[Show abstract][Hide abstract] ABSTRACT: The utility of bone mineral density (BMD) testing in chronic kidney disease (CKD) is not known. We performed a meta-analysis of studies reporting on BMD and fracture in CKD. All but one study was cross-sectional. BMD was lower in those with CKD and fractures compared to those without fractures.
CKD is associated with an increased risk of fracture. The utility of dual energy X-ray absorptiometry (DXA) to assess fracture risk in CKD is unknown.
We performed an updated meta-analysis and systematic review of published studies that reported on the association between DXA and fracture (morphometric spine or clinical nonspine) in predialysis and dialysis CKD. We identified 2,894 potential publications, retrieved 292 for detailed review, and included 13. All but one study was cross-sectional and three reported on the ability of DXA to discriminate fracture status in predialysis CKD. Results were pooled using a random effects model and statistical heterogeneity was assessed using the I (2) statistic.
BMD was statistically significantly lower at the femoral neck, lumbar spine, the 1/3 and ultradistal radius in subjects with fractures compared to those without regardless of dialysis status. For example, femoral neck BMD was 0.06 g/cm(2) lower in dialysis subjects and 0.102 g/cm(2) lower in predialysis subjects with fractures compared to those without. Lumbar spine BMD was 0.05 g/cm(2) lower in dialysis subjects and 0.108 g/cm(2) lower in predialysis subjects with fractures compared to those without. Our meta-analysis was limited to studies with small numbers of subjects and even smaller numbers of fractures. All of the studies were observational and only one was prospective. There was statistical heterogeneity at the lumbar spine, 1/3 and ultradistal radius.
Our findings suggest that BMD can discriminate fracture status in predialysis and dialysis CKD. Larger, prospective studies are needed.
Osteoporosis International 12/2014; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathophysiology of atypical fractures is unknown. We compared characteristics of patients with atypical femoral fractures and hip fractures in typical locations of the femur. Patients with atypical fracture reported a longer duration of use of bisphosphonates, had higher body mass index, and higher total hip bone mineral density. Further studies are needed.
This study aims to describe the characteristics of patients with typical and atypical fractures of the femur assessed in a tertiary care osteoporosis center.
We abstracted clinical, laboratory, and radiographic data on subjects with a history of a low-impact fracture at the femur and/or hip (confirmed by review of radiograph and/or radiology report) from January 2008 to October 2011. Available radiographs were reviewed and fracture categorized as typical or atypical by a radiologist blinded to the original diagnosis.
Radiology reports were available for 72 subjects: 40 hip fractures in typical locations (typical fracture), 16 atypical femoral fracture (atypical fracture), and 16 were excluded. While both those with typical and atypical fractures reported taking bisphosphonates at the time of fracture, duration of use was longer with atypical fractures (104.2 ± 42.0 months) compared with typical (71.1 ± 62.8 months) (p = 0.04). Body mass index (BMI) was higher in patients with atypical fractures (26.2 ± 3.2 kg/m(2)) than in those with typical (23.1 ± 4.3 kg/m(2)) (p = 0.006). Total bone mineral density (BMD) was higher in patients with atypical fracture (0.795 ± 0.102) versus typical (0.686 ± 0.130) (p = 0.003) Previous history of cancer was reported by 7 of 16 patients with atypical and 7 of 40 patients with typical fracture (p = 0.04).
Compared to those with typical fractures, patients with atypical fracture report a longer duration of use of bisphosphonates, higher BMI, and higher total hip BMD. Future studies should examine if these differences contribute to the pathophysiology of atypical fractures.
[Show abstract][Hide abstract] ABSTRACT: Fractures are common in chronic kidney disease (CKD). The optimal methods by which to assess fracture risk are unknown, in part, due to a lack of prospective studies. We determined if bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA), and/or high resolution peripheral quantitative computed tomography (HRpQCT) could predict fractures in men and women ≥ 18 years old with stages 3 to 5 CKD. BMD was measured by DXA (at the total hip, lumbar spine, ultradistal, and 1/3 radius) and by HRpQCT (at the radius), and subjects were followed for 2 years for incident morphometric spine fractures and low-trauma clinical fractures. The mean age of the subjects was 62 years with equal numbers having stages 3, 4 and 5 CKD. Over 2 years there were 51 fractures in 35 subjects. BMD by DXA at baseline was significantly lower at all sites among those with incident fractures vs. those without. For example, the mean BMD at the total hip in those with incident fractures was 0.77 g/cm2 (95% Confidence Interval (CI): 0.73-0.80) and in those without fracture was 0.95 g/cm2 (95% CI: 0.92-0.98). Almost all baseline HRpQCT measures were lower in those with incident fracture vs. those without. For example, volumetric BMD in those with incident fractures was 232 mgHA/cm3 (95% CI: 213-251) and in those without fracture was 317.6 mgHA/cm3 (95% CI: 306-329.1). Bone loss occurred in all subjects, but was significantly greater among those with incident fractures. Our data demonstrate that low BMD (by DXA and HRpQCT) and a greater annualized percent decrease in BMD are risk factors for subsequent fracture in men and women with predialysis CKD. This article is protected by copyright. All rights reserved
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2014; · 6.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.Kidney International advance online publication, 15 January 2014; doi:10.1038/ki.2013.547.
Kidney International 01/2014; · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Kidney International 01/2014; 85(1):20-2. · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 3-5 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 1.02-1.25); however, OPG did not discriminate fracture status well (area under the receiver operating characteristic curve 0.61, 95 % CI 0.52-0.70). OPG is associated with fractures in men and women with stage 3-5 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.
Journal of Bone and Mineral Metabolism 10/2013; · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed the ability of the World Health Organization's fracture risk assessment tool (FRAX), bone mineral density (BMD), and age to discriminate fracture status in adults with pre-dialysis chronic kidney disease (CKD). In adults with CKD, FRAX was able to discriminate fracture status but performed no better than BMD alone.
Patients with CKD are at increased risk for fracture but the best method to assess fracture risk is not known.
We assessed the ability of the World Health Organization's FRAX, compared with BMD at the femoral neck (FN), and age to discriminate fracture status (prevalent clinical nonspine and/or morphometric vertebral) in men and women, 18 years and older with pre-dialysis CKD. Results are presented as area under receiver operator characteristic curves (AUC) with 95 % confidence intervals (CI).
We enrolled 353 subjects; mean age was 65 ± 14 years; weight was 79 ± 18 kg, and estimated glomerular filtration rate was 28 ml/min/1.73 m(2). About one third of the subjects had a prevalent clinical nonspine and/or morphometric vertebral fracture. FRAX was able to discriminate among those with prevalent clinical nonspine fractures (AUC, 0.72; 95 % CI, 0.65-0.78), morphometric vertebral fractures (AUC, 0.66; 95 % CI, 0.59-0.73), and any fracture (AUC, 0.71; 95 % CI, 0.65-0.77). The discriminative ability of BMD at the FN alone was similar to FRAX for morphometric vertebral and any fractures; FRAX performed better than BMD for prevalent clinical nonspine fractures (AUC for BMD alone, 0.66; 95 % CI, 0.60-0.73). Compared to FRAX, the AUC for age alone was lower for all fracture types.
Among men and women with CKD, FRAX is able to discriminate fracture status but performs no better than BMD alone.
Osteoporosis International 10/2013; 25(1). · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Organic nitrates uncouple bone turnover, improve bone mineral density, and improve trabecular and cortical components of bone. These changes in turnover, strength and geometry may translate into an important reduction in fractures. However, before proceeding with a large fracture trial, there is a need to identify the nitrate formulation that has both the greatest efficacy (with regards to bone turnover markers) and gives the fewest headaches. Ascertaining which nitrate formulation this may be is the purpose of the current study.Methods and design: This will be an open-label randomized, controlled trial conducted at Women's College Hospital comparing five formulations of nitrates for their effects on bone turnover markers and headache. We will recruit postmenopausal women age 50 years or older with no contraindications to nitroglycerin. Our trial will consist of a run-in phase and a treatment phase. We will enroll 420 women in the run-in phase, each to receive all of the 5 potential treatments in random order for 2 days, each with a 2-day washout period between treatments. Those who tolerate all formulations will enter the 12-week treatment phase and be randomly assigned to one of five groups: 0.3 mg sublingual nitroglycerin tablet, 0.6 mg of the sublingual tablet, a 20 mg tablet of isosorbide mononitrate, a 160 mg nitroglycerin transdermal patch (used for 8 h), and 15 mg of nitroglycerin ointment as used in a previous trial by our group. We will continue enrolment until we have randomized 210 women or 35 women per group. Concentrations of bone formation (bone-specific alkaline phosphatase and procollagen type I N-terminal propeptide) and bone resorption (C-telopeptides of collagen crosslinks and N-terminal crosslinks of collagen) agents will be measured in samples taken at study entry (the start of the run in phase) and 12 weeks. Subjects will record the frequency and severity of headaches daily during the run-in phase and then monthly after that. We will use the 'multiple comparisons with the best' approach for data analyses, as this strategy allows practical considerations of ease of use and tolerability to guide selection of the preparation for future studies.
Data from this protocol will be used to develop a randomized, controlled trial of nitrates to prevent osteoporotic fractures.Trial registration: ClinicalTrials.gov Identifier: NCT01387672. Controlled-Trials.com: ISRCTN08860742.
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonates are widely used for the treatment of osteoporosis and are generally well tolerated. However, the United States Food and Drug Administration safety reports have highlighted the issue of renal safety in bisphosphonate-treated patients. All bisphosphonates carry labeled "warnings" or a contraindication for use in patients with severe renal impairment (creatinine clearance <30 or <35 mL/min). Data from pivotal trials and their extension studies of bisphosphonates approved for the management of osteoporosis were obtained via PubMed, and were reviewed with support from published articles available on PubMed. Renal safety analyses of pivotal trials of oral alendronate, risedronate and ibandronate for postmenopausal osteoporosis showed no short- or long-term effects on renal function. Transient post-infusion increases in serum creatinine have been reported in patients receiving intravenous ibandronate and zoledronic acid, however studies showed that treatment with these agents did not result in long-term renal function deterioration in clinical trial patients with osteoporosis. All bisphosphonate therapies have "warnings" for use in patients with severe renal impairment. Clinical trial results have shown that even in elderly, frail osteoporotic patients with renal impairment, intravenous bisphosphonate therapy administration in accordance with the prescribing information did not result in long-term renal function decline. Physicians should follow guidelines for bisphosphonate therapies administration at all times.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2013; · 6.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: Context: Calcium and vitamin D are recommended for bone health, but there are
concerns about adverse risks. Some clinical studies suggest that calcium intake
may be cardioprotective, whereas others report increased risk associated with
calcium supplements. Both low and high serum levels of 25-hydroxyvitamin D have
been associated with increased mortality. Objective: The purpose of this study
was to determine the association between total calcium and vitamin D intake and
mortality and heterogeneity by source of intake. Design: The Canadian Multicentre
Osteoporosis Study cohort is a population-based longitudinal cohort with a
10-year follow-up (1995-2007). Setting: This study included randomly selected
community-dwelling men and women. Participants: A total of 9033 participants with
nonmissing calcium and vitamin D intake data and follow-up were studied.
Exposure: Total calcium intake (dairy, nondairy food, and supplements) and total
vitamin D intake (milk, yogurt, and supplements) were recorded. Outcome: The
outcome variable was all-cause mortality. Results: There were 1160 deaths during
the 10-year period. For women only, we found a possible benefit of higher total
calcium intake, with a hazard ratio of 0.95 (95% confidence interval, 0.89-1.01)
per 500-mg increase in daily calcium intake and no evidence of heterogeneity by
source; use of calcium supplements was also associated with reduced mortality,
with hazard ratio of 0.78 (95% confidence interval, 0.66-0.92) for users vs
nonusers with statistically significant reductions remaining among those with
doses up to 1000 mg/d. These associations were not modified by levels of
concurrent vitamin D intake. No definitive associations were found among men.
Conclusions: Calcium supplements, up to 1000 mg/d, and increased dietary intake
of calcium may be associated with reduced risk of mortality in women. We found no
evidence of mortality benefit or harm associated with vitamin D intake.
The Journal of Clinical Endocrinology and Metabolism 07/2013; 98(7):3010-8. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Recent data suggest that women with type 2 diabetes mellitus (T2DM) might be more susceptible to fractures due to an impaired adaptive response to mechanical load, despite reportedly higher bone mineral density (BMD). The purpose of this study was to use an engineering beam analysis to calculate and compare the load stresses on the femurs of healthy women and women with T2DM and compare these levels to conventional measures of femoral neck BMD.Materials/Methods
We studied 3658 women who participated in the Canadian Multicentre Osteoporosis Study (CaMos), and who had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized into two groups based on the presence or absence of self-reported T2DM. We computed stress in megapascals (MPa) at the infero-medial margin of the femoral neck in a one-legged stance using an engineering beam analysis incorporating dimensions and geometry from DXA scans using the HSA method. We used linear regression (SAS 9.3) to determine the association between T2DM status and stress. We also determined the association between T2DM status and femoral neck BMD.ResultsStresses were 4.5% higher in T2DM women than in non-diabetics (11.03 ± 0.18 vs. 10.56 ± 0.04 MPa; p = 0.0093). Femoral neck BMD was 4.2% greater in women with T2DM than in non-diabetics (0.74 ± 0.002 vs. 0.71 ± 0.01 g/cm2; p = 0.0008).Conclusions
Despite higher femoral neck BMD, higher stress indicates weaker skeletal geometry for a given load, and suggests an impaired skeletal adaptive response to load may be present in women with T2DM.
Metabolism: clinical and experimental 06/2013; · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumour induced osteomalacia (TIO) is a rare and often unrecognized cause of hypophosphatemia. We report on a case of TIO due to a hemangiopericytoma originating from the left nasal sinus. The patient was a 55-year-old male with a 3-year history of left hip pain and an undisplaced left hip fracture. Biochemical testing demonstrated low levels of serum phosphate and serum 1,25-dihydroxyvitamin D, and an elevated level of fibroblast growth factor 23. Octreotide scanning demonstrated uptake in the left nasal sinus area and a computed tomography scan revealed a left nasal sinus mass. The patient underwent surgical resection of the mass and histology was consistent with a sinonasal hemangiopericytoma. His serum phosphate levels normalized almost immediately after surgery and he had complete resolution of hip pain. Our case highlights the importance of considering TIO when assessing patients with low serum phosphate.
World journal of clinical cases : WJCC. 04/2013; 1(1):59-63.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Fractures in men and women after kidney transplantation are associated with morbidity (including acute and chronic pain), mortality, and high economic costs. METHODS: We systematically reviewed cohort studies that provided estimates on incidence and risk factors for fracture in kidney transplant recipients. We abstracted data in duplicate and assessed the methodological quality of each study on a 17-point scale (17 representing the highest quality). RESULTS: We screened 2715 articles, reviewed 81, and included 10 studies totaling 262,678 recipients (study mean, 26,268 recipients; range, 61-77,430). The average follow-up ranged from 1.7 to 5.3 years. The study quality scores ranged from 8 to 13. Fracture sites varied by study resulting in a highly variable incidence rate ranging from 3.3 to 99.6 fractures per 1000 person-years. Similarly, the 5-year cumulative incidence for fracture varied ranging from 0.85% to 27%. Common factors associated with an increased fracture risk were older age, female sex, the presence of diabetes, and receipt of dialysis before transplantation. Other less common but statistically significant risk factors were a previous history of fracture and receipt of a kidney from a deceased (vs. living) donor. CONCLUSIONS: There is poor consensus on the incidence and risk factors for fractures in kidney transplant recipients. Previous studies vary substantially in quality, fracture definitions, and the characteristics of recipients studied. Future research should clarify fracture incidence and risk, which will inform the design of future prevention trials and guide prognostication.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Clinical Densitometry 03/2013; · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 (NO) is a novel agent that has the potential to influence cortical bone, is inexpensive, widely available and has limited side effects. In this review, we will evaluate the in vitro and in vivo data that support the concept that NO is important in bone cell function, review the observational, case control and randomized trial data on organic nitrates and the effects of these agents on bone turnover, geometry and strength.