Economic impact of work disability due to chronic low back pain from the patient perspective.

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.

Costs of patient management over 18 months following a hip, clinical vertebral, distal forearm, or proximal humerus fragility fracture in France-results from the ICUROS study.

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. INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical and MRI outcomes of subacromial impingement syndrome with conservative treatment: a 21-month prospective study.

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.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

Comparative study of psychometric properties of three assessment tools for degenerative rotator cuff disease.

OBJECTIVE:: To compare psychometric properties of Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, Shoulder Pain and Disability Index (SPADI) and Constant-Murley scale, in patients with degenerative rotator cuff disease (DRCD). DESIGN:: Longitudinal cohort. SETTING:: One French university hospital. METHODS:: The scales were applied twice at one-week interval before physiotherapy and once after physiotherapy two months later. The perceived improvement after treatment was self-assessed on a numerical scale (0-4). The test-retest reliability of the DASH, SPADI and Constant-Murley scales was assessed before treatment by the intraclass correlation coefficient (ICC). The responsiveness was assessed by the paired t-test ( P < 0.05) and standardized mean difference (SMD). The correlation between the percentage of variation in scale scores and the self-assessed improvement score after treatment was measured by the Spearman coefficient. RESULTS:: Fifty-three patients were included. Twenty-six only were available for reliability. The test-retest reliability was very good for the DASH (ICC = 0.97), SPADI (0.95) and Constant-Murley (0.92). The scale score was improved after treatment for each scale ( P < 0.05). The SMD was moderate for the DASH (0.56) and SPADI (0.56) scales, and small for the Constant-Murley (0.44). The correlation between the percentage of variation in scores and self-assessed improvement score after treatment was high, moderate and not significant for the SPADI (0.59, P < 0.0001), DASH (0.42, P < 0.01) and Constant-Murley scales, respectively. CONCLUSION:: The test-retest reliability of the DASH, SPADI and Constant-Murley scales is very good for patients with DRCD. The highest responsiveness was achieved with the SPADI.

Diagnostic performance and impact on patient management of 68Ga-DOTA-TOC PET/CT for detecting osteomalacia-associated tumours.

PURPOSE: Oncogenic osteomalacia is an endocrine disorder induced by small benign tumours (TIO) producing excessive fibroblast growth factor-23 (FGF23). The only way of curing oncogenic osteomalacia is surgical resection of the culprit TIO, which is extremely difficult to detect using conventional imaging modalities due to its small size and variable location in the body. Since TIO frequently overexpress somatostatin receptors, a clinical utility of SPECT or PET with radiolabelled somatostatin analogues has been reported. Among them, 68Ga-DOTA-TOC has recently been granted a marketing authorization, facilitating its routine application. We report here the results of the first series evaluating the diagnostic performance of 68Ga-DOTA-TOC PET/CT in detecting TIO and its impact on patient management. METHODS: 68Ga-DOTA-TOC PET/CT and clinical and imaging data from 15 patients with clinical and biochemical signs of oncogenic osteomalacia were retrospectively reviewed. The 68Ga-DOTA-TOC PET/CT findings were compared with the results of post-surgical pathology and clinical and biochemical follow-up. RESULTS: 68Ga-DOTA-TOC PET/CT resulted in the detection of one focus suspicious for TIO in nine of 15 patients (60%), and a tumour was surgically removed in eight. Post-operative pathology confirmed a TIO in those eight patients whose symptoms diminished promptly and biochemical anomalies resolved. 68Ga-DOTA-TOC PET/CT sensitivity, specificity and accuracy were 73%, 67% and 71%, respectively. 68Ga-DOTA-TOC PET/CT findings affected patient management in 67% of cases. In particular, 68Ga-DOTA-TOC PET/CT was able to detect the TIO with a negative or a false-positive result of a previous 111In-pentetreotide SPECT/CT in 5/8 patients (63%) or a previous FDG PET/CT in 7/11 patients (64%). No close relationship was found between the positivity of 68Ga-DOTA-TOC PET/CT and the serum level of a biochemical marker. However, a true-positive result of 68Ga-DOTA-TOC PET/CT was obtained in only one patient with a non-elevated serum level of FGF23. CONCLUSION: 68Ga-DOTA-TOC PET/CT is an accurate imaging modality in the detection of TIO; in particular, it is worthwhile after failure of somatostatin receptor SPECT(/CT) or FDG PET/CT.

An open-label, prospective, observational study of the efficacy of bisphosphonate therapy for painful osteoid osteoma.

OBJECTIVES: To assess the efficacy of bisphosphonate therapy on bone pain in patients with osteoid osteoma (OO) (main objective), and to describe bisphosphonate-induced changes in nidus mineralisation and regional bone-marrow oedema (BMO). METHODS: A prospective, observational study was conducted from 2011 to 2014. Patients with risk factors for complications of percutaneous or surgical ablation or recurrence after ablation, were offered once monthly intravenous bisphosphonate treatment until significant pain alleviation was achieved. RESULTS: We included 23 patients. The first two patients received pamidronate and the next 21 zoledronic acid (mean, 2.95 infusions per patient). Bisphosphonate therapy was successful in 19 patients (83%), whose mean pain visual analogue scale score decreased by 76.7%; this pain-relieving effect persisted in 17 patients (74%) with a mean follow-up time of 36 months. Computed tomography (CT) demonstrated a mean nidus density increase of 177.7% (p = 0.001). By magnetic resonance imaging (MRI), mean decreases were 38.4% for BMO surface area and 30.3% for signal intensity (p = 0.001 and p = 0.000, respectively). CONCLUSIONS: In 17/23 patients with painful OO managed conservatively with bisphosphonates, long-term final success was achieved. Bisphosphonates may accelerate the spontaneous healing of OO. KEY POINTS: • 19/23 patients with OO managed with bisphosphonates experienced significant pain relief • Pain relief was sustained in 17/23 patients, mean follow-up of 36 months • CT demonstrated a significant increase in nidus mineralisation • MRI demonstrated a significant decrease in bone marrow oedema • Bisphosphonate therapy may accelerate the spontaneous healing of OO.

Detection of SQSTM1/P392L post-zygotic mutations in Paget's disease of bone.

Paget's disease of bone (PDB) is transmitted, in one-third of cases, in an autosomal dominant mode of inheritance with incomplete penetrance. The SQSTM1/P392L germinal mutation is the most common mutation associated with PDB. Given the focal nature of PDB, one team of investigators showed that SQSTM1/P392L somatic mutations could occur in pagetic bone lesions in the absence of germinal mutations detectable in the peripheral blood. The objectives of this study were to develop a reliable method to detect SQSTM1/P392L post-zygotic mutations, by optimizing a polymerase chain reaction (PCR)-clamping method reported to be effective in detecting post-zygotic mutations in peripheral blood from patients with fibrous dysplasia; and to evaluate the frequency of this post-zygotic mutation in PDB patients. We used a locked nucleic acid (LNA) specifically designed for the SQSTM1/P392L mutation, which blocks the wild-type allele amplification during the PCR. DNA from 376 pagetic patients and 297 controls, all without any SQSTM1/P392L germinal mutation, was analyzed. We found that 4.8 % of PDB patients and 1.4 % of controls were carriers of this post-zygotic mutation [p = 0.013, OR 3.68 (1.23; 11.00)]. PDB patient carriers of a post-zygotic mutation had a lower number of affected bones and Renier's index than patients carrying a germinal mutation, suggesting a lower disease extension. We also demonstrated that this post-zygotic mutation was restricted to the monocytic lineage. These results confirmed that LNA PCR clamping is effective for the detection of SQSTM1/P392L post-zygotic mutations, which may occur in patients with PDB.

Effect of dynamic humeral centring (DHC) treatment on painful active elevation of the arm in subacromial impingement syndrome. Secondary analysis of data from an RCT.

BACKGROUND: The physiotherapy dynamic humeral centring (DHC) aims to prevent subacromial impingement of rotator cuff tendons during elevation of the arm. The objective of the study was to determine whether DHC acts via an effect on subacromial impingement mechanism by assessing its effect on painful elevation of the arm in subacromial impingement syndrome. METHODS: This is a secondary analysis of results of a randomised controlled trial of the effectiveness of DHC. Sixty-nine patients with subacromial impingement syndrome were prospectively included. Patients and the assessor were blinded to the study hypothesis and treatment, respectively. Patients underwent DHC or non-specific mobilisation as a control for 6 weeks in 15 supervised individual outpatient sessions with home exercises. Outcomes were pain-free range of motion and presence of painful arc of the shoulder, both in active flexion and abduction of the arm at 3 months. RESULTS: At 3 months, pain-free range of motion, both flexion and abduction, was greater in the DHC group than in the mobilisation group. The number of patients with painful arc during flexion was decreased in the DHC group. CONCLUSIONS: DHC improves painful active elevation of the arm. We suggest that DHC may act via a specific effect on subacromial impingement mechanism.

Arthro-distension with early and intensive mobilization for shoulder adhesive capsulitis: A randomized controlled trial.

BACKGROUND: There 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. OBJECTIVES: To 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. METHODS: This 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. RESULTS: There 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°. CONCLUSIONS: The 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 REGISTRATION: NCT00724113.

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations.

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.

Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

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 .

Inhibition of IL-6 in the treatment of fibrous dysplasia of bone: The randomized double-blind placebo-controlled TOCIDYS trial.

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.

Value of a clinical test of sub-acromial impingement to predict response to physiotherapy with dynamic humeral centering: A preliminary study.

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.

Assessment of dynamic humeral centering in shoulder pain with impingement syndrome: a randomised clinical trial.

OBJECTIVES: Treatment for degenerative rotator cuff disease of the shoulder includes physiotherapy. Dynamic humeral centering (DHC) aims at preventing subacromial impingement, which contributes to the disease. The goal of this study was to assess the effectiveness of DHC. METHOD: 69 patients with shoulder pain and impingement syndrome were prospectively included in a single-centre randomised trial with a 12-month follow-up. Patients and assessor were blinded to the study hypothesis and treatment, respectively. DHC and non-specific mobilisation as control were performed for 6 weeks, in 15 supervised individual outpatient sessions, and patients performed daily home exercises. The planned primary outcome was the Constant score including subscores for pain, activity, mobility and strength at 3 months. Secondary outcomes were the Constant score and subscores at 12 months, and medication use for pain at 3 and 12 months. RESULTS: The DHC group did not differ from the control group in the total Constant score at 3 months. However, the DHC group showed a higher Constant subscore for pain (12.2 (SD 2.8) vs 9.9 (2.9), least square means difference 2.1, 95% CI 0.7 to 3.5, p=0.004). At 3 months, the DHC group also showed a higher rate of no medication use (96.7% vs 71%, proportional difference 25.7, 95% CI 3.7 to 51.9, p=0.012). There was no other intergroup difference. CONCLUSIONS: There was no difference in the total Constant score between DHC and controls. However, pain was improved at 3 months after DHC. The differences found in subscores for pain should be explored in future studies. Trial registration clinicaltrials.gov Identifier: NCT 01022775.

More severe phenotype of early-onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A.

BACKGROUND: Early-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 RESULTS: We 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. CONCLUSION: Severe 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.

[Advances treatment of osteoporosis: new molecules, new strategies]. / Avancées thérapeutiques: nouvelles molécules, nouvelles stratégies.

Practitioners already have a wide range of effective drugs for the treatment of osteoporosis, but new options are needed to prevent fractures in patients with this chronic and disabling disease. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss, based on inhibition of bone resorption by osteoclasts (anti-RANK ligand antibodies and cathepsin K inhibitors) or stimulation of bone formation by osteoblasts (anti-sclerostin antibodies). These future treatments (anti-RANK ligand antibodies should shortly be available) will add osteoporosis to the growing list of disorders amenable to targeted biotherapies.

Lumbar spinal stenosis and disc alterations affect the upper lumbar spine in adults with achondroplasia.

In achondroplasia, lumbar spinal stenosis arises from congenital dysplasia and acquired degenerative changes. We here aimed to describe the changes of the lumbar spinal canal and intervertebral disc in adults. We included 18 adults (age ≥ 18 years) with achondroplasia and lumbar spinal stenosis. Radiographs were used to analyze spinal-pelvic angles. Antero-posterior diameter of the spinal canal and the grade of disc degeneration were measured by MRI. Antero-posterior diameters of the spinal canal differed by spinal level (P < 0.05), with lower values observed at T12-L1, L1-2 and L2-3. Degrees of disc degeneration differed by intervertebral level, with higher degrees observed at L1-2, L2-3 and L3-4. A significant correlation was found between disc degeneration and thoraco-lumbar kyphosis at L2-3, between antero-posterior diameter of the spinal canal and lumbar lordosis at T12-L1 and L2-3, and between antero-posterior diameter of the spinal canal and thoraco-lumbar kyphosis at L1-2. Unlike the general population, spinal stenosis and disc degeneration involve the upper part of the lumbar spine in adults with achondroplasia, associated with thoraco-lumbar kyphosis and loss of lumbar lordosis.