Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause - the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.

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T-Cell Mediated Inflammation in Postmenopausal Osteoporosis.

The elevation of ambient temperature beyond the thermoneutral zone leads to heat stress, which is a growing health and welfare issue for homeothermic animals aiming to maintain relatively constant reproducibility and survivability. Particularly, global warming over the past decades has resulted in more hot days with more intense, frequent, and long-lasting heat waves, resulting in a global surge in animals suffering from heat stress. Heat stress causes pathophysiological changes in animals, increasing stress sensitivity and immunosuppression, consequently leading to increased intestinal permeability (leaky gut) and related neuroinflammation. Probiotics, as well as prebiotics and synbiotics, have been used to prevent or reduce stress-induced negative effects on physiological and behavioral homeostasis in humans and various animals. The current data indicate dietary supplementation with a Bacillus subtilis-based probiotic has similar functions in poultry. This review highlights the recent findings on the effects of the probiotic Bacillus subtilis on skeletal health of broiler chickens exposed to heat stress. It provides insights to aid in the development of practical strategies for improving health and performance in poultry.

Bacillus subtilis-Based Probiotic Improves Skeletal Health and Immunity in Broiler Chickens Exposed to Heat Stress.

Systemic, chronic, low-grade inflammation (SCLGI) underlies the pathogenesis of various widespread diseases. It is often associated with bone loss, thus connecting chronic inflammation to the pathogenesis of osteoporosis. In postmenopausal women, osteoporosis is accompanied by SCLGI development, likely owing to estrogen deficiency. We propose that SCGLI persistence in osteoporosis results from failed inflammation resolution, which is mainly mediated by specialized, pro-resolving mediators (SPMs). In corroboration, SPMs demonstrate encouraging therapeutic effects in various preclinical models of inflammatory disorders, including bone pathology. Since numerous data implicate gut dysbiosis in osteoporosis-associated chronic inflammation, restoring balanced microbiota by supplementing probiotics and prebiotics could contribute to the efficient resolution of SCGLI. In the present review, we provide evidence for this hypothesis and argue that efficient SCGLI resolution may serve as a novel approach for treating osteoporosis, complementary to traditional anti-osteoporotic medications. 

Targeting chronic inflammation as a potential adjuvant therapy for osteoporosis.

Microbiome First Medicine is a suggested 21st century healthcare paradigm that prioritizes the entire human, the human superorganism, beginning with the microbiome. To date, much of medicine has protected and treated patients as if they were a single species. This has resulted in unintended damage to the microbiome and an epidemic of chronic disorders [e.g., noncommunicable diseases and conditions (NCDs)]. Along with NCDs came loss of colonization resistance, increased susceptibility to infectious diseases, and increasing multimorbidity and polypharmacy over the life course. To move toward sustainable healthcare, the human microbiome needs to be front and center. This paper presents microbiome-human physiology from the view of systems biology regulation. It also details the ongoing NCD epidemic including the role of existing drugs and other factors that damage the human microbiome. Examples are provided for two entryway NCDs, asthma and obesity, regarding their extensive network of comorbid NCDs. Finally, the challenges of ensuring safety for the microbiome are detailed. Under Microbiome-First Medicine and considering the importance of keystone bacteria and critical windows of development, changes in even a few microbiota-prioritized medical decisions could make a significant difference in health across the life course.

Microbiome First Medicine in Health and Safety.

Aim. Probiotics are considered to be bone metabolism regulators, and their efficacy as an adjuvant treatment option for osteoporosis is still controversial. The purpose of this study is to compare the available data from randomized controlled trials (RCT) of probiotics in the treatment of osteoporosis and osteopenia. Methods. As of June 2021, databases such as Medline, Embase, Web of Science, and Central Cochrane Library have been used for English-language literature searches and CNKI and China Biomedical Database have been used for Chinese-language literature searches. RevMan 5.3 was used for bias risk assessment, heterogeneity detection, and meta-analysis. This research has been registered in PROSPERO (CRD42020085934). Results. This systematic review and meta-analysis included 10 RCTs involving 1156. Compared with the placebo, the absolute value of lumbar spine’s BMD was not statistically significant (WMD 0.04 (−0.00, 0.09), , random effect model), while the percentage of lumbar spine’s BMD was higher (SMD 1.16 (0.21, 2.12), , random effect model). Compared with the control group, the percentage of total hip’s BMD was not statistically significant (SMD 0.52 (−0.69, 1.73), , random effect model). The safety analysis showed that, compared with control group, the adverse events in the experimental group were not statistically significant (RR 1.02 (0.92, 1.12), , fixed effect model). Conclusion. Probiotics may be safety supplements to improve the lumbar spine’s BMD of patients with osteoporosis and osteopenia. More large-sample, random-controlled, high-quality RCTs are needed to further verify the effectiveness and safety of probiotics in intervening osteoporosis or osteopenia.

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The Improving Effect and Safety of Probiotic Supplements on Patients with Osteoporosis and Osteopenia: A Systematic Review and Meta-Analysis of 10 Randomized Controlled Trials.

Objective Osteoporosis is a common disease in postmenopausal women. Several studies have analysed the associations between dietary supplementation with probiotics and bone health in postmenopausal women, but the results are still controversial. We conducted this meta-analysis to assess the effects of probiotics supplement on bone mineral density (BMD) and bone turnover markers for postmenopausal women. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, EMBASE and the Cochrane Library from their inception to November 2020 for randomised controlled trials (RCTs) assessing probiotic supplements and osteoporosis in postmenopausal women. Study-specific risk estimates were combined using random-effect models. Results Five RCTs (n=497) were included. Probiotic supplements were associated with a significantly higher BMD in the lumbar spine (standardised mean difference, SMD=0.27, 95% CI 0.09 to 0.44) than in control. There was no difference between probiotic supplements and BMD in hips (SMD=0.22, 95% CI −0.07 to 0.52). Collagen type 1 cross-linked C-telopeptide levels in the treatment groups were significantly lower than those of the placebo group (SMD=−0.34, 95% CI −0.60 to −0.09). In subgroup meta-analysis, levels of bone-specific alkaline phosphatase, osteoprotegerin, osteocalcin and tumour necrosis factor did not differ between the probiotic and placebo groups. Conclusions We conclude cautiously that supplementation with probiotics could increase lumbar BMD. More RCTs are recommended to validate or update these results.

https://bmjopen.bmj.com/content/bmjopen/11/3/e041393.full.pdf

Probiotic supplements and bone health in postmenopausal women: a meta-analysis of randomised controlled trials.

The presence of left atrial/left atrial appendage thrombosis is associated with a higher risk of thromboembolic events in patients with atrial fibrillation. The optimal antithrombotic strategy is not established to date. Our aim was to compare the efficacy and safety profile of novel oral anticoagulants with warfarin in the treatment of left atrial/left atrial appendage thrombosis. We conducted a systematic search in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and 3 Chinese databases for all randomized controlled trials and cohort studies (PROSPERO, CRD42021238952) from inception to 7 May 2021. Two authors independently performed the articles selection, data extraction, and quality assessment. The efficacy outcome was the resolution of left atrial/left atrial appendage thrombosis, and the safety outcomes were bleeding and stroke/transient ischemic attack. One randomized controlled trial and 5 cohort studies were included, with a total of 353 patients. Compared with warfarin, novel oral anticoagulants were associated with increased probability of left atrial/left atrial appendage thrombosis resolution (OR = 2.20; 95% CI, 1.35–3.60; I 2 = 0%). Compared with warfarin, novel oral anticoagulants had a similar risk of bleeding (OR = 0.91; 95% CI, 0.39–2.13; I 2 = 0%). There was no evidence of increased risk of stroke/transient ischemic attack (OR = 0.42; 95% CI, 0.12–1.45; I 2 = 0%). Novel oral anticoagulants were more effective than warfarin in promoting the resolution of left atrial/left atrial appendage thrombosis, without increased risks of bleeding and stroke/transient ischemic attack. Our study provides valuable insight into clinical practice. Further well-designed randomized controlled trials are needed to fully evaluate the benefits and risks in these patients. PROSPERO Registration No.: CRD42021238952. 

https://doi.org/10.1016/j.curtheres.2022.100670

Cong Luo

Papers

Probiotic supplements and bone health in postmenopausal women: a meta-analysis of randomised controlled trials.

Efficacy and Safety Profile of Novel Oral Anticoagulants in the Treatment of Left Atrial Thrombosis: A Systematic Review and Meta-Analysis