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 β‐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.
In vivo studies used 5/6 nephrectomy with parathyroidectomy and replacement of exogenous PTH to eliminate the osteogenic effect of PTH comparing the bone effects of calcitriol vs calcimimetic. The osteogenesis of mesenchymal stem cells in presence of calcitriol was also evaluated. Results show calcimimetic increases bone formation, while calcitriol reduces it. In vitro, calcitriol presence reduces mineralization and osteogenesis of stem cells into osteoblasts. In this experimental study and independently of PTH, we demonstrate that calcitriol administration reduces bone formation.
Chronic kidney disease–mineral and bone disorder (CKD-MBD) encompasses laboratory and bone abnormalities and vascular calcification and has deleterious effects on clinical outcomes. KDOQI (Kidney ...Disease Outcomes Quality Initiative), an initiative of the National Kidney Foundation, addressed this issue with the publication of a clinical practice guideline for bone metabolism and disease in CKD in 2003, and 2 years later, a new definition and classification scheme for CKD-MBD was developed following a KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference. The initial KDIGO guideline on CKD-MBD was then published in 2009. New evidence was subsequently reviewed at the 2013 KDIGO Controversies Conference, and in 2017, KDIGO issued a clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. This commentary presents the views of the KDOQI CKD-MBD work group convened by the National Kidney Foundation. The KDOQI work group agrees with most of the KDIGO guideline update recommendations, particularly the suggestions regarding bone mineral density testing, joint assessments of longitudinal trends in mineral metabolism markers, and dietary phosphate counseling focused on phosphate additives. However, the KDOQI work group has some concerns about the suggestions related to hypocalcemia and hypercalcemia, phosphate-binder choice, and treatment of abnormal parathyroid hormone concentrations. The overall goal of this commentary is to provide a broad discussion for the US nephrology community regarding CKD-MBD and its diagnosis, prevention, and treatment.
The prevalence of vitamin D deficiency is high in patients with chronic kidney disease (CKD). Vitamin D deficiency is associated with various bone disorders such as osteoporosis by affecting bone ...mineralization. Current international guidelines recommend vitamin D supplementation in CKD as well as in the general population. However, the effect of various forms of vitamin D on bone health in CKD remains unclear. Few randomized controlled studies have evaluated the effects of vitamin D supplementation on bone mineral density and bone turnover markers; however, the findings of these studies are heterogeneous. This review aimed to present comprehensive and current findings on the effects of native vitamin D supplementation on bone biomarkers and bone mineral density in CKD. We infered that native vitamin D treatment could improve some bone biomarkers, particularly in predialysis CKD patients with severe vitamin D deficiency. Our findings also draw attention to the fact that vitamin D is an important factor in treatment. However, it is essential to design better-quality and comprehensive controlled studies to obtain clear findings.
The diagnosis of renal osteodystrophy is challenging. Bone biopsy is the gold standard, but it is invasive and limited to one site of the skeleton. The ability of biomarkers to estimate the ...underlying bone pathology is limited. 18F-Sodium Fluoride positron emission tomography (18F-NaF PET) is a noninvasive quantitative imaging technique that allows assessment of regional bone turnover at clinically relevant sites. The hypothesis of this study was, that 18F-NaF PET correlates with bone histomorphometry in dialysis patients and could act as a noninvasive diagnostic tool in this patient group.
This was a cross-sectional diagnostic test study. 26 dialysis patients with biochemical abnormalities indicating mineral and bone disorder were included. All the participants underwent a 18F-NaF PET scan and a bone biopsy. Fluoride activity in the PET scan was measured in the lumbar spine and at the anterior iliac crest. Dynamic and static histomorphometric parameters of the bone biopsy were assessed. As histomorphometric markers for bone turnover we used bone formation rate per bone surface (BFR/BS) and activation frequency per year (Ac.f).
There was a statistically significant correlation between fluoride activity in the 18F-NaF PET scan and histomorphometric parameters such as bone formation rate, activation frequency and osteoclast and osteoblast surfaces and mineralized surfaces. 18F-NaF PET's sensitivity to recognize low turnover in respect to non-low turnover was 76% and specificity 78%. Because of the small number of patients with high turnover, we were unable to demonstrate significant predictive value in this group.
A clear correlation between histomorphometric parameters and fluoride activity in the 18F-NaF PET scan was established. 18F-NaF PET may possibly be a noninvasive diagnostic tool in dialysis patients with low turnover bone disease, but further research is needed.
•The diagnosis of subtypes of renal osteodystrophy is challenging.•Bone biopsy is the golden standard, but there is a need for a noninvasive method.•18F-PET correlates with histomorphometric markers in the bone biopsy.•18F-PET may work as a diagnostic method in dialysis patients with low turnover.
Abstract
Controlling the excessive fracture burden in patients with chronic kidney disease (CKD) Stages G4–G5D remains an impressive challenge. The reasons are 2-fold. First, the pathophysiology of ...bone fragility in patients with CKD G4–G5D is complex and multifaceted, comprising a mixture of age-related (primary male/postmenopausal), drug-induced and CKD-related bone abnormalities. Second, our current armamentarium of osteoporosis medications has not been developed for, or adequately studied in patients with CKD G4–G5D, partly related to difficulties in diagnosing osteoporosis in this specific setting and fear of complications. Doubts about the optimal diagnostic and therapeutic approach fuel inertia in daily clinical practice. The scope of the present consensus paper is to review and update the assessment and diagnosis of osteoporosis in patients with CKD G4-G5D and to discuss the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture. As such, it aims to stimulate a cohesive approach to the management of osteoporosis in patients with CKD G4–G5D to replace current variations in care and treatment nihilism.
Disorders of bone remodeling Feng, Xu; McDonald, Jay M
Annual review of pathology,
01/2011, Letnik:
6
Journal Article
Recenzirano
Odprti dostop
The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry ...out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms.
Histomorphometric analysis of a transiliac bone biopsy is the gold standard for the diagnosis of renal osteodystrophy (ROD). This procedure is costly, invasive and usually performed with a trephine ...with an internal diameter of 7.5 mm. Our objective was to evaluate the accuracy of ROD diagnosis on halved histological bone sections to determine if they are comparable to the standard 7.5 mm samples.
We included 68 bone biopsies performed in CKD patients for diagnostic purposes with a 7.5 mm diameter trephine. Quantitative histomorphometric analysis of the whole bone samples was performed including assessment of bone mineralization, turnover and volume. Each histological section (representing the whole 7.5 mm diameter biopsy) was then divided lengthwise in two hemisections (representing the 3.5 mm diameter biopsy). Histomorphometric analysis was repeated this time on the two hemibiopsies for each sample, blinded from initial results. Diagnoses were classified as osteitis fibrosa, adynamic bone disease, mixed uremic bone disease, osteomalacia or other. Correlations between the whole sample and the hemibiopsies for each parameter were studied. Concordance between the various bone parameters and final ROD diagnosis obtained from the whole section versus the two hemi sections was evaluated.
Highly significant correlations were found between parameters measured on the whole section and the corresponding hemisections, with r coefficient of 0.98 for osteoid surface and thickness and bone formation rate, 0.97 for osteoclast surface, and 0.96 for bone volume (p < 0.001). Final diagnosis was in full accordance between the whole biopsy and the two corresponding hemi-biopsies in 91% of cases.
Accurate diagnosis of ROD type was obtained by evaluation of bone surface areas of 3 mm diameter. These data suggest that small invasive bone biopsies might provide accurate ROD diagnostics while decreasing both invasiveness and cost of the procedure.
•Renal osteodystrophy (ROD) is associated with increased cardiovascular and fracture risks.•A bone biopsy is the only tool for accurate diagnosis of ROD.•7 mm-wide bone biopsies are invasive and less and less available worldwide.•Halved bone samples (3 mm) yield accurate diagnosis compared to full samples (7.5 mm).•Smaller trephines should be evaluated for less invasive and cheaper ROD management.
Abstract The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel ...cardiovascular risk factors have been identified. New advances in the causes of the CKD-MBD are discussed in this review. They demonstrate that repair and disease processes in the kidneys release factors to the circulation that cause the systemic complications of CKD. The discovery of WNT inhibitors, especially Dickkopf 1 (Dkk1), produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. This lead to the discovery that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, wherein it stimulates fibrosis, and decreases tubular klotho expression. Activin A binds to the type 2 activin A receptor, ActRIIA, which is variably affected by CKD in the vasculature. In diabetic/atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC), ActRIIA signaling is inhibited and contributes to CKD induced VSMC dedifferentiation, osteogenic transition and neointimal atherosclerotic calcification. In nondiabetic/nonatherosclerotic aortas, CKD increases VSMC ActRIIA signaling, and vascular fibroblast signaling causing the latter to undergo osteogenic transition and stimulate vascular calcification. In both vascular situations, a ligand trap for ActRIIA prevented vascular calcification. In the skeleton, activin A is responsible for CKD stimulation of osteoclastogenesis and bone remodeling increasing bone turnover. These studies demonstrate that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease.
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.
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.
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.
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.
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.
•There are no satisfactory non-ionizing and non-invasive methods to quantify BMD accurately in patients.•We report the feasibility of 31PMRI as a non-ionizing diagnostic tool to compute BMD.•Quantitative measurements of BMD are feasible on humans in clinical MRI with suitable hardware and pulse sequences within an acceptable scan time
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