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Circulating Gut Microbiota Metabolite Trimethylamine N-Oxide (TMAO) and Changes in Bone Density in Response to Weight Loss Diets: The POUNDS Lost Trial.
Zhou, T, Heianza, Y, Chen, Y, Li, X, Sun, D, DiDonato, JA, Pei, X, LeBoff, MS, Bray, GA, Sacks, FM, et al
Diabetes care. 2019;(8):1365-1371
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Abstract
OBJECTIVE Type 2 diabetes is related to obesity and altered bone health, and both are affected by gut microbiota. We examined associations of weight loss diet-induced changes in a gut microbiota-related metabolite trimethylamine N-oxide (TMAO), and its precursors (choline and l-carnitine), with changes in bone mineral density (BMD) considering diabetes-related factors. RESEARCH DESIGN AND METHODS In the 2-year Preventing Overweight Using Novel Dietary Strategies trial (POUNDS Lost), 264 overweight and obese participants with measurement of BMD by DXA scan were included in the present analysis. The participants were randomly assigned to one of four diets varying in macronutrient intake. Association analysis was performed in pooled participants and different diet groups. Changes in blood levels of TMAO, choline, and l-carnitine from baseline to 6 months after the dietary intervention were calculated. RESULTS We found that a greater reduction in plasma levels of TMAO from baseline to 6 months was associated with a greater loss in whole-body BMD at 6 months and 2 years (P = 0.03 and P = 0.02). The greater reduction in TMAO was also associated with a greater loss in spine BMD (P = 0.005) at 2 years, independent of body weight changes. The associations were not modified by baseline diabetes status and glycemic levels. Changes in l-carnitine, a precursor of TMAO, showed interactions with dietary fat intake in regard to changes of spine BMD and hip BMD at 6 months (all P < 0.05). Participants with the smallest decrease in l-carnitine showed less bone loss in the low-fat diet group than the high-fat diet group (P spine = 0.03 and P hip = 0.02). CONCLUSIONS TMAO might protect against BMD reduction during weight loss, independent of diet interventions varying in macronutrient content and baseline diabetes risk factors. Dietary fat may modify the relation between change in plasma l-carnitine level and changes in BMD. Our findings highlight the importance of investigating the relation between TMAO and bone health in patients with diabetes.
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Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta-analysis.
Li, X, Li, T, Cheng, Y, Lu, Y, Xue, M, Xu, L, Liu, X, Yu, X, Sun, B, Chen, L
Diabetes/metabolism research and reviews. 2019;(7):e3170
Abstract
BACKGROUND The aim of the study is to update and determine the effects of sodium glucose cotransporter 2 (SGLT2) inhibitor therapy on fracture and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM). METHODS We identified 27 eligible randomized controlled trials (RCTs) that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20 895 T2DM participants, with an average duration of 64.22 weeks. The relative risk (RR) of bone fracture and weighted mean difference (WMD) of changes in the BMD from baseline were determined to evaluate the risk of fracture. The degree of heterogeneity was evaluated by the I2 statistic, and publication bias was estimated using a funnel plot and Egger test. RESULTS The pooled RR was 1.02 (95% CI [0.81, 1.28]) with low heterogeneity, indicating that SGLT2 inhibitor treatment was not correlated with a higher risk of fracture. Additionally, no increased risk was found for patients with different ages, sexes, and levels of HbA1c and some biochemical indicators. Three trials with 1303 patients reported a change in the BMD from baseline. SGLT2 inhibitor treatment did not decrease the BMD at four skeletal sites (lumbar spine, femoral neck, total hip, and distal forearm), and the overall WMD was 0.08 (95% CI [-0.09, 0.26]). No significant publication bias was detected. CONCLUSIONS No increased risk for bone fracture was detected in patients with T2DM treated with SGLT2 inhibitors in this meta-analysis. SGLT2 inhibitor therapy did not appear to affect bone health, but more long-term detailed data are needed to validate this conclusion.
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[Osteoporosis-frequent comorbidity in patients with rheumatism].
Gaubitz, M
Zeitschrift fur Rheumatologie. 2019;(3):249-254
Abstract
Osteoporosis is one of the most frequent comorbidities in inflammatory rheumatic diseases. The immune system is substantially involved in the regulation of bone homeostasis and chronic inflammatory diseases influence this equilibrium at several levels. Besides the immunologically mediated inflammatory activity, immobility and glucocorticoid treatment are further risk factors for osteoporosis. Diagnostic and therapeutic recommendations are based on the current guidelines for osteoporosis of the Governing Body on Osteoporosis (DVO). Monitoring of the risk factors and bone mineral density testing is meaningful in each patient with a newly diagnosed rheumatic disease. In the case of a T-score ≤-1.5 a specific drug treatment with bisphosphonates, teriparatide or denosumab should be started together with optimizing preventive measures, such as reduction of glucocorticoid dosage, calcium and vitamin D intake and life style modifications. The risk of osteonecrosis of the jaw (ONJ) in patients with osteoporosis is small; however, there appears to be a significant increase in multiple vertebral fractures after discontinuation of denosumab.
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The Ketogenic Diet and Its Effect on Bone Mineral Density: A Retrospective Observational Cohort Study.
Draaisma, JMT, Hampsink, BM, Janssen, M, van Houdt, NBM, Linders, ETAM, Willemsen, MA
Neuropediatrics. 2019;(6):353-358
Abstract
BACKGROUND During long-term follow-up of children treated with the ketogenic diet therapy (KDT) have an increased incidence of bone fractures. However, the exact contribution of KDT to a decreased bone mineral density (BMD) remains unclear. OBJECTIVE This study aimed to evaluate (changes in) BMD in children treated with KDT and to evaluate whether intravenous bisphosphonate therapy may be effective. DESIGN In this retrospective, observational cohort study, all children treated with KDT from 2010 until 2018 at the Radboudumc Amalia Children's hospital were included. Patients who were on KDT for more than 6 months and who had at least two dual-energy X-ray (DXA)-scans were eligible for inclusion for longitudinal analysis. Z-scores of DXA-scans were compared over the course of time. RESULTS In 34 out of 68 patients, one or more lumbar DXA-scans were performed, with a mean lumbar Z-score of -1.32 ± 1.74. Of these 68 patients, 8.8% got a fracture during KDT, and also 8.8% got kidney stones. In 20 patients, more than one DXA-scan was performed. A statistically not significant decrease in BMD (0.22 Z-score/year) was found. However, there was an increase in BMD in the five patients treated with intravenous bisphosphonate therapy. This was statistically significant in comparison to the nonbisphosphonate treated group (p = 0.034). CONCLUSION Children on KDT have low normal BMD which may decrease further during KDT. For this reason monitoring of BMD is crucial, as is monitoring of kidney stones and hypercalciuria. Intravenous bisphosphonate therapy may have a positive effect, when other therapies have failed.
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Daidzein and genistein have differential effects in decreasing whole body bone mineral density but had no effect on hip and spine density in premenopausal women: A 2-year randomized, double-blind, placebo-controlled study.
Nayeem, F, Chen, NW, Nagamani, M, Anderson, KE, Lu, LW
Nutrition research (New York, N.Y.). 2019;:70-81
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Abstract
Soy isoflavones are potentially beneficial phytoestrogens, but their tissue-selective effects in women are poorly understood. We tested the hypothesis that soy isoflavones affect bone mineral density (BMD), which may be influenced by individual differences in isoflavone metabolism and serum calcium levels. Ninety-nine healthy premenopausal women were randomized to isoflavones (136.6 mg aglycone equivalence) and 98 to placebo for 5 days per week for up to 2 years. BMD, serum calcium, and urinary excretion of daidzein and genistein were measured before and during treatment. In 129 adherent subjects, we found that isoflavone exposure, determined by urinary excretion levels, but not by dose assignment, interacted with serum calcium in affecting whole body BMD, but not hip and spine BMD. The regression coefficient was -0.042 for genistein excretion (GE) and 0.091 for the interaction between GE and serum calcium (all P < .05). Daidzein excretion had similar but marginal effect. Genistein significantly decreased whole body BMD only at low normal serum calcium levels but increased whole body BMD at higher serum calcium levels. Comparing maximum to minimum GE, mean changes in whole body BMD were +0.033 and -0.113 g/cm2 at serum calcium levels of 10 and 8.15 mg/dL, respectively. These associations were not evident by intention-to-treat analysis, which could not model for inter-individual differences in isoflavone metabolism. In summary, soy isoflavones decrease whole body BMD only when serum calcium is low. Isoflavones are dietary substances that may influence calcium homeostasis by releasing calcium from bone while sparing the common fracture risk sites hip and spine.
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Bone mineral density in virologically suppressed people aged 60 years or older with HIV-1 switching from a regimen containing tenofovir disoproxil fumarate to an elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide single-tablet regimen: a multicentre, open-label, phase 3b, randomised trial.
Maggiolo, F, Rizzardini, G, Raffi, F, Pulido, F, Mateo-Garcia, MG, Molina, JM, Ong, E, Shao, Y, Piontkowsky, D, Das, M, et al
The lancet. HIV. 2019;(10):e655-e666
Abstract
BACKGROUND Tenofovir alafenamide is associated with less renal and bone toxicity than tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing tenofovir disoproxil fumarate to one containing tenofovir alafenamide in participants aged 60 years and older. METHODS We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA <50 copies per mL), aged 60 years or older, on a tenofovir disoproxil fumarate-containing regimen and were randomly assigned (2:1) via an interactive web-response system to open-label elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg) daily or continued therapy containing tenofovir disoproxil fumarate (300 mg). Participants were stratified by spine and hip bone mineral density categories. Primary endpoints were change from baseline to week 48 in spine and hip bone mineral density with a null hypothesis of zero between-group difference tested at a significance level of 0·05. This study was registered with ClinicalTrials.gov, NCT02616783. FINDINGS Between Dec 22, 2015, and March 21, 2018, 167 participants were randomly assigned to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (n=111 [66%]) or tenofovir disoproxil fumarate (n=56 [34%]). One participant in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group did not receive treatment and was excluded from all analyses. At week 48, the mean percentage change in spine bone mineral density was 2·24% (SD 3·27) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and -0·10% (3·39) in the tenofovir disoproxil fumarate group (between-group difference 2·43% [95% CI 1·34-3·52]; p<0·0001), and mean percentage change in hip bone mineral density was 1·33% (2·20) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and -0·73% (3·21) in the tenofovir disoproxil fumarate group (difference 2·04% [1·17-2·90]; p<0·0001). The most common adverse events were nasopharyngitis (12 [11%]), back pain (nine [8%]), and diarrhoea (eight [7%]) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and bronchitis (six [11%]), vitamin D deficiency (four [7%]), and arthralgia (four [7%]) in the tenofovir disoproxil fumarate group. 22 (20%) participants in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and one (2%) participant in the tenofovir disoproxil fumarate group had an adverse event that was considered to be related to treatment. No treatment-related serious adverse events were observed. The proportions of adverse events leading to premature treatment discontinuation were similar between groups (four [4%] in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and one (2%) in the tenofovir disoproxil fumarate group). INTERPRETATION The significantly improved bone mineral density, overall safety, and efficacy data show the feasibility of switching from a regimen containing tenofovir disoproxil fumarate to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV aged 60 years or older. FUNDING Gilead Sciences.
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Associations of Smoking and Alcohol and Coffee Intake with Fracture and Bone Mineral Density: A Mendelian Randomization Study.
Yuan, S, Michaëlsson, K, Wan, Z, Larsson, SC
Calcified tissue international. 2019;(6):582-588
Abstract
The causal associations of smoking and alcohol and coffee intake with fracture and bone mineral density are unknown. We investigated the associations using Mendelian randomization (MR). Summary-level data from UK Biobank for bone fractures (main outcome) (53,184 cases; 373,611 non-cases) and estimated bone mineral density (eBMD) (n = 426,824 individuals) were used. Single-nucleotide polymorphisms associated with smoking initiation (n = 378) and alcohol (n = 99) and coffee (n = 15) intake at the genome-wide significance threshold (P = 5 × 10-8) were identified from published genome-wide association studies. Univariable and multivariable inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO methods were used for statistical analyses. Genetic predisposition to smoking initiation was associated with fracture but not eBMD. The odds ratio of fracture per one-unit increase in log odds of smoking was 1.09 (95% confidence interval 1.04, 1.15; P = 8.58 × 10-4) after adjustment for alcohol intake in the multivariable MR analysis. The association remained in complementary analyses. Genetically predicted alcohol and coffee intake was not associated with fracture or eBMD. Nevertheless, genetic liability to alcohol dependence, based on variants in the ALD1B gene, was associated with fracture and lower eBMD. The odds ratio was 1.06 (95% confidence interval 1.01, 1.12; P = 0.018) per genetically predicted one-unit higher log odds of liability to alcohol dependence. This MR study strengthens the causal inference on an association between smoking and higher fracture risk but found no linear association of modestly higher alcohol and coffee intake with fracture or BMD. However, alcohol dependence may increase fracture risk.
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The next step after anti-osteoporotic drug discontinuation: an up-to-date review of sequential treatment.
Guañabens, N, Moro-Álvarez, MJ, Casado, E, Blanch-Rubió, J, Gómez-Alonso, C, Díaz-Guerra, GM, Del Pino-Montes, J, Valero Díaz de Lamadrid, C, Peris, P, Muñoz-Torres, M, et al
Endocrine. 2019;(3):441-455
Abstract
Several antiresorptive drugs, like bisphosphonates and denosumab, are currently available for the treatment of osteoporosis due to their evidenced efficacy in reducing fracture risk at mid-term. Osteoanabolic therapies, like teriparatide, whose treatment duration is limited to 2 years, have also shown efficacy in the reduction of fracture risk. However, depending on the severity of osteoporosis and the presence of other associated risk factors for fracture, some patients may require long-term treatment to preserve optimal bone strength and minimize bone fracture risk. Given the limited duration of some treatments, the fact that most of the antiresorptive drugs have not been assessed beyond 10 years, and the known long-term safety issues of these drugs, including atypical femoral fractures or osteonecrosis of the jaw, the long-term management of these patients may require an approach based on drug discontinuation and/or switching. In this regard, interest in sequential osteoporosis therapy, wherein drugs are initiated and discontinued over time, has grown in recent years, although the establishment of an optimal and individualized order of therapies remains controversial. This review reports the currently available clinical evidence on the discontinuation effects of different anti-osteoporotic drugs, as well as the clinical outcomes of the different sequential treatment regimens. The objective of this article is to present up-to-date practical knowledge on this area in order to provide guidance to the clinicians involved in the management of patients with osteoporosis.
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Association between brown adipose tissue and bone mineral density in humans.
Sanchez-Delgado, G, Martinez-Tellez, B, Garcia-Rivero, Y, Acosta, FM, Alcantara, JMA, Amaro-Gahete, FJ, Llamas-Elvira, JM, Gracia-Marco, L, Ruiz, JR
International journal of obesity (2005). 2019;(8):1516-1525
Abstract
BACKGROUND Brown adipose tissue (BAT) seems to play a role in bone morphogenesis. A negative association has been reported between BAT and bone mineral density (BMD) in women, but not in men. A panel of experts has recently published a set of recommendations for BAT assessment, and thus, to re-address previously reported associations is needed. This study aimed to investigate the association between cold-induced BAT 18F-Fluorodeoxyglucose (18F-FDG) uptake and BMD in young healthy adults. METHODS Ninety-eight healthy adults (68 women; 22 ± 2.2 years old; 24.3 ± 4.5 kg/m2) cold-induced BAT was assessed by means of an 18F-FDG positron emission tomography-computed tomography (PET-CT) scan preceded by a personalized cold stimulation. The cold exposure consisted in 2 h in a mild cold room at 19.5-20 °C wearing a water perfused cooling vest set 4 °C above the individual shivering threshold. Total body and lumbar spine BMD were assessed by a whole-body DXA scan. RESULTS We found no association between BMD and cold-induced BAT volume, mean, and maximal activity (all P > 0.1) in neither young and healthy men nor women. These results remained unchanged when adjusting by height, by body composition, and by objectively assessed physical activity. Sensitivity analyses using the criteria to quantify cold-induced BAT-related parameters applied in previous studies did not change the results. CONCLUSIONS In summary, our study shows that there is no association between cold-induced BAT and BMD in young healthy adults. Moreover, our data support the notion that previously shown associations between BAT and BMD in healthy non-calorically restricted individuals, could be driven by methodological issues related to BAT assessment and/or sample size limitations.
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Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial.
Miller, PD, Hattersley, G, Lau, E, Fitzpatrick, LA, Harris, AG, Williams, GC, Hu, MY, Riis, BJ, Russo, L, Christiansen, C
Bone. 2019;:137-140
Abstract
BACKGROUND Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE. METHODS Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites. RESULTS At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds. CONCLUSIONS In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.