Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference.

A new definition and classification of chronic kidney disease-mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.

Fractures in chronic kidney disease: pursuing the best screening and management.

PURPOSE OF REVIEW: Osteoporotic fractures are common and cause increased sickness and death. Men and women with chronic kidney disease (CKD) are at particularly high risk of osteoporotic fractures. Currently, however, there are no guidelines concerning noninvasive methods to assess fracture risk in CKD. Further, approved treatments to prevent fractures in otherwise healthy men and women are only recommended for use with caution in those with CKD. This review focuses on the recent data that support the use of noninvasive methods to assess fracture risk in CKD and highlights new therapies that could be used in fracture prevention in CKD. RECENT FINDINGS: Data from prospective studies demonstrate that low bone mineral density predicts fracture in CKD patients. Post-hoc analyses demonstrate that agents approved for the treatment of postmenopausal osteoporosis (bisphosphonates, denosumab and teriparatide) when given to those with CKD are well tolerated and potentially efficacious with respect to fracture risk reduction. SUMMARY: To date, patients, and nephrologists taking care of them, have largely ignored fracture risk assessment and treatment in CKD. This should change given recent data. Further studies are needed, specifically bone histomorphometric studies, which will increase our understanding of CKD-mineral bone disease (MBD) pathophysiology, and randomized clinical trials of therapy in patients with CKD.

Teriparatide and bone turnover and formation in a hemodialysis patient with low-turnover bone disease: a case report.

Teriparatide, a recombinant form of parathyroid hormone, is an anabolic agent approved for use in women and men with osteoporosis. However, it is not well studied in people with chronic kidney disease (CKD). We report on a patient with stage 5 CKD treated with dialysis who presented to our clinic with multiple fractures, including bilateral nondisplaced pelvic fractures resulting in chronic pain and interfering with the patient's ability to work. Bone histomorphometry demonstrated low-turnover bone disease, and he was treated with 20µg of teriparatide (subcutaneous injection) every morning for 24 months. Within 6 months of initiating therapy, the patient's pain resolved and he was able to resume work. Serum calcium and phosphate levels remained within reference ranges throughout his treatment, and he sustained no further fractures. During 24 months of treatment, bone mineral density was maintained at the lumbar spine, and there was an increase of 4% at the femoral neck and total hip. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. In our patient, 24-month treatment with teriparatide was safe and effective; however, larger studies are needed to determine the efficacy of teriparatide in the dialysis-dependent CKD population.

Bone kidney interactions.

The fact that bone disease and kidney disease co-exist is well known. Formally, this inter-relationship is called chronic kidney disease mineral bone disorder or CKD-MBD. Traditionally, it was thought that bone played a passive role in CKD-MBD - specifically that kidney disease caused disordered mineral metabolism which resulted in bone disease and ultimately fractures. More recently however our understanding of bone function in general and the role that bone plays in CKD-MBD in particular, has changed. This chapter will briefly review epidemiology of fractures in chronic kidney disease (CKD) and the roles that imaging and measuring markers of mineral metabolism can play in assessing fracture risk. We will then review more recent data consistent with the concept MBD occurs early in the course of CKD and, via the secretion of novel molecules and/or signalling pathways, the bone can influence other organ systems.

Bone imaging and fracture risk assessment in kidney disease.

Fractures are more common and are associated with greater morbidity and morality in patients with kidney disease than in members of the general population. Thus, it is troubling that in chronic kidney disease (CKD) patients there has been a paradoxical increase in fracture rates over the past 20 years compared to the general population. Increased fracture incidence in CKD patients may be driven in part by the lack of screening for fracture risk. In the general population, dual energy X-ray absorptiometry (DXA) is the clinical standard to stratify fracture risk, and its use has contributed to decreases in fracture incidence. In contrast, in CKD, fracture risk screening with DXA has been uncommon due to its unclear efficacy in predicting fracture and its inability to predict type of renal osteodystrophy. Recently, several prospective studies conducted in patients across the spectrum of kidney disease have demonstrated that bone mineral density measured by DXA predicts future fracture risk and that clinically relevant information regarding fracture risk is provided by application of the World Health Organization cutoffs for osteopenia and osteoporosis to DXA measures. Furthermore, novel high-resolution imaging tools, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have been used to elucidate the effects of kidney disease on cortical and trabecular microarchitecture and bone strength and to identify potential targets for strategies that protect against fractures. This review will discuss the updated epidemiology of fractures in CKD, fracture risk screening by DXA, and the utility of state-of-the art imaging methods to uncover the effects of kidney disease on the skeleton.

Fractures in chronic kidney disease: neglected, common, and associated with sickness and death.

Bone fractures in dialysis patients have been poorly studied in the past. Tentori et al. partially fill this gap, assessing the incidence of post-fracture morbidity and mortality in patients of the Dialysis Outcomes and Practice Patterns Study (DOPPS). A high frequency of fractures and increased adverse outcomes following a fracture were observed. The nephrology community should pay more attention to bone fractures in dialysis patients.

The three-year incidence of fracture in chronic kidney disease.

Knowing a person's fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m(2)), gender, and age (40-65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials.

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.

BACKGROUND: Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. METHODS: We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. FINDINGS: Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98). INTERPRETATION: Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. FUNDING: None.

Osteoprotegerin and fractures in men and women with chronic kidney disease.

Fractures are common in men and women with chronic kidney disease (CKD) but the best tool to identify those at high risk is unknown. Increased circulating osteoprotegerin(OPG) is associated with fractures in postmenopausal women. We determined if serum OPG was associated with prevalent fractures (self-reported low trauma fractures since 40 years of age and/or prevalent vertebral fractures identified by radiographs) in men (n = 97) and women (n = 67) with stage 3­5 CKD. Analyses were performed unadjusted and adjusted for stage of CKD. Results are expressed as mean ± standard deviation(SD), and as odds ratio (OR) per SD increase in OPG with 95 % confidence intervals (CI). The mean age was 62.7 ± 16.3 years, and mean weight was 78.9 ± 18.7 kg. Compared to those without fractures, those with fractures(n = 55) were older (p < 0.01). Serum OPG increased as kidney function decreased, and OPG was higher in those with fractures compared to those without (9.42 ± 4.08 vs 8.06 ± 3.11 pmol/L, p = 0.02). After adjusting for stage of CKD, increased OPG was associated with an increased fracture risk (OR 1.13, 95 % CI 1.02­1.25); however, OPG did not discriminate fracture status well (area under the receiver operating characteristic curve 0.61, 95 % CI 0.52­0.70). OPG is associated with fractures in men and women with stage 3­5 CKD; however, the ability of OPG to discriminate fracture status is poor and cannot be used in isolation to assess fracture risk. Further studies should examine the ability of OPG in combination with other risk factors to better discriminate fracture status in men and women with CKD.

Heterogeneity in skeletal load adaptation points to a role for modeling in the pathogenesis of osteoporotic fracture.

Genetic, environmental, or hormonal factors may cause heterogeneity in skeletal load response. Individuals with reduced sensitivity to load should require higher strains to generate an adaptive response, consequently have weaker bones and fracture more frequently. The purpose of our study was to determine if stresses (proportional to strains) at the femoral neck under equivalent loads were higher in women with a history of fractures compared with women without fractures. We studied postmenopausal women participating in the Canadian Multicentre Osteoporosis Study who had available hip structure analysis data from dual-energy X-ray absorptiometry scans (n = 2168). Women were categorized into 2 groups based on their number of self-reported fractures. We computed stress (megapascals) at the inferomedial margin of the femoral neck in a one-legged stance mode using a 2-dimensional engineering beam analysis. We used linear regression (SAS 9.3) to determine associations between stress, geometry parameters, and number of fractures. Postmenopausal women with 1 or more fractures had higher stress (2.6%), lower narrow neck bone mineral density (4.2%), cross-sectional area (3.9%), and section modulus (9.6%) than postmenopausal women without fractures (all p < 0.05). These findings provide evidence of heterogeneity in load response and suggest an important role for modeling in the pathogenesis of osteoporotic fracture.

Secondary and tertiary hyperparathyroidism.

We reviewed the etiology and management of secondary and tertiary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH) that is appropriate and in response to a stimulus, most commonly low serum calcium. In secondary hyperparathyroidism, the serum calcium is normal and the PTH level is elevated. Tertiary hyperparathyroidism is characterized by excessive secretion of PTH after longstanding secondary hyperparathyroidism, in which hypercalcemia has ensued. Tertiary hyperparathyroidism typically occurs in men and women with chronic kidney disease usually after kidney transplant. The etiology and treatment of secondary hyperparathyroidism is relatively straightforward whereas data on the management of tertiary hyperparathyroidism is limited to a few small trials with short follow-up.

The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian Multicentre Osteoporosis Study (CaMos).

OBJECTIVES: Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk. METHODS: We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1-L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years. RESULTS: In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up. CONCLUSIONS: PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study.

Tests of neuromuscular function are associated with fractures in patients with chronic kidney disease.

BACKGROUND: Fractures are common in individuals with chronic kidney disease (CKD), and tests of neuromuscular function (NMT) discriminate well among fractured and non-fractured patients with Stage 5 CKD on dialysis. The ability of NMT to discriminate fracture status in patients with Stages 3-5 CKD is unknown. METHODS: In this cross-sectional study, we sought to determine in adult patients with Stages 3-5 CKD (eGFR by the Modification of Diet in Renal Disease equation) if NMT [timed up and go (TUG), 6-min walk (6MW) and grip strength] could discriminate fracture status (self-reported low-trauma fractures since age 40 and/or vertebral fractures by morphometry). We conducted logistic regression and receiver-operating characteristic (ROC) curves for each predictor [expressed as area under the ROC curves (AUROC) with 95% confidence intervals (CI)]. RESULTS: Data was available for 125 men and 86 women. The mean age was 63.3 ± 15.5 years, duration of CKD was 96.7 ± 125.3 months and one-third had diabetes. Patients with fractures were older and fell more frequently (P < 0.05). After adjusting for age, weight and sex, for every standard deviation increase in TUG and 6MW, the risk of fracture increased [odds ratio (OR): 1.68; 95% CI: 1.40-2.02] and decreased (OR: 0.53; 95% CI: 0.52-0.54), respectively. Both the TUG and 6MW could discriminate among those with and without fractures (AUROC: 0.90; 95% CI:0.84-0.95, AUROC: 0.87; 95% CI: 0.80-0.94, respectively). CONCLUSIONS: The TUG and 6MW are able to discriminate fracture status in patients with Stages 3-5 CKD. These tests do not require specialized expertise/equipment and are an inexpensive method to assess for the presence of fractures.

Bone and kidney disease: diagnostic and therapeutic implications.

Fractures are common in patients with chronic kidney disease (CKD), but the diagnosis and treatment of bone disease in CKD are difficult due to the multiple etiologies of bone disease in these patients. Noninvasive imaging, including bone mineral density by dual energy x-ray absorptiometry, can be useful in diagnosing osteoporosis in predialysis CKD; however, consensus on the diagnosis of osteoporosis among those with advanced CKD-particularly stage 5 CKD patients on dialysis-is lacking. Treatments approved for osteoporosis in postmenopausal women may be used in patients with stage 1 to 3 CKD. Furthermore, post-hoc analyses show efficacy and safety of oral bisphosphonates, raloxifene, and denosumab in stage 4 CKD for short-term treatment. However, treatment decisions are more difficult in stage 5 CKD. Bone biopsy may be required, and most treatments, if used, would be off label. Overall, the diagnosis and treatment of bone disease in patients with CKD require further research.

Determination of bone architecture and strength in men and women with stage 5 chronic kidney disease.

Fractures are common in men and women with dialysis-dependent chronic kidney disease (stage 5D CKD) and are associated with substantial morbidity and mortality. The clinical utility of dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), noninvasive measures of bone mass and architecture that reflect fracture risk in healthy men and women, is uncertain in patients with stage 5D CKD. This review will outline the epidemiology and etiology of fractures and will summarize the published data that describe the association between fractures, bone mass, and bone strength in stage 5D CKD. Fracture risk assessment in stage 5D CKD is complicated as the etiology of fractures is multifactorial and includes impairments in bone quantity and quality. Cross-sectional data suggest that bone density by DXA is lower among stage 5D CKD patients with fractures compared with those without, and that this may be particularly true at cortical sites. However, DXA does not capture bone microarchitecture and cannot differentiate between cortical and trabecular bone. Some, but not all studies, that measure cortical and trabecular bone by pQCT in stage 5D CKD, demonstrate a preferential decrease in cortical bone; however, these studies are limited by small sample sizes and cross-sectional study design. No studies have reported on longitudinal relationships between bone architecture, strength, and incident fractures in patients with stage 5D CKD. Further research is needed to identify noninvasive measures of bone strength that can be used for fracture risk assessment in stage 5D CKD.

Nitric oxide donors for the treatment of osteoporosis.

The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment is necessary to alleviate this increase in fractures. Current treatments decrease fractures at trabecular bone sites (spine) but have limited effects at cortical sites (hip, legs, forearm, and upper arm)-the most common sites of osteoporotic fracture. Treatments are also limited by costs, side effects, and lack of availability. Nitric oxide is a novel agent that has the potential to influence cortical bone, is inexpensive, is widely available, and has limited side effects. In this review we evaluate the in vitro and in vivo data which support the concept that nitric oxide is important in bone cell function, review the observational and case-control studies reporting on subjects taking organic nitrates that act as nitric oxide donors, and review the effects of nitrates on bone mineral density measurements and fracture risk.

Reducing the risk of re-fracture in the dialysis population: is it time to consider therapy with PTH analogues?

Dialysis patients are at high risk for fracture, with published rates in excess of a 20% probability of fracture over the next 10 years of dialysis. Unfortunately, there is no accepted methodology for quantifying this risk in advance of the first fracture; conventional bone densitometry performs unreliably in this role, in contrast to its utility in elderly patients with osteoporosis. The KDIGO clinical guidelines emphasize the importance of bone turnover in the development of renal osteodystrophy with high bone turnover strongly associated with uncontrolled secondary hyperparathyroidism, and adynamic bone disease (ABD) defined as a very low bone turnover state associated with functional hypoparathyroidism. It is likely that fractures occur in association with both extremes of uremic bone turnover, in addition to the known risk factors for developing osteoporosis prior to an individual developing end-stage renal failure. No systematic evidence has been forthcoming on therapy to reduce the risk of re-fracture after a dialysis patient presents with a first fracture. Anti-resorptive therapy might be effective in high turnover uremic bone disease and has been demonstrably effective in reducing fracture risk in osteoporotic patients, but there is only post hoc evidence that cinacalcet might reduce the incidence of fractures, and almost no evidence on outcomes from the use of bisphosphonates in dialysis patients. Fractures associated with ABD present a particular challenge. Although aluminum intoxication has been an important cause of skeletal fracturing in the past, this is a rare event today, when nonaluminum containing dietary phosphate binders are routinely prescribed. We suggest that the use of an anabolic agent would be a more plausible approach to the management of ABD (rather than anti-resorptive agents) and propose that a "proof-of-concept" trial with a PTH analogue such as teriparatide should be considered for these patients.

Spine-hip T-score difference predicts major osteoporotic fracture risk independent of FRAX(®): a population-based report from CAMOS.

The WHO fracture risk assessment tool (FRAX(®)) estimates an individual's 10-yr major osteoporotic and hip fracture probabilities. When bone mineral density (BMD) is included in the FRAX calculation, only the femoral neck measurement can be used. Recently, a procedure was reported for adjusting major osteoporotic fracture probability from FRAX with femoral neck BMD based on the difference (offset) between the lumbar spine and the femoral neck T-score values. The objective of the current analysis was to independently evaluate this algorithm in a population-based cohort of 4575 women and 1813 men aged 50 yr and older from the Canadian Multicentre Osteoporosis Study. For women and men combined, there was a 15% (95% confidence interval 7-24%) increase in major osteoporotic fracture risk for each offset T-score after adjusting for FRAX probability calculated with femoral neck BMD. The effect was stronger in women than men, but a significant sex interaction was not detected. Among the full cohort, 5.5% had their risk category reclassified after using the offset adjustment. Sex- and age-dependent offsets (equivalent to an offset based on Z-scores) showed improved risk classification among individuals designated to be at moderate risk with the conventional FRAX probability measurement. In summary, the T-score difference between the lumbar spine and femoral neck is an independent risk factor for major osteoporotic fractures that is independent of the FRAX probability calculated with femoral neck BMD.

Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial.

CONTEXT: Nitroglycerin stimulates bone formation and inhibits bone resorption, is inexpensive, and is widely available. Its effects on bone density, bone structure, and bone strength are unknown. OBJECTIVES: To determine if nitroglycerin increases lumbar spine bone mineral density (BMD) and to evaluate changes in hip BMD, bone geometry, and density at the radius and tibia, and markers of bone turnover. DESIGN, SETTING, AND PARTICIPANTS: A single-center, double-blind, placebo-controlled randomized trial conducted in Toronto, Ontario, Canada, for 24 months starting in November 2005 and completed in March 2010, of 243 postmenopausal women with lumbar spine T scores of between 0 and -2.0 who completed a 1-week run-in period taking nitroglycerin ointment. Intervention Nitroglycerin ointment (15 mg/d) or placebo applied at bedtime for 24 months. MAIN OUTCOME MEASURES: Areal BMD at the lumbar spine, femoral neck, and total hip. Secondary outcomes included indices of bone geometry and strength at the distal radius and tibia, and biomarkers of bone formation (bone-specific alkaline phosphatase) and bone resorption (urine N -telopeptide). RESULTS: At 2 years, women randomized to the nitroglycerin group had significant increases in areal BMD at the lumbar spine (from 1.05 to 1.14 g/cm(2) vs placebo from 1.06 to 1.08 g/cm(2); percentage change, 6.7%; 95% confidence interval [CI], 5.2%-8.2%; P < .001); total hip (from 0.92 to 0.97 g/cm(2) vs placebo from 0.93 to 0.92 g/cm(2); 6.2%; 95% CI, 5.6%-7.0%; P < .001); and femoral neck (from 0.88 to 0.93 g/cm(2) vs placebo from 0.87 to 0.86 g/cm(2); 7.0%; 95% CI, 5.5%-8.5%; P < .001). At 2 years, nitroglycerin also increased volumetric trabecular BMD (11.9% and 8.5%), cortical thickness (13.9% and 24.6%), periosteal circumference (7.4% and 2.9%), polar section modulus (10.7% and 9.8%), and polar moment of inertia (7.3% and 14.5%) at the radius and tibia, respectively (all P < .001); and increased bone-specific alkaline phosphatase by 34.8% and decreased urine N -telopeptide by 54.0% (P < .001). Incidence of serious adverse events did not differ between nitroglycerin (5 [4.2%]) and placebo (5 [4.3%]) groups. Among those women who continued treatment for 24 months, headaches were reported by 40 (35%) in nitroglycerin and 6 (5.4%) in placebo groups during the first month, decreasing substantially after 12 months. CONCLUSION: Among postmenopausal women, nitroglycerin ointment modestly increased BMD and decreased bone resorption. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN94484747.