A retrospective clinical study in Graves disease with COVID-19 infection in China (preprint)

Background Corona Virus Disease 2019 (COVID-19) is the most prevalent global pandemic in recent times. Graves disease (GD), an autoimmune thyroid disease, is a clinical syndrome caused by excessive thyroid hormones. Our study is to understand the current epidemiological situation of COVID-19 infection in GD patients, and to analyze whether COVID-19 will affect the thyroid function, thyroid autoantibody and metabolism of GD patients.Methods 109 GD patients were followed by Shanghai General Hospital Thyroid Disease Center (TDC) from November 2022 to June 2023. There were three groups defined, i.e., pre, one-month after and three months after infection with COVID-19. SPSS was used to analyze the recruited data.Results 109 GD patients are infected with COVID-19 (72.48%), uncontrolled GD patients with high FT3 had a higher COVID-19 infection rate (79.31%). As for thyroid function in 35 GD patients with antithyroid drug (ATD) maintenance stage, there were significant differences in FT3, FT4, TT3 and TT4 before and after being infected with COVID-19. What’s more, there’s a significant difference between GD patients in one month and three months after COVID-19 infection of high TSAb group (p = 0.048) but no significant difference between pre and one month. What’s more, there were significant differences in TT3, TT4 of GD patients after infected COVID-19 in non. And Phosphorus (P), 25-hydroxyvitamin D (25-OH-D3), Procollagen type 1 N-terminal propeptide (P1NP) in GD patients were be affected by COVID-19 infection.Conclusion GD patients with uncontrolled thyroid function group are susceptible to COVID-19. COVID-19 may affect the thyroid function of GD in TT3, TT4, TSAb high level group infection. COVID-19 vaccine is conducive to the stability of GD patients' condition. And COVID-19 may affect the bone metabolism in GD patients before and after COVID-19 infection. But there is no effect on glucose metabolism or lipid metabolism.

Suppressive effect of isofraxidin on the overexpression of IL-6 and its molecular mechanism (preprint)

Interleukin-6 (IL-6) is a pleiotropic cytokine that has many biological activities, including inflammation, hematopoiesis, bone metabolism, embryonic development, and other fundamental processes. Recently, IL-6 has been widely recognized as an important pro-inflammatory cytokine involved in cytokine storm pathogenesis during severe inflammatory diseases, such as coronavirus disease 2019 (COVID-19). Therefore, IL-6 is considered to be a therapeutic target for inhibiting cytokine storm. In the present study, we investigated the suppressive effect of isofraxidin, a major coumarin compound of Acanthopanax senticosus, on the overexpression of IL-6 and its molecular mechanism. When human hepatocellular carcinoma cell lines, HuH-7 and HepG2, were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA), a marked induction of IL-6 mRNA expression was observed in HuH-7 cells compared with HepG2 cells. Isofraxidin significantly suppressed TPA-induced IL-6 mRNA expression in HuH-7 cells in a dose-dependent manner. Furthermore, isofraxidin inhibited TPA-induced phosphorylation of ERK1/2 in a dose dependent manner. Similarly, the MAPK/ERK inhibitor U0126 suppressed TPA-induced IL-6 mRNA expression. However, isofraxidin had no effects on TPA-induced phosphorylation of SAPK/JNK, Akt (Ser473), and STAT3 (Tyr705), nuclear translocation of NF-κB p65, and degradation of IκB. Taken together, isofraxidin suppresses TPA-induced overexpression of IL-6 mRNA by selectively inhibiting the activation of the MAPK/ERK pathway in HuH-7 cells, indicating that isofraxidin may be an effective anti-inflammatory agent for treating cytokine storm.

Influence of Vitamin D Supplementation on Bone Mineral Content, Bone Turnover Markers and Fracture Risk in South African Schoolchildren: Multicentre Double-Blind Randomised Placebo-Controlled Trial (ViDiKids) (preprint)

Background: Randomised controlled trials (RCT) to determine the influence of vitamin D on bone mineral content (BMC) and fracture risk in children of Black African ancestry are lacking.Methods: We conducted a sub-study nested within a Phase 3 RCT of weekly oral supplementation with 10,000 IU vitamin D3 in HIV-uninfected Cape Town schoolchildren of Black African ancestry aged 6-11 years. Outcomes were BMC at the whole body less head (WBLH) and lumbar spine (LS) and serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3), parathyroid hormone (PTH) and bone turnover markers. Incidence of fractures was an outcome of the main trial.Findings: 1682 children were enrolled in the main trial, of whom 450 also participated in the sub-study. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs. placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6, P<0.001) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI -0.94 to -0.17, P=0.005). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI -1.3 to 0.8), or for serum concentrations of bone turnover markers (P≥0.28). In the main trial, allocation did not influence fracture risk (adjusted odds ratio 0.70, 95% CI 0.27 to 1.85, P=0.48).Interpretation: Weekly vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC, bone turnover markers or fracture risk.FUNDING: Medical Research CouncilTrial Registration: Registered on the South African National Clinical Trials Register (DOH-27-0916-5527) and ClinicalTrials.gov (ref NCT02880982).Funding: This research was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also received support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). Declaration of Interest: ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref NCT04641195); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests.Ethical Approval: The trial was sponsored by Queen Mary University of London, approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2).

Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).

CONTEXT: Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations of Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population. Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects. OBJECTIVE: The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1. RESULTS: Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder. No adverse effects were reported following burosumab administration. CONCLUSION: The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1.

Toxoplasma gondii infection as a risk factor for osteoporosis: a case-control study.

BACKGROUND: More than one-third of the total world population is infected by Toxoplasma gondii (T. gondii). T. gondii has been linked to various diseases, such as cancer, mental disorders, type 2 diabetes mellitus (T2DM), etc. However, the effects of T. gondii infection on the risk of osteoporosis are unclear. Our study aimed to uncover evidence to determine whether patients exposed to T. gondii have an increased or decreased risk of osteoporosis in people with abnormal bone mineral density (BMD) by using case-control study. METHODS: A total of 729 patients, including 316 osteopenia and 413 osteoporosis patients of Han Chinese ancestry were selected in the study. Their blood samples were collected and the levels of specific IgG antibodies against T. gondii were measured using ELISA assay. We obtained some information about the patients from the medical record that included demographic indexes and clinical data. A logistic regression analysis was used to evaluate the effects of T. gondii infection on femur osteoporosis, lumbar osteoporosis and compound osteoporosis. Potential interaction was analyzed using multifactor dimensionality reduction software 1.0.0 (MDR 1.0.0). RESULTS: 113 positive patients with T. gondii infections have been detected, including 80 cases of osteoporosis and 33 cases of osteopenia, the infection rates of T. gondii were 19.37% (80/413) and 10.44% (33/316), respectively. The patients with T.gondii infections were at a 2.60 times higher risk of suffering from compound osteoporosis than those without T. gondii infections (OR = 2.60, 95% CI 1.54-4.39, P < 0.001), but not associated with femur osteoporosis (OR = 1.01, 95% CI 0.43-2.34, P = 0.989) and lumbar osteoporosis (OR = 0.84, 95% CI 0.34-2.07, P = 0.705) after adjusting for the covariates. Moreover, a significantly higher risk of compound osteoporosis in the individuals with all two factors (T. gondii infection, Female) was observed compared with reference group (without T. gondii infection, male) under the interaction model (OR = 11.44, 95%CI = 5.44-24.05, P < 0.001). And the individuals with all two factors (T. gondii infection, over 70 years) exhibited a 8.14-fold higher possibility of developing compound osteoporosis compared with reference group (without T. gondii infection, under 70 years) (OR = 8.14, 95% CI 3.91-16.93, P < 0.001). We further stratified by age and sex, and found that women with T. gondii infection was more likely to develop compound osteoporosis than those without infection(OR = 3.12, 95% CI 1.67-5.81, P < 0.001), but we not found the association between T. gondii infection and compound osteoporosis in males (OR = 1.36, 95% CI 0.37-4.94, P = 0.645). CONCLUSIONS: T. gondii infection is a risk factor for osteoporosis, especially compound osteoporosis. Meanwhile, it is very necessary for patients with osteoporosis to further diagnose and treat T. gondii infection, especially women.

COVID-19 illness and treatment decrease bone mineral density of surviving hospitalized patients.

OBJECTIVE: The number patients surviving COVID-19 hospitalization is steadily increasing. Follow-up management for these patients relies on an understanding of the long-term effects of COVID-19. Specifically, there are insufficient data about the lasting effects of COVID-19 on bone health. We aim in this study to evaluate whether COVID-19 illness and treatment adversely affect the bone health of surviving patients. PATIENTS AND METHODS: We assessed the bone mineral density (BMD) of hospitalized COVID-19 patients at diagnosis and at follow-up visits. Using the chest computed tomography (CT) scans of patients that were obtained for clinical management at diagnosis and follow-up visits, BMD was retrospectively measured by quantitative CT. The effect of COVID-19 severity markers and treatment-related factors on BMD were also assessed. RESULTS: BMD decreased by a mean of 8.6% (± 10.5%) from diagnosis to follow-up. The follow-up visits occurred at a mean of 81 (± 48) days after hospital discharge. The BMD decrease was significantly greater than expected for age-related annual BMD loss. The osteoporosis ratio increased two-fold after hospitalization for COVID-19 because of this substantial bone loss. On multivariable linear regression, only severity of COVID-19 pneumonia on initial chest CT and total steroid dose were predictive of change in BMD after COVID-19 hospitalization. CONCLUSIONS: Secondary osteoporosis may occur as a post-acute sequela of COVID-19. Therefore, the bone health status of patients surviving COVID-19 hospitalization should be monitored closely at follow-up visits, to facilitate the prevention and early treatment of osteoporosis complications.

SARS-CoV-2 infection induces inflammatory bone loss in golden Syrian hamsters (preprint)

Extrapulmonary complications of different organ systems have been increasingly recognized in patients with severe or chronic Coronavirus Disease 2019 (COVID-19). However, limited information on the skeletal complications of COVID-19 is known, even though inflammatory diseases of the respiratory tract have been known to perturb bone metabolism and cause pathological bone loss. In this study, we characterized the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on bone metabolism in an established golden Syrian hamster model for COVID-19. SARS-CoV-2 causes significant multifocal loss of bone trabeculae in the long bones and lumbar vertebrae of all infected hamsters. The bone loss progressively worsens from the acute phase to the post-recovery phase. Mechanistically, the bone loss was associated with SARS-CoV-2-induced cytokine dysregulation which upregulates osteoclastic differentiation of monocyte-macrophage lineage. The pro-inflammatory cytokines further trigger a second wave of cytokine storm in the skeletal tissues to augment their pro-osteoclastogenesis effect. Our findings in this established hamster model suggest that pathological bone loss may be a neglected complication which warrants more extensive investigations during the long-term follow-up of COVID-19 patients. The benefits of potential prophylactic and therapeutic interventions against pathological bone loss should be further evaluated. O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/463665v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@c5b1d6org.highwire.dtl.DTLVardef@11e8728org.highwire.dtl.DTLVardef@13b8902org.highwire.dtl.DTLVardef@1a00cfe_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractSARS-CoV-2 infection causes pathological bone loss in golden Syrian hamsters through induction of cytokine storm and inflammation-induced osteoclastogenesis.

Changes in Body Composition and Cardiometabolic Health After Detraining in Older Men with Osteosarcopenia: 6-Month Follow-Up of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST) Study.

PURPOSE: Temporary cessation of exercise but maintenance of habitual physical activity might be a frequent situation in older people's lives. Particularly the COVID-19 induced lockdown of exercise training facilities with individual outdoor activities still being allowed might be a blueprint for this potentially harmful scenario. Thus, the aim of the present study was to determine the effects of 6 months of detraining after 18 months of high-intensity resistance exercise (HIT-RT) on body composition and cardiometabolic outcomes in predominately obese older men with osteosarcopenia. MATERIALS AND METHODS: Community-dwelling predominately obese men 72-91 years old with low muscle and bone mass (n=43) were randomly assigned to an 18-month HIT-RT (EG: n=21) or a non-training control group (CG, n=22). After the intervention, participants of the EG discontinued HIT-RT for 6 months, but increased their habitual physical activity. Study outcomes were group differences in detraining changes ("effects") for lean body mass (LBM), total and abdominal body fat rate (determined by dual-energy x-ray absorptiometry) and the Metabolic Syndrome Z-Score (MetSZ). We applied an intention-to-treat analysis with multiple imputation to analyze the data. RESULTS: After the 18-month HIT-RT, we observed significant positive training effects for LBM, total and abdominal body fat rate and the MetSZ (all p<0.001). Abrupt cessation of HIT-RT for 6 months resulted in significantly higher unfavorable changes in the HIT-RT compared with the CG for LBM (p=0.001), total body fat (p=0.003) and the MetSZ (p=0.003), apart from abdominal body fat (p=0.059). However, significant overall effects were still present after 24 months for LBM and body fat indices but not for the MetSZ. CONCLUSION: The present study clearly indicates the unfavorable effects of 6 months of detraining after HIT-RT. Correspondingly, exercise protocols particularly for older people should focus on continuous exercise with short regeneration periods rather than on intermitted protocols with pronounced training breaks.

Osteosarcopenic adiposity syndrome update and the role of associated minerals and vitamins.

The objectives are to present an updated synopsis on osteosarcopenic adiposity (OSA) syndrome and evaluate the roles of selected micronutrients in its prevention and management. OSA refers to the concurrent deterioration of bone (osteopenia/osteoporosis), muscle (sarcopenia) and adipose tissue expansion. It portrays the most advanced stage in a continuum of body composition disorders. Although OSA has been widely studied involving the populations of different backgrounds, its prevalence is hard to collate because different methodologies and criteria were used for its diagnosis. Another critical health aspect is the presence of low-grade chronic inflammation (LGCI) which contributes to OSA and vice versa. Nutrition is important in the prevention and management of both OSA and LGCI. Although micronutrients act in numerous metabolic and physiological processes, their roles here are presented in relation to OSA (and its components) and LGCI in general and relevant to the COVID-19 pandemic. These include calcium, magnesium, phosphorus, potassium, sodium and vitamins D and K; their interactions, physiological ratios and synergism/antagonism are discussed as well. In conclusion, calcium, magnesium and vitamin D have a profound impact on OSA and its components, and the latter two also on LGCI. Potassium and vitamin K are vital in bone, muscle functioning and possibly adipose tissue modification. Both, but particularly vitamin D, surfaced as important modulators of immune system with application in COVID-19 infections. While both phosphorus and sodium have important roles in bone, muscle and can impact adiposity, due to their abundance in food, their intake should be curbed to prevent possible damaging effects.

Changes in Menopausal Risk Factors in Early Postmenopausal Osteopenic Women After 13 Months of High-Intensity Exercise: The Randomized Controlled ACTLIFE-RCT.

The menopausal transition is a critical period in women's lives. Exercise might be the most promising non-pharmaceutic intervention to address the large variety of risk factors related to the pronounced estradiol decline during peri- and early-postmenopause. The aim of this study was to determine the effect of an 18-month multipurpose exercise program on risk factors and symptoms related to the menopausal transition. Fifty-four women 1-5 years postmenopause with osteopenia or osteoporosis were randomly assigned 1) to a high impact weight-bearing/high-intensity/velocity resistance training group (EG: n=27) exercising three times a week or 2) to an attendance control group (CG: n=27) that performed low-intensity exercise once a week. Both groups were supplemented with cholecalciferol and calcium. The primary study endpoint was bone mineral density (BMD) at lumbar spine (LS) and total hip, secondary outcomes were lean body mass (LBM), total and abdominal body percentage, metabolic syndrome Z-Score (MetS-Z), menopausal symptoms and muscle strength and power. Due to COVID-19, the study was stopped after 13 months. We observed significant effects for BMD-LS (EG: 0.002±.018 versus CG: -.009±0.018 mg/cm2, p=0.027) but not for BMD total hip (EG: -0.01±.016 versus CG: -.009±0.020 mg/cm2, p=0.129). LBM improved significantly in the EG and decreased in the CG (0.39±1.08 vs -0.37±1.34 kg, p=0.026). Total and abdominal body fat improved significantly in the EG and was maintained in the CG (-1.44±1.49 vs -0.02±1.55 kg, p=0.002 and -1.50±2.33 vs 0.08±2.07 kg, p=0.011). Significant effects in favor of the EG were also determined for menopausal symptoms (p=0.029), hip/leg extension strength (p<0.001) and power (p<0.001). However, changes of the MetS-Z did not differ significantly (p=0.149) between EG and CG. In summary, with minor exceptions, we demonstrated the effectiveness of a multipurpose exercise protocol dedicated to early-postmenopausal women on various risk factors and complaints related to the menopausal transition.

Nutritional and Behavioral Approaches to Body Composition and Low-Grade Chronic Inflammation Management for Older Adults in the Ordinary and COVID-19 Times.

As more insight is gained into personalized health care, the importance of personalized nutritional and behavioral approaches is even more relevant in the COVID-19 era, in addition to the need for further elucidation regarding several diseases/conditions. One of these concerning body composition (in this context; bone, lean and adipose tissue) is osteosarcopenic adiposity (OSA) syndrome. OSA occurs most often with aging, but also in cases of some chronic diseases and is exacerbated with the presence of low-grade chronic inflammation (LGCI). OSA has been associated with poor nutrition, metabolic disorders and diminished functional abilities. This paper addresses various influences on OSA and LGCI, as well as their mutual action on each other, and provides nutritional and behavioral approaches which could be personalized to help with either preventing or managing OSA and LGCI in general, and specifically in the time of the COVID-19 pandemic. Addressed in more detail are nutritional recommendations for and roles of macro- and micronutrients and bioactive food components; the microbiome; and optimal physical activity regimens. Other issues, such as food insecurity and nutritional inadequacy, circadian misalignment and shift workers are addressed as well. Since there is still a lack of longer-term primary studies in COVID-19 patients (either acute or recovered) and interventions for OSA improvement, this discussion is based on the existing knowledge, scientific hypotheses and observations derived from similar conditions or studies just being published at the time of this writing.