Traditional and Non-traditional Risk Factors for Osteoporosis in CKD.

Osteoporosis is a state of bone fragility with reduced skeletal resistance to trauma, and consequently increased risk of fracture. A wide range of conditions, including traditional risk factors, lifestyle choices, diseases and their treatments may contribute to bone fragility. It is therefore not surprising that the multi-morbid patient with chronic kidney disease (CKD) is at a particularly high risk. CKD is associated with reduced bone quantity, as well as impaired bone quality. Bone fragility in CKD is a composite of primary osteoporosis, accumulation of traditional and uremia-related risk factors, assaults brought on by systemic disease, and detrimental effects of drugs. Some risk factors are modifiable and represent potential targets for intervention. This review provides an overview of the heterogeneity of bone fragility in CKD.

Risks of Hip and Nonvertebral Fractures in Patients With CKD G3a-G5D: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage. STUDY DESIGN: Systematic review and meta-analysis. STUDY POPULATION: Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D. SELECTION CRITERIA FOR STUDIES: Observational studies. DATA EXTRACTION: Data extraction was conducted by 1 reviewer and checked by a second reviewer. ANALYTICAL APPROACH: MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs. RESULTS: 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients (<65 years) had higher relative risk (RR, 7.66; 95% CI, 2.76-21.26) than older patients (>65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures. LIMITATIONS: We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures. CONCLUSIONS: Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.

Diagnostic Accuracy of Biomarkers and Imaging for Bone Turnover in Renal Osteodystrophy.

Background Renal osteodystrophy is common in advanced CKD, but characterization of bone turnover status can only be achieved by histomorphometric analysis of bone biopsy specimens (gold standard test). We tested whether bone biomarkers and high-resolution peripheral computed tomography (HR-pQCT) parameters can predict bone turnover status determined by histomorphometry.Methods We obtained fasting blood samples from 69 patients with CKD stages 4-5, including patients on dialysis, and 68 controls for biomarker analysis (intact parathyroid hormone [iPTH], procollagen type 1 N-terminal propeptide [PINP], bone alkaline phosphatase [bALP], collagen type 1 crosslinked C-telopeptide [CTX], and tartrate-resistant acid phosphatase 5b [TRAP5b]) and scanned the distal radius and tibia of participants by HR-pQCT. We used histomorphometry to evaluate bone biopsy specimens from 43 patients with CKD.Results Levels of all biomarkers tested were significantly higher in CKD samples than control samples. For discriminating low bone turnover, bALP, intact PINP, and TRAP5b had an areas under the receiver operating characteristic curve (AUCs) of 0.82, 0.79, and 0.80, respectively, each significantly better than the iPTH AUC of 0.61. Furthermore, radius HR-pQCT total volumetric bone mineral density and cortical bone volume had AUCs of 0.81 and 0.80, respectively. For discriminating high bone turnover, iPTH had an AUC of 0.76, similar to that of all other biomarkers tested.Conclusions The biomarkers bALP, intact PINP, and TRAP5b and radius HR-pQCT parameters can discriminate low from nonlow bone turnover. Despite poor diagnostic accuracy for low bone turnover, iPTH can discriminate high bone turnover with accuracy similar to that of the other biomarkers, including CTX.

Bone biopsy practice patterns across Europe: the European renal osteodystrophy initiative-a position paper.

Renal osteodystrophy (ROD) is a heterogeneous group of metabolic bone diseases complicating progressive chronic kidney disease (CKD). Bone biomarkers and bone imaging techniques may help to assess bone health and predict fractures in CKD but do have important inherent limitations. By informing on bone turnover and mineralization, a bone biopsy may help to guide prevention and treatment of ROD and its consequences. According to a recent survey conducted among European nephrologists, bone biopsies are performed rather exceptionally, both for clinical and research purposes. Obviously, clinical research in the field of ROD is threatened by vanishing clinical and pathological expertise, small patient cohorts and scientific isolation. In March 2016, the European Renal Osteodystrophy (EU-ROD) initiative was created under the umbrella of the ERA-EDTA CKD-mineral and bone disorder (MBD) Working Group to revitalize bone biopsy as a clinically useful tool in the diagnostic workup of CKD-MBD and to foster research on the epidemiology, implications and reversibility of ROD. As such, the EU-ROD initiative aims to increase the understanding of ROD and ultimately to improve outcomes in CKD patients.

Fragility fractures and osteoporosis in CKD: pathophysiology and diagnostic methods.

Both chronic kidney disease (CKD) and osteoporosis are major public health problems associated with an aging population. Osteoporosis is characterized by reduced bone mineral density, while CKD results in qualitative changes in bone structure; both conditions increase the predisposition to fragility fractures. There is a significant coprevalence of osteoporotic fractures and CKD, particularly in the elderly population. Not only is the risk of fracture higher in the CKD population, but clinical outcomes are significantly worse, with substantial health care costs. Management of osteoporosis in the CKD population is particularly complex given the impact of renal osteodystrophy on bone quality and the limited safety and hard outcome data for current therapy in patients with severe CKD or on dialysis therapy. In this review, we discuss the pathophysiology of osteoporosis, the impact of CKD on bone strength, and the role of novel imaging techniques and biomarkers in predicting underlying renal osteodystrophy on bone histomorphometry in the context of CKD.

Bone Turnover Markers: Basic Biology to Clinical Applications.

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide); and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable factors (eg, age, gender, ethnicity) and controllable factors, particularly relating to collection conditions (eg, fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics, and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.

Management of fracture risk in CKD-traditional and novel approaches.

The coexistence of osteoporosis and chronic kidney disease (CKD) is an evolving healthcare challenge in the face of increasingly aging populations. Globally, accelerating fracture incidence causes disability, impaired quality of life and increased mortality. Consequently, several novel diagnostic and therapeutic tools have been introduced for treatment and prevention of fragility fractures. Despite an especially high fracture risk in CKD, these patients are commonly excluded from interventional trials and clinical guidelines. While management of fracture risk in CKD has been discussed in recent opinion-based reviews and consensus papers in the nephrology literature, many patients with CKD stages 3-5D and osteoporosis are still underdiagnosed and untreated. The current review addresses this potential treatment nihilism by discussing established and novel approaches to diagnosis and prevention of fracture risk in patients with CKD stages 3-5D. Skeletal disorders are common in CKD. A wide variety of underlying pathophysiological processes have been identified, including premature aging, chronic wasting, and disturbances in vitamin D and mineral metabolism, which may impact bone fragility beyond established osteoporosis. We discuss current and emerging concepts of CKD-mineral and bone disorders (CKD-MBD) and integrate management of osteoporosis in CKD with current recommendations for management of CKD-MBD. While many diagnostic and therapeutic approaches to osteoporosis can be applied to patients with CKD, some limitations and caveats need to be considered. Consequently, clinical trials are needed that specifically study fracture prevention strategies in patients with CKD stages 3-5D.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

The role of static bone histomorphometry in diagnosing renal osteodystrophy.

BACKGROUND: Bone biopsy is the gold standard test to diagnose renal osteodystrophy (ROD). There is a preference to perform bone biopsy during renal transplantation but tetracycline bone labelling is usually not possible. We aimed to test if histomorphometry static parameters can identify low and high bone turnover as assessed by dynamic measurement using double tetracycline labelling. METHODS: 43 CKD stages 4-5D had trans-iliac bone biopsy using a 4 mm Jamshidi trephine and needle after tetracycline labelling. Quantitative histomorphometry was performed using the Bioquant Osteo histomorphometry system. Normal bone turnover was defined as bone formation rate/bone surface (BFR/BS) of 18-38 µm3/µm2/year. Static parameters of bone turnover included osteoblast surface/bone surface (Ob.S/BS, %), osteoclast surface/bone surface (Oc.S/BS, %) and erosion surface/bone surface (ES/BS, %). Receiver operating characteristics (ROC) analysis was used to evaluate diagnostic accuracy of these static parameters for low and high bone turnover (based on BFR/BS). RESULTS: Median (IQR) for BFR/BS in this study was 32.12 (17.76-48.25) µm3/µm2/year. 26% of patients had low, 34% had normal and 40% had high bone turnover. The area under the ROC curve (AUC) for Ob.S/BS, Oc.S/BS and ES/BS were non-significant indicating poor accuracy for identifying low bone turnover. The AUC for Ob.S/BS was 0.697 (95% CI 0.538 to 0.827) indicating fair accuracy for identifying high bone turnover. Oc.S/BS and ES/BS had non-significant AUCs for high bone turnover. CONCLUSIONS: Static histomorphometry parameters for bone turnover are unable to replace dynamic parameter in diagnosing ROD. Tetracycline bone labelling is still required.

Vascular calcification relationship to vascular biomarkers and bone metabolism in advanced chronic kidney disease.

BACKGROUND: Vascular calcification (VC) and renal osteodystrophy are important complications of advanced chronic kidney disease (CKD). High resolution peripheral quantitative computed tomography (HRpQCT) is able to assess bone microstructure in renal osteodystrophy and lower leg arterial calcification (LLAC) is usually seen as an incidental finding. LLAC can be a useful quantitative assessment of VC in CKD but the relationship between LLAC and vascular biomarkers and bone is unknown. We aimed to assess the relationship between LLAC and biomarkers, bone turnover and microstructure. METHODS: In this cross-sectional study, fasting blood samples were taken from 69 CKD stages 4-5D patients and 68 healthy controls. HRpQCT of distal tibia and radius were performed. 43 CKD patients had trans-iliac bone biopsy after tetracycline labelling. RESULTS: LLAC was more severe in CKD than controls (median [IQR] 1.043 [0.05-16.52] vs 0 [0-0.55] mgHA, p < 0.001). CKD patients with diabetes (28%) had significantly higher LLAC compared to non-diabetic CKD (median [IQR] 24.07 [3.42-61.30] vs 0.23 [0-3.78] mgHA, p < 0.001). LLAC mass in CKD correlated with serum phosphate (rho = 0.29, p < 0.05), calcium x phosphate product (rho = 0.31, p < 0.05), intact parathyroid hormone (rho = 0.38, p < 0.01), intact fibroblast growth factor-23 (iFGF23) (rho = 0.40, p = 0.001), total alkaline phosphatase (rho = 0.41, p < 0.001), bone alkaline phosphatase (rho = 0.29, p < 0.05), osteocalcin (rho = 0.32, p < 0.05), osteoprotegerin (rho = 0.40, p = 0.001) and dephosphorylated-uncarboxylated matrix Gla protein (rho = 0.31, p < 0.05). LLAC in CKD also correlated with worse distal tibia cortical bone mineral density, thickness and porosity. No association was found between LLAC and bone turnover, mineralization or volume on biopsy in CKD. In multivariate analysis, only age, diabetes, iPTH and iFGF23 were independently associated with LLAC in CKD. CONCLUSIONS: High levels of PTH and FGF23, along with older age and the presence of diabetes may all play independent roles in the development of LLAC in advanced CKD.

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study.

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bone disorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4-7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25-5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07-60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP <150 µg/L compared with those with total BGP ≥150 µg/L (OR = 3.15, 95% CI 1.46-6.76, p = .003). In contrast, there was no such effect in those untreated (total BGP <150 µg/L versus total BGP ≥150 µg/L: OR = 1.21, 95% CI 0.66-2.23, p = .54]; p = .049 for effect modification by sevelamer). Sevelamer may interfere with MK4 levels in HD patients and interact with low BGP levels to increase bone fractures in CKD patients. © 2020 American Society for Bone and Mineral Research (ASBMR).

Patient selection criteria for primary total hip Arthroplasty in displaced intracapsular hip fractures: Are they appropriate?

INTRODUCTION: This study aims to determine, by outcome analysis, the appropriateness of current criteria employed to select patients for total hip arthroplasty (THA) as the primary treatment for displaced intracapsular hip fracture (DICHF). This study is intended to inform prospective randomised controlled trials investigating the efficacy of THA as a primary treatment. MATERIALS AND METHODS: Contemporary THA eligibility criteria were derived from recent publications relating to pre-fracture residence, mobility and independence. Outcome data were analysed for 96 patients (19% of 506 consecutive patients with DICHF between March 2003 and February 2005) who fulfilled those criteria. The variables analysed included age, gender, co-existing injuries, co-morbidities, social circumstances, mobility, independence, delay to surgery, readmission and death. The 96 patients included in the study were followed for 3 years. The primary outcome was the combined achievement of home or warden-assisted accommodation at 3 months, no patient readmission within 6 weeks of discharge and survival to 1 year. Secondary outcome was survival to 3 years. RESULTS: At 3 months, 86 patients (90%) had returned home, three (3.1%) required nursing or residential home placement, four (4.2%) were still resident in a community hospital and three (3.1%) had died. A total of ten patients failed to return to their own home. Eight patients (8.3%) were readmitted within 6 weeks. At 1 year, eight patients (8.3%) had died; by 3 years, the mortality rate was 25%. Patients not achieving return to home were older (84.8 years vs. 79.7 years, p = 0.19), prior to fracture weremore likely to use a walking aid (odds ratio [OR] 2.35) or required home support (OR 1.74). The number of co-morbidities was not an association. Backward selection applied to the above data produced an OR of 1.12 (confidence interval [CI] 1.01-1.21) for age as a variable in patients successfully discharged home, so that for each increase in age by year, the odds of home not being the final destination increased by 12%. These factors were also reflected in the patients requiring readmission within 6 weeks from discharge. CONCLUSIONS: If maintaining a high level of activity and independence is the expectation in patients considered for THA for DICHFs, then current selection criteria appear to be appropriate in identifying those capable of returning home, remaining independent and surviving to 1 year compared to the whole DICHF population. With a 75% 3-year survival, the postulated benefit of THA will not be realised in many patients and this needs to be considered. Cost-effectiveness trials are required before broad practice change occurs.