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Effects of Myo-inositol Hexaphosphate (SNF472) on Bone Mineral Density in Patients Receiving Hemodialysis: An Analysis of the Randomized, Placebo-Controlled CaLIPSO Study.
Bushinsky, DA, Raggi, P, Bover, J, Ketteler, M, Bellasi, A, Rodriguez, M, Sinha, S, Garg, R, Perelló, J, Gold, A, et al
Clinical journal of the American Society of Nephrology : CJASN. 2021;(5):736-745
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Abstract
BACKGROUND AND OBJECTIVES In the CaLIPSO study, intravenous administration of SNF472 (300 or 600 mg) during hemodialysis significantly attenuated progression of coronary artery and aortic valve calcification. SNF472 selectively inhibits formation of hydroxyapatite, the final step in cardiovascular calcification. Because bone mineral is predominantly hydroxyapatite, we assessed changes in bone mineral density in CaLIPSO. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients with coronary artery calcification at screening (Agatston score of 100-3500 U) were randomized 1:1:1 to receive placebo, 300 mg SNF472, or 600 mg SNF472 as an intravenous infusion during hemodialysis three times weekly for 52 weeks. Dual-energy x-ray absorptiometry (DXA) scans were obtained at baseline (screening) and end of treatment, and between-group changes from baseline were compared using analysis of covariance. RESULTS Among 274 randomized patients, 202 had evaluable DXA scans at baseline and postrandomization (the DXA-modified intention-to-treat population). Mean (95% confidence interval) changes in total-hip bone mineral density from baseline to week 52 were -1.5% (-2.7% to -0.3%), -1.5% (-2.7% to -0.4%), and -2.5% (-3.8% to -1.2%) in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Mean (95% confidence interval) changes in femoral-neck bone mineral density from baseline to week 52 were -0.3% (-1.6% to 1.0%), -1.0% (-2.3% to 0.2%), and -2.6% (-4.0% to -1.3%), respectively. Regression analyses showed no correlation between change in coronary artery calcium volume and change in bone mineral density at either location. Changes in serum alkaline phosphatase, calcium, magnesium, phosphate, and intact parathyroid hormone levels were similar across treatment groups. Clinical fracture events were reported for four of 90, three of 92, and six of 91 patients in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. CONCLUSIONS Bone mineral density decreased modestly in all groups over 1 year. In the 600 mg SNF472 group, the reduction appeared more pronounced. Reported fractures were infrequent in all groups. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Effect of SNF472 on Progression of Cardiovascular Calcification in End-Stage-Renal-Disease (ESRD) Patients on Hemodialysis (HD), NCT02966028.
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The fracture predictive ability of a musculoskeletal composite score in old men - data from the MrOs Sweden study.
Cronholm, F, Rosengren, BE, Nilsson, JÅ, Ohlsson, C, Mellström, D, Ribom, E, Karlsson, MK
BMC geriatrics. 2019;(1):90
Abstract
BACKGROUND Detection of high-risk individuals for fractures are needed. This study assessed whether level of physical activity (PA) and a musculoskeletal composite score could be used as fracture predictive tools, and if the score could predict fractures better than areal bone mineral density (aBMD). METHODS MrOs Sweden is a prospective population-based observational study that at baseline included 3014 men aged 69-81 years. We assessed femoral neck bone mineral content (BMC), bone area, aBMD and total body lean mass by dual energy X-ray absorptiometry, calcaneal speed of sound by quantitative ultrasound and hand grip strength by a handheld dynamometer. PA was assessed by the Physical Activity Scale for the Elderly (PASE) questionnaire. We followed the participants until the date of first fracture, death or relocation (median 9.6 years). A musculoskeletal composite score was calculated as mean Z-score of the five measured traits. A Cox proportional hazards model was used to analyze the association between the musculoskeletal traits, the composite score and incident fractures (yes/no) during the follow-up period. Data are presented as hazard ratios (HR) with 95% confidence intervals (95% CI) for fracture for a + 1 standard deviation (SD) change (+ 1 Z-score) in the various musculoskeletal traits as well as the composite score. We used a linear regression model to estimate the association between level of PA, measured as PASE-score and the different musculoskeletal traits as well as the composite score. RESULTS A + 1 SD higher composite score was associated with an incident fracture HR of 0.61 (0.54, 0.69), however not being superior to aBMD in fracture prediction. A + 1 SD higher PASE-score was associated with both a higher composite score and lower fracture incidence (HR 0.83 (0.76, 0.90)). CONCLUSIONS The composite score was similar to femoral neck aBMD in predicting fractures, and also low PA predicted fractures. This highlights the need of randomized controlled trials to evaluate if PA could be used as a fracture preventive strategy.
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Lumbar Spine Bone Mineral Apparent Density in Children: Results From the Bone Mineral Density in Childhood Study.
Kindler, JM, Lappe, JM, Gilsanz, V, Oberfield, S, Shepherd, JA, Kelly, A, Winer, KK, Kalkwarf, HJ, Zemel, BS
The Journal of clinical endocrinology and metabolism. 2019;(4):1283-1292
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CONTEXT Dual-energy X-ray absorptiometry (DXA) is a cornerstone of pediatric bone health assessment, yet differences in height-for-age confound the interpretation of areal bone mineral density (aBMD) measures. To reduce the confounding of short stature on spine bone density, use of bone mineral apparent density (BMAD) and height-for-age Z-score (HAZ)‒adjusted aBMD (aBMDHAZ) are recommended. However, spine BMAD reference data are sparse, and the degree to which BMAD and aBMDHAZ account for height-related artifacts in bone density remains unclear. OBJECTIVE We developed age-, sex-, and population ancestry‒specific spine BMAD reference ranges; compared height-adjustment methods in accounting for shorter stature; and assessed the stability of these measures over time. DESIGN Secondary analysis of data from a previous longitudinal study. PARTICIPANTS Children and adolescents aged 5 to 19 years at baseline (n = 2014; 922 males; 22% black) from the Bone Mineral Density in Childhood Study. MAIN OUTCOME MEASURES Lumbar spine BMAD and aBMDHAZ from DXA. RESULTS Spine BMAD increased nonlinearly with age and was greater in blacks and females (all P < 0.001). Age-specific spine BMAD z-score reference curves were constructed for black and non‒black males and females. Overall, both BMAD and aBMDHAZz scores reduced the confounding influence of shorter stature, but neither was consistently unbiased across all age ranges. Both BMAD and aBMDHAZz scores tracked strongly over 6 years (r = 0.70 to 0.80; all P < 0.001). CONCLUSION This study provided robust spine BMAD reference ranges and demonstrated that BMAD and aBMDHAZ partially reduced the confounding influence of shorter stature on bone density.
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Growth, stool consistency and bone mineral content in healthy term infants fed sn-2-palmitate-enriched starter infant formula: A randomized, double-blind, multicentre clinical trial.
Béghin, L, Marchandise, X, Lien, E, Bricout, M, Bernet, JP, Lienhardt, JF, Jeannerot, F, Menet, V, Requillart, JC, Marx, J, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(3):1023-1030
Abstract
BACKGROUND Palmitate in breast milk is predominantly located in the triacylglycerol sn-2 position, while infant formulae contain palmitate predominantly in the sn-1 and sn-3 positions. During digestion, palmitate in the sn-1 and sn-3 positions is hydrolyzed to free palmitic acid that can subsequently complex with calcium to form insoluble soaps; this may partially explain why formula-fed infants have harder stools than breast-fed infants. METHODS This large (n = 488) randomized, double-blind, multicentre trial investigated whether increasing the sn-2 palmitate content of infant formula improves stool consistency and bone mineral content (measured by dual-energy x-ray absorptiometry), without affecting growth or health. From ∼1 week to 4 months of age, infants were exclusively fed one of three formulae: i) control formula (CF; 16% of total palmitate at sn-2; n = 162), (ii) experimental formula 1 (EF1; 43% of total palmitate at sn-2; n = 166) or (iii) experimental formula 2 (EF2; 51% of total palmitate at sn-2; n = 160). RESULTS Intention-to-treat analysis showed softer stools in both EF groups (vs. CF) at ages 2 weeks and 1 and 2 months (p ≤ 0.01), but not 3 and 4 months. At 4 months, all groups had similar growth outcomes while bone mineral content was significantly higher in EF1 (p = 0.0012) and EF2 (p = 0.0002) compared with CF. Comparison of reported adverse events up to 12 months revealed no differences among groups. All 3 infant formulae exhibited equally good digestive tolerance. CONCLUSIONS Formulae enriched in sn-2 palmitate fed in early infancy are safe, improve stool consistency (from 2 weeks to 2 months) and increase bone mineral content (at 4 months).
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A community-based study of the relationship between calcaneal bone mineral density and systemic parameters of blood glucose and lipids.
Gu, LJ, Lai, XY, Wang, YP, Zhang, JM, Liu, JP
Medicine. 2019;(27):e16096
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Osteoporosis (OP) is a disease characterized by decreased bone mineral density (BMD) and an increased risk of osteoporotic fractures. Nutritional factors (including glucose and fats lipids), have been implicated in OP.We hypothesized that the levels of blood glucose and lipids could be biomarkers for predicting the risk of OP. To test this hypothesis, we evaluated the potential relationship between BMD and levels of blood glucose and lipids via a community-based study in China.This was a community-based cross-section analysis, and a total of 8584 cases were investigated. The BMD of the left calcaneus was measured using an ultrasonic bone densitometer. The levels of blood glucose (fasting blood glucose [FBG], 2-h blood glucose [2hBG], and glycosylated hemoglobin [HbAlc]), and lipids (triglyceride [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]) were measured and analyzed.In our study population, the levels of FBG, 2hBG, HbAlc, TC, LDL-C and HDL-C were higher in the OP group than in the low bone density and the normal bone density groups, while the levels of HbAlc, TC, and LDL-C in the low bone density group were higher than those in the normal bone density group. In males, the level of blood LDL-C in the low bone density group was higher than that in the normal bone density group. In postmenopausal subjects, the levels of FBG, 2hBG and HbA1C were higher than those in the normal bone density groups, and the level of HbA1C in the low bone density group was higher than that in the normal bone density group. Pearson linear trend analysis demonstrated that BMD was positively associated with TC and LDL-C in males and negatively associated with FBG, 2hBG and HbA1C in postmenopausal females. Moreover, logistic analysis showed that BMD was correlated with TC in premenopausal females and HbA1C in postmenopausal females.OP is generally associated with abnormal levels of blood glucose and/or lipids; nevertheless, the relationship between OP and abnormal levels of blood glucose and/or lipids is complicate and different subpopulations may have different susceptibilities. Therefore, further detailed studies are warranted.
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Effect of Weight Change Following Intentional Weight Loss on Bone Health in Older Adults with Obesity.
Kammire, DE, Walkup, MP, Ambrosius, WT, Lenchik, L, Shapses, SA, Nicklas, BJ, Houston, DK, Marsh, AP, Rejeski, WJ, Beavers, KM
Obesity (Silver Spring, Md.). 2019;(11):1839-1845
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OBJECTIVE This study aimed to examine change in bone mineral density (BMD) and trabecular bone score among older adult weight regainers (WR) and weight maintainers (WM). METHODS Observational data come from 77 older adults (mean age: 67 [SD 5] years; 69% women; 70% white) with obesity (mean BMI: 33.6 [SD 3.7] kg/m2 ) who lost weight during an 18-month weight loss intervention. Total body mass and body composition, along with regional (total hip, femoral neck, lumbar spine) BMD and trabecular bone score, were measured at baseline, 18 months, and 30 months. WR (n = 36) and WM (n = 41) categories were defined as a ≥ 5% or < 5% weight gain from 18 to 30 months, respectively. RESULTS Among skeletal indices, only total hip BMD was significantly reduced during the 18-month intervention period in both WRs (-3.9%; 95% CI: -5.8% to -2.0%) and WMs (-2.4%; 95% CI: -4.3% to -0.5%; P = 0.07). After adjustment for relevant baseline covariates and weight change from 0 to 18 months, 30-month change in total hip BMD was -2.6% (95% CI: -4.3% to -0.9%) and -3.9% (95% CI: -5.7% to -2.1%) among WRs and WMs, respectively (P = 0.07). CONCLUSIONS Loss of hip BMD persists in the year after a weight loss intervention among older adults with obesity, regardless of weight regain status.
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Circulating serum vitamin D levels and total body bone mineral density: A Mendelian randomization study.
Sun, JY, Zhao, M, Hou, Y, Zhang, C, Oh, J, Sun, Z, Sun, BL
Journal of cellular and molecular medicine. 2019;(3):2268-2271
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Until recently, randomized controlled trials have not demonstrated convincing evidence that vitamin D, or vitamin D in combination with calcium supplementation could improve bone mineral density (BMD), osteoporosis and fracture. It remains unclear whether vitamin D levels are causally associated with total body BMD. Here, we performed a Mendelian randomization study to investigate the association of vitamin D levels with total body BMD using a large-scale vitamin D genome-wide association study (GWAS) dataset (including 79 366 individuals) and a large-scale total body BMD GWAS dataset (including 66,628 individuals). We selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. All these three methods did not show statistically significant association of genetically increased vitamin D levels with total body BMD. Importantly, our findings are consistent with recent randomized clinical trials and Mendelian randomization study. In summary, we provide genetic evidence that increased vitamin D levels could not improve BMD in the general population. Hence, vitamin D supplementation alone may not be associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture.
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Reduced Bone Loss Is Associated With Reduced Mortality Risk in Subjects Exposed to Nitrogen Bisphosphonates: A Mediation Analysis.
Bliuc, D, Tran, T, van Geel, T, Adachi, JD, Berger, C, van den Bergh, J, Eisman, JA, Geusens, P, Goltzman, D, Hanley, DA, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(11):2001-2011
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Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. © 2019 American Society for Bone and Mineral Research.
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Association of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study.
Carbone, LD, Bůžková, P, Fink, HA, Raiford, M, Le, B, Isales, CM, Shikany, JM, Coughlin, SS, Robbins, JA
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(4):643-652
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Interest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women ≥65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95% CI, 1.04 to 1.66) and highest (HR 1.53; 95% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. © 2018 American Society for Bone and Mineral Research.
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Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): Effects on Bone Structure and Architecture.
Donlon, CM, LeBoff, MS, Chou, SH, Cook, NR, Copeland, T, Buring, JE, Bubes, V, Kotler, G, Manson, JE
Contemporary clinical trials. 2018;:56-67
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UNLABELLED Vitamin D supplements are often used to benefit skeletal health, although data on effects of daily high-dose vitamin D alone on bone density and structure are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, randomized, placebo-controlled trial testing effects of high-dose supplemental vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (FAs; 1 g/day) for the primary prevention of cancer and cardiovascular disease. The study has a mean treatment period of 5 years among 25,874 U.S. men ≥50 years and women ≥55 years old from all 50 states. The ancillary study, VITAL Effects on Bone Structure and Architecture, is testing effects of vitamin D3 and/or omega-3 FAs on musculoskeletal outcomes and body composition in a subcohort of 771 participants. At in-person visits at the Harvard Catalyst Clinical and Translational Science Center (CTSC), participants completed bone density/architecture, body composition, and physical performance assessments at baseline and two-year follow-up. Baseline characteristics were evenly distributed among treatment groups, suggesting that any uninvestigated confounders will be evenly distributed; sex differences were also analyzed. Future analyses of the two-year follow-up visits will elucidate whether daily high-dose, supplemental vitamin D3 and/or omega-3 FAs improve musculoskeletal outcomes, helping to advance clinical and public health recommendations. CLINICAL TRIAL REGISTRATION NUMBER NCT01747447.