Introduction Il est admis que les lésions de dysplasie fibreuse peuvent augmenter de taille au cours de la croissance, en cas de transformation kystique anévrysmale, dans un contexte d’acromégalie ou lors de modifications hormonales telles que la grossesse. Une modification structurale à l’âge adulte doit faire évoquer une possible mais rare dégénérescence sarcomateuse. Cependant, chez l’adulte, le suivi systématique des lésions dysplasiques par imagerie n’est pas toujours recommandé. Nous rapportons ici cinq cas de patients atteints de dysplasie fibreuse rachidienne chez qui une progression est constatée à l’âge adulte, en dehors des contextes habituellement reconnus. Résultats Cas 1 : femme de 54 ans atteinte d’une forme monostotique de L1 documentée en biologie moléculaire, n’ayant jamais reçu de bisphosphonates, chez qui la progression est constatée entre 2014 et 2023, à la suite d’une douleur révélant une fracture vertébrale avec extension de la lésion sous-jacente. Cas 2 (Fig. 1) : femme, 52 ans, qui présente une forme polyostotique lytique costale gauche et rachidienne thoracique (allant de K4 à K6 et de T4 à T6) chez qui une progression est mise en évidence entre 2007 et 2023 à la faveur d’une accentuation douloureuse révélant une fracture vertébrale jugée instable, nécessitant une intervention chirurgicale. Cas 3 (Fig. 2) : homme de 54 ans, atteint d’une forme polyostotique du clivus et du rachis cervical, pratiquement asymptomatique, chez qui la lésion évolue nettement en regard de la dent de l’odontoïde, exposant à un risque neurologique à court/moyen terme. On note dans son cas un TRP bas à 79 % mais une phosphatémie normale basse à 0,87mmol/L. Cas 4 : homme de 55 ans, présentant une dysplasie fibreuse polyostotique avec notamment atteinte corporéale de C2 et apophysaire transverse gauche, chez qui on constate une progression de l’atteinte lytique pédiculaire entre 2018 et 2023. Ce patient présente également un TRP bas à 71 % sans hypophosphatémie. Cas 5 : femme de 52 ans, dont le diagnostic de DF polyostotique est connu et prouvé histologiquement depuis 2009, traitée par 5 cycles de pamidronate entre 2016 et 2019. On constate différentes modifications de taille de lésions entre 2011 et 2023 avec notamment une augmentation des anomalies des épineuses de L3 et L5. Conclusion Ces observations concernent des adultes d’âge moyen, autour de 50 ans, aussi bien des femmes que des hommes, atteints de formes mono- ou polyostotiques. Cette série de cinq cas de progression des lésions dysplasiques rachidiennes chez des adultes observés depuis 2023 nous incite à proposer aux patients ayant une localisation au squelette axial un suivi par tomodensitométrie, dont la fréquence serait adaptée en fonction de la taille des lésions et des symptômes cliniques. Une recherche de progression structurale proposée à un grand nombre de patients permettrait de préciser l’incidence de cette entité, ainsi que d’identifier de potentiels facteurs de risque.

What is this summary about? This is a plain language summary of a clinical research study called LUMINA-1. This study investigated a medicine called garetosmab in adults with fibrodysplasia ossificans progressiva, or FOP. FOP is a very rare disease that causes new bone to form in places where it does not usually develop (also known as heterotopic ossification). In FOP, when bone is formed in areas it is not supposed to, it results in mature heterotopic bone. The build-up of new bone makes it difficult for people with FOP to move, which means they often require the use of a wheelchair or other mobility aid. People with FOP who took part in the study were experiencing bone formation in areas where new bone should not form, flare-ups (episodes of localized swelling, pain, and/or warmth), and worsening joint movement. What were the results? People with FOP were given garetosmab or placebo every 4 weeks as a liquid infusion through a vein for 28 weeks. After 28 weeks, those who were receiving placebo were switched to garetosmab and treated for 28 weeks. This part was known as the open-label portion of the trial, which is when all people received garetosmab treatment. Treatment with garetosmab did not change the mature heterotopic bone in people with FOP, but it did stop new bone lesions from forming in areas where they should not. Treatment with garetosmab also reduced the number of flare-ups. During the trial, common side effects were nosebleeds, loss of eyebrows or eyelashes, and skin and soft tissue infections. Five people died during the open-label portion of the trial, when all were on garetosmab. Their deaths appeared consistent with the known causes of death and life expectancy of people with FOP who were of a similar age and severity of disease. There was no clear pattern that linked the deaths with how garetosmab works. However, a causal relationship between deaths and garetosmab could not be ruled out. What do the results of the study mean? The LUMINA-1 study showed that in people with FOP, garetosmab stopped new heterotopic bone from developing in areas that it should not and also reduced flare-ups. This shows that garetosmab may be a useful treatment for people with FOP. More testing is needed to better understand the benefits and risks of garetosmab. Clinical Trial Registration: NCT03188666 (ClinicalTrials.gov) (LUMINA-1)

La certification périodique des professionnels de santé en France est en place depuis le 1er janvier 2023. Pour autant, l'ensemble du dispositif n'est pas encore opérationnel mais les textes réglementaires sont en cours de finalisation et la communication sur le dispositif est importante dès maintenant. La périodicité de certification est de 6 ans (9 années pour le premier cycle des médecins déjà en exercice). Cette certification périodique sera enregistrée par les Ordres professionnels qui seront à même de prendre les mesures correctives en cas d'insuffisance professionnelle. Les référentiels de certification sont en cours d'élaboration par les conseils nationaux professionnels de chaque profession ou spécialité. Ils comporteront un menu d'actions relevant de quatre domaines : actualisation des connaissances et compétences, renforcement de la qualité des pratiques, amélioration des relations avec les patients et meilleure prise en compte de la santé personnelle. Les actions seront enregistrées au fil de l'eau dans un portail informatique, de façon la plus simple et automatisée possible pour rendre le dispositif de certification accessible à tous et performant. L'objectif est une amélioration de la qualité des soins. The periodic certification of health professionals has been in place since January 1st, 2023. However, the entire system is not yet operational, but the regulatory texts are being finalized and communication on the system is important right now. The periodicity of certification is 6 years (9 years for the first cycle of doctors already in practice). This periodic certification will be recorded by the Professional Orders, which will be able to take corrective measures in the event of professional insufficiency. The good practices frameworks are being developed by the national professional councils, one for each profession or specialty. They will include a menu of actions in four areas: updating knowledge and skills, strengthening the quality of practices, improving doctor-patient relationships, and taking greater account of his(her) own personal health. The actions will be recorded over time in a computer portal, in the simplest and most automated way possible to make the certification system accessible to all and efficient. The goal is to improve the quality of care.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

BackgroundThere are several therapeutic options for the management of shoulder adhesive capsulitis (AC). The superiority of arthro-distension over intra-articular steroid injection (ISI) for AC remains controversial.ObjectivesTo evaluate the efficacy of a single arthro-distension procedure combined with early and intensive mobilization (ADM) and physiotherapy, versus ISI and physiotherapy, in people with AC lasting ≥3 months.MethodsThis was a prospective, 2 parallel-group, 2-center, observer-blind randomized controlled trial conducted in tertiary care settings. Adults with AC were randomly assigned to the treatment or control group. Efficacy was assessed using the self-administered Shoulder Pain and Disability Index (SPADI). Total, pain and disability SPADI scores 15 days, 6 weeks, and 3, 6 and 12 months after the procedure (total SPADI at 15 days: primary outcome; other outcomes were secondary) were compared between groups using analysis of covariance (ANCOVA). A post hoc analysis stratified on the initial range of passive glenohumeral abduction, which had not been pre-specified, was conducted.ResultsThere were 33 participants in each group. Both groups improved over time. Mean (SD) total SPADI score at 15 days was 33.8 (19.6) in the treatment group and 32.8 (17.5) in the control group, p = 0.393. There were no significant differences for any variables in the overall sample. The post hoc analysis found ADM to be associated with a significant decrease in total SPADI score at 15 days compared with ISI (p = 0.049) in individuals with initial passive glenohumeral abduction >45°.ConclusionsThe effects of ADM on pain and function were not statistically different from those of ISI. However, ADM may be useful in individuals with initial passive glenohumeral abduction >45°.Database registrationNCT00724113.

OBJECTIVES:Low back pain (LBP) is one of the main expenditure items for health systems. Data on the economic impact of LBP are uncommon from the patient perspective. The aim of this study was to estimate the economic impact of work disability related to chronic LBP from the patient perspective. METHODS:We conducted a cross-sectional analysis from patients aged over 17 years suffering from non-specific LBP for at least 3 months. Systematic medical, social and economic assessments were collected: pain duration and intensity; functional disability with the Quebec Back Pain Disability Scale (0-100); quality of life with the Dallas Pain Questionnaire; job category; employment status; duration of work disability due to LBP, and income. Factors associated with loss of income were identified by multivariable logistic regression analysis. RESULTS:We included 244 workers (mean age 43 ± 9 years; 36% women); 199 patients had work disability, including 196 who were on sick leave, 106 due to job injury. Three were unemployed due to layoff for incapacity. The mean loss of income for patients with work disability was 14% [SD 24, range -100 to 70] and was significantly less for patients on sick leave due to job injury than on sick leave not related to job injury (p < 0.0001). On multivariable analysis, the probability of loss of income with LBP was about 50% less for overseers and senior managers than workers or employees (odds ratio 0.48 [95% confidence interval 0.23-0.99]). CONCLUSION:Work disability due to LBP resulted in loss of income in our study. The loss of income depended on the type of social protection and job category. It was reduced for patients on sick leave related to work injury and for overseers and senior managers.

Abstract Disclosure: K.M. Dahir: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Ultragenyx, Inozyme, AM Pharma. Grant Recipient; Self; Regeneron Pharmaceuticals, Alexion Pharmaceuticals, Inc., AstraZeneca, Ultragenyx. J. McGinniss: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E. Forleo-Neto: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Mellis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. M. Di Rocco: Research Investigator; Self; Regeneron Pharmaceuticals, Ipsen. R. Keen: Advisory Board Member; Self; International Clinical Council on FOP and IFOPA Registry. Research Investigator; Self; Ipsen, Regeneron Pharmaceuticals, Clementia. P. Orcel: Research Investigator; Self; Regeneron Pharmaceuticals. C. Roux: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Amgen Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Kyowa, Kirin Brewery, Alexion Pharmaceuticals, Inc. J. Tabarkiewicz: Speaker; Self; Merck, Novartis Pharmaceuticals. Other; Self; SoftSystem. J. Bachiller-Corral: Research Investigator; Self; Regeneron Pharmaceuticals. A.M. Cheung: Consulting Fee; Self; Ipsen. Grant Recipient; Self; Ipsen, Incyte, Regeneron Pharmaceuticals. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Clementia, Incyte, Regeneron Pharmaceuticals. K. Mohammadi: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Rankin: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.N. Economides: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Gonzalez Trotter: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. F.S. Kaplan: Research Investigator; Self; Regeneron Pharmaceuticals, Clementia, Ipsen. M.W. Eekhoff: Grant Recipient; Self; Regeneron Pharmaceuticals, Ipsen, AstraZeneca, IMI, IFOPA. R.J. Pignolo: Grant Recipient; Self; Regeneron Pharmaceuticals, Clementia, Ipsen, Incyte. Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant disorder driven by missense mutations in ACVR1. This results in inappropriate activation by activin-A. FOP is characterized by progressive heterotopic ossification and painful soft tissue inflammatory events known as flare-ups. Garetosmab, an investigational, fully human monoclonal antibody against activin-A, prevents formation of new heterotopic ossification lesions in FOP. Here we describe the impact of garetosmab on flare-up events in the LUMINA-1 study (NCT03188666). Methods: This was a post hoc analysis of phase 2 LUMINA-1, a randomized double-blind placebo-controlled study that evaluated the safety and efficacy of garetosmab 10 mg/kg/every 4 weeks intravenous vs placebo in adult patients with FOP over 28 weeks (Period 1), followed by a 28-week open-label treatment period (Period 2) and subsequent open-label extension (Period 3). Patient-reported flare-ups were collected via a patient diary and severity of symptoms was reported as mild, moderate, or severe. Clinician-reported flare-ups were collected as adverse events. Results: In Period 1, there was a significant reduction in the proportion of patients reporting one or more flare-ups (35% vs 71%, p=0.032) and clinician-reported flare-ups (10% vs 42%, p=0.039) with garetosmab vs placebo, respectively. The overall number of patient-reported flare-ups (13 vs 34) and mean days experiencing new flare-ups (42.6 days vs 65.4 days) were also reduced with garetosmab vs placebo, respectively. Most flare-ups occurred in the back in garetosmab-treated patients, and most flare-ups occurred in the lower extremities and back for those on placebo. Pain was the most frequent symptom among both cohorts. Flare-up associated joint stiffness and severity of flare-up associated symptoms were nominally reduced at both patient and flare-up level of assessment in those treated with garetosmab. No patients reported severe swelling or severe decrease in movement. One patient reported severe pain and joint stiffness in the garetosmab cohort. In Period 2, there were significant reductions in the proportion of patients experiencing flare-ups (68% vs 14%, p=0.0002) and number of patient-reported flares (31 vs 11) among those who crossed over from placebo in Period 1 to garetosmab. Patients who continued on garetosmab through Period 2 maintained a sustained reduction in number of flare-ups (12 vs 6) and proportion of patients experiencing flare-ups (33.3% vs 22.2%). Reductions were maintained through the open-label extension. Conclusions: Patients treated with garetosmab experienced significant and sustained reductions in the frequency, duration, and severity of flare-ups. The ability of garetosmab to reduce flare-up events may provide a clinically meaningful benefit for patients with FOP. Presentation: Sunday, June 18, 2023

BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody ( n = 20) or placebo ( n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met ( P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .

BACKGROUND:Dynamic humeral centering (DHC) is a physiotherapy modality that aims to prevent sub-acromial impingement of rotator cuff tendons. We recently developed a new clinical manoeuver - the Viggo-Cochin test - to enhance the ability of the Neer test to detect sub-acromial impingement. Here we hypothesised whether the DHC effect may differ between individuals with positive and negative Viggo-Cochin test results.OBJECTIVE:To assess the association between DHC and Viggo-Cochin test results.METHODS:Individuals with shoulder pain due to sub-acromial impingement underwent the Neer and Viggo-Cochin tests at baseline. They were assessed before and after DHC by the Shoulder Pain and Disability Index (SPADI). A positive response to DHC was defined as a 20% reduction in the SPADI.RESULTS:We included 50 individuals (53 shoulders). The response to DHC did not differ by Neer test result at baseline: OR 0.73 [95% CI 0.22-2.38] (p= 0.601). By contrast, the response to DHC was 5-fold higher with a positive than negative Viggo-Cochin test result: OR 5.11 [95% CI 1.47-17.78] (p= 0.010).CONCLUSIONS:We found a higher clinical response to DHC with a positive than negative Viggo-Cochin test result at baseline in individuals with shoulder pain due to rotator cuff disease.

BACKGROUND:Information is lacking on the natural history of early stages of degenerative rotator cuff disease. Such information can be obtained by using clinical and imaging assessment after conservative treatment in affected patients.HYPOTHESIS:Subacromial impingement syndrome is a clinical presentation that can be associated with early stages of the disease. We aimed to describe the natural history of degenerative rotator cuff disease from the early stages by studying clinical and imaging outcomes in non-operated patients with subacromial impingement syndrome.PATIENTS AND METHODS:Patients with subacromial impingement syndrome were prospectively included. They had conservative treatment and were assessed before treatment and during at least 12-month follow-up. Assessment included clinical evaluation on a 0- to 100-point Constant scale and subscales as well as MRI of the rotator cuff. Clinical results were compared to baseline MRI findings and according to lesional progression.RESULTS:We included 26 patients with mean age 59.1 (SD 9.6), mean pain duration 23.1 (31.3) months; mean total Constant score 39.1 (12.1). Overall, 9 patients had no tear, 9 had a partial tear and 8 had a full-thickness tear. Mean follow-up was 21 (SD 10) months. Total Constant score and subscores improved at follow-up in the overall sample. Patients without tear and those with partial or full-thickness tear at baseline showed clinical improvement. MRI of the rotator cuff at follow-up indicated lesional worsening in 7 patients. However, clinical improvement did not differ by lesional progression or not.CONCLUSION:We report on 21-month clinical and MRI assessments of degenerative rotator cuff disorders including early stages of the disease. Clinical improvement was not related to MRI changes over time. Further investigations are needed to verify our findings in larger study populations.

Le conflit ischio-fémoral (CIF) est une cause inhabituelle de douleur de hanche. Certains sports contraignants peuvent causer ce conflit, comme la danse. Nous rapportons le cas d’une danseuse de ballet de 11 ans présentant un CIF bilatéral secondaire à un surentraînement et à une hypertrophie du muscle carré fémoral. Ce syndrome est fréquemment évoqué dans le domaine de l’orthopédie suite à une prothèse de hanche. Le CIF bilatéral est rare et doit être recherché dans le cadre d’un sport intense comme la danse lorsque toute autre cause a été éliminée.

Increased interleukin-6 (IL-6) has been observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS) and is possibly involved in the increased bone destruction and bone pain characterizing this disease. The TOCIDYS trial was a randomized, placebo-controlled, 1 year, cross-over, proof-of-concept trial, conducted in patients not responding to bisphosphonates, using monthly intra-venous tocilizumab (a monoclonal antibody to the IL-6 receptor) at 8 mg/kg or a matching placebo for 6 months. Over the following 6 months, they received tocilizumab if they first had placebo, and vice-versa. We measured change in serum CTX after 6 months of treatment, compared with baseline (primary endpoint). Other endpoints were the change in bone pain, change in P1NP, bone alkaline phosphatase, osteocalcin and ICTP, and variation of quality of life. The analysis relied on ANOVA, with sequence of treatment, period and treatment as factors and accounting for a potential carry-over effect. We have randomized 8 patients with FD/MAS in each sequence who all completed the first 6 months treatment period. During the second 6 months period, 3 patients stopped therapy, so the efficacy analysis set included 13 patients. We observed no significant change in serum CTX and other biochemical markers of bone turnover between the tocilizumab and placebo groups. There was no significant change in the level of bone pain on tocilizumab, although 3 patients had a sharp decrease in pain while on active drug, with progressive relapse on placebo for 2 of them, but with some degree of improvement in a few patients while on placebo. The SF-36 quality of life scale was not significantly changed. We conclude that tocilizumab does not decrease bone turnover in FD/MAS when administered in patients who fail to respond to bisphosphonates. Tocilizumab does not reduce bone pain in most patients, but a substantial effect in a subset cannot be ruled out in this trial powered for markers but not for pain.

A 58-year-old woman presented to the rheumatology department at Lariboisière Hospital (Paris, France) in May, 2021. She had been referred to the hospital by her general practitioner for suspected fibrous dysplasia of the cranial vault. She had been taking chlormadinone acetate (10 mg per day) for the treatment of uterine fibroids for 15 years, but stopped in 2020. At that time, she was advised by her gynaecologist to have a brain MRI to assess the risk of meningioma associated with long-term use of this progestin and antiandrogen medication. MRI examination, plus a CT scan for further investigation, were done on the same day in March, 2021, and the radiological diagnosis at the time was fibrous dysplasia. At the hospital, accurate interpretation of her MRI and CT scans led to the diagnosis of several en-plaque meningiomas, mainly located in the right and left frontal and parietal regions, associated with large adjacent bony hyperostosis resulting in bony bumps (figure). Because the patient was not affected by the frontal deformities, which were painless, and no brain oedema was seen on MRI, clinical and radiological monitoring was scheduled for 9–12 months later.

This observational study prospectively assessed direct and indirect costs related to patient management over 18 months following hip, clinical vertebral, humeral, or distal forearm fracture events in France. It appears that their levels were much higher than the previous estimates, raising the burden of osteoporosis-related fractures on public health expenditures. This prospective observational study assessed the costs related to patient management over the 18-month period following the event of a hip, clinical vertebral, humeral, or distal forearm fracture in France. Individuals aged ≥ 50 years old with the diagnosis of a fragility fracture in six French University Hospitals were enrolled in the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS). All resources used over the defined period and related to fracture and the underlying osteoporosis management were collected by questionnaires at baseline, 4 months, 12 months, and 18 months. Information was collected by direct or phone contact completed by patients’ records and interviews of partner, family, and general practitioners. Costs were estimated from a societal perspective, including direct and indirect costs. We implemented recursive partitioning analysis (RPA), a statistical learning algorithm to identify predictors of costs. Four hundred thirty-one patients (mean age 72.5 years; 84.6% women) were evaluated. Among them, 17.6% had a prior fracture in the last 5 years. Approximately half of the whole group lived alone in the community, and 56.8% were from a low- or middle-income category. Over the 18-month period of evaluation, total costs (including initial fracture-related and follow-up ones) were 23 926 €, 14 561 €, and 6 905 € for the hip, clinical vertebral, and distal forearm fracture, respectively. Over a year, costs related to a humeral fracture were 10 319 €. The RPA identified mobility impairment prior to fracture as a predictor of increase in costs related to fracture. Our study for the first time prospectively assessed total costs related to the four main osteoporotic fractures in France. It appears that their levels were much higher than previous estimates, raising the burden of osteoporosis-related fractures on public health expenditures.

Une augmentation de la production d’interleukine-6 (IL-6) par les cellules souches mutées a été observée dans le tissu dysplasique des patients atteints de dysplasie fibreuse des os (DF). Elle participe à l’augmentation de la résorption osseuse et pourrait jouer un rôle dans la douleur osseuse caractéristique de la maladie. Nous avons donc testé la valeur de l’inhibition de l’action de l’IL-6 dans une étude pilote pour déterminer si cela réduirait la résorption et la douleur osseuses. L’essai TOCIDYS était un essai randomisé, contrôlé contre placebo, sur une durée d’un an, en plan croisé, conduit chez des patients qui ne répondaient pas aux bisphosphonates. Les patients recevaient une perfusion intra-veineuse mensuelle de tocilizumab à la dose de 8 mg/kg ou un placebo identique pendant 6 mois. Pendant les 6 mois suivants, ils recevaient le tocilizumab s’ils avaient eu le placebo initialement, et vice-versa. Le critère de jugement principal était la variation de CTX sérique après 6 mois de traitement, par rapport à l’inclusion. Les autres critères de jugement étaient la variation de douleur osseuse au site le plus douloureux, la variation de P1NP, de phosphatase alcaline osseuse, d’ostéocalcine et d’ICTP, ainsi que la modification de qualité de vie. L’analyse statistique a reposé sur une analyse de variance incluant la séquence, la période et le traitement, et en tenant compte de l’effet carry-over potentiel. Nous avons randomisé 8 patients avec une DF dans chaque séquence (14 femmes, 2 hommes, d’âge moyen 50,5 ± 1,2 ans), dont 5 avec le syndrome de McCune-Albright, qui ont tous terminé la période des 6 premiers mois de traitement. Pendant la deuxième période, un patient dans le groupe placebo a retiré son consentement, alors que dans le groupe tocilizumab un patient a arrêté l’étude à cause d’événements indésirables et un a retiré son consentement. L’analyse d’efficacité porte donc sur 13 patients. L’effet carry-over n’étant pas statistiquement significatif, les deux périodes ont pu être analysées. Le niveau de douleur médian à l’inclusion était de 6/10 (5 ;6). Nous n’avons pas observé de variation significative du CTX et des autres marqueurs biochimiques osseux entre les deux groupes. De même, il n’y a pas eu de réduction significative de la douleur sous tocilizumab, même si 3 patients ont eu une baisse franche de douleur sous traitement actif, avec une rechute progressive sous placebo pour deux d’entre eux. Les divers domaines de l’échelle SF-36 de qualité de vie n’ont pas varié significativement dans le temps et selon les groupes. Cet essai clinique a été lancé avant qu’un modèle animal de la DF n’existe. Cette étude a été conduite dans un groupe particulier de malades atteints de DF qui avaient reçu des doses substantielles de bisphosphonates auparavant. Le tocilizumab n’a pas réduit le remodelage osseux dans la DF. Le tocilizumab n’a pas réduit la douleur osseuse chez la plupart des patients, même si un effet ne peut être exclu chez certains individus, dans cet essai ayant suffisamment de puissance pour les marqueurs osseux mais pas pour la douleur.

AbstractBackgroundEarly‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprotein receptor‐related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility.Method and ResultsWe used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1‐L4 BMD Z‐score −2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single‐variant LRP5 carriers, double‐variant carriers had a significantly lower BMD Z‐score (−4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait.ConclusionSevere forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two‐variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next‐generation sequence analyses of bone fragility.