Proton Pump Inhibitors and Bone Health: An Update Narrative Review.

Proton pump inhibitors (PPIs) are an antacid drug often used in acid-related disorders. They decrease acid secretion in the stomach by blocking an enzyme called H+/K+ ATPase which controls acid production. Introduced to the market in 1989, their use has increased rapidly worldwide and they are now among the top 10 most prescribed drugs in the United States. As of 2015, the FDA has already approved six drugs of this class (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole). Recently, the risks and benefits of long-term PPI use were questioned and many studies indicated that their use should be carefully considered, especially in young patients, whose treatment with these drugs could last many years. Even greater concerns have been raised about a potential positive association between PPIs and osteoporotic fracture risk including the hip, spine and wrist. Although based on observational studies, there is substantial evidence associating the long-term use of PPIs and fracture. This relationship is only partially admitted due to the lack of consistent effects of PPIs on bone mineral density loss. Therefore, this narrative review aimed to discuss the recent findings pertaining to the risk of osteoporotic fracture associated with PPIs, in particular prolonged use, and to call for further research to elucidate the mechanisms associated with this bone fragility.

Gene Expression and Chondrogenic Potential of Cartilage Cells: Osteoarthritis Grade Differences.

Recent data suggest that cells isolated from osteoarthritic (OA) cartilage express mesenchymal progenitor cell (MPC) markers that have the capacity to form hyaline-like cartilage tissue. Whether or not these cells are influenced by the severity of OA remains unexplored. Therefore, we analyzed MPC marker expression and chondrogenetic potential of cells from mild, moderate and severe OA tissue. Human osteoarthritic tibial plateaus were obtained from 25 patients undergoing total knee replacement. Each sample was classified as mild, moderate or severe OA according to OARSI scoring. mRNA expression levels of MPC markers-CD105, CD166, Notch 1, Sox9; mature chondrocyte markers-Aggrecan (Acan), Col II A1, hypertrophic chondrocyte and osteoarthritis-related markers-Col I A1, MMP-13 and ALPL were measured at the tissue level (day 0), after 2 weeks of in vitro expansion (day 14) and following chondrogenic in vitro re-differentiation (day 35). Pellet matrix composition after in vitro chondrogenesis of different OA-derived cells was tested for proteoglycans, collagen II and I by safranin O and immunofluorescence staining. Multiple MPC markers were found in OA cartilage resident tissue within a single OA joint with no significant difference between grades except for Notch1, which was higher in severe OA tissues. Expression levels of CD105 and Notch 1 were comparable between OA cartilage-derived cells of different disease grades and bone marrow mesenchymal stem cell (BM-MSC) line (healthy control). However, the MPC marker Sox 9 was conserved after in vitro expansion and significantly higher in OA cartilage-derived cells compared to its levels in the BM-MSC. The in vitro expansion of cartilage-derived cells resulted in enrichment while re-differentiation in reduction of MPC markers for all three analyzed grades. However, only moderate OA-derived cells after the in vitro chondrogenesis resulted in the formation of hyaline cartilage-like tissue. The latter tissue samples were also highly positive for collagen II and proteoglycans with no expression of osteoarthritis-related markers (collagen I, ALPL and MMP13). MPC marker expression did not differ between OA grades at the tissue level. Interestingly after in vitro re-differentiation, only moderate OA-derived cells showed the capacity to form hyaline cartilage-like tissue. These findings may have implications for clinical practice to understand the intrinsic repair capacity of articular cartilage in OA tissues and raises the possibility of these progenitor cells as a candidate for articular cartilage repair.

Does the Severity of Obesity Influence Bone Mineral Density Values in Premenopausal Women?

The aim of this study was to compare bone mineral content (BMC), bone mineral density (BMD), and geometric indices of hip bone strength among 3 groups of adult obese premenopausal women (severely obese, morbidly obese, and super morbidly obese). This study included 65 young adult premenopausal women whose body mass index (BMI) > 35 kg/m2. They were divided into 3 groups using international cut-offs for BMI. Body composition and bone variables were measured by DXA. DXA measurements were completed for the whole body (WB), lumbar spine, total hip (TH), and femoral neck (FN). Geometric indices of FN strength (cross-sectional area, cross-sectional moment of inertia [CSMI], section modulus [Z], strength index [SI], and buckling ratio) were calculated by DXA. Results showed that age and height were not significantly different among the 3 groups. WB BMC values were higher in super morbidly obese women compared to severely and morbidly obese women. WB BMD, L1-L4 BMD, total hip BMD, FN BMD, cross-sectional area, CSMI, Z, and buckling ratio values were not significantly different among the 3 groups. SI values were lower in super morbidly obese compared to morbidly and severely obese women. In the whole population (n = 65), body weight, BMI, lean mass, fat mass, and trunk fat mass were positively correlated to WB BMC and negatively correlated to SI. Weight and lean mass were positively correlated to WB BMD and CSMI. Our findings suggest that the severity of obesity does not influence BMD values in premenopausal women.

Limb Muscular Strength and Bone Mineral Density in Elderly Subjects with Low Skeletal Muscle Mass Index.

The aim of the current study was to investigate the relationships between limb muscular strength and bone mineral density (BMD) in a group of elderly subjects with low skeletal muscle mass index (SMI).55 elderly Lebanese subjects (35 women and 20 men) participated in the current study. Handgrip, one-repetition maximum (1-RM) dumbbell curl (1-RM biceps), 1-RM lying one arm triceps (1-RM triceps), 1-RM calf raise, 1-RM leg extension and 1-RM leg curl were evaluated using validated methods.In both genders, 1-RM biceps, 1-RM triceps, 1-RM leg extension and 1-RM leg curl were positively correlated to total hip BMD. The current study shows that limb muscular strength is positively correlated to hip BMD in elderly subjects with low SMI. This may have clinical implications in the field of osteoporosis prevention in elderly subjects with low SMI.

Animal Model for Glucocorticoid Induced Osteoporosis: A Systematic Review from 2011 to 2021.

Clinical and experimental data have shown that prolonged exposure to GCs leads to bone loss and increases fracture risk. Special attention has been given to existing emerging drugs that can prevent and treat glucocorticoid-induced osteoporosis GIOP. However, there is no consensus about the most relevant animal model treatments on GIOP. In this systematic review, we aimed to examine animal models of GIOP centering on study design, drug dose, timing and size of the experimental groups, allocation concealment, and outcome measures. The present review was written according to the PRISMA 2020 statement. Literature searches were performed in the PubMed electronic database via Mesh with the publication date set between April, 2011, and February 2021. A total of 284 full-text articles were screened and 53 were analyzed. The most common animal species used to model GIOP were rats (66%) and mice (32%). In mice studies, males (58%) were preferred and genetically modified animals accounted for 28%. Our work calls for a standardization of the establishment of the GIOP animal model with better precision for model selection. A described reporting design, conduction, and selection of outcome measures are recommended.

Cumulative Effects of Strontium Ranelate and Impact Exercise on Bone Mass in Ovariectomized Rats.

OBJECTIVE: To explore the effect of physical exercise (EXE), strontium ranelate (SR), or their combination on bone status in ovariectomized (OVX) rats. DESIGN: Sixty female Wistar rats were randomized to one of five groups: sham (Sh), OVX (O), OVX+EXE (OE), OVX+SR (OSR), and OVX+EXE+SR (OESR). Animals in EXE groups were subjected to 10 drops per day (45 cm in height); rats in SR groups received 625 mg/kg/day of SR, 5 days/week for 8 weeks. Bone mineral density (BMD) and bone mineral content (BMC, dual-energy X-ray absorptiometry (DXA)), mechanical strength of the left femur (three-point bending test), and femur microarchitecture of (micro-computed tomography imaging, microCT) analyses were performed to characterize biomechanical and trabecular/cortical structure. Bone remodeling, osteocyte apoptosis, and lipid content were evaluated by ELISA and immunofluorescence tests. RESULTS: In OVX rats, whole-body BMD, trabecular parameters, and osteocalcin (OCN) levels decreased, while weight, lean/fat mass, osteocyte apoptosis, and lipid content all increased. EXE after ovariectomy improved BMD and BMC, trabecular parameters, cross-sectional area (CSA), moment of inertia, and OCN levels while decreasing osteocyte apoptosis and lipid content. SR treatment increased BMD and BMC, trabecular parameters, CSA, stiffness, OCN, and alkaline phosphatase (ALP) levels. Furthermore, fat mass, N-telopeptide (NTX) level, osteocyte apoptosis, and lipid content significantly decreased. The combination of both EXE and SR improved bone parameters compared with EXE or SR alone. CONCLUSION: EXE and SR had positive and synergistic effects on bone formation and resorption.

Sarcopenia negatively affects hip structure analysis variables in a group of Lebanese postmenopausal women.

BACKGROUND: The current study's purpose is to compare hip structural analysis variables in a group of postmenopausal women with sarcopenia and another group of postmenopausal women with normal skeletal muscle mass index. To do so, the current study included 8 postmenopausal women (whose ages ranged between 65 and 84 years) with sarcopenia and 60 age-matched controls (with normal skeletal muscle mass index (SMI)). Body composition and bone parameters were evaluated by dual-energy X-ray absorptiometry (DXA). RESULTS: Weight, lean mass, body mass index, femoral neck cross-sectional area (FN CSA), FN section modulus (Z), FN cross sectional moment of inertia (CSMI), intertrochanteric (IT) CSA, IT Z, IT CSMI, IT cortical thickness (CT), femoral shaft (FS) CSA, FS Z and FS CSMI were significantly greater (p < 0.05) in women with normal SMI compared to women with sarcopenia. In the whole population, SMI was positively associated with IT CSA, IT Z, IT CSMI, IT CT, FS CSA, FS Z, FS CSMI, FS CT but negatively correlated to IT buckling ratio (BR) and FS BR. CONCLUSION: The current study suggests that sarcopenia has a negative effect on hip bone strength indices in postmenopausal women.

Influence of sarcopenia on bone health parameters in a group of eumenorrheic obese premenopausal women.

INTRODUCTION: The aim of this study was to compare bone mineral density (BMD) and geometric indices of hip bone strength in a group of obese sarcopenic premenopausal women (n = 27) and a group of obese premenopausal women with normal appendicular lean mass (ALM)/body mass index ratio (BMI) (n = 26). MATERIALS AND METHODS: The ALM/BMI criterion of The Foundation for the National Institute of Health was used; women with an ALM/BMI ratio < 0.512 m2 were considered obese sarcopenic. Body composition and bone variables were measured by DXA. DXA measurements were completed for the whole body (WB), lumbar spine (L1-L4), total hip (TH) and femoral neck (FN). Hip geometry parameters including cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), section modulus (Z), strength index (SI) and buckling ratio (BR) were derived by DXA. RESULTS: Age, weight and BMI were not significantly different between the two groups. Height, lean mass, skeletal muscle mass index, ALM and the ratio ALM/BMI were significantly higher in obese women with normal ALM/BMI ratio compared to obese sarcopenic women. Fat mass percentage was significantly higher in obese sarcopenic women compared to obese women with normal ALM/BMI ratio. WB BMC, TH BMD, FN BMD, CSA, CSMI and Z were significantly higher in obese women with normal ALM/BMI ratio compared to obese sarcopenic women. In the whole population (n = 53), ALM and the ratio ALM/BMI were positively correlated to WB BMC, CSA, CSMI and Z. CONCLUSION: The present study suggests that sarcopenia negatively influences bone mineral density and hip geometry parameters before menopause in eumenorrheic obese women.

Enthesopathy-An Underappreciated Role in Osteoarthritis?

Osteoarthritis (OA) continues to be a debilitating disease worldwide, to date, no therapies have been definitely proven to modify disease progression or moderate symptom relief long term other than joint replacement. A contributing factor may be the lack of attention to the potential role of the periarticular enthesis and development and progression of OA. The enthesis is the site of attachment for a tendon, ligament, or joint capsule to the bony skeleton, thereby allowing centralized transmission and dissipation of mechanical loads. Because of this design, the enthesis is a site of stress concentration subject to inflammation during sports-related activities or spondyloarthropathies, which may lead to long-term degeneration. Our hypothesis is that functional incompetence of the enthesis resulting from either degenerative or inflammatory changes could be an initiating factor for OA and may thus provide a novel basis for the development of future disease management in this phenotype of patients.

Osteoarthritis biomarker responses and cartilage adaptation to exercise: A review of animal and human models.

Regular physical activity has been suggested as having both preventive and therapeutic benefits for individuals with osteoarthritis (OA). However, evidence of whether exercise and which type of exercise constitutes a benefit or a risk in the development and progression of OA remains debatable. This may be due to the evaluation of the effect of physical activity or new disease-modifying OA drugs which is currently based on radiographic criteria (eg, joint space width) and the lack of correlation with clinical signs and symptoms (eg, pain and loss of function). Moreover, OA typically manifests itself as changes within the joint space and subchondral bone as well as the whole joint structure, including progressive degradation of cartilage, menisci, ligaments, and synovial inflammation. Biomarkers are being developed to quantify joint remodeling and disease progression notably involving the articular cartilage and synovial fluid. The primary purpose of this review was to evaluate the current literature and to provide further insight based on OA biomarkers and the role physical activity plays in the management of OA. Osteoarthritis biomarkers together with radiographic imaging evidence will ideally guide healthcare providers to incorporate exercise recommendations into clinical management and offer patients evidence-based and individually tailored exercise prescriptions.

Physical Performance Variables and Bone Mineral Density in a Group of Young Overweight and Obese Men.

The aim of this study was to explore the relationships between performances obtained in different physical tests and bone parameters (bone mineral density [BMD], bone mineral content, hip geometry indices, and trabecular bone score [TBS]) in a group of young Lebanese overweight and obese adult men. Fifty-two overweight and/or obese (body mass index > 25 kg/m2) young men whose ages range from 18 to 35 yr participated in this study. Weight and height were measured, and body mass index was calculated. Body composition, BMD, cross-sectional area and section modulus (Z) of the femoral neck (FN), and TBS were measured by dual-energy X-ray absorptiometry. Maximum oxygen consumption (VO2 max, in liter per minute) was determined by direct measurement while exercising on a medical treadmill. One-repetition-maximum half-squat and maximum power (P max) of the lower limbs were measured using validated exercises. Lean mass was a positive determinant of whole-body bone mineral content (r = 0.71, p < 0.001), FN cross-sectional area (r = 0.51, p < 0.001), and FN Z (r = 0.58, p < 0.001). VO2 max (in liter per minute) was a positive determinant of whole-body BMD (r = 0.47, p < 0.001), total hip BMD (r = 0.43, p < 0.01), and FN BMD (r = 0.42, p < 0.01). VO2 max (in milliliter per minute per kilogram) was a positive determinant of TBS (r = 0.30, p < 0.05). One repetition maximum was a positive determinant of L1-L4 BMD (r = 0.33, p < 0.05). This study suggests that VO2 max (in liter per minute) is a positive determinant of BMD, and VO2 max (in milliliter per minute per kilogram) is a positive determinant of TBS in overweight and obese men.

TGF-beta-induced early gene-1 overexpression promotes oxidative stress protection and actin cytoskeleton rearrangement in human skin fibroblasts.

BACKGROUND: Transforming growth factor beta inducible early gene-1 (TIEG-1), a member of the Krüppel-like factor, was identified as a primary response gene for TGF-ß. The role of TIEG-1 in skin repair has been mainly addressed in vivo on TIEG-1 null mice model and the mechanism remains unexplored. METHODS: We investigated the modulation of TIEG-1 expression in normal human skin fibroblasts by either down-expressing or overexpressing the gene. We evaluated reactive oxygen species production and the cell viability of treated cells. The effect of TIEG-1 overexpression was monitored by wound healing assay and immunofluorescence staining of actin fibers organization and alpha-smooth muscle actin (α-SMA). Western blots were carried out to identify the level of expression or phosphorylation of key proteins such as cofilin, Rho GTPases, and p38 mitogen-activated protein kinase (p38 MAPK). RESULTS: TIEG-1 down-regulation had a deleterious effect on the cell viability. It was significantly reduced (65±5%) and exposure to ultraviolet further increased this effect (47±3%). By contrast, cells overexpressing TIEG-1 had a reduced reactive oxygen species production (75%) compared to control and mock-transfected cells. This overexpression also resulted in formation of actin stress fibers and increased α-SMA expression and an enhanced wound healing feature. RhoB GTPase was upregulated and phosphorylation of cofilin and p38 MAPK was observed. CONCLUSION: TIEG-1 overexpression in normal human skin fibroblasts results in improved resistance to oxidative stress, myofibroblast-like conversion that involved RhoB signaling pathway with cofilin and p38 MAPK proteins activation. GENERAL SIGNIFICANCE: This study enlightens the role of TIEG-1 role in skin biology.

Progenitor Cells from Cartilage: Grade Specific Differences in Stem Cell Marker Expression.

Recent research has confirmed the presence of Mesenchymal stem cell (MSC)-like progenitors (MPC) in both normal and osteoarthritic cartilage. However, there is only limited information concerning how MPC markers are expressed with osteoarthritis (OA) progression. The purpose of this study was to compare the prevalence of various MPC markers in different OA grades. Human osteoarthritic tibial plateaus were obtained from ten patients undergoing total knee replacement. Each sample had been classified into a mild or severe group according to OARSI scoring. Tissue was taken from each specimen and mRNA expression levels of CD105, CD166, Notch 1, Sox9, Acan and Col II A1 were measured at day 0 and day 14 (2 weeks in vitro). Furthermore, MSC markers: Nucleostemin, CD90, CD73, CD166, CD105 and Notch 1 were studied by immunofluorescence. mRNA levels of MSC markers did not differ between mild and severe OA at day 0. At day 14, protein analysis showed that proliferated cells from both sources expressed all 6 MSC markers. Only cells from the mild OA subjects resulted in a significant increase of mRNA CD105 and CD166 after in vitro expansion. Moreover, cells from the mild OA subjects showed significantly higher levels of CD105, Sox9 and Acan compared with those from severe OA specimens. Results confirmed the presence of MSC markers in mild and severe OA tissue at both mRNA and protein levels. We found significant differences between cells obtained from mild compared to severe OA specimens suggests that mild OA derived cells may have a greater MSC potential.

Effect of the alcohol consumption on osteocyte cell processes: a molecular imaging study.

We have previously shown microarchitectural tissue changes with cellular modifications in osteocytes following high chronic alcohol dose. The aim of this study was to assess the dose effect of alcohol consumption on the cytoskeleton activity, the cellular lipid content and modulation of differentiation and apoptosis in osteocyte. Male Wistar rats were divided into three groups: Control (C), Alcohol 25% v/v (A25) or Alcohol 35% v/v (A35) for 17 weeks. Bone mineral density (BMD) was assessed by DXA, osteocyte empty lacunae, lacunae surface, bone marrow fat with bright field microscopy. Osteocyte lipid content was analysed with transmission electron microscopy (TEM) and epifluorescence microscopy. Osteocyte apoptosis was analysed with immunolabelling and TEM. Osteocyte differentiation and cytoskeleton activity were analysed with immunolabelling and real time quantitative PCR. At the end of the protocol, BMD was lower in A25 and A35 compared with C, while the bone marrow lipid content was increased in these groups. More empty osteocyte lacunae and osteocyte containing lipid droplets in A35 were found compared with C and A25. Cleaved caspase-3 staining and chromatin condensation were increased in A25 and A35 versus C. Cleaved caspase-3 was increased in A35 versus A25. CD44 and phosphopaxillin stainings were higher in A35 compared with C and A25. Paxillin mRNA expression was higher in A35 versus A25 and C and sclerostin mRNA expression was higher in A35 versus C. We only observed a dose effect of alcohol consumption on cleaved caspase-3 osteocyte immunostaining levels and on the number of lipid droplets in the bone marrow.

Changes in prevalence of calcaneal spurs in men & women: a random population from a trauma clinic.

BACKGROUND: This study reports the changing prevalence of ankle (Achilles and plantar) spurs with age, in order to comment on their significance to rheumatologists. METHODS: 1080 lateral ankle radiographs from each of 9 (50 men and 50 women) age cohorts from 2 to 96 years old of patients attending a trauma clinic were examined and spurs classified as small or large. RESULTS: The prevalence of both Achilles and plantar spurs in relation to the age categories and sex was variable. Overall, there was 38% of the population who had a spur (Achilles or plantar) and only third (11%) with spurs at both sites (Achilles and plantar). Large spurs were more prevalent in older individuals (40 to 79 years). There were no large plantar spurs in individuals <40 years of age and only 2% for the Achilles. The prevalence of spurs (Achilles and plantar) was significantly higher for woman than men in individuals <50 years of age. There was a notable moderate positive correlation (r = 0.71) between both plantar and Achilles spurs for women <30 years of age but no correlation for men (r = -0.03). CONCLUSION: Plantar and Achilles spurs are highly prevalent in older people and the radiographic appearance of spurs differs between men and women. In individuals < 50 years of age, spur (Achilles and plantar) formation is more common in women than in men. Additionally, there was a notable moderate positive correlation between Achilles and plantar spurs for women <30 years of age.

Performance of Radiological and Biochemical Biomarkers in Predicting Radio-Symptomatic Knee Osteoarthritis Progression.

Imaging biomarkers permit improved approaches to identify the most at-risk patients encountering knee osteoarthritis (KOA) progression. This study aimed to investigate the utility of trabecular bone texture (TBT) extracted from plain radiographs, associated with a set of clinical, biochemical, and radiographic data, as a predictor of long-term radiographic KOA progression. We used data from the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium dataset. The reference model made use of baseline TBT parameters adjusted for clinical covariates and radiological scores. Several models based on a combination of baseline and 24-month TBT variations (TBT∆TBT) were developed using logistic regression and compared to those based on baseline-only TBT parameters. All models were adjusted for baseline clinical covariates, radiological scores, and biochemical descriptors. The best overall performances for the prediction of radio-symptomatic, radiographic, and symptomatic progression were achieved using TBT∆TBT parameters solely, with area under the ROC curve values of 0.658 (95% CI: 0.612-0.705), 0.752 (95% CI: 0.700-0.804), and 0.698 (95% CI: 0.641-0.756), respectively. Adding biochemical markers did not significantly improve the performance of the TBT∆TBT-based model. Additionally, when TBT values were taken from the entire subchondral bone rather than just the medial, lateral, or central compartments, better results were obtained.

Radiographic Biomarkers for Knee Osteoarthritis: A Narrative Review.

Conventional radiography remains the most widely available imaging modality in clinical practice in knee osteoarthritis. Recent research has been carried out to develop novel radiographic biomarkers to establish the diagnosis and to monitor the progression of the disease. The growing number of publications on this topic over time highlights the necessity of a renewed review. Herein, we propose a narrative review of a selection of original full-text articles describing human studies on radiographic imaging biomarkers used for the prediction of knee osteoarthritis-related outcomes. To achieve this, a PubMed database search was used. A total of 24 studies were obtained and then classified based on three outcomes: (1) prediction of radiographic knee osteoarthritis incidence, (2) knee osteoarthritis progression and (3) knee arthroplasty risk. Results showed that numerous studies have reported the relevance of joint space narrowing score, Kellgren-Lawrence score and trabecular bone texture features as potential bioimaging markers in the prediction of the three outcomes. Performance results of reviewed prediction models were presented in terms of the area under the receiver operating characteristic curves. However, fair and valid comparisons of the models' performance were not possible due to the lack of a unique definition of each of the three outcomes.

Short-term variations in trabecular bone texture parameters associated to radio-clinical biomarkers improve the prediction of radiographic knee osteoarthritis progression.

The present study aims to examine whether the short-term variations in trabecular bone texture (TBT) parameters, combined with a targeted set of clinical and radiographic data, would improve the prediction of long-term radiographic knee osteoarthritis (KOA) progression. Longitudinal (baseline, 24 and 48-month) data, obtained from the Osteoarthritis Initiative cohort, were available for 1352 individuals, with preexisting OA (1 < Kellgren-Lawrence < 4) at baseline. KOA progression was defined as an increase in the medial joint space narrowing score from the 24-months to the 48-months control point. 16 regions of interest were automatically selected from each radiographic knee and analyzed using fractal dimension. Variations from baseline to 24 months in TBT descriptors as well as selected radiographic and clinical readings were calculated. Different logistic regression models were developed to evaluate the progression prediction performance when associating TBT variations with the selected clinical and radiographic readings. The most predictive model was mainly determined using the area under the receiver operating characteristic curve (AUC). The proposed prediction model including short-term variations in TBT parameters, associated with clinical covariates and radiographic scores, improved the capacity of predicting long-term radiographic KOA progression (AUC of 0.739), compared to models based solely on baseline values (AUC of 0.676, p-value < 0.008).

Effectiveness of Shiatsu on Fatigue in Patients with Axial Spondyloarthritis: Protocol for a Randomized Cross-Over Pilot Study.

INTRODUCTION: Spondyloarthritis (SpA) is a serious chronic inflammatory rheumatism implying different painful and crippling symptoms that require a multidisciplinary approach for the patient. Fatigue is one of the less well treated symptoms, even if its repercussion on everyday life is noticeable. Shiatsu is a Japanese preventive and well-being therapy that aims to promote better health. However, the effectiveness of shiatsu in SpA-associated fatigue has never been studied yet in a randomized study. METHODS AND ANALYSIS: We describe the design of SFASPA (Etude pilote randomisée en cross-over évaluant l'efficacité du Shiatsu sur la FAtigue des patients atteints de SPondyloarthrite Axiale), a single-center, randomized controlled cross-over trial with allocation of patients according to a ratio (1:1) evaluating the effectiveness of shiatsu in SpA-associated fatigue. The sponsor is the Regional Hospital of Orleans, France. The two groups of 60 patients each will receive three "active" shiatsu and three sham shiatsu treatments (120 patients, 720 shiatsu). The wash-out period between the active and the sham shiatsu treatments is 4 months. PLANNED OUTCOMES: The primary outcome is the percentage of patients responding to the FACIT-fatigue score. A response to fatigue is defined as an improvement, i.e., an increase of ≥ 4 points in the FACIT-fatigue score, which corresponds to the "minimum clinically important difference" (MCID). Differences in the evolution of activity and impact of the SpA will be assessed on several secondary outcomes. An important aim of this study is also to gather material for further trials with higher proof of evidence. TRIAL REGISTRATION: NCT05433168, date of registration, June 21st, 2022 (clinicaltrials.gov).