The purpose of our study was to explore the effect of nitrogen-containing bisphosphonate (N-BP) on vascular calcification (VC) through animal experiments and a meta-analysis.

In our animal experiments, Sprague-Dawley (SD) rats were randomly divided into a control group, a VC group, a low-dose zoledronic acid (ZOL) (20 µg/kg) group and a high-dose ZOL (100 µg/kg) group. The calcification of the aortic arch was observed by alizarin red staining. The calcium content of the aortic arch was measured. In our systematic review and meta-analysis, databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wanfang database, were searched from their inception to December 20, 2023. Eligible studies comparing N-BP versus no N-BP in the treatment of VC were included.

In our animal experiment, the red-stained calcification structure in the low-dose ZOL group was slightly reduced and the red-stained calcification structure in the high-dose ZOL group was significantly reduced compared with that in the VC. The calcium content in the low-dose ZOL group was slightly lower than that in the VC group, but the difference was not significant (P = 0.08). The calcium content in the high-dose ZOL group was significantly lower than that in the VC group (P < 0.0001). Our meta-analysis of human studies revealed that N-BP did not reduce the arterial calcification score (P = 0.46). Our meta-analysis of animal studies revealed that N-BP did not significantly reduce the arterial calcification score (P = 0.09), but N-BP reduced the arterial calcification area (P < 0.00001), arterial calcium content (P = 0.009) and PO4 content (P = 0.0001).

Our animal experiment revealed that high-dose ZOL inhibited VC, but low-dose ZOL did not significantly inhibit VC. Our meta-analysis of human studies revealed that N-BP was not effective in the treatment of VC, but our meta-analysis of animal studies suggested a role of N-BP in inhibiting VC.

The efficacy and safety of bisphosphonate therapy for the treatment of osteoporosis and osteopenia in the setting of chronic kidney disease (CKD) is unclear.

To determine the effect of bisphosphonate therapy on fractures, bone mineral density (BMD), and adverse events in adults across the spectrum of CKD and dialysis.

Systematic review and individual patient-level meta-analysis.

Searches of Ageline, CINAHL, the Cochrane Library, EMBASE, and Medline from inception to August 25, 2016, supplemented with manual screening and clinicalstudydatarequest.com. Authors were contacted for individual patient-level data.

Randomized, placebo-controlled trials with 100 or more participants that evaluated the treatment of primary osteoporosis/osteopenia in adult men and women with bisphosphonate therapy.

Study characteristics, quality, and data were assessed independently by 2 reviewers. Outcome measures were fractures, BMD, and adverse events including decline in estimated glomerular filtration rate (eGFR) and hypocalcemia (calcium <2.00 mmol/L).

Single-stage individual patient-level meta-analysis.

Of 39 eligible studies, individual patient-level data was available for 7 studies, all of which were studies of ibandronate. Of 7428 participants (5010 ibandronate, 2418 placebo), 100% were female, 98.6% were white, the mean body mass index was 25.7 kg/m2 (SD 3.9), 18.9% were smokers and there were 740 fracture events. The mean eGFR was 69.1 mL/min/1.73 m2 (SD 15.9) including 14.5%, 54.9%, 27.5%, 3.0%, and 0.2% stages G1, G2, G3A, G3B, and G4 CKD. Ibandronate increased hip and lumbar spine BMD and decreased the risk of fracture in the overall population (hazard ratio (HR) 0.871, 95% confidence interval (CI) 0.746, 1.018) but in patients with stage G3B CKD, it increased the risk of fracture (HR 3.862, 95% CI 1.156, 12.903). Ibandronate did not impact eGFR over 12 months but increased the risk of hypocalcemia (HR 1.324, 95% CI 1.056, 1.660) with no evidence of any effect modification by CKD stage (all tests of interaction p > 0.05).

Clinically significant heterogeneity among studies, lack of long-term follow-up and bone biopsy results, limited representation of stage G4 and G5 CKD patients.

Chronic kidney disease potentially modifies the efficacy but not the safety of bisphosphonate therapy in osteopenia and osteoporosis.

PROSPERO CRD42020145613.

To determine whether bisphosphonates and NF-κB ligand (RANKL) inhibitors delay coronary artery calcification (CAC).

A systematic review was conducted.

MEDLINE, EMBASE and CENTRAL.

Longitudinal studies investigating CAC progression in adults (>18 years) taking either a bisphosphonate or denosumab compared with those who did not.

Study and participant characteristics, and primary outcome ( ∆ CAC from baseline to follow-up) were extracted. The Risk Of Bias In Non-Randomised Studies-of Interventions (ROBINS-I) and Risk-of-Bias Tool for Randomised Trials (RoB2) tools were used to assess the risk of bias for observational and randomised controlled trials (RCTs), respectively. Outcome measures were reported.

Four observational studies and one RCT (n=377) were included. Three studies solely reported the effect of bisphosphonates on ∆ CAC; one study (n=56) demonstrated a statistically significant CAC reduction in the intervention group (-372 mm3/year) compared with control (+159 mm3/year) (p<0.01). One study (n=14) demonstrated a difference in ∆ CAC between intervention (+880 mm3/year) versus control (+2220 mm3/year), however, no p value comparing groups was reported. One study (n=115) found no statistically significant difference between intervention and control.One study (n=42) exclusively investigated the effect of RANKL on ∆ CAC; there was a statistically significant reduction in CAC at 6-month follow-up between intervention (-133±124 modified Agatston unit (AU)) and control (+188±72 modified AU), p=0.03.One study (n=150) compared both bisphosphonates and denosumab to control and found no statistically significant difference between either intervention group and control over 24 months. Meta-analysis was not performed due to limited, heterogeneous studies.

There is insufficient evidence supporting the correlation between bisphosphonate or RANKL inhibitor use and CAC progression. Further research is warranted.

Background: Potentially inappropriate medication prescribing is prevalent and well studied in older adults. However, limited data are available on inappropriate drug dosing in those with dementia or cognitive impairment and renal impairment. Objectives: We aimed to examine the prevalence of, and factors associated with, inappropriate drug dosing in older patients with dementia or cognitive impairment and renal impairment. Methods: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and the Cochrane Handbook for Systematic Reviews of Interventions. We searched Medline, Embase, CINAHL, and PubMed for studies on inappropriate drug dosing in older patients with dementia or cognitive impairment and renal impairment, published from 1 January 2000 to 31 August 2024, with English language restriction following the PICOS search strategy. Two reviewers independently screened all titles and abstracts, extracted data from included studies, and undertook quality assessment using the Joanna Briggs Institute (JBI) tool. Descriptive statistics were used to summarise and present findings. Results: In total, eight retrospective cohort studies were included. Of the total number of patients with dementia who had renal impairment (n = 5250), there were 2695 patients (51.3%; range: 0-60%) who had inappropriate drug dosing. Drugs commonly prescribed in inappropriate doses in patients with dementia who had renal impairment included memantine, baclofen, nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, digoxin, morphine, and allopurinol. The studies did not identify statistically significant risk factors for inappropriate drug dosing. Conclusions: Inappropriate drug dosing among older adults with dementia or cognitive impairment and renal impairment appears to occur frequently. While our findings should be interpreted with caution owing to the small number of studies and substantial heterogeneity, proactive prevention, recognition, and management of inappropriate drug dosing in this population is warranted.

Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of 18F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether 18F-FDG and 18F-NaF uptake was predictive of abdominal aortic aneurysm expansion.

Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with 18F-FDG and 18F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl2 or saline stimulation. In the 1-week cohort (n=25), the correlation between 18F-FDG or 18F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential 18F-FDG and 18F-NaF uptake or calcification volume was examined.

In the 1-week cohort, the maximum standard unit value of 18F-FDG and 18F-NaF uptake correlated with CD68- (r=0.82; P=0.001) and von Kossa staining-positive areas (r=0.89; P<0.001), respectively. In the time course cohort, 18F-FDG and 18F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, 18F-FDG showed high uptake at weeks 1 and 2, whereas a high 18F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with 18F-FDG and 18F-NaF uptake and calcification volume, especially at 1 and 2 weeks (18F-NaF [1 week]: r=0.61, 18F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; P<0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with 18F-NaF uptake at 1 week being the strongest predictor.

The uptake of 18F-NaF and 18F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with 18F-NaF uptake being the strongest predictor.

This review aims to describe the pathogenic factors involved in bone-vessel anomalies in CKD which are the object of numerous experimental and clinical research.

Knowledge on the pathophysiological mechanisms involved in the regulation of vascular calcification and mineral-bone disorders is evolving. Specific bone turnover anomalies influence the vascular health while recent studies demonstrate that factors released by the calcified vessels also contribute to bone deterioration in CKD. Current therapies used to control mineral dysregulations will impact both the vessels and bone metabolism. Available anti-osteoporotic treatments used in non-CKD population may negatively or positively affect vascular health in the context of CKD. It is essential to study the bone effects of the new therapeutic options that are currently under investigation to reduce vascular calcification. Our paper highlights the complexity of the bone-vascular axis and discusses how current therapies may affect both organs in CKD.

Up to now, there is no unequivocal intervention to mitigate vascular calcification (VC) in patients with hemodialysis. This network meta-analysis aimed to systematically evaluate the clinical efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet in treating vascular calcification.

A comprehensive study search was performed using PubMed, Web of Science, the Cochrane Library, EMBASE and China National Knowledge Internet (CNKI) to collect randomized controlled trials (RCTs) of sodium thiosulfate, bisphosphonates, and cinacalcet for vascular calcification among hemodialysis patients. Then, network meta-analysis was conducted using Stata 17.0 software.

In total, eleven RCTs including 1083 patients were qualified for this meta-analysis. We found that cinacalcet (SMD - 0.59; 95% CI [-0.95, -0.24]) had significant benefit on vascular calcification compared with conventional therapy, while sodium thiosulfate or bisphosphonates did not show such efficiency. Furthermore, as for ranking the efficacy assessment, cinacalcet possessed the highest surface under the cumulative ranking curve (SUCRA) value (88.5%) of lessening vascular calcification and was superior to sodium thiosulfate (50.4%) and bisphosphonates (55.4%). Thus, above results suggested that cinacalcet might be the most promising drug for vascular calcification treatment in hemodialysis patients. Mechanistically, our findings illustrated that cinacalcet reduced serum calcium (SMD - 1.20; 95% CI [-2.08, - 0.33]) and showed the tendency in maintaining the balance of intact Parathyroid Hormone (iPTH) level.

This network meta-analysis indicated that cinacalcet appear to be more effective than sodium thiosulfate and bisphosphonates in mitigating vascular calcification through decreasing serum calcium and iPTH. And cinacalcet might be a reasonable option for hemodialysis patients with VC in clinical practice.

[ http://www.crd.york.ac.uk/PROSPERO ], identifier [CRD42022379965].

This study conducted a meta-analysis to analyze the efficacy and safety of osteoporosis medications in kidney transplant recipients and patients with chronic kidney disease (CKD). PubMed, Embase, the Cochrane Central Register of Controlled Trials were searched from the date of their inception through October 21, 2022. We performed a meta-analysis of the efficacy and safety of osteoporosis medications in adult patients with stage 3-5 CKD or kidney transplant recipients enrolled in randomized clinical trials (RCTs). We calculated the standard mean deviations with 95% confidence intervals (CI) for bone mineral density (BMD) and T scores after 6 and 12 months treatment, pooled odds ratio and 95% CI for fracture risk, and summarized adverse events. The inclusion criteria were met by 27 studies. Out of this, 19 studies were included for the meta-analysis. In stage 3-4 CKD patients, alendronate increased lumbar spine BMD. In patients at stage 5 CKD and undergoing hemodialysis, alendronate and raloxifene increased lumbar spine BMD. After 6 months, the BMD of kidney transplant recipients was seen to be significantly increased; however, there was no difference after 12 months, and the risk of fracture did not reduce. Thus, there is no evidence that these medications reduce the risk of fracture, and their effect on BMD and fracture remains unproven. These medications may increase the incidence of adverse events and their safety needs to be further evaluated. Therefore, we cannot draw a definitive conclusion about the efficacy and safety of osteoporosis medications in the above group of patients.

Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded). Osteoporosis: compromised bone strength (low bone mass, disturbance of microarchitecture) predisposing to fracture. By definition, osteoporosis is diagnosed if the bone mineral density T‑score is ≤ -2.5. Furthermore, osteoporosis is diagnosed if a low-trauma (inadequate trauma) fracture occurs, irrespective of the measured T‑score (not graded). The prevalence of osteoporosis, osteoporotic fractures and CKD is increasing worldwide (not graded). PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD): Definition of CKD-MBD: a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; renal osteodystrophy; vascular calcification (not graded). Increased, normal or decreased bone turnover can be found in renal osteodystrophy (not graded). Depending on CKD stage, routine monitoring of calcium, phosphorus, alkaline phosphatase, PTH and 25-OH-vitamin D is recommended (2C). Recommendations for treatment of CKD-MBD: Avoid hypercalcemia (1C). In cases of hyperphosphatemia, lower phosphorus towards normal range (2C). Keep PTH within or slightly above normal range (2D). Vitamin D deficiency should be avoided and treated when diagnosed (1C).

Densitometry (using dual X‑ray absorptiometry, DXA): low T‑score correlates with increased fracture risk across all stages of CKD (not graded). A decrease of the T‑score by 1 unit approximately doubles the risk for osteoporotic fracture (not graded). A T-score ≥ -2.5 does not exclude osteoporosis (not graded). Bone mineral density of the lumbar spine measured by DXA can be increased and therefore should not be used for the diagnosis or monitoring of osteoporosis in the presence of aortic calcification, osteophytes or vertebral fracture (not graded). FRAX can be used to aid fracture risk estimation in all stages of CKD (1C). Bone turnover markers can be measured in individual cases to monitor treatment (2D). Bone biopsy may be considered in individual cases, especially in patients with CKD G5 (eGFR < 15 ml/min/1.73 m2) or CKD 5D (dialysis).

Hypocalcemia should be treated and serum calcium normalized before initiating osteoporosis therapy (1C). CKD G1-G2 (eGFR ≥ 60 ml/min/1.73 m2): treat osteoporosis as recommended for the general population (1A). CKD G3-G5D (eGFR < 60 ml/min/1.73 m2 to dialysis): treat CKD-MBD first before initiating osteoporosis treatment (2C). CKD G3 (eGFR 30-59 ml/min/1.73 m2) with PTH within normal limits and osteoporotic fracture and/or high fracture risk according to FRAX: treat osteoporosis as recommended for the general population (2B). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) with osteoporotic fracture (secondary prevention): Individualized treatment of osteoporosis is recommended (2C). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) and high fracture risk (e.g. FRAX score > 20% for a major osteoporotic fracture or > 5% for hip fracture) but without prevalent osteoporotic fracture (primary prevention): treatment of osteoporosis may be considered and initiated individually (2D). CKD G4-5D (eGFR < 30 ml/min/1.73 m2 to dialysis): Calcium should be measured 1-2 weeks after initiation of antiresorptive therapy (1C).

Resistance training prioritizing major muscle groups thrice weekly (1B). Aerobic exercise training for 40 min four times per week (1B). Coordination and balance exercises thrice weekly (1B). Flexibility exercise 3-7 times per week (1B).

Patients with chronic kidney disease develop vascular calcification, owing to impaired calcium and phosphate metabolism. The prevention of vascular calcification is important to improve the prognosis of such patients. In this study, we investigated whether treatment with FYB-931, a novel bisphosphonate compound, prevents vascular calcification in rat aortic rings cultured in high-phosphate medium for 9 days, assessed by measurement of the calcium content and the degree of calcium deposition, visualized using von Kossa staining. The effect on the transformation of calciprotein particles (CPPs) from primary to secondary CPPs was assessed using a fluorescent probe-based flow cytometric assay. FYB-931 dose-dependently prevented high phosphate-induced aortic calcification, but failed to rapidly cause the regression of high phosphate-induced vascular calcification once it had developed. Furthermore, the treatment dose-dependently inhibited the high phosphate-induced transformation from primary to secondary CPPs. In addition, the treatment with FYB-931 prevented the transformation from primary to secondary CPPs in vitamin D₃-treated rats as a model of ectopic calcification, consistent with the results from rat aortic rings. In conclusion, treatment with FYB-931 prevents high phosphate-induced rat aortic vascular calcification by altering the dynamics of CPP transformation. This finding suggests that inhibition of the transformation from primary to secondary CPPs is an important target for the prevention of vascular calcification in patients with chronic kidney disease.

Patients with CKD have a 4-fivefold higher rate of fractures. The incidence of fractures increases with deterioration of kidney function. The process of skeletal changes in CKD patients is characterized by compromised bone strength because of deterioration of bone quantity and/or quality. The fractures lead to a deleterious effect on the quality of life and higher mortality in patients with CKD. The pathogenesis of bone loss and fracture is complex and multi-factorial. Renal osteodystrophy, uremic milieu, drugs, and systemic diseases that lead to renal failure all contribute to bone damage in CKD patients. There is no consensus on the optimal diagnostic method of compromised bone assessment in patients with CKD. Bone quantity and mass can be assessed by dual-energy x-ray absorptiometry (DXA) or quantitative computed tomography (QCT). Bone quality on the other side can be assessed by non-invasive methods such as trabecular bone score (TBS), high-resolution bone imaging methods, and invasive bone biopsy. Bone turnover markers can reflect bone remodeling, but some of them are retained by kidneys. Understanding the mechanism of bone loss is pivotal in preventing fracture in patients with CKD. Several non-pharmacological and therapeutic interventions have been reported to improve bone health. Controlling laboratory abnormalities of CKD-MBD is crucial. Anti-resorptive therapies are effective in improving BMD and reducing fracture risk, but there are uncertainties about safety and efficacy especially in advanced CKD patients. Accepting the prevalent of low bone turnover in patients with advanced CKD, the osteo-anabolics are possibly promising. Parathyroidectomy should be considered a last resort for intractable cases of renal hyperparathyroidism. There is a wide unacceptable gap in osteoporosis management in patients with CKD. This article is focusing on the updated management of CKD-MBD and osteoporosis in CKD patients. Chronic kidney disease deteriorates bone quality and quantity. The mechanism of bone loss mainly determines pharmacological treatment. DXA and QCT provide information about bone quantity, but assessing bone quality, by TBS, high-resolution bone imaging, invasive bone biopsy, and bone turnover markers, can guide us about the mechanism of bone loss.

Whether bisphosphonates and RANKL inhibitors play a novel role in delaying cardiovascular calcification is unknown. Their action on regulatory enzymes in the mevalonic acid pathway, which is implicated in both bone and lipid metabolism, may be a novel therapeutic target to manage coronary artery disease (CAD). Such therapies may particularly be relevant in those for whom traditional cardiovascular therapies are no longer sufficient to control disease progression.

We will perform a systematic review which aims to synthesise evidence regarding whether use of bisphosphonates or use of the RANKL inhibitor denosumab delays coronary artery calcium (CAC) progression. Eligible studies will include longitudinal studies investigating CAC progression in patients aged >18 years taking either a bisphosphonate or denosumab compared with those who do not. Embase, MEDLINE and Cochrane will be searched using prespecified search terms. Studies will be screened by title and abstract independently and then in full to determine suitability for inclusion in the review. Extracted data will include that relating to study and participant characteristics. The primary outcome will be the CAC score. Secondary outcomes will include aortic and carotid artery calcification. Meta-analysis will be performed if sufficient data are available.

This study does not require ethics as it is a systematic review of the literature. The results of the review described within this protocol will be distributed via presentations at relevant conferences and publication within a peer-reviewed journal.

The systematic review pertaining to this protocol is registered with PROSPERO (Registration ID: CRD42022312377).

Patients with chronic kidney disease (CKD) have high risk of fracture in part due to cortical bone deterioration. The goal of this study was to assess the impact of two different bisphosphonates and dosing regimens on cortical microstructure (porosity, thickness, area) and bone mechanical properties in animal models of CKD.

In experiment 1, Male Cy/+ (CKD) rats were treated with either a single dose or ten fractionated doses of zoledronate at 18 weeks of age. Fractionated animals received 1/10th of single dose given weekly for 10 weeks, with study endpoint at 28 weeks of age. In experiment 2, male C57Bl/6 J mice were given dietary adenine (0.2%) to induce CKD. Bisphosphonate treated groups were given either a single dose of zoledronate or weekly risedronate injections for 4 weeks. Cortical microstructure was assessed via μCT and mechanical parameters evaluated by monotonic bending tests.

Exp 1: CKD rats had higher blood urea nitrogen (BUN) and parathyroid hormone (PTH) compared to NL littermate controls. Single dose zoledronate had significantly higher cortical porosity in CKD S.Zol (2.29%) compared to NL control (0.04%) and untreated CKD (0.14%) (p = 0.004). Exp 2: All adenine groups had significantly higher BUN and PTH compared to control mice. Mice treated with single dose zoledronate (Ad + Zol) had the highest porosity (~6%), which was significantly higher compared to either Ad or Ad + Ris (~3%; p < 0.0001) and control mice had the lowest cortical porosity (0.35%). In both experiments, mechanics were minimally affected by any bisphosphonate dosing regimen.

A single dose of zoledronate leads to higher cortical porosity compared to more frequent dosing of bisphosphonates (fractionated zoledronate or risedronate). Bisphosphonate treatment demonstrated limited effectiveness in preventing cortical bone microstructure deterioration with mechanical parameters remaining compromised due to CKD and/or secondary hyperparathyroidism irrespective of bisphosphonate treatment.

Background: Chronic kidney disease (CKD) is associated with bone and mineral metabolism. In this study we evaluated the comparative efficacies and safety of osteoporosis medications in patients with CKD or a history of kidney transplantation, and make recommendations for the best choice of osteoporosis treatment among patients with CKD or a history of kidney transplantation. Methods: We systemically searched for randomized controlled trials published in PubMed, Embase, and Cochrane databases up to June 2020. Network-meta analysis was used to compare the relative effectiveness of different treatments. A random-effects model was used when heterogeneity was expected. The safety of different treatments was also evaluated in terms of reported major adverse events. Results: A total of 17 studies with data from 10,214 patients who had stage 2-5 CKD, were receiving dialysis, or had a history of kidney transplantation were included in the network meta-analysis. Treatment with teriparatide, denosumab, alendronate, and raloxifene were all associated with a significantly reduced risk of fractures compared to treatment with placebos [teriparatide: odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.10-0.35; denosumab: OR = 0.40, 95% CI: 0.27-0.58; alendronate: OR = 0.61, 95% CI: 0.40-0.92; raloxifene: OR = 0.52, 95% CI: 0.41-0.67]. The rank probability and the surface under the cumulative ranking (SUCRA) values suggested that teriparatide ranked the highest for improvement in vertebral bone mineral density (BMD) (SUCRA = 97.8%), whereas denosumab ranked the highest for improvement in femoral neck BMD (SUCRA = 88.3%). Conclusion: Teriparatide and denosumab seem to be the most effective treatments for preventing bone loss and reducing the risk of fracture in our network comparison. However, because of the limitations and potential biases in the reviewed studies, there is still some uncertainty about the best treatment options for osteoporosis in patients with CKD or a history of kidney transplantation. Systematic Review Registration: [PROSPERO], identifier [CRD42020209830].

The risk of bone fracture is high in patients with chronic kidney disease (CKD), and aggressive treatment to reduce fragility fracture risk is the major strategy. However, the outcomes of osteoporosis medications in patients with CKD remain unclear.

Patients with stage 3-5 CKD during 2011-2019 were enrolled. Patients were divided into two groups based on receiving osteoporosis medications (bisphosphonates, raloxifene, teriparatide or denosumab) or not. Two groups were matched at a 1:1 ratio by using propensity scores. The outcomes of interest were bone fractures, cardiovascular (CV) events and all-cause mortality. Cox proportional hazard regression models were applied to identify the risk factors. Additional stratified analyses by cumulative dose, treatment length and menopause condition were performed.

67 650 patients were included. After propensity score matching, 1654 patients were included in the study and control group, respectively. The mean age was 70.2±12.4 years, and 32.0% of patients were men. After a mean follow-up of 3.9 years, the incidence rates of bone fracture, CV events and all-cause mortality were 2.0, 1.7 and 6.5 per 1000 person-months, respectively. Multivariate analysis results showed that osteoporosis medications reduced the risk of CV events (HR, 0.35; 95% CI, 0.18 to 0.71; p=0.004), but did not alleviate the risks of bone fracture (HR, 1.48; 95% CI, 0.73 to 2.98; p=0.28) and all-cause mortality (HR, 0.93; 95% CI, 0.67 to 1.28; p=0.65). Stratified analysis showed that bisphosphonates users have most benefits in the reduction of CV events (HR, 0.26; 95% CI, 0.11 to 0.64; p=0.003). In conclusion, osteoporosis medications did not reduce the risk of bone fractures, or mortality, but improved CV outcomes in patients with CKD.

The European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) CKD-MBD working group, in collaboration with the Committee of Scientific Advisors of the International Osteoporosis Foundation, published a position paper for the diagnosis and management of osteoporosis in patients with CKD stages 4-5D (eGFR < 30 ml/min 1.73 m²). The present article reports and summarizes the main recommendations included in this 2021 document. The following areas are reviewed: diagnosis of osteoporosis; risk factors for fragility fractures; fracture risk assessment; intervention thresholds for pharmacological intervention; general and pharmacological management of osteoporosis; monitoring of treatment, and systems of care, all in patients with CKD stages 4-5D. Guidance is provided for clinicians caring for CKD stages 4-5D patients with osteoporosis, allowing for a pragmatic individualized diagnostic and therapeutic approach as an alternative to current variations in care and treatment nihilism.

This article aims to review the methods used for the assessment of fracture risk and the use of osteoporosis medications for fracture prevention in the population with CKD, and highlights the difficulties faced by clinicians in the management of these patients and the latest recommendations and guidelines. Chronic kidney disease (CKD) and osteoporosis often co-exist in older adults, and they present a major healthcare challenge. CKD mineral and bone disorder (CKD-MBD) occurs as renal function declines and this syndrome affects most patients in CKD stages 4 and 5. The biochemical abnormalities of CKD-MBD, renal bone disease and risk factors associated with age-related bone loss and osteoporosis lead to a cumulative effect on fracture risk and mortality. There is a need for routine evaluation of fracture risk and fracture prevention in this population. Measurement of bone mineral density (BMD) and the use of the FRAX tool have predictive value for incident fractures in the general population and in CKD. This enables physicians to identify CKD patients most at risk of sustaining a fragility fracture and allows a more targeted approach to fracture prevention. Data analysis from the pivotal trials of therapeutic agents used in osteoporosis show that these drugs can be considered in mild and moderate CKD (stages 1-3 CKD). Off-label drug use in patients with CKD-MBD and more severe renal impairment (CKD stages 4 and 5) could offer significant benefits to sub-groups of patients when carefully tailored to each individual's bone turnover and calcium and phosphate balance. However, this requires a selective approach and treatment decisions based on inference from pathophysiology while we await further trials. Guidelines advocate the correction and/or reduction of the biochemical abnormalities of CKD-MBD before initiation of treatment with osteoporosis drugs and close monitoring during treatment.

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

Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism.

To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D).

We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included.

Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence).

Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.

Patients with chronic kidney disease (CKD) have an increased fracture risk because of impaired bone quality and quantity. Low bone mineral density predicts fracture risk in all CKD stages, including advanced CKD (CKD G4-5D). Pharmacological therapy improves bone mineral density and reduces fracture risk in moderate CKD. Its efficacy in advanced CKD remains to be determined, although pilot studies suggest a positive effect on bone mineral density. Currently, antiresorptive agents are the most commonly prescribed drugs for the prevention and therapy of osteoporosis. Their use in advanced CKD has been limited by the lack of large clinical trials and fear of causing kidney dysfunction and adynamic bone disease. In recent decades, adynamic bone disease has evolved as the most predominant form of renal osteodystrophy, commonly associated with poor outcomes, including premature mortality and progression of vascular calcification. Evolving evidence indicates that reduction of bone turnover by parathyroidectomy or pharmacological therapies, such as calcimimetics and antiresorptive agents, are not associated with premature mortality or accelerated vascular calcification in CKD. In contrast, chronic inflammation, oxidative stress, malnutrition, and diabetes can induce low bone turnover and associate with poor prognosis. Thus, the conditions causing suppression of bone turnover rather than the low bone turnover per se may account for the perceived association with outcomes. Anabolic treatment, in contrast, has been suggested to improve turnover and bone mass in patients with advanced CKD and low bone turnover; however, uncertainty about safety even exceeds that of antiresorptive agents. Here, we critically review the pathophysiological concept of adynamic bone disease and discuss the effect of low bone turnover on the safety and efficacy of anti-osteoporosis pharmacotherapy in advanced CKD.

The key players of the chronic kidney disease-mineral and bone disorders (CKD-MBD) are calcium, phosphate, PTH, FGF23, and the vitamin D hormonal system. The progressive reduction of kidney function greatly modifies the tightly interrelated mechanisms that control these parameters. As a result, important changes occur in the bone and mineral hormonal axis, leading to changes in bone turnover with relevant consequences in clinical outcomes, such as decrease in bone mass with increased bone fragility and bone fractures and increased vascular and valvular calcification, also with great impact in the cardiovascular outcomes. So far, the knowledge of the mineral and bone disorders in CKD and the increased variety of efficacious therapies should lead to a better prevention and management of CKD-MBD.

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.

Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.

The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.

This was a new-user cohort study design with propensity score matching.

Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4.

Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m2 were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m2 within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4.

Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure.

Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.

Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.

Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.

Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.

Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data.

This study is registered as EUPAS10029.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.

The effects of long-term exposure to denosumab in individuals with renal insufficiency are unknown.

This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and 3) using data from the pivotal phase 3, double-blind, 3-year FREEDOM (NCT00089791) and open-label, 7-year extension (NCT00523341) studies.

Women age 60 to 90 years with a bone mineral density (BMD) T-score of less than -2.5 to greater than -4.0 at the total hip or lumbar spine were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months (long-term arm) or placebo (cross-over arm) in FREEDOM; eligible participants could enroll in the extension to receive denosumab 60 mg subcutaneously every 6 months. Change in estimated glomerular filtration rate (eGFR) from study baseline and annualized rates of fracture and adverse events (AEs) were the main outcome measures.

Most participants (1259/1969 [64%] long-term arm; 1173/1781 [66%] crossover arm) with baseline CKD stage 2 or 3 remained within the same CKD subgroup at study completion; less than 3% progressed to CKD stage 4. Participants in all eGFR subgroups showed similar, persistent BMD gains over time and a low incidence of fractures. The percentage of participants reporting serious AEs was similar among renal subgroups (normal, CKD stage 2, CKD stage 3a, CKD stage 3b) both for the long-term (54% vs 52% vs 57% vs 58%) and crossover (43% vs 42% vs 43% vs 68%) arms, except CKD stage 3b subgroup, crossover arm.

The safety and efficacy of denosumab did not differ among participants with mild to moderate CKD.

Theoretically bisphosphonates could accelerate or retard vascular calcification. In subjects with low GFR, the position is further confounded by a combination of uncertain pharmacokinetics (GI absorption is poor and inconsistent at all levels of renal function and the effect of low GFR generally is to increase bioavailability) and a highly variable skeletal substrate with extremes of turnover that increase unpredictably further. Although bisphosphonates reduce bone formation by 70-90% in subjects with normal GFR and reduce the ability of bone to buffer exogenous calcium fluxes, in bisphosphonate treated postmenopausal women accelerated vascular calcification has not been documented. The kidneys assist with this buffering, but the capacity to modulate calcium excretion declines as GFR falls, increasing the risk of hypercalcaemia in the event of high calcium influx. In the ESRD patient, decreased buffering capacity substantially increases the risk of transient hypercalcaemia, especially in the setting of dialysis, and as such may promote vascular calcification which is highly prevalent in the CKD population. Low bone turnover may thus be less of a vascular problem in patients with preserved renal function and a bigger problem when the GFR is low. In patients with stage 4 and 5 CKD, adynamic bone disease associates with the severity and progression of arterial calcification, including coronary artery calcification, and further suppression of bone turnover by a bisphosphonate might exacerbate an already high predisposition to vascular calcification. No convincing signal of harm has emerged from clinical studies thus far. For example 51 individuals with CKD stage 3-4 treated with either alendronate 70 mg per week or placebo for 18 months showed no difference in the rate of vascular calcifications. Conversely an observational study of women with stage 3-4 CKD with pre-existing cardiovascular disease found an increased risk of mortality with a hazard ratio of 1.22 (1.04-1.42) in those given bisphosphonates. Direct suppression of vascular calcification by bisphosphonates is probably confined to etidronate - treatment of soft tissue calcification was a recognized indication for this drug and etidronate markedly reduced progression of vascular calcification in CKD patients. Bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. Thus the efficacy of etidronate as treatment for soft tissue calcification brought with it a problematic tendency to cause osteomalacia. In contrast, conventional doses of nitrogen-containing bisphosphonates fail to yield circulating concentrations sufficient to exert direct anti-calcifying effects, at least in patients with good renal function and studies using alendronate and ibandronate have yielded inconsistent vascular outcomes.

To test the hypothesis that bisphosphonates reduce AMI risk among new users and to assess whether the effect depends on the duration of treatment.

Case-control study nested in a primary cohort composed of patients aged 40 to 99 years, with at least 1-year registry in the BIFAP database throughout the study period 2002-2015. Out of this cohort, incident AMI cases were identified and five controls per case were randomly selected, matched by exact age, sex, and index date. The association of AMI with current, recent and past use of bisphosphonates was assessed by computing adjusted odds ratios (AOR) and their corresponding 95% confidence interval (CI) through an unconditional logistic regression. Only initiators of bisphosphonates were considered.

A total of 23,590 cases of AMI and 117,612 controls were included. The mean age was 66.8 (SD 13.4) years, and 72.52% was male, in both groups. About 276 (1.17%) cases and 1458 (1.24%) controls were current users of bisphosphonates yielding an AOR of 0.98 (95% CI 0.854-1.14). Recent and past use were not associated with a reduced risk, either, nor was it found a reduction with treatment duration (AOR less than 1 year = 0.92; 95% CI 0.73-1.15; AOR more than 1 year = 1.03; 95% CI 0.86-1.23). Stratified analysis by age, sex and background cardiovascular risk did not show an effect modification by these variables.

The results do not support a cardioprotective effect of bisphosphonates regardless of the duration of treatment, age, sex or background cardiovascular risk. However, a small protective effect could have been masked if patients with osteoporosis have had a background higher risk of AMI.

Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one's short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD.

This study evaluated whether zoledronic acid (ZA) inhibited the progression of abdominal aortic calcification (AAC) over 3 years in 502 postmenopausal women with osteoporosis. AAC progressed in a similar proportion of participants in the ZA (29%) and placebo (31%) groups, suggesting no effect of ZA on AAC progression.

Bisphosphonate use is associated with reduced risk of all-cause mortality and cardiovascular events. The underlying mechanisms are uncertain but may include effects on vascular calcification. This study aimed to evaluate the effect of zoledronic acid (ZA) on abdominal aortic calcification (AAC) in postmenopausal women with osteoporosis.

This was a post hoc analysis of the HORIZON Pivotal Fracture Trial that included 502 postmenopausal women (mean age 72.5 years) with osteoporosis (234 received ZA and 268 placebo). AAC scores (range, 0-8) were assessed from paired spine X-rays at baseline and after 3 years. Progression of AAC was defined as any increase in AAC score. The association between change in hip and femoral neck bone mineral density and change in AAC score was also assessed.

At baseline, 292 (58.2%) participants had AAC (i.e., AAC score > 0), with AAC scores similar in the two intervention groups (median [interquartile range], 1 [0 to 2] for both; p = 0.98). Over 3 years, AAC progressed in a similar proportion of participants in both groups (ZA 29% and placebo 31%; p = 0.64). Change in bone mineral density and change in AAC score were not correlated.

Once-yearly zoledronic acid did not affect progression of AAC over 3 years in postmenopausal women with osteoporosis.

ClinicalTrials.gov identifier: NCT00049829.

Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the 'point of no return'. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

Chronic kidney disease (CKD) is associated with the development of mineral and bone disorders (MBD), including renal osteodystrophy (ROD). ROD is a global disorder of bone strength that is associated with an increased fracture risk. The use of bisphosphonates for fracture risk reduction in CKD remains controversial. This review provides a synopsis of the state-of-the literature regarding the safety and potential antifracture benefits of bisphosphonates in CKD patients.

In preclinical studies of animals with CKD 3-4 and evidence of CKD-MBD, bisphosphonates resulted in changes in bone quality that improve bone strength. Bone turnover was generally reduced to a similar extent in animals with and without CKD. Post hoc analyses of randomized trials in patients with CKD 3-4 reported increases in bone mineral density (BMD) and fracture reduction that were similar in patients with and without CKD. There are no primary clinical trial data in patients with CKD-MBD.

In patients with CKD without evidence of CKD-MBD, the use of bisphosphonates should follow general population guidelines. The lack of data for patients with CKD 4-5D and evidence of CKD-MBD makes treatment decisions challenging. Clinical studies are urgently needed to provide data on the safety and antifracture benefits of bisphosphonates in these cohorts.

In patients with chronic kidney disease (CKD) or those undergoing hemodialysis, pathological calcific deposition known as ectopic calcification occurs in soft tissue, resulting in a life-threatening disorder. A potent and effective inhibitor of ectopic calcification is eagerly expected. In the current study, the effects of FYB-931, a novel bisphosphonate compound synthesized for the prevention of ectopic calcification, were compared with those of etidronate using both in vitro and in vivo models. In vitro, FYB-931 inhibited calcification of human aortic smooth muscle cells induced by high phosphate medium in a concentration-dependent manner, and the effect was slightly more potent than that of etidronate. In vivo, rats were administered with three subcutaneous injections of vitamin D3 to induce vascular calcification, and were given FYB-931 (1.5, 5, or 10 mg/kg) or etidronate (9, 30, or 60 mg/kg) orally once daily for 14 days. The increased aortic phosphorus content as an index of vascular calcification was inhibited by both FYB-931 and etidronate in a dose-dependent manner; however, FYB-931 was 10 times more potent than etidronate. FYB-931 inhibited serum tartrate-resistant acid phosphatase (TRACP) activity as a bone resorption marker 5.2 times more potently than etidronate. FYB-931, but not etidronate, significantly decreased serum phosphorus levels. The preferential inhibition of aortic calcification by FYB-931 suggested that possible additional effect including a decline in serum phosphorus may lead to an advantage in terms of its efficacy.

Chronic kidney disease (CKD) is associated with bone loss and fractures. The purpose of this review is to provide clinicians with an overview of the underlying pathogenesis of CKD-associated osteoporosis, and a summary of the current diagnostic and therapeutic approaches to this disease.

In 2017, the Kidney Disease Improving Global Outcomes Committee on Bone Quality updated their guidelines to include screening for osteoporosis and fracture risk by dual energy X-ray absorptiometry in patients with CKD. Once a diagnosis of osteoporosis and/or fracture risk is established, it is not clear how nephrologists should manage their patients. Patients with CKD should be screened for CKD-associated osteoporosis and considered for strategies that prevent bone loss and fractures. Assessment of bone turnover via imaging, biochemical testing, or bone biopsy can help guide the choice of therapy. Randomized controlled trials are needed to assess safety and efficacy of treatments to prevent bone loss and fractures.

Renal osteodystrophy (ROD) is the bone component of chronic kidney disease mineral and bone disorder (CKD-MBD). ROD affects bone quality and strength through the numerous hormonal and metabolic disturbances that occur in patients with kidney disease. Collectively these disorders in bone quality increase fracture risk in CKD patients compared with the general population. Fractures are a serious complication of kidney disease and are associated with higher morbidity and mortality compared with the general population. Furthermore, at a population level, fractures are at historically high levels in patients with end-stage kidney disease (ESKD), whereas in contrast the general population has experienced a steady decline in fracture incidence rates. Based on these findings, it is clear that a paradigm shift is needed in our approach to diagnosing and managing ROD. In clinical practice, our ability to diagnose ROD and initiate antifracture treatments is impeded by the lack of accurate noninvasive methods that identify ROD type. The past decade has seen advances in the noninvasive measurement of bone quality and strength that have been studied in kidney disease patients. Below we review the current literature pertaining to the epidemiology, pathology, diagnosis, and management of ROD. We aim to highlight the pressing need for a greater awareness of this condition and the need for the implementation of strategies that prevent fractures in kidney disease patients. Research is needed for more accurate noninvasive assessment of ROD type, clinical studies of existing osteoporosis therapies in patients across the spectrum of kidney disease, and the development of CKD-specific treatments. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

CKD mineral and bone disease is a common complication of kidney disease, and it affects the majority of patients with moderate to severe CKD. Recently, prospective studies have shown that measurement of bone mineral density by dual energy x-ray absorptiometry predicts incident fracture, providing nephrologists the ability to risk classify patients for skeletal fragility and targeted antifracture strategies for the first time. Furthermore, an expanding body of literature and anecdotal evidence suggest that pharmacologic agents used to treat osteoporosis in the general population can be safely used in patients with CKD. This review highlights the effects of the Kidney Disease Improving Global Outcomes updates on the management of CKD-associated osteoporosis, discusses recent investigations on the effects of antiosteoporotic agents in patients with CKD, and provides an overview of novel antiosteoporosis agents and the potential challenges related to their use in CKD.

Cardiovascular (CV) disease is the leading cause of mortality in patients with type 2 diabetes mellitus. A major factor in the pathogenesis of CV disease is vascular calcification (VC), which is accelerated in type 2 diabetes mellitus. Calcification of the vessel wall contributes to vascular stiffness and left ventricular hypertrophy whereas intimal calcification may predispose to plaque rupture and CV death. The pathogenesis of VC is complex but appears to be regulated by the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) signaling pathway, which is involved in bone remodeling. Within the bone, OPG prevents RANKL from binding to receptor activator of nuclear factor-κB and inhibiting bone resorption. Outside of the bone, the clinical significance of OPG blocking RANKL is not well understood, but OPG knockout mice that lack OPG develop early and severe VC. This minireview outlines some of the research on OPG/RANKL in the pathogenesis of VC and discusses potential therapies, which may reduce VC and CV burden in humans.

Patients with CKD have accelerated vascular stiffening contributing significantly to excess cardiovascular morbidity and mortality. Much of the arterial stiffening is thought to involve vascular calcification (VC), but the pathogenesis of this phenomenon is complex, resulting from a disruption of the balance between promoters and inhibitors of calcification in a uremic milieu, along with derangements in calcium and phosphate metabolic pathways. Management of traditional cardiovascular risk factors to reduce VC may be influential but has not been shown to significantly improve mortality. Control of mineral metabolism may potentially reduce the burden of VC, although using conventional approaches of restricting dietary phosphate, administering phosphate binders, and use of active vitamin D and calcimimetics, remains controversial because recommended biochemical targets are hard to achieve and clinical relevance hard to define. Increasing time on dialysis is perhaps another therapy with potential effectiveness in this area. Despite current treatments, cardiovascular morbidity and mortality remain high in this group. Novel therapies for addressing VC include magnesium and vitamin K supplementation, which are currently being investigated in large randomized control trials. Other therapeutic targets include crystallization inhibitors, ligand trap for activin receptors and BMP-7. This review summarizes current treatment strategies and therapeutic targets for the future management of VC in patients with CKD.