How to predict and treat increased fracture risk in chronic kidney disease.

Men and women with chronic kidney disease (CKD) are at an increased risk of fracture, and this risk increases as kidney function deteriorates. Fractures are associated with morbidity, mortality and economic costs. Despite this, there is a paucity of data regarding how to evaluate risk for fractures in CKD and how to treat high-risk patients. Evidence suggests that bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) is associated with fractures and can also predict future fractures in predialysis (stages 1-3) patients with CKD. In the absence of considerable abnormalities in markers of mineral metabolism, treatment with antiresorptive agents in men and women with early CKD at high fracture risk may be appropriate. Of note, recent data suggest that low BMD as measured by DXA can also predict fractures in patients with more advanced CKD (stages 4, 5 and 5D). However, treatment in patients with advanced CKD requires bone biopsy, the gold standard to assess bone turnover, prior to treatment. Further research, focusing on noninvasive methods to assess fracture risk and bone turnover, together with randomized controlled trials of treatments to reduce fractures in patients at all stages of CKD, is required.

Low bone mineral density and fractures in stages 3-5 CKD: an updated systematic review and meta-analysis.

SUMMARY: 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. INTRODUCTION: 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. METHODS: 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 I2 statistic. RESULTS: 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/cm2 lower in dialysis subjects and 0.102 g/cm2 lower in predialysis subjects with fractures compared to those without. Lumbar spine BMD was 0.05 g/cm2 lower in dialysis subjects and 0.108 g/cm2 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. CONCLUSIONS: Our findings suggest that BMD can discriminate fracture status in predialysis and dialysis CKD. Larger, prospective studies are needed.

The clinical utility of FRAX to discriminate fracture status in men and women with chronic kidney disease.

UNLABELLED: 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. INTRODUCTION: Patients with CKD are at increased risk for fracture but the best method to assess fracture risk is not known. METHODS: 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). RESULTS: 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. CONCLUSIONS: Among men and women with CKD, FRAX is able to discriminate fracture status but performs no better than BMD alone.

The effects of organic nitrates on osteoporosis: a systematic review.

Current treatments for osteoporosis are limited by lack of effect on cortical bone, side effects, and, in some cases, cost. Organic nitrates, which act as nitric oxide donors, may be a potential alternative. This systematic review summarizes the clinical data that reports on the effects of organic nitrates and bone. Organic nitrates, which act as nitric oxide donors, are novel agents that have several advantages over the currently available treatments for osteoporosis. This systematic review summarizes the clinical data that reports on the effects of organic nitrates on bone. We searched Medline (1966 to November 2012), EMBASE (1980 to November 2012), and the Cochrane Central Register of Controlled Trials (Issue 11, 2012). Keywords included nitrates, osteoporosis, bone mineral density (BMD), and fractures. We identified 200 citations. Of these, a total of 29 were retrieved for more detailed evaluation and we excluded 19 manuscripts: 15 because they did not present original data and four because they did not provide data on the intervention or outcome of interest. As such, we included ten studies in literature review. Of these ten studies two were observational cohort studies reporting nitrate use was associated with increased BMD; two were case control studies reporting that use of nitrates were associated with lower risk of hip fracture; two were randomized controlled trials (RCT) comparing alendronate to organic nitrates for treatment of postmenopausal women and demonstrating that both agents increased lumbar spine BMD. The two largest RCT with the longest follow-up, both of which compared effects of organic nitrates to placebo on BMD in women without osteoporosis, reported conflicting results. Headaches were the most common adverse event among women taking nitrates. No studies have reported on fracture efficacy. Further research is needed before recommending organic nitrates for the treatment of postmenopausal osteoporosis.

Fracture risk assessment in patients with chronic kidney disease.

Fractures are common in patients with chronic kidney disease (CKD) and associated with substantially high morbidity and mortality. Bone mass measurements are commonly used to assess fracture risk in the general population, but the utility of these measurements in patients with CKD, and specifically among those on hemodialysis, is unclear. This review will outline the epidemiology and etiology of fractures in patients with CKD with a particular emphasis on men and women on hemodialysis. As well, we will summarize the published data, which describes the association between risk factors for fracture (including bone mass measurements, biochemical markers of mineral metabolism, and muscle strength) and fractures in patients with CKD. Patients with CKD suffer from fractures due to impairments in bone quantity, bone quality, and abnormalities of neuromuscular function. There is a paucity of evidence on the associations between bone quality, bone turnover markers, neuromuscular function, and fractures in patients with CKD. Furthermore, the complex etiology of fractures combined with the technical limitations of bone mineral density testing, both by dual energy X-ray absorptiometry (DXA) and by peripheral quantitative tomography (pQCT), limits the clinical utility of bone mass measurements for fracture prediction in CKD; this is particularly true among patients with stages 4 and 5 CKD. Further prospective studies to identify noninvasive measures of bone strength that can be used for fracture risk assessment are needed.

Bone mineral density by DXA and HR pQCT can discriminate fracture status in men and women with stages 3 to 5 chronic kidney disease.

UNLABELLED: Fractures are common in chronic kidney disease (CKD). We determined if bone mineral density testing by dual energy X-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR pQCT) could discriminate fracture status in CKD patients. Both tests were able to discriminate fracture status. Further, the addition of HR pQCT measurements to DXA measurements did not improve fracture discrimination. INTRODUCTION: The optimal method to identify individuals with CKD at high fracture risk is unknown. METHODS: We determined if bone mineral density (BMD) by DXA and HR pQCT could discriminate fracture status in 211 adult men and women with stages 3 to 5 CKD, attending predialysis clinics in Toronto Canada, using logistic regression. Results are expressed as the odds ratio (OR) of fracture (prevalent vertebral and/or low trauma since age 40 years) per standard deviation decrease in the predictor adjusted for age, weight, sex, and CKD stage. We constructed receiver operating characteristic curves to examine the discriminative ability of BMD measures for fracture. RESULTS: Most participants were Caucasian men with a mean age of 63.3 ± 15.5 years. There were 77 fractures in 74 participants. Decreases in BMD were associated with increased fracture risk: OR = 1.56 (95% confidence interval (CI), 1.41 to 1.71) for BMD by DXA at the ultradistal radius, and OR = 1.24 (95% CI, 1.12 to 1.36) for cortical area by HR pQCT. Further, while both tests were able to discriminate fracture status, the addition of HR pQCT measures to BMD by DXA did not improve fracture discrimination ability. CONCLUSIONS: Among CKD patients not yet requiring renal replacement therapy, BMD by DXA is able to discriminate fracture status.

The effects of exercise and physical activity participation on bone mass and geometry in postmenopausal women: a systematic review of pQCT studies.

The cumulative risk of fracture for a postmenopausal woman over the age of 50 can reach up to 60%. Exercise has the potential to modify fracture risk in postmenopausal women through its effects on bone mass and geometry; however, these effects are not well characterized. To determine the effects of exercise on bone mass and geometry in postmenopausal women, we conducted a systematic review of the literature. We included all randomized controlled trials, cross-sectional studies, and prospective studies that used peripheral quantitative computed tomography to assess the effects of exercise on bone mass and geometry in this population. Exercise effects appear to be modest, site-specific, and preferentially influence cortical rather than trabecular components of bone. Exercise type also plays a role, with the most prominent mass and geometric changes being observed in response to high-impact loading exercise. Exercise appears to positively influence bone mass and geometry in postmenopausal women. However, further research is needed to determine the types and amounts of exercise that are necessary to optimize improvements in bone mass and geometry in postmenopausal women and determine whether or not these improvements are capable of preventing fractures.

Nitrate use and changes in bone mineral density: the Canadian Multicentre Osteoporosis Study.

UNLABELLED: Nitrates may have beneficial effects on bone. To determine if nitrates were associated with increased bone mineral density (BMD), we conducted a secondary analysis using data from subjects in a prospective study. Subjects reporting nitrate use had increased BMD compared with non-users, confirming that nitrates have positive BMD effects in women and men. INTRODUCTION: Prior studies suggest positive associations between nitrates and bone. METHODS: We used linear regression models, stratified by gender and adjusted for age, weight, and baseline differences, to determine the association between daily nitrate use and BMD among subjects participating in the Canadian Multicentre Osteoporosis Study. All results are reported as annualised percent change in BMD at the hip and spine among nitrate users compared to non-users. RESULTS: We included 1,419 men (71 reported daily nitrate use) and 2,587 women (97 reported daily nitrate use). Male non-users had decreased hip BMD (-1.3%; 95% confidence interval [95%CI] = -1.6 to -1.1) and increased spine BMD (2.8%; 95%CI = 2.5 to 3.1). Male nitrate users had increased hip BMD (1.4%; 95%CI = 0.1 to 2.8) and spine BMD (4.5%; 95%CI = 3.2 to 5.7). Among women, non-users had decreased hip BMD (-1.9; 95%CI = -2.1 to -1.7) and increased spine BMD (2.1%; 95%CI = 1.9 to 2.4) whilst users had an increase in hip BMD (2.0%; 95%CI = 1.2 to 2.8) and spine BMD (4.1%; 95%CI = 3.4 to 4.9). CONCLUSION: Nitrate use is associated with increased BMD at the hip and spine in men and women.

Risk factors for low bone mass in healthy 40-60 year old women: a systematic review of the literature.

UNLABELLED: Based on a systematic review of the literature, only low body weight and menopausal status can be considered with confidence, as important risk factors for low BMD in healthy 40-60 year old women. The use of body weight to identify high risk women may reduce unnecessary BMD testing in this age group. INTRODUCTION: BMD testing of perimenopausal women is increasing but may be unnecessary as fracture risk is low. Appropriate assessment among younger women requires identification of risk factors for low BMD specific to this population. METHODS: We conducted a systematic literature review of risk factors for low BMD in healthy women aged 40-60 years. Articles were retrieved from six databases and reviewed for eligibility and methodological quality. A grade for overall strength of evidence for each risk factor was assigned. RESULTS: There was good evidence that low body weight and post-menopausal status are risk factors for low BMD. There was good or fair evidence that alcohol and caffeine intake, and reproductive history are not risk factors. There was inconsistent or insufficient evidence for the effect of calcium intake, physical activity, smoking, age at menarche, history of amenorrhea, family history of OP, race and current age on BMD. CONCLUSIONS: Based on current evidence in Caucasians, we suggest that, in healthy women aged 40-60 years, only those with a low body weight (< 70 kg) be selected for BMD testing. Further research is necessary to determine optimal race-specific discriminatory weight cut-offs and to evaluate the risk factors for which there was inconclusive evidence.

Hyperhomocysteinaemia and aortic calcification are associated with fractures in patients on haemodialysis.

BACKGROUND: Fractures and atherosclerosis are common in patients with renal failure; this may be due to hyperhomocysteinemia. AIM: To examine the relationships between fractures, vascular calcification and homocysteine levels in haemodialysis patients. DESIGN: Cross-sectional survey. METHODS: We enrolled 37 men and 15 women who had been on haemodialysis for at least 1 year. We identified prevalent spine fractures by radiographs. Non-spine fractures were identified by self-report and confirmed by review of radiographs or radiology reports. We classified the presence and severity of lumbar aortic calcifications with lateral lumbar radiographs. We measured serum homocysteine in all subjects within 30 days of study entry. RESULTS: After adjusting for age and weight, increased levels of homocysteine were associated with an increased risk fracture (OR per mmol/l increase in homocysteine 1.6, 95%CI 1.2-2.0), as was the presence of aortic calcification (OR 1.6, 95%CI 1.2-2.1). Homocysteine and lumbar aortic calcification were highly correlated (r = 0.86). DISCUSSION: Hyperhomocysteinaemia may explain the relationship between fractures and atherosclerosis in patients with renal failure.

Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures.

Nitric oxide slows bone remodeling and bone loss in animals. Because nitroglycerin and other nitrates increase nitric oxide levels, we hypothesized that nitrate use may be associated with greater bone mineral density (BMD) and decreased risk of fracture in humans. Further, intermittent nitrate use may be associated with greater benefits than daily nitrate use, which results in tachyphylaxis. We tested this hypothesis using data from the Study of Osteoporotic Fractures. We prospectively studied 6201 elderly women of whom 317 took nitrates on a daily basis and 74 used them intermittently. We measured BMD at the hip and the heel and adjusted all comparisons for multiple potential confounders. We found that women taking daily nitrates had slightly greater hip BMD (difference, 13%; 95% confidence interval [CI], 0.14-4.1%) but the same heel BMD (difference, 0%; 95% CI -2.6-2.6%) as nonusers. By contrast, women using nitrates intermittently had substantially greater hip (difference, 2.6%; 95% CI, 0.4-6.8%) and heel BMD (difference, 53%; 95% CI, 2.6-11%) than nonusers. This study suggests that the intermittent administration of nitrates may enhance BMD.

Bone mineral density testing and osteoporosis education improve lifestyle behaviors in premenopausal women: a prospective study.

One way to decrease the risk of osteoporosis is to maximize peak bone mass. Peak bone mass may be moderately influenced by lifestyle behaviors: increasing calcium and exercise, decreasing alcohol intake and smoking may increase peak bone mass. We examined the effects of osteoporosis education and bone mineral density (BMD) testing on self-reported lifestyle behaviors in 669 premenopausal women enrolled in a prospective study to assess determinants of peak bone mass. Study participants completed a questionnaire that assessed lifestyle behaviors, received pamphlets about osteoporosis, and had BMD testing. One year later, the women completed a similar questionnaire. After education about osteoporosis and BMD testing, women reported that they were less likely to smoke (odds ratio [OR] = 0.55; 95% confidence interval [95% CI]: 0.28-1.0), consume alcohol (OR = 0.13; 95% CI: 0.04-0.34), and caffeinated beverages (OR = 0. 43; 95% CI: 0.27-0.68). Women were more likely to use calcium supplements (OR = 4.3; 95% CI: 3.04-6.2), vitamin D supplements (OR = 12.6; 95% CI: 7.4-22.9), and drink at least one glass of milk a day (OR = 13.3; 95% CI: 7.8-23.9). Further, women with low bone mass were more likely to use calcium supplements (OR = 1.7; 95% CI: 1.2-2.3) and vitamin D supplements (OR = 1.6; 95% CI:1.1-2.2) compared with women who had normal bone mass. Thus, our intervention improved self-reported lifestyle behaviors in premenopausal women. Such behaviors may ultimately increase peak bone mass and decrease the risk of developing osteoporosis.

Older women with diabetes have an increased risk of fracture: a prospective study.

To determine whether type 2 diabetes is associated with fracture in older women, we analyzed data from 9654 women, age 65 yr or older, in the Study of Osteoporotic Fractures. Diabetes with age at onset 40 yr or older was reported by 657 women, of whom 106 used insulin. A total of 2624 women experienced at least one nonvertebral fracture during an average follow-up of 9.4 yr, and 388 had at least one vertebral fracture during an average interval of 3.7 yr. Although diabetes was associated with higher bone mineral density, it was also associated with a higher risk of specific fractures. Compared with nondiabetics, women with diabetes who were not using insulin had an increased risk of hip [relative risk (RR), 1.82; 95% confidence interval (CI), 1.24-2.69] and proximal humerus (RR, 1.94; 95% CI, 1.24-3.02) fractures in multivariate models controlling for age, body mass index, bone density, and other factors associated with fractures and diabetes. Insulin-treated diabetics had more than double the risk of foot (multivariate adjusted RR, 2.66; 95% CI, 1.18-6.02) fractures compared with nondiabetics. This study indicates that diabetes is a risk factor for hip, proximal humerus, and foot fractures among older women, suggesting that fracture prevention efforts should be a consideration in the treatment of diabetes.

Serum fructosamine level and the risk of hip fracture in elderly women: a case-cohort study within the study of osteoporotic fractures.

PURPOSE: While a high serum fructosamine level may be an indicator of undiagnosed diabetes, a low level may be indicative of poor nutrition or frailty. As malnutrition is a risk factor for osteoporosis, low serum fructosamine levels may be associated with an increased risk of osteoporotic fracture. We examined the association between serum fructosamine levels and the risk of subsequent hip and vertebral fracture. SUBJECTS AND METHODS: We performed a case-cohort study within the Study of Osteoporotic Fractures. Subjects were elderly, ambulatory, community-dwelling, Caucasian, women. Fructosamine levels were measured in baseline serum. Incident vertebral fractures were identified by comparing baseline spinal radiographs to those obtained an average of 3.5 years later. Hip fractures were confirmed by radiograph. We randomly selected 101 women who suffered a hip fracture, 100 women who developed a vertebral fracture, and 276 controls. We compared fructosamine levels in women with subsequent osteoporotic fractures to controls. All analyses were adjusted for age, weight, and use of estrogens. RESULTS: Women with fructosamine levels in the lowest decile (< or = 223 micromol/L) had a three-fold increase in the risk of hip fracture (95% confidence interval 1.4-6.4), compared with all other women. Adjustment for markers of frailty, including smoking, functional status, and serum albumin levels, reduced the strength of this association. No clear association was observed between serum fructosamine level and the risk of vertebral fracture. CONCLUSION: Low serum fructosamine levels, which likely reflect frailty or malnutrition, may be a useful clinical tool to identify women at risk for hip fracture.

Vinblastine and erythromycin: an unrecognized serious drug interaction.

Vinblastine and erythromycin are among the most commonly used chemotherapeutic and antimicrobial agents, respectively. No interaction between the two has ever been reported. Towards the end of a phase I study of vinblastine plus oral cyclosporin (to reverse multidrug resistance), three patients also received erythromycin to raise their cyclosporin levels. All developed severe toxicity consistent with a much higher vinblastine dose than was actually given. This apparent potentiation of vinblastine toxicity has not been previously described.

Risk factors for posterior capsular pearling after uncomplicated extracapsular cataract extraction and plano-convex posterior chamber lens implantation.

We retrospectively reviewed 542 consecutive cases of extracapsular cataract extraction with implantation of a plano-convex laser ridge posterior chamber intraocular lens. We were interested in the incidence and probability of the development of postcapsular epithelial pearling that required laser capsulotomy and the risk factors associated with it. After four years of follow-up, 21% of all cases had developed pearling. Over the same period, the probability of pearling, as determined by the Kaplan-Meier curves, was 29% with a 95% confidence interval between 22% and 36%. After one year of follow-up, the probability of pearling was 5%; after two years, 15%; after three years, 24%. Younger age (50 years or less), larger optic, and smaller IOL were identified as significant risk factors when each of these factors was analyzed separately. When all risk factors were studied together, and after applying confounding statistics, only younger age was identified as a significant risk factor (P = .003).

New bioactive compounds of plant origin.

Crude extracts of Withania somnifera (WS) and Polygonum equisetiforme (PE) as well as the pure compounds isolated therefrom were screened for antibacterial and antifungal activity against 20 bacterial and 17 fungal cultures. The crude extract of PE and WS inhibited the growth of T. mentagrophyte, M. canis and A. boydii at an MIC of 450-500 microg/ml whereas the pure compounds inhibited the growth at MIC of 300-350 micro/ml. Species of Corynebacterium, Bacillus, Streptococcus and Staphylococcus were found to be highly susceptible to both the crude sad the pure compounds. MIC values of both crude extracts for different organisms tested were found to be higher (200-350 microg/ml) than the pure compounds (150-170 microg/ml). The crude extract of PE did not inhibit the growth of Ps. aeruginosa, however, the pure compound was found to be bacteriostatic. Brine shrimp and BALB/c mice lethality test indicated that these extracts maybe toxic at high concentration.