous bilateral femur neck fracture. Physicians should have a high index of suspicion for this condition not to miss a chronic disease with multiple sequelae. Furthermore, these fractures carry a high risk of complications and mortality, so they should be addressed promptly.

Ten tips on how to assess bone health in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) experience a several-fold increased risk of fracture. Despite the high incidence and the associated excess morbidity and premature mortality, bone fragility in CKD, or CKD-associated osteoporosis, remains a blind spot in nephrology with an immense treatment gap. Defining the bone phenotype is a prerequisite for the appropriate therapy of CKD-associated osteoporosis at the patient level. In the present review, we suggest 10 practical 'tips and tricks' for the assessment of bone health in patients with CKD. We describe the clinical, biochemical, and radiological evaluation of bone health, alongside the benefits and limitations of the available diagnostics. A bone biopsy, the gold standard for diagnosing renal bone disease, is invasive and not widely available; although useful in complex cases, we do not consider it an essential component of bone assessment in patients with CKD-associated osteoporosis. Furthermore, we advocate for the deployment of multidisciplinary expert teams at local, national, and potentially international level. Finally, we address the knowledge gaps in the diagnosis, particularly early detection, appropriate "real-time" monitoring of bone health in this highly vulnerable population, and emerging diagnostic tools, currently primarily used in research, that may be on the horizon of clinical practice.

A challenging case of severe bilateral septic arthritis with osteomyelitis of the sternoclavicular joint in a patient with end-stage renal disease.

Septic arthritis of the sternoclavicular joint (SCJ) is a rare condition that comprises <1% of all joint infections. We report a case of severe bilateral septic arthritis of the SCJ in a patient with end-stage renal disease on peritoneal dialysis. A 44-year-old female presented with right SCJ infection 1 month after recovering from a tenckhoff catheter exit-site infection. She completed 6 weeks of antibiotics however this progressed to bilateral SCJ septic arthritis with osteomyelitis necessitating multiple surgical debridement and excision of bilateral clavicular heads. Further imaging showed signs of renal osteodystrophy and degenerative joint changes resembling calcium pyrophosphate deposition. Patients with end-stage renal disease have multiple risk factors including immune system dysfunction, renal osteodystrophy and dialysis access sites that increase susceptibility to bacteraemia and seeding. Therefore in such patients, prompt assessment is necessary to ensure expeditious diagnosis and treatment of this potentially debilitating condition. A multidisciplinary team involving various specialties is crucial for the holistic care for such patients and to reduce the risk of recurrence.

Diagnosis and therapeutic decisions of osteoporosis in chronic kidney disease.

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.

Vascular calcification in peritoneal dialysis patients and its association with bone-derived molecules and bone histomorphometry / Calcificación vascular en pacientes en diálisis peritoneal y su asociación con moléculas derivadas de hueso e histomorfometría ósea

Introduction: Data regarding vascular calcification (VC) in contemporary peritoneal dialysis (PD) patients is scarce. Bone–vascular axis has been demonstrated in hemodialysis (HD). However, studies showing the link between bone disease and VC in PD patients are lacking. The role of sclerostin, dickkopf-related protein 1 (DKK-1), receptor activator for nuclear factor kB ligand and osteoprotegerin (OPG) in VC in PD remains to clarify. Materials and methods: Bone biopsy was performed in 47 prevalent PD patients with histomorphometric analysis. Patients were submitted to pelvis and hands X-ray to evaluate VC using the Adragão score (AS). Relevant clinical and biochemical data was collected. Results: Thirteen patients (27.7%) had positive AS (AS≥1). Patients with VC were significantly older (58.9 vs. 50.4 years, p=0.011), had a lower dialysis dose (KT/V 2.0 vs. 2.4, p=0.025) and a higher glycosylated hemoglobin (7.2 vs. 5.4%, p=0.001). There was not any laboratorial parameter of mineral and bone disease used in clinical practice different between patients with or without VC. All diabetic patients had VC but only 8.1% of non-diabetic had VC (p<0.001). Patients with VC showed significantly higher erythrocyte sedimentation rate (ESR) (91.1 vs. 60.0mm/h, p=0.001), sclerostin (2250.0 vs. 1745.8pg/mL, p=0.035), DKK-1 (1451.6 vs. 1042.9pg/mL, p=0.041) and OPG levels (2904.9 vs. 1518.2pg/mL, p=0.002). On multivariate analysis, only ESR remained statistically significant (OR 1.07; 95% CI 1.01–1.14; p=0.022). Bone histomorphometric findings were not different in patients with VC. There was no correlation between bone formation rate and AS (r=−0.039; p=0.796). Conclusion: The presence of VC was not associated with bone turnover and volume evaluated by bone histomorphometry. Inflammation and diabetes seem to play a more relevant role in VC in PD. (AU)

Introducción Los datos sobre calcificación vascular (CV) en pacientes contemporáneos en diálisis peritoneal (DP) son escasos. En pacientes en hemodiálisis, se ha demostrado la existencia de una conexión entre hueso y sistema vascular; sin embargo, faltan estudios que muestren el vínculo entre la enfermedad ósea y la CV en pacientes en DP. Si la esclerostina, la proteína relacionada con Dickkopf 1 (DKK-1), el ligando del receptor activador para el factor nuclear κB (RANKL) y la osteoprotegerina (OPG) tienen un papel en la CV en pacientes en DP aún no está claro. Materiales y métodos Se realizó biopsia ósea en 47 pacientes prevalentes en DP y se analizó mediante histomorfometría. También se tomaron radiografías de pelvis y manos a los pacientes para evaluar la CV mediante el Índice de Adragão (IA). Además, se analizaron datos clínicos y bioquímicos relevantes. Resultados: Trece pacientes (27,7%) tuvieron IA positivo (IA ≥ 1). Los pacientes con CV eran significativamente mayores (58,9 vs 50,4 años, p=0,011) tenían menor dosis de diálisis (KT/V 2,0 vs 2,4, p=0,025) y niveles más elevados de hemoglobina glicosilada (7,2 vs 5,4%, p=0,001). No hubo ningún parámetro de laboratorio de enfermedad mineral y ósea utilizado en la práctica clínica diferente entre pacientes con o sin CV. Todos los pacientes diabéticos mostraron CV, sin embargo, solo el 8,1% de los no diabéticos tenían CV (p <0,001). Además, los pacientes con CV mostraron una velocidad de sedimentación globular más elevada (VSG) (91,1 vs. 60,0mm/h, p=0,001) y mayores concentraciones séricas de esclerostina (2.250,0 vs. 1.745,8 pg/ml, p=0,035), DKK-1 (1451,6 vs 1042,9 pg/ml, p=0,041) y OPG (2.904,9 vs. 1.518,2 pg/ml, p=0,002). En el análisis multivariante, solo la VSG fue estadísticamente significativa (OR 1,07; IC del 95%: 1,01-1,14; p=0,022)... (AU)

Bone and bone derived factors in kidney disease.

Purpose of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality. Despite its pervasive nature, effective treatments for CKD-MBD are lacking, emphasizing the urgency to advance understanding and therapeutic interventions. Bone metabolism intricacies, influenced by factors like 1,25 dihydroxy vitamin D, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), along with intrinsic osseous mechanisms, play pivotal roles in CKD. Skeletal abnormalities precede hormonal changes, persisting even with normalized systemic mineral parameters, necessitating a comprehensive approach to address both aspects. Recent findings: In this review, we explore novel pathways involved in the regulation of systemic mineral bone disease factors, specifically examining anemia, inflammation, and metabolic pathways. Special emphasis is placed on internal bone mechanisms, such as hepatocyte nuclear factor 4α, transforming growth factor-ß1, and sclerostin, which play crucial roles in the progression of renal osteodystrophy. Summary: Despite advancements, effective treatments addressing CKD-MBD morbidity and mortality are lacking, necessitating ongoing research for novel therapeutic targets.

Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview.

Chronic kidney disease (CKD) is a global health issue with a rising prevalence, affecting 697.5 million people worldwide. It imposes a substantial burden, contributing to 35.8 million disability-adjusted life years (DALYs) and 1.2 million deaths in 2017. The mortality rate for CKD has increased by 41.5% between 1990 and 2017, positioning it as a significant cause of global mortality. CKD is associated with diverse health complications, impacting cardiovascular, neurological, nutritional, and endocrine aspects. One prominent complication is CKD-mineral and bone disorder (MBD), a complex condition involving dysregulation of bone turnover, mineralization, and strength, accompanied by soft tissue and vascular calcification. Alterations in mineral metabolism, including calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and Klotho, play pivotal roles in CKD-MBD. These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy (ROD). Vascular calcification (VC) is a key component of CKD-MBD, accelerated by CKD. The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). VC is closely linked to cardiovascular events and mortality, emphasizing its prognostic significance. Various serum markers and imaging techniques, including lateral plain X-ray, Kauppila Score, Adragao Score, and pulse wave velocity, aid in VC detection. Additionally, pQCT provides valuable information on arterial calcifications, offering an advantage over traditional scoring systems. CKD poses a substantial global health burden, and its complications, including CKD-MBD and VC, significantly contribute to morbidity and mortality. Understanding the intricate relationships between mineral metabolism, bone disorders, and vascular calcification is crucial for effective diagnosis and therapeutic interventions.

Bone Health ECHO Case Report: Fractures and Hypercalcemia in a Patient with Stage 5 Chronic Kidney Disease.

Bone Health ECHO (Extension for Community Healthcare Outcomes) is a virtual community of practice with the aim of enhancing global capacity to deliver best practice skeletal healthcare. The prototype program, established at the University of New Mexico, has been meeting online weekly since 2015, focusing on presentation and discussion of patient cases. These discussions commonly cover issues that are relevant to a broad range of patients, thereby serving as a force multiplier to improve the care of many patients. This is a case report from Bone Health ECHO about a patient with stage 5 chronic kidney disease, hypercalcemia, and low bone density, and the discussion that followed.

Potential Role of Bone Metabolism Markers in Kidney Transplant Recipients.

BACKGROUND: The impact of treatments, suppressing the immune system, persistent hyperparathyroidism, and other risk factors on mineral and bone disorder (MBD) after kidney transplantation is well-known. However, there is limited knowledge about their effect on bone metabolism biomarkers. This study aimed to investigate the influence of kidney transplant on these markers, comparing them to patients undergoing hemodialysis and healthy individuals. METHODS: In this cross-sectional study, three groups were included: kidney transplant patients (n = 57), hemodialysis patients (n = 26), and healthy controls (n = 31). Plasma concentrations of various bone metabolism biomarkers, including Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, and fibroblast growth factor 23, were measured. Associations between these biomarkers and clinical and laboratory data were evaluated. RESULTS: A total of 114 patients participated. Transplant recipients had significantly lower levels of Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, and fibroblast growth factor 23 compared to hemodialysis patients. Alkaline phosphatase levels positively correlated with osteopontin (r = 0.572, p < 0.001), while fibroblast growth factor 23 negatively correlated with 25-hydroxyvitamin D (r = -0.531, p = 0.019). The panel of bone biomarkers successfully predicted hypercalcemia (area under the curve [AUC] = 0.852, 95% confidence interval [CI] = 0.679-1.000) and dyslipidemia (AUC = 0.811, 95% CI 0.640-0.982) in transplant recipients. CONCLUSION: Kidney transplantation significantly improves mineral and bone disorders associated with end-stage kidney disease by modulating MBD markers and reducing bone metabolism markers, such as Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, and sclerostin. Moreover, the panel of bone biomarkers effectively predicted hypercalcemia and dyslipidemia in transplant recipients.

Sagliker Syndrome in a Patient With Secondary Hyperparathyroidism and Chronic Kidney Disease: A Case Report From Palestine.

Sagliker syndrome (SS) is a rare complication in patients with chronic kidney disease (CKD) on prolonged dialysis due to uncontrolled secondary hyperparathyroidism (SHPT). SS manifests with a constellation of clinical manifestations, including short stature, craniomaxillofacial abnormalities, hearing loss, and neuropsychiatric disorders. This article reports a 33-year-old male patient with CKD who complained of progressive disfiguring facial changes, multiple recurrent fractures, and shortened height. The condition affects his quality of life. On workup, his lab results showed highly elevated serum levels of parathyroid hormone, alkaline phosphatase (ALP), calcium, and phosphate. His comorbidities and poor health status limit his ability to do parathyroidectomy (Ptx). A reliable diagnostic approach must be considered, enabling physicians to make earlier interventions and get better outcomes.

Quantitative 31P magnetic resonance imaging on pathologic rat bones by ZTE at 7T.

BACKGROUND: Osteoporosis is characterized by low bone mineral density (BMD), which predisposes individuals to frequent fragility fractures. Quantitative BMD measurements can potentially help distinguish bone pathologies and allow clinicians to provide disease-relieving therapies. Our group has developed non-invasive and non-ionizing magnetic resonance imaging (MRI) techniques to measure bone mineral density quantitatively. Dual-energy X-ray Absorptiometry (DXA) is a clinically approved non-invasive modality to diagnose osteoporosis but has associated disadvantages and limitations. PURPOSE: Evaluate the clinical feasibility of phosphorus (31P) MRI as a non-invasive and non-ionizing medical diagnostic tool to compute bone mineral density to help differentiate between different metabolic bone diseases. MATERIALS AND METHODS: Fifteen ex-vivo rat bones in three groups [control, ovariectomized (osteoporosis), and vitamin-D deficient (osteomalacia - hypo-mineralized) were scanned to compute BMD. A double-tuned (1H/31P) transmit-receive single RF coil was custom-designed and in-house-built with a better filling factor and strong radiofrequency (B1) field to acquire solid-state 31P MR images from rat femurs with an optimum signal-to-noise ratio (SNR). Micro-computed tomography (µCT) and gold-standard gravimetric analyses were performed to compare and validate MRI-derived bone mineral densities. RESULTS: Three-dimensional 31P MR images of rat bones were obtained with a zero-echo-time (ZTE) sequence with 468 µm spatial resolution and 12-17 SNR on a Bruker 7 T Biospec having multinuclear capability. BMD was measured quantitatively on cortical and trabecular bones with a known standard reference. A strong positive correlation (R = 0.99) and a slope close to 1 in phantom measurements indicate that the densities measured by 31P ZTE MRI are close to the physical densities in computing quantitative BMD. The 31P NMR properties (resonance linewidth of 4 kHz and T1 of 67 s) of ex-vivo rat bones were measured, and 31P ZTE imaging parameters were optimized. The BMD results obtained from MRI are in good agreement with µCT and gravimetry results. CONCLUSION: Quantitative measurements of BMD on ex-vivo rat femurs were successfully conducted on a 7 T preclinical scanner. This study suggests that quantitative measurements of BMD are feasible on humans in clinical MRI with suitable hardware, RF coils, and pulse sequences with optimized parameters within an acceptable scan time since human femurs are approximately ten times larger than rat femurs. As MRI provides quantitative in-vivo data, various systemic musculoskeletal conditions can be diagnosed potentially in humans.

Plasma activin A rises with declining kidney function and is independently associated with mortality in patients with chronic kidney disease.

Background: Plasma (p-)activin A is elevated in chronic kidney disease-mineral and bone disorder (CKD-MBD). Activin A inhibition ameliorates CKD-MBD complications (vascular calcification and bone disease) in rodent CKD models. We examined whether p-activin A was associated with major adverse cardiovascular events (MACE), all-cause mortality and CKD-MBD complications in CKD patients. Methods: The study included 916 participants (741 patients and 175 controls) from the prospective Copenhagen CKD cohort. Comparisons of p-activin A with estimated glomerular filtration rate (eGFR), coronary and thoracic aorta Agatston scores, and bone mineral density (BMD) were evaluated by univariable linear regression using Spearman's rank correlation, analysis of covariance and ordinal logistic regression with adjustments. Association of p-activin A with rates of MACE and all-cause mortality was evaluated by the Aalen-Johansen or Kaplan-Meier estimator, with subsequent multiple Cox regression analyses. Results: P-activin A was increased by CKD stage 3 (124-225 pg/mL, P < .001) and correlated inversely with eGFR (r = -0.53, P < 0.01). P-activin A was associated with all-cause mortality [97 events, hazard ratio 1.55 (95% confidence interval 1.04; 2.32), P < 0.05] after adjusting for age, sex, diabetes mellitus (DM) and eGFR. Median follow-up was 4.36 (interquartile range 3.64-4.75) years. The association with MACE was not significant after eGFR adjustment. Agatston scores and BMD were not associated with p-activin A. Conclusion: P-activin A increased with declining kidney function and was associated with all-cause mortality independently of age, sex, DM and eGFR. No association with MACE, vascular calcification or BMD was demonstrated.

Trabecular bone score as a marker of skeletal fragility across the spectrum of chronic kidney disease: a systematic review and meta-analysis.

CONTEXT: The impairment of bone microarchitecture is a key determinant of skeletal fragility in patients with chronic kidney disease (CKD). Trabecular bone score (TBS) has been developed as a reliable non-invasive index of bone quality. However, its utility in this setting is still debated. OBJECTIVE: The aim of this systematic review and meta-analysis was to summarize the available evidence about TBS as a marker of skeletal fragility across the spectrum of CKD. METHODS: PubMed/Medline, EMBASE and Cochrane Library databases were systematically searched until July 2023 for studies reporting data about TBS in patients with CKD. Effect sizes were pooled through a random-effect model. RESULTS: Compared to controls, lower TBS values were observed in CKD patients not on dialysis (-0.057, 95%CI:[-0.090, -0.024], p < 0.01), in dialysis patients (-0.106, 95%CI:[-0.141, -0.070], p < 0.01) and in kidney transplant recipients (KTRs) (-0.058, 95%CI:[-0.103, -0.012], p = 0.01). With respect to fracture risk, TBS was able to predict incident fractures in non-dialysis patients at unadjusted analyses (hazard ratio (HR) per standard deviation decrease: 1.45, 95%CI:[1.05,2.00], p = 0.02), though only a non-significant trend was maintained when fully adjusting the model for FRAX® (HR = 1.26, 95%CI:[0.88,1.80], p = 0.21). Dialysis patients with prevalent fractures had lower TBS values compared to unfractured ones (-0.070, 95% CI:[-0.111, -0.028], p < 0.01). Some studies supported a correlation between TBS and fracture risk in KTRs, but results could not be pooled due to the lack of sufficient data. CONCLUSIONS: CKD patients are characterized by an impairment of bone microarchitecture, as demonstrated by lower TBS values, across the whole spectrum of kidney disease. TBS can also be helpful in the discrimination of fracture risk, with lower values being correlated with a higher risk of prevalent and incident fractures.

Bone marrow-derived exosomes promote inflammation and osteoclast differentiation in high-turnover renal osteodystrophy.

Introduction: Renal osteodystrophy (ROD) is a type of bone metabolic disorder in patients with chronic kidney disease (CKD). Inflammation is associated with bone loss in ROD. However, its precise mechanism has not yet been elucidated. The present study was conducted to investigate whether exosomes (Exos) in bone marrow (BM) are involved in the pathogenesis of high-turnover ROD.Methods: Bone mass, osteoclast number, and pro-inflammatory cytokines levels of BM supernatant were detected in adenine-induced ROD rats. The effect of Exos derived from BM (BM-Exos) of ROD (ROD-Exos) on inflammatory genes and osteoclast differentiation of BM-derived macrophages (BMMs) were further examined. Then, exosomal miRNA sequencing was performed and an miRNA-mRNA-pathway network was constructed.Results: we found increased osteoclasts and decreased bone mass in ROD rats, as well as inflammatory activation in the BM niche. Furthermore, BMMs from ROD rats displayed overproduction of proinflammatory cytokines and increased osteoclast differentiation, accompanied by nuclear factor κB (NF-κB) signaling activation. Mechanistically, we found that ROD-Exos activates NF-κB signaling to promote the release of proinflammatory cytokines and increase osteoclast differentiation of BMMs. Meanwhile, a total of 24 differentially expressed miRNAs were identified between BM-Exos from ROD and normal control (NC). The miRNA-mRNA-pathway network suggests that rno-miR-9a-5p, rno-miR-133a-3p, rno-miR-30c-5p, rno-miR-206-3p, and rno-miR-17-5p might play pivotal roles in inflammation and osteoclast differentiation. Additionally, we validated that the expression of miR-9a-5p is upregulated in ROD-Exos.Conclusion: The BM niche of ROD alters the miRNA cargo of BM-Exos to promote inflammation and osteoclast differentiation of BMMs, at least partially contributing to the pathogenesis of high-turnover ROD.