Background Few data are available on the incidence of osteoporosis (OP) in end-stage pulmonary diseases, particularly in lung transplant candidates. Yet, organ transplantation can be accompanied by low bone mineral density (BMD) owing to immunosuppressive therapy, particularly with oral glucocorticoids (GCs) use. Objectives Our primary aim was to evaluate the prevalence and therapeutic management of OP in lung transplant candidates. Our second objective was to determine the risk factors associated with OP, including the type of respiratory disorder. Methods We included 198 patients (103 women) out of 388 screened for lung transplantation at our institution between January 1998 and December 2020. BMD, measured by Dual-energy X-ray absorptiometry (DXA, Hologic (t-m)) at the lumbar spine (LS), total hip (TH), and femoral neck (FN), vertebral fracture assessment (VFA), as well as previous major osteoporotic fracture (MOF), were recorded. We systematically collected well-recognized OP risk factors, along with other factors suspected of affecting BMD such as inhaled (i) GCs use, pulmonary function tests, hypoxemia and type of pulmonary disorder. Results OP, as defined by BMD values (T-score ≤ -2.5) and/or fragility fracture (FF), MOF and/or vertebral fractures (VF), was observed in 118 patients (59.6%). Among these patients, 54 (45.8%) had only a T-score ≤ -2.5, while 36 (30.5%) had only an FF, with predominant vertebral fractures (77.8%). The median age (IQR) of the study population was 58 years (53.0-62.0), and 59 years in OP patients (54.2-62.0). Mean T-scores (±SD) were -1.62±1.52 at the LS, -1.43±1.05 at the TH and -1.98±1.14 at the FN. Mean T-scores (±SD) in OP patients were -2.15±1.31, -1.87±0.93 and -2.44±1.03, respectively. The mean (±SD) ten-year probability of major osteoporotic fracture assessed by the FRAX algorithms (FRAX score) was 11.6±11.2 %, and the mean FRAX adjusted to GCs dose (±SD) was 12.0±12.1 %. Nighty-eight patients (49.5%) achieved intervention threshold adjusted for age based on FRAX results and 110 patients (55.6%) when FRAX was adjusted to GCs dose. Seventy-eight OP patients (66.1%) achieved the FRAX intervention threshold, of whom 53 (67.9%) received calcium and/or vitamin D and 33 (42.3%) had received an add-on therapy, mostly a bisphosphonate (n=23, 69.7%) or denosumab (n=4, 12.1%). Eighty-four OP patients (71.2%) achieved the FRAX intervention threshold adjusted to GCs dose, of whom 59 (70.2%) received calcium and/or vitamin D and 37 (44.5%) had received an add-on therapy, mostly a bisphosphonate (n=25, 67.6%) or denosumab (n=5, 13.5%). Thirty-six OP patients (30.5%), 18 patients (33.3%) with only a T-score ≤ -2.5 and 12 patients with only an FF, did not receive any medication. In total, 153 patients had a chronic obstructive pulmonary disease (COPD, 77.3%), 33 an interstitial lung disease (ILD, 16.3%) and 12 (6.1%) suffered from another pulmonary disease. Among OP patients, 102 had a COPD (86.4%), 12 an ILD (10.2%) and 4 (3.4%) suffered from another pulmonary disease. Lower BMI, iGCs use, COPD, reduced FVC and severely impaired FEV1/FVC ratio were associated with OP. GCs treatment was associated with FF, regardless of the daily dosage. Conclusion Most of lung transplant candidates were suffering from OP and one third suffered from FF. Thus, performing DXA and VFA should be recommended in lung transplant candidates in order to start adequate osteoporosis treatment before lung transplantation. This is even more important in COPD patients, as this population displays an increased risk of OP compared to other end-stage diseases. OP diagnosis is important in those patients as their risk of fracture is likely to increase after transplantation. The large proportion of untreated (or insufficiently treated) patients stressed the need to develop specific strategies in this field. Finally, controlling some risk factors is crucial for the management and prevention of OP, for instance by, at least, tapering the dosage of both oral and inhaled GCs. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Edwin Curraj: None declared, François Carlier: None declared, Michel Dumonceaux: None declared, Patrick Evrard: None declared, Benoit Rondelet: None declared, Jean-Pierre Devogelaer: None declared, Yves Boutsen Speakers bureau: UCB, Grant/research support from: Viatris, Galapagos, Biogen, Amgen.

Background EULAR recommends methotrexate (MTX), combined with short-term glucocorticoids as first-line treatment for early Rheumatoid Arthritis (RA). In the CareRA trial, the COBRA-Slim regimen (MTX 15 mg/w + step-down prednisone 30, 20, 12.5, 10, 7.5, 5 mg/d), including a treat to target (T2T) approach starting with addition of leflunomide and only at a later stage bDMARDs, provided the best balance between efficacy, safety and cost-effectiveness. The potential advantage of temporary bDMARD use earlier in the T2T setting needs further investigation. Objectives To determine the long-term effectiveness of accelerated access to a temporary course of etanercept compared to addition of leflunomide in patients with early RA who insufficiently respond to initial COBRA-Slim induction therapy. Methods DMARD-naïve patients with a recent diagnosis of RA (≤1 year ago) were included in the 2-year, open-label, multicentre, pragmatic randomised controlled superiority trial Care in Early RA 2020 (CareRA2020). All patients started the COBRA-Slim induction regimen. Patients were classified as insufficient responders if, even despite MTX dose increase, they did not achieve DAS28-CRP ≤3.2 between week 8 and week 32 or if DAS28-CRP was ≥2.6 at week 32 regardless of MTX dose. Insufficient responders were randomised to either Standard COBRA-Slim (addition of leflunomide 10 mg/d) or COBRA-Slim Bio-induction (addition of etanercept 50 mg/w for 24 weeks). Additional treatment adaptations followed the T2T principle. Primary outcome was the difference in DAS28-CRP over time, determined via a linear mixed model including random intercepts and a random slope for time, adjusting for baseline DAS28-CRP and seropositivity. Missing data were imputed with the Expectation-Maximisation algorithm. Results In total, 276 patients were included, of which 155 (56%) were classified as sufficient and 121 (44%) as insufficient responders. Of the insufficient responders, 9 patients were not randomised by investigator decision, 2 were randomisation errors, 55 were randomised to Standard COBRA-Slim, and 55 to COBRA-Slim Bio-Induction. The mean ± SD area under the DAS28-CRP curve over 104 weeks was 232 ± 66 for the initial sufficient responders, 310 ± 82 for the Standard COBRA-Slim group, and 316 ± 73 for the COBRA-Slim Bio-induction group. Both randomisation groups had comparable DAS28-CRP scores over time (ß = -0.095, 95% CI (-0.299 to 0.108), p=0.351). At the end of the trial, 82% (127/155), 9% (5/55), and 36% (20/55) of patients were on csDMARD monotherapy in the initial sufficient responders, Standard COBRA-Slim, and COBRA-slim Bio-induction group, respectively. Moreover, 6% (9/155) sufficient responders, 58% (32/55) in the Standard COBRA-Slim, and 45% (25/55) in the COBRA-Slim Bio-induction group were treated with a b- or tsDMARD. Conclusion More than half of the CareRA2020 participants achieved remission with COBRA-Slim induction therapy. DAS28-CRP over 104 weeks was not superior with COBRA-Slim Bio-induction versus the Standard COBRA-Slim T2T regimen in initial insufficient responders. However, compared to the Standard COBRA-Slim group, more patients in the Bio-induction group were treated with csDMARD monotherapy and less with advanced therapies at the end of the study. Acknowledgements The CareRA2020 trial was funded by the Belgian Health Care Knowledge Centre (KCE) Trials Program, a national public funding program of non-commercial trials. Disclosure of Interests None Declared.

Background Blocking TNF alpha (TNFα) with monoclonal antibodies (mAbs) has been successful in the treatment of rheumatoid arthritis. However primary and secondary resistances are frequent and impose treatment changes. Active immunization with a TNF-Kinoid that safely induces self polyclonal anti-TNFα antibodies (Abs) could be an alternative to anti-TNFα mAbs Objectives We evaluated the immunogenicity and safety of TNF-K in patients with rheumatoid arthritis and secondary resistance to TNF blockers. Methods TNFα-Kinoid (TNF-K, Neovacs SA, Paris, France) is an immunotherapeutic composed of recombinant human TNFα conjugated to KLH, inactivated and adjuvanted with ISA-51 emulsion. 40 patients with active rheumatoid arthritis (DAS28≥3.2) with history of positive clinical response to TNF-blockers followed by secondary failure (35% IFX,30% ADA, 42.5% ETA) were enrolled in a double-blind, placebo-controlled, phase 2 study to evaluate three different intramuscular doses of TNF-K (90, 180, 360 mcg) and two immunization schedules (D0 and 28 or D0, 7 and 28). Immune responses were evaluated through titration of anti-TNFα and anti-KLH Abs. Clinical response was evaluated by the ACR and EULAR core set response. Results No related serious adverse event has been reported. Few minor transient local and systemic reactions have been recorded following immunization. Anti-TNFα Abs were induced in 50%, 75% and 91% of patients at 90 mcg, 180 mcg and 360 mcg, respectively. 100% of patients with three injections of 180 or 360 mcg had immunogenic response against 67% in two injections groups. Among the 21 patients who developed anti-TNF Abs, 48% present a moderate to good response according to EULAR score as opposed to only 31% of the 16 patients without Abs. A mean decrease of -14% of the C reactive protein level is measured in patients with Abs while in patients without Abs, the mean CRP level increased by 5%The mean decrease of the DAS28 score is -0.8 points in patients with Abs while it is only -0.5 in patients without Abs. Conclusions Active immunization with TNFα kinoid to induce a polyclonal, self-anti-TNFα antibody response is safe and immunogenic. A clinical and biological response were observed in some patients included in this preliminary phase 2 study and further studies are needed to confirm this new approach in RA. Disclosure of Interest P. Durez: None Declared, P. Miranda: None Declared, A. Toncheva: None Declared, A. Berman: None Declared, O. L. Rillo: None Declared, Y. Boutsen: None Declared, T. Kehler: None Declared, E. Mociran: None Declared, L. Soto Saez: None Declared, B. Fautrel: None Declared, X. Mariette: None Declared, P. Sokalov: None Declared, E. Lucero: None Declared, T. Vlak: None Declared, S. Grazio: None Declared, K. Mastrovic: None Declared, R. Chirieac: None Declared, G. Grouard-Vogel Employee of: Neovacs, O. Dhellin Employee of: Neovacs, S. Ouary Employee of: Neovacs, B. Fanget Employee of: Neovacs, P. Vandepapelière Employee of: Neovacs, M.-C. Boissier Consultant for: Neovacs

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies.

Mechanical loading is a major regulator of bone mass and geometry. The osteocytes network is considered the main sensor of loads, through the shear stress generated by strain induced fluid flow in the lacuno-canalicular system. Intracellular transduction implies several kinases and phosphorylation of the estrogen receptor. Several extra-cellular mediators, among which NO and prostaglandins are transducing the signal to the effector cells. Disuse results in osteocytes apoptosis and rapid imbalanced bone resorption, leading to severe osteoporosis. Exercising during growth increases peak bone mass, and could be beneficial with regards to osteoporosis later in life, but the gain could be lost if training is abandoned. Exercise programs in adults and seniors have barely significant effects on bone mass and geometry at least at short term. There are few data on a possible additive effect of exercise and drugs in osteoporosis treatment, but disuse could decrease drugs action. Exercise programs proposed for bone health are tedious and compliance is usually low. The most practical advice for patients is to walk a minimum of 30 to 60 minutes per day. Other exercises like swimming or cycling have less effect on bone, but could reduce fracture risk indirectly by maintaining muscle mass and force.

Paget’s disease of bone (PDB) is a potentially crippling condition. Pain, fracture, spinal stenosis, nerve entrapment, vascular steal syndrome, secondary osteoarthritis, bone deformity, dental problems, deafness, excessive bleeding during orthopaedic surgery, rare sarcomatous degeneration, and hypercalcaemia constitute complications that may impair the quality of life. The therapeutic approach varies from symptomatic (analgesics, anti-inflammatory drugs) to more specific drugs such as increasingly potent bisphosphonates. Studies such as the PRISM study should in the future help to determine the superiority or not of aggressive treatment over symptomatic treatment in the prevention of complications. Various oral and/or intravenous (I.V.) bisphosphonates have been tested and are currently on the market. The most recently available nitrogen-containing bisphosphonate, I.V. zoledronic acid, is the most potent therapy available for the treatment of PDB. Its therapeutic efficacy, its long-term effect on biologic activity and its good tolerance currently supports its use as a first-line therapeutic option in patients suffering from PDB.

Cancer treatment-induced bone loss (CTIBL) is one of the most important side effects of adjuvant antineoplastic treatment in hormone-dependent neoplasms. Chemotherapy, GnRH analogs and tamoxifen can induce marked bone loss in premenopausal women with early breast cancer. Aromatase inhibitors (AIs) are replacing tamoxifen as the preferred treatment for postmenopausal women. As a class effect, steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs increase bone turnover and cause bone loss (4%-5% over 2 years). When compared to tamoxifen, the risk of getting a clinical fracture under AI treatment is increased by 35%-50%. In patients with prostate cancer, androgen deprivation therapy (ADT) increases bone turnover, reduces bone mass (4%-5% per year) and increases the fracture rate depending on the duration of therapy. Zoledronic acid can prevent accelerated bone loss induced by goserelin in premenopausal women, by letrozole in postmenopausal women and by ADT in men. More limited data indicate that weekly alendronate or risedronate could also be effective for preventing CTIBL. Initiation of therapy early, prior to the occurrence of severe osteoporosis, rather than after, may be more effective. Bisphosphonate treatment should be considered in osteoporotic but also in osteopenic patients if other risk factor(s) for fractures are present.

Dual energy X-ray absorptiometry (DXA) measurements from different manufacturers provide different bone mineral density (BMD) values and derived T-scores and Z-scores. These differences result partly from technical differences in the algorithms for the determination of bone mineral content and bone area and partly from the use of different manufacturer-derived reference databases. The present study was to implement a uniform expression of BMD in all male patients by using standardized BMD (sBMD) values and referring to a newly established national male reference sample. In 8 bone densitometry centers throughout Belgium 229 young healthy men were measured on Hologic (Bedford, MA) or GE-Lunar (Madison, WI) bone densitometers. Quality control procedures were implemented and site cross-calibration performed using the European Spine Phantom. Absolute BMD values were converted to standardized values by validated formulas (sBMD). Clinically acceptable between-center differences were noted. No discrepancy was observed in terms of mean sBMD and standard deviations at the lumbar spine and proximal femur between the Belgian and the US reference populations. Region-specific sBMD thresholds for the diagnosis of male osteoporosis were calculated. The current data provide a basis to implement a nation-wide, uniform expression of BMD in male patients and allow harmonization of the BMD-based diagnosis and treatment of osteoporosis in men.

Camurati-Engelmann disease (CED, MIM # 131300) was diagnosed in a 27-year-old woman, who had pain in her lower legs. There was no history of hearing loss (or CED) in her family. She had been suffering from progressive hearing impairment since childhood. Serial audiograms demonstrated progressive mixed hearing loss from the age of 11 years onwards, for which she underwent successful stapes surgery bilaterally at the age of 13–18 years. Clinical (‘juvenile’) otosclerosis was found with stapes footplate fixation. Unfortunately, the sensorineural hearing loss component proved to be progressive bilaterally after surgery. At the age of 30 years, she experienced more rapid deterioration of her hearing loss in the right ear and episodes of vertigo. Vestibular examinations demonstrated progressive vestibular impairment, ‘otospongiotic’ lesions with encroachment on the cochlear and vestibular labyrinth were found on high resolution CT scans at the age of 40 years; the internal auditory canal was normal bilaterally. CED may have formed a chance combination with juvenile otosclerosis in our patient, or otosclerosis may be part of the CED phenotype.