Periodontal Disease and Autoimmunity: What We Have Learned from Microbiome Studies in Rheumatology

The oral cavity is home to vast populations of commensal microbial organisms which constitute the ‘healthy oral microbiome.’ Periodontitis is a destructive, infectious, inflammatory condition affecting the gums. Initially, a biofilm structure develops, causing localized inflammation. This biofilm is then colonized by certain anaerobic bacteria, including the ‘red complex’ organisms. There is an increasing interest in the communication between these organisms and host immune surveillance, a dialog which may plays an important role in the development of autoimmune diseases. Studies have shown an association between periodontitis and other inflammatory conditions including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and systemic lupus. The advent of accessible 16S ribosomal sequencing has led to exciting developments in the characterization of the human microbiome and the ability to study this interaction in more detail. The transmucosal communication between periodontitis and host immunity may provide avenues of discovery regarding the etiology and progression of rheumatic diseases

Efficacy of osteoporosis pharmacological treatments in men: a systematic review and meta-analysis.

peer reviewed[en] INTRODUCTION: The objective of this systematic review and meta-analysis is to systematically identify and review the efficacy of pharmacological treatments in men with osteoporosis. METHODS: Medline (via Ovid) and Cochrane CENTRAL were searched up to May 2023 for any randomized controlled trial (RCT) evaluating the efficacy of osteoporotic treatment on the evolution of Bone Mineral Density (BMD) and incidence of fractures of men suffering from primary osteoporosis. If at least two studies used the same pharmacological treatment and evaluated the same outcome, a random effect model meta-analysis was applied to reported pooled mean difference (MD) and 95% confidence interval (CI). RESULTS: From the 1,061 studies identified through bibliographic search, 21 RCTs fitted the inclusion criteria. Bisphosphonates (k = 10, n = 2992 men with osteoporosis) improved all three BMD sites compared to placebo; lumbar spine: MD + 4.75% (95% CI 3.45, 6.05); total hip: MD + 2.72% (95% CI 2.06; 3.37); femoral neck: MD + 2.26% (95% CI 1.67; 2.85). Denososumab (k = 2, n = 242), Teriparatide (k = 2, n = 309) and Abaloparatide (k = 2, n = 248) also produced significant improvement of all sites BMD compared to placebo. Romosozumab was only identified in one study and was therefore not meta-analysed. In this study, Romosozumab increased significantly BMD compared to placebo. Incident fractures were reported in 16 RCTs but only four reported fractures as the primary outcome. Treatments were associated with a lower incidence of fractures. CONCLUSIONS: Medications used in the management of osteoporosis in women appear to provide similar benefits in men with osteoporosis. Therefore, the algorithm for the management of osteoporosis in men could be similar to the one previously recommended for the management of osteoporosis in women

Novel formulations of oral bisphosphonates in the treatment of osteoporosis.

Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk-benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes

New insights into the impact of neuro-inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is considered to be, in many respects, an archetypal autoimmune disease that causes activation of pro-inflammatory pathways resulting in joint and systemic inflammation. RA remains a major clinical problem with the development of several new therapies targeted at cytokine inhibition in recent years. In RA, biologic therapies targeted at inhibition of tumor necrosis factor alpha (TNFα) have been shown to reduce joint inflammation, limit erosive change, reduce disability and improve quality of life. The cytokine TNFα has a central role in systemic RA inflammation and has also been shown to have pro-inflammatory effects in the brain. Emerging data suggests there is an important bidirectional communication between the brain and immune system in inflammatory conditions like RA. Recent work has shown how TNF inhibitor therapy in people with RA is protective for Alzheimer's disease. Functional MRI studies to measure brain activation in people with RA to stimulus by finger joint compression, have also shown that those who responded to TNF inhibition showed a significantly greater activation volume in thalamic, limbic, and associative areas of the brain than non-responders. Infections are the main risk of therapies with biologic drugs and infections have been shown to be related to disease flares in RA. Recent basic science data has also emerged suggesting that bacterial components including lipopolysaccharide induce pain by directly activating sensory neurons that modulate inflammation, a previously unsuspected role for the nervous system in host-pathogen interactions. In this review, we discuss the current evidence for neuro-inflammation as an important factor that impacts on disease persistence and pain in RA

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration

A Need to Meet Patient Expectations

Funding Information: Open access funding provided by Università degli Studi di Palermo within the Nicola Veronese reports personal fees from IBSA, Mylan, and Fidia outside of the submitted work. Cyrus Cooper reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB outside of the submitted work. Jean-Yves Reginster reports CRUI-CARE Agreement. Funding Information:grants from IBSA-Genevrier, Mylan, CNIEL, and Radius Health (through his institution); consulting fees from IBSA-Genevrier, Mylan, CNIEL, Radius Health, and Pierre Fabre; fees for participation in review activities from IBSA-Genevrier, Mylan, CNIEL, Radius Health, and Teva; and payment for lectures from Ag-Novos, CERIN, CNIEL, Dairy Research Council (DRC), Echolight, IBSA-Genevrier, Mylan, Pfizer Consumer Health, Teva, and Theramex outside of the submitted work. Olivier Bruyère reports grants or lecture fees from Amgen, Aptissen, Biophytis, IBSA, MEDA, Mylan, Novartis, Sanofi, Servier, SMB, TRB Chemedica, UCB, and Viatris outside of the submitted work. Ali Mobasheri declares personal fees from Abbott, Abbvie, Achē Laboratórios Farmacêuticos, Galapagos, GSK Consumer Healthcare, Kolon TissueGene, Laboratoires Expansciences, Merck, Pacira Biosciences, Pfizer, Sanofi, and Servier. François Rannou reports grants or lecture fees from Pierre Fabre, Mylan, MSD, Thuasne, IBSA, Pfizer, Genévrier, Expanscience, Scarcell, Skindermic, and Peptinov. Ida K. Haugen reports grants from Pfizer and is a consultant for Novartis outside of the submitted work. Elaine M. Dennison declares grants/fees from Pfizer, Lilly, UCB, and Viatris. Philip G. Conaghan is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health), and reports consultancies or lecture fees from AbbVie, Amgen, AstraZeneca, Eli Lilly, Galapagos, GSK, Grunenthal, Pfizer, Novartis, and UCB. Nasser M. Al-Daaghri, Antonella Fioravanti, Sara Cheleschi, Jean-Pierre Pelletier, Maarten de Wit, Etienne Cavalier, Radmila Matijevic, Germain Honvo, Régis Pierre Radermecker, René Rizzoli, Jaime Branco, Andrea Laslop, María Concepción Prieto Yerro, Alberto Migliore, Gabriel Herrero-Beaumont, and Nicholas R. Fuggle declare that they have no conflicts of interest. Publisher Copyright: © 2022, The Author(s).Knee osteoarthritis (OA) is one of the most common and disabling medical conditions. In the case of moderate to severe pain, a single intervention may not be sufficient to allay symptoms and improve quality of life. Examples include first-line, background therapy with symptomatic slow-acting drugs for OA (SYSADOAs) or non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) performed a review of a multimodal/multicomponent approach for knee OA therapy. This strategy is a particularly appropriate solution for the management of patients affected by knee OA, including those with pain and dysfunction reaching various thresholds at the different joints. The multimodal/multicomponent approach should be based, firstly, on different combinations of non-pharmacological and pharmacological interventions. Potential pharmacological combinations include SYSADOAs and NSAIDs, NSAIDs and weak opioids, and intra-articular treatments with SYSADOAs/NSAIDs. Based on the available evidence, most combined treatments provide benefit beyond single agents for the improvement of pain and other symptoms typical of knee OA, although further high-quality studies are required. In this work, we have therefore provided new, patient-centered perspectives for the management of knee OA, based on the concept that a multimodal, multicomponent, multidisciplinary approach, applied not only to non-pharmacological treatments but also to a combination of the currently available pharmacological options, will better meet the needs and expectations of patients with knee OA, who may present with various phenotypes and trajectories.publishersversionpublishe

Does accelerated epigenetic ageing predict accelerated future musculoskeletal ageing?

The ability to predict those at risk of more rapid musculoskeletal ageing is vital if therapeutic strategies are to be successful. Precise description of the ageing musculoskeletal phenotype combined with the mapping of epigenetic changes, specifically those within the DNA methylome, enable precise age prediction and ‘epigenetic clocks’ have been formulated to capture ‘biological’ ageing. With this in mind, the broad aims of my thesis are:• To describe the longitudinal change in bone microarchitecture and muscle strength• To investigate the association between baseline epigenetic age acceleration and musculoskeletal outcomes• To identify novel epigenetic marks which are associated with key musculoskeletal indices of grip strength and bone mineral density through Epigenome-Wide Association StudyThis thesis is focused on the Hertfordshire Cohort Study (HCS); a group of community-dwelling, older adults in which baseline blood samples are available for epigenetic analysis. In 2017 I led a musculoskeletal phenotyping pass of the cohort including grip dynamometry, dual-energy X-ray absorptiometry (DXA) and High Resolution peripheral quantitative computed tomography (HR-pQCT) to complement the same assessments which had previously been performed in 2011-12. Longitudinal change in HR-pQCT parameters, grip strength and hip bone mineral density was analysed and the determinants of HR-pQCT parameter change were examined. Using DNA from whole blood leukocytes at HCS baseline (1998-2004) DNA methylation was measured and epigenetic age acceleration calculated (HorvathAge, GrimAge and PhenoAge). The relationship between epigenetic age acceleration at baseline (1998-2004) and musculoskeletal phenotype was examined. In additional exploratory analyses an epigenome-wide approach was utilised to elucidate specific CpG sites associated with cross-sectional grip strength and total femoral neck bone mineral density.Baseline values of HR-pQCT parameters and greater decline in trabecular Bone Mineral Density (BMD) were associated with fracture and change in trabecular BMD was associated with a single-nucleotide polymorphism (SNP) in the WNT16 gene (β= -0.28 (-0.50,-0.07), p=0.011). Greater epigenetic age acceleration, as calculated via the new iterations of the epigenetic clocks (in particular GrimAge), was associated with lower maximum grip strength (β= -1.25 (-2.24,-0.26), p<0.02) and gait speed (β= (-0.04 (-0.09,-0.00), p<0.05) at multiple time points in males. In epigenome-wide analyses, methylation of a CpG site proximal to ECE1 was associated with maximum grip strength (adjusted p<0.05) and biologically plausible pathways including those governing the regulation of the actin cytoskeleton were significantly associated with total femoral neck bone mineral density (p<0.05).These findings are largely hypothesis building and require further investigation and replication. However, they do add to our current understanding of skeletal changes associated with ageing, the ability of epigenetic clocks to predict future musculoskeletal phenotypes and identify novel loci of methylation which are associated with musculoskeletal ageing

A review of epigenetics and its association with ageing of muscle and bone.

Ageing is defined as the ‘increasing frailty of an organism with time that reduces the ability of that organism to deal with stress’. It has been suggested that epigenetics may underlie the observation that some individuals appear to age faster than others. Epigenetics is the study of changes which occur in an organism due to changes in expression of the genetic code rather than changes to the genetic code itself; that is, epigenetic mechanisms impact upon the function of DNA without changing the DNA sequence. It is important to recognise that epigenetic changes, in contrast to genetic changes, can vary according to different cell types and therefore can demonstrate significant tissue-specificity. There are different types of epigenetic mechanisms: histone modification, non-coding RNAs and DNA methylation. Epigenetic clocks have been developed using statistical techniques to identify the optimal combination of CpG sites (from methylation arrays) to correlate with chronological age. This review considers how epigenetic factors may affect rates of ageing of muscle and bone and provides an overview of current understanding in this area. We discuss studies using first-generation epigenetic clocks, as well as the second-generation iterations, which appear to show stronger associations with the ageing muscle phenotype. We also review epigenome-wide association studies that have been performed in various tissues examining relationships with osteoporosis and fracture. It is hoped that an understanding of this area will lead to interventions that might prevent or reduce rates of musculoskeletal ageing in later life

Epigenetic regulation of bone mass

Osteoporosis, characterised by low bone mass, poor bone structure, and an increased risk of fracture, is a major public health problem. There is increasing evidence that the influence of the environment on gene expression, through epigenetic processes, contributes to variation in BMD and fracture risk across the lifecourse. Such epigenetic processes include DNA methylation, histone and chromatin modifications and non-coding RNAs. Examples of associations with phenotype include DNA methylation in utero linked to maternal vitamin D status, and to methylation of target genes such as OPG and RANKL being associated with osteoporosis in later life. Epigenome-wide association studies and multi-omics technologies have further revealed susceptibility loci, and histone acetyltransferases, deacetylases and methylases are being considered as therapeutic targets. This review encompasses recent advances in our understanding of epigenetic mechanisms in the regulation of bone mass and osteoporosis development, and outlines possible diagnostic and prognostic biomarker applications