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PurposeOlder adults are more likely to be vitamin D deficient. The aim of the study was to determine whether these patients have worse outcomes with COVID-19.MethodsWe conducted a prospective cohort study between 1 March and 30 April 2020 to assess the importance of vitamin D deficiency in older patients with COVID-19. The cohort consisted of patients aged ≥65 years presenting with symptoms consistent with COVID-19 (n=105). All patients were tested for serum 25-hydroxyvitamin D (25(OH)D) levels during acute illness. Diagnosis of COVID-19 was confirmed via viral reverse transcriptase PCR swab or supporting radiological evidence. COVID-19-positive arm (n=70) was sub-divided into vitamin D-deficient (≤30 nmol/L) (n=39) and -replete groups (n=35). Subgroups were assessed for disease severity using biochemical, radiological and clinical markers. Primary outcome was in-hospital mortality. Secondary outcomes were laboratory features of cytokine storm, thoracic imaging changes and requirement of non-invasive ventilation (NIV).ResultsCOVID-19-positive arm demonstrated lower median serum 25(OH)D level of 27 nmol/L (IQR=20–47 nmol/L) compared with COVID-19-negative arm, with median level of 52 nmol/L (IQR=31.5–71.5 nmol/L) (p value=0.0008). Among patients with vitamin D deficiency, there was higher peak D-dimer level (1914.00 μgFEU/L vs 1268.00 μgFEU/L) (p=0.034) and higher incidence of NIV support and high dependency unit admission (30.77% vs 9.68%) (p=0.042). No increased mortality was observed between groups.ConclusionOlder adults with vitamin D deficiency and COVID-19 may demonstrate worse morbidity outcomes. Vitamin D status may be a useful prognosticator.

Objective To examine use of magnetic resonance imaging (MRI) of knees with no radiographic evidence of osteoarthritis to determine the prevalence of structural lesions associated with osteoarthritis and their relation to age, sex, and obesity.Design Population based observational study.Setting Community cohort in Framingham, MA, United States (Framingham osteoarthritis study).Participants 710 people aged >50 who had no radiographic evidence of knee osteoarthritis (Kellgren-Lawrence grade 0) and who underwent MRI of the knee.Main outcome measures Prevalence of MRI findings that are suggestive of knee osteoarthritis (osteophytes, cartilage damage, bone marrow lesions, subchondral cysts, meniscal lesions, synovitis, attrition, and ligamentous lesions) in all participants and after stratification by age, sex, body mass index (BMI), and the presence or absence of knee pain. Pain was assessed by three different questions and also by WOMAC questionnaire.Results Of the 710 participants, 393 (55%) were women, 660 (93%) were white, and 206 (29%) had knee pain in the past month. The mean age was 62.3 years and mean BMI was 27.9. Prevalence of “any abnormality” was 89% (631/710) overall. Osteophytes were the most common abnormality among all participants (74%, 524/710), followed by cartilage damage (69%, 492/710) and bone marrow lesions (52%, 371/710). The higher the age, the higher the prevalence of all types of abnormalities detectable by MRI. There were no significant differences in the prevalence of any of the features between BMI groups. The prevalence of at least one type of pathology (“any abnormality”) was high in both painful (90-97%, depending on pain definition) and painless (86-88%) knees.Conclusions MRI shows lesions in the tibiofemoral joint in most middle aged and elderly people in whom knee radiographs do not show any features of osteoarthritis, regardless of pain.

Objective To investigate whether calcium supplements increase the risk of cardiovascular events.Design Patient level and trial level meta-analyses.Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010.Study selection Eligible studies were randomised, placebo controlled trials of calcium supplements (≥500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates.Results 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038).Conclusions Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

BackgroundStüve-Wiedemann syndrome (SWS) is characterised by bowing of the lower limbs, respiratory distress and hyperthermia that are often responsible for early death. Survivors develop progressive scoliosis and spontaneous fractures. We previously identified LIFR mutations in most SWS cases, but absence of LIFR pathogenic changes in five patients led us to perform exome sequencing and to identify homozygosity for a FAM46A mutation in one case [p.Ser205Tyrfs*13]. The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae.Methods and resultsThis prompted us to screen FAM46A in 25 OI patients with no known mutations.We identified a homozygous deleterious variant in FAM46A in two affected sibs with typical OI [p.His127Arg]. Another homozygous variant, [p.Asp231Gly], also classed as deleterious, was detected in a patient with type III OI of consanguineous parents using homozygosity mapping and exome sequencing.FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins but its exact function is presently unknown. Nevertheless, there are lines of evidence pointing to a relevant role of FAM46A in bone development. By RT-PCR analysis, we detected specific expression of FAM46A in human osteoblasts andinterestingly, a nonsense mutation in Fam46a has been recently identified in an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones.ConclusionWe conclude that FAM46A mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.

Objectives To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.Design Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies.Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36 282 community dwelling postmenopausal women.Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.Results In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P=0.04), stroke (1.20 (1.00 to 1.43), P=0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P=0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28 072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).Conclusions Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

ObjectivesThis cross-sectional study aims to evaluate the association between calcium and vitamin D supplementation for osteoporosis treatment and the development of kidney stones while investigating the impact of urinary calcium excretion on kidney stone risk among patients receiving this supplementation treatment.DesignThe study involved collecting data from 204 Chinese Han patients aged 50–89 with osteoporosis in the southwest region of China. These patients had been on daily doses of 600 mg of calcium carbonate and 0.5 µg alfacalcidol for at least 1 year. The study employed univariate analysis and multivariable logistic regression to identify risk factors for kidney stones, with independent t-tests used to compare differences between groups.SettingData were collected from patients in the southwest region of China, covering the period from July 2019 to December 2023.ParticipantsThe study included 204 patients with osteoporosis, all of whom had been receiving the specified calcium and vitamin D supplements for the duration of the study.ResultsThe study found that a history of recurrent kidney stones was an independent risk factor for the development of kidney stones. Patients with kidney stones who had a history of recurrent stones exhibited significantly higher levels of 24-hour urinary calcium excretion (1.00±0.62 vs 0.57±0.54, p=0.026) compared with those without such a history.ConclusionsThe results suggest that a history of recurrent kidney stones independently increases the risk of kidney stones in patients undergoing calcium and vitamin D supplementation for osteoporosis, likely due to increased urinary calcium excretion.

ObjectiveThe study intended to assess the pooled prevalence of vitamin D deficiency (VDD) and its associated factors among patients with type 2 diabetes mellitus (T2DM).DesignThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were employed to plan and conduct this systematic review and meta-analysis.Data sourcesPubMed, Medline, Google Scholar, Web of Science, Science Direct and the Worldwide Science database were searched from their inception to 31 January 2023.MethodsData were extracted using a standardised data extraction format prepared in Microsoft Excel. The inverse variance (I2) test was used to evaluate the presence of heterogeneity across the included studies. To identify the possible source of heterogeneity, subgroup analysis was carried out. Funnel plot symmetry, Begg’s and Egger’s tests were used to evaluate the existence of publication bias. In addition, factors associated with VDD among patients with T2DM were examined. All statistical analyses were carried out with STATA V.14 software.ResultsA total of 54 studies with 38 016 study participants were included in the study. The pooled prevalence of VDD among patients with T2DM was found to be 64.2% (95% CI 60.6% to 67.8%) with a substantial level of heterogeneity (I2=98.2%; p<0.001). Results of the subgroup analysis indicated that the pooled prevalence of VDD among patients with T2DM was highest (70.9%) in African nations and lowest (57.1%) in Middle East countries. Being female (pooled OR (POR) 1.60, 95% CI 1.29 to 1.97), having poor glycaemic control (POR 2.50; 95% CI 1.74 to 3.59), hypertension (POR 1.21; 95% CI 1.08 to 1.36), obesity (body mass index ≥25) (POR 1.68; 95% CI 1.16 to 2.44), dyslipidaemia (POR 2.54, 95% CI 1.37 to 4.73), albuminuria (POR 2.22, 95% CI 1.71 to 2.95), nephropathy (POR 1.58; 95% CI 1.08 to 2.31) and retinopathy (POR 1.48: 95% CI 1.17 to 1.89) were predictors of VDD among patients with T2DM.ConclusionsMore than half of patients with T2DM were suffering from VDD. Being female, having poor glycaemic control, hypertension, obesity, dyslipidaemia, albuminuria, nephropathy and retinopathy were the predictors of VDD among patients with T2DM.

IntroductionNovel strategies are needed to address the rising burden of osteoporosis and fragility fractures. High-intensity resistance and impact (HiRIT) exercise has shown benefit in improving bone density in postmenopausal women with osteoporosis/osteopenia. Whether HiRIT can enhance the therapeutic effects of osteoporosis pharmacotherapy has not been established. ROLEX-DUO is a randomised controlled trial designed to assess the efficacy of romosozumab on various bone and muscle outcomes in combination with different exercise interventions in women with postmenopausal osteoporosis/osteopenia.Methods and analysisROLEX-DUO is an 8-month randomised placebo-controlled trial conducted at two tertiary referral centres for patients with osteoporosis/osteopenia in Sydney, New South Wales, Australia. The study is implementing the combination of romosozumab or placebo with different forms of exercise in postmenopausal women with osteoporosis/osteopenia without recent fragility fracture (n=102). Eligible women will be randomised 1:1:1 into one of three groups: (1) romosozumab with supervised HiRIT, (2) romosozumab with unsupervised low-intensity exercise or (3) placebo with unsupervised low-intensity exercise. Co-primary outcomes are the mean percentage change in lumbar spine bone mineral density (BMD), and mean change in five times sit-to-stand test performance (seconds) at 8 months. Secondary/exploratory outcomes include BMD changes at the femoral neck, total hip and distal radius, three-dimensional dual-energy X-ray absorptiometry (DXA) hip outcomes, DXA-derived lean and fat mass, serum markers of bone turnover (procollagen type 1 peptide, C-telopeptide of type 1 collagen) and bone biomarkers (dickkopf-1), serum extracellular vesicle analyses, 36-Item Short Form Survey (SF-36) quality-of-life scores, Menopause-Specific Quality Of Life (MENQOL) Questionnaire menopause symptom burden scores, number of falls and fractures. Mixed-effects models will be performed to compare longitudinal outcome results between groups using intention-to-treat analysis.Ethics and disseminationThe trial was approved by the Northern Sydney Local Health District Human Research Ethics Committee (2022/ETH01794, protocol V.8, dated 03 July 2024). Participants will provide written informed consent prior to inclusion. Findings will be disseminated via peer-reviewed journals, scientific conferences and summary reports to funding bodies.Trial registration numberACTRN12623000867695.

IntroductionOsteogenesis imperfecta (OI) is a rare genetic disease associated with multiple fractures throughout life. It is often treated with osteoporosis medications but their effectiveness at preventing fractures is unknown. The Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid trial will determine if therapy with teriparatide (TPTD) followed by zoledronic acid (ZA) can reduce the risk of clinical fractures in OI.Methods and analysisIndividuals aged ≥18 years with a clinical diagnosis of OI are eligible to take part. At baseline, participants will undergo a spine X-ray, and have bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at the spine and hip. Information on previous fractures and previous bone targeted treatments will be collected. Questionnaires will be completed to assess pain and other aspects of health-related quality of life (HRQoL). Participants will be randomised to receive a 2-year course of TPTD injections 20 µg daily followed by a single intravenous infusion of 5 mg ZA, or to receive standard care, which will exclude the use of bone anabolic drugs. Participants will be followed up annually, have a repeat DXA at 2 years and at the end of study. Spine X-rays will be repeated at the end of study. The duration of follow-up will range between 2 and 8 years. The primary endpoint will be new clinical fractures confirmed by X-ray or other imaging. Secondary endpoints will include participant reported fractures, BMD and changes in pain and HRQoL.Ethics and disseminationThe study received ethical approval in December 2016. Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results will inform clinical practice by determining if TPTD/ZA can reduce the risk of fractures in OI compared with standard care.Trial registration numberISRCTN15313991.