High rate of progression to symptomatic multiple myeloma in patients with smoldering myeloma and isolated osteoporotic vertebral fracture.

Multiple myeloma (MM) frequently causes vertebral fractures (VF). Some are lytic lesions and others have the aspect of benign osteoporotic fractures not requiring anti-myeloma treatment. We explored outcome of these patients with smoldering myeloma (SM) and osteoporotic VF. In this retrospective bi-centric study, patients were identified using a systematic keyword search on electronic medical records. Patients with SM and isolated VF of osteoporotic aspect without indications for myeloma-specific therapy were included. Overall, 13 (7 %) of the 184 identified patients had SM and VF confirmed to be osteoporotic (median number of VF was 3). During follow-up, 12 (92 %) patients evolved to symptomatic MM, 7 (54 %) of them within 18 months (early progressors). Myeloma defining events were new lytic bone lesions in 7 patients (53.8 %). The serum calcium level was significantly higher in the early progressor group (median 2.35 IQR [2.31-2.38] and 2.28 IQR [2.21-2.29] respectively, p = 0.003). Early progressors had a higher number of VF at diagnosis (3.0 [2.0-5.5] vs 1.0 [1.0-2.5], p = 0.18) and more frequently evolved to symptomatic MM because of lytic bone lesions (5 [71 %] vs 2 [33 %], p = 0.13) compared to late progressors. VF of osteoporotic appearance in the context of SM is a rare situation but at high risk of rapid progression to symptomatic MM, suggesting that they may represent bone fragility linked to MM infiltration rather than solely osteoporotic fractures. Further studies are needed to assess if earlier treatment might be beneficial in this population.

Do subjective components of disease activity contribute to heterogeneity in opioid prescriptions in inflammatory rheumatic diseases? Results from ESPOIR and DESIR cohorts.

OBJECTIVES: To determine whether subjective components of disease activity are associated with heterogeneity in opioid prescription in inflammatory rheumatic diseases (IRDs) after accounting for objective inflammatory markers. METHODS: Data from two prospective observational cohorts of early IRDs (ESPOIR for rheumatoid arthritis (RA) and DESIR for spondyloarthritis (SpA)) were included. Opioid prescription duration (converted to monthly binary opioid prescription), disease activity (Disease activity score 28 (DAS28) for RA; Axial spondyloarthritis disease activity score-C-reactive protein (ASDAS-CRP) for SpA) and its components were measured respectively at 13 and 9 occasions spanning 10- and 6-years of follow-up. Group-based trajectory modelling defined opioid-prescription trajectories and mixed-models characterised the evolution of disease activity and its subjective components by opioid-prescription trajectories. RESULTS: Four distinct opioid-prescription trajectories: no/low (60.5% and 54.3%), declining (14.7% and 15.8%), augmenting (11.9% and 10.7%), and persistent (12.9% and 19.1%) were identified in RA and SpA respectively (60% were prescribed opioids at least once). Those with regular opioid prescriptions (up to 30%) are often older, less educated, have higher BMI and worse disease. No/low trajectory was the reference for examining evolution of disease activity and subjective components (n=810 RA, n=679 SpA). In IRDs, consistently higher disease activity throughout follow-up were seen with persistent (DAS28(ß=0.4-0.8); ASDAS-CRP(ß=0.4-0.6)), and augmenting (DAS28(ß=0.2-0.5); ASDAS-CRP(ß=0.3-0.6)) trajectories and until 3- or 4-years of follow-up (DAS28(ß=0.3-0.4); ASDAS-CRP(ß=0.2-0.3)) with declining trajectory. Likewise, despite accounting for objective inflammation, subjective components had worse scores over follow-up in augmenting and persistent trajectory. CONCLUSIONS: Non-inflammatory pain mechanisms amplify subjective outcomes, thus, worsening composite measures like disease activity.

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.

Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults.

BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.

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 .

Efficacy and management of tocilizumab in polymyalgia rheumatica: results of a multicenter retrospective observational study.

OBJECTIVES: The efficacy of anti-IL6 receptors such as Tocilizumab (TCZ) was demonstrated in patients with Polymyalgia Rheumatica (PMR) in two recent randomized controlled trials. The objective of this multicentre retrospective study was to assess the efficacy of TCZ in PMR patients requiring GC-sparing treatment, as well as different strategies for TCZ withdrawal. METHODS: We conducted a multicentre study in French tertiary health care departments for patients with PMR. PMR patients receiving off-label TCZ between 2015 and 2022 were included. The primary end point was the proportion of patients tapering to glucocorticoids (GCs) ≤5mg/day 6 months after the first TCZ infusion. The secondary endpoints were the proportion in whom GC was discontinued during follow-up, and the proportion of patients in whom TCZ was discontinued. RESULTS: Fifty-three PMR patients were included. Thirty-one (31) patients suffered from active PMR despite csDMARDs. GCs were ≤5mg/day in 77% of the patients (95% confidence interval [CI95%]: 36-89) at 6 months, and in 97% of the patients at 12 months. Six and 12 months after the first TCZ infusion, the proportions of GC-free patients were 22.5% (CI95%: 12.7-37.8) and 58.3% (CI95%: 43.2-74.1), respectively. Among TCZ withdrawal strategies, TCZ infusion spacing and TCZ dose reduction were more successful (success in 87% and 79% of attempts, respectively) than TCZ discontinuation (success in 52% of attempts; p= 0.012 and p= 0.039, respectively). CONCLUSION: In GC-dependent PMR patients, treatment with TCZ led to a drastic decrease in GC dose and remission of PMR. TCZ dose reduction or TCZ infusion spacing are good options to consider in TCZ withdrawal.

Development of Spinal Enthesopathies in Adults With X-linked Hypophosphatemia.

CONTEXT: Musculoskeletal complications are the main manifestations in adults with X-linked hypophosphatemia (XLH). Enthesopathy significantly impairs quality of life. OBJECTIVE: To identify the risk factors associated with the development and progression of spinal enthesopathies in adults with XLH. DESIGN AND SETTING: We conducted a retrospective study in the French Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism. PATIENTS: Adults XLH patients with 2 EOS® imaging performed at least 2 years apart at the same center between June 2011 and March 2022. The progression of enthesopathies was defined as a new enthesopathy at least 1 intervertebral level in patients with or without presence of enthesopathy at baseline. MAIN OUTCOME MEASURES: Demographic, treatment, PHEX mutation with the progression of enthesopathies. RESULTS: Fifty-one patients (66.7% of women, mean age 42.1 ± 13.4 years) underwent 2 EOS imaging with an average interval of 5.7 (± 2.31) years.Progression of spinal enthesopathies was observed in 27 (52.9%) patients. In univariate analysis, patients with a progression of spinal enthesopathies were significantly older (P < .0005), were significantly older at treatment initiation (P = .02), presented with dental complications (P = .03), received less frequently treatment during childhood with phosphate and/or vitamin D analogs (P = .06), and presented more frequently with hip osteoarthritis (P = .002) at baseline. In multivariate analysis, none of these factors was associated with a progression of spinal enthesopathies. CONCLUSION: This study confirms the high proportion of patients with a progression of spinal enthesopathies. Age seems to be the main factor associated with progression.

The Association between Oxytocin and Lower Limb Osteoarthritis: A Prospective Cohort Study.

Oxytocin (OT), a neuropeptide best known for its role in emotional and social behaviors, has been linked to osteoarthritis (OA). This study aimed to investigate the serum OT level in hip and/or knee OA patients and to study its association with disease progression. Patients from the KHOALA cohort with symptomatic hip and/or knee OA (Kellgren and Lawrence (KL) scores of 2 and 3) and follow-up at 5 years were included in this analysis. The primary endpoint was structural radiological progression, which was defined as an increase of at least one KL point at 5 years. Logistic regression models were used to estimate the associations between OT levels and KL progression while controlling for gender, age, BMI, diabetes and leptin levels. Data from 174 hip OA patients and 332 knee OA patients were analyzed independently. No differences in OT levels were found between the 'progressors' and 'non-progressors' groups among the hip OA patients and knee OA patients, respectively. No statistically significant associations were found between the OT levels at baseline and KL progression at 5 years, the KL score at baseline or the clinical outcomes. Higher structural damage at baseline and severe structural progression of hip and knee osteoarthritis did not appear to be associated with a low serum OT level at baseline.

Effectiveness of Geniculate Artery Embolization for Chronic Pain after Total Knee Replacement-A Pilot Study.

PURPOSE: To evaluate the efficacy and safety of embolization of hyperemic synovial tissue for the treatment of persistent pain after total knee arthroplasty (TKA). MATERIALS AND METHODS: Twelve patients with persistent pain after TKA were enrolled in this prospective, single-center pilot study. Genicular artery embolization (GAE) was performed using 75-µm spherical particles. The patients were assessed using a 100-point Visual Analog Scale (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline and 3 and 6 months thereafter. Adverse events were recorded at all time points. RESULTS: A mean of 1.8 ± 0.8 abnormal hyperemic genicular arteries were identified and embolized, with a median volume of diluted embolic material of 4.3 mL in all 12 (100%) patients. The mean VAS score on walking improved from 73 ± 16 at baseline to 38 ± 35 at the 6-month follow-up (P < .05). The mean KOOS pain score improved from 43.6 ± 15.5 at baseline to 64.6 ± 27.1 at the 6-month follow-up (P < .05). At the 6-month follow-up, 55% and 73% of the patients attained a minimal clinically important change in pain and quality of life, respectively. Self-limited skin discoloration occurred in 5 (42%) patients. The VAS score increased by more than 20 immediately after embolization in 4 (30%) patients, who required analgesic treatment for 1 week. CONCLUSION: GAE is a safe method of treating persistent pain after TKA that demonstrates potential efficacy at 12 months.

Zoledronate and osteonecrosis of the jaw in osteoporosis: incidence and risk factors. Analysis of the French Pharmacovigilance Database.

INTRODUCTION: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) have been characterized with the use of oral bisphosphonates in osteoporosis and zoledronate in oncology. Uncertainties remain, though, with the occurrence of BRONJ related to the use of zoledronate in osteoporosis. OBJECTIVES: We aimed to estimate the incidence and characterize the risk factors of zoledronate-associated BRONJ in osteoporosis as compared with oral bisphosphonates in real life setting. METHODS: Cases of BRONJ associated with zoledronate, alendronate or risedronate were extracted from the French pharmacovigilance database up to 2020. The incidence of BRONJ was estimated as their respective numbers related to cases of BRONJ in patients treated with bisphosphonates for osteoporosis, over the same period, according to the Medic'AM database. RESULTS: Between 2011 and 2020, BRONJ incidence with zoledronate was 9.6/100,000 patient-year (PY), significantly higher than with alendronate (5.1/100,000 PY, P<0.001), and risedronate (2.0/100,000 PY, P<0.001). The number of patients treated with bisphosphonates has steadily decreased by 44.5% over 10 years. Meanwhile, the incidence of BRONJ decreased (5.8/100,000 PY in 2011; 1.5/100,000 in 2020), although a rebound was observed in 2018, including 47.6% of BRONJ following denosumab. Apart from classical risk factors, recent dental cares stood out in more than 40% of BRONJ, and zoledronate had a shorter exposure time than oral bisphosphonates. CONCLUSIONS: In a real-life setting, our data confirm that zoledronate-associated BRONJ in osteoporosis is scarce, seeming slightly more common compared with oral bisphosphonates. We also raise awareness of dental care guidelines and greater vigilance when using bisphosphonates in patients with previous exposure to denosumab.

Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.

OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; ß=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391.

Impact of anterior cruciate ligament surgery on the development of knee osteoarthritis: A systematic literature review and meta-analysis comparing non-surgical and surgical treatments.

Introduction: Context: The development of knee osteoarthritis (OA) after anterior cruciate ligament (ACL) injury is now widely recognized. The impact of surgical or non-surgical management on the development of post-traumatic osteoarthritis is still debated in the medical community.Here, we present a meta-analysis comparing the impact of surgical or non-surgical management of ACL injuries on the development of knee OA. Method: A systematic literature review was conducted using data from the PubMed, EMBASE, Medline, and Cochrane libraries from February to May 2019. Only randomized clinical trials published between 2005 and 2019 with a non-surgical group and a surgical group were included to explore the onset or progression of knee OA after ACL injury. Trials had to have at least one radiographic endpoint (Kellgren-Lawrence scoring system). Heterogeneity was assessed using the Cochrane's Q and I2 statistical methods. Results: Only three randomized controlled trials met the inclusion criteria and were selected for meta-analysis. Of the 343 injured knees included in the studies, 180 underwent ACL reconstruction and 163 underwent non-surgical treatment. The relative risk of knee osteoarthritis was higher after surgery than after non-surgical treatment (RR 1.72, CI 95% [1.18-2.53], I2 â€‹= â€‹0%). Conclusion: The results of this meta-analysis suggest a predisposition to knee osteoarthritis after ACL reconstruction surgery compared with non-surgical management. Due to the small number of good quality studies available, further well-conducted randomised studies are needed to confirm these findings.

FCH-PET/CT in Primary Hyperparathyroidism With Discordant/Negative MIBI Scintigraphy and Ultrasonography.

CONTEXT: The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains unknown. OBJECTIVE: To evaluate the sensitivity and specificity of FCH-PET/CT in a cohort of osteoporotic patients with nPHPT and discordant or negative [99mTc]Tc-sestamibi scintigraphy and ultrasonography who all underwent parathyroidectomy (PTX). DESIGN: Longitudinal retrospective cohort study in patients referred for osteoporosis with mild biological primary hyperparathyroidism. SETTING: Tertiary referral center with expertise in bone metabolism and surgical management of hyperparathyroidism. PATIENTS: Among 109 patients with PHPT analyzed, 3 groups were individualized according to total serum calcium (tCa) and ionized calcium (iCa): 32 patients with hypercalcemia (HtCa group), 39 patients with normal tCa and elevated iCa (NtCa group), and 38 patients with both normal tCa and iCa (NiCa). All patients had biochemical follow-up confirming or not the success of PTX. MAIN OUTCOME MEASURES: To evaluate the performance of FCH-PET/CT in terms of sensitivity and specificity, and to compare with first-line imaging procedures in the setting of nPHPT. RESULTS: The sensitivity of FCH-PET/CT was 67% in the hypercalcemic group, 48% in the NtCa group (P = .05 vs HtCa), and 33% in the NiCa group (P = .004 vs HtCa). Specificity ranged from 97% to 99%. FCH-PET/CT was positive in 64.3% of patients with negative conventional imaging, with biochemical resolution after PTX in 77.8% of patients. Triple negative imaging was observed in 20 patients, with PHPT resolution in 85% of these patients. CONCLUSION: This study highlights the contribution of FCH-PET/CT in a well-phenotyped cohort of normocalcemic patients with discordant or negative findings in [99mTc]Tc-sestamibi scintigraphy and ultrasonography. However, negative imaging in nPHPT does not rule out the possibility of surgical cure by an experienced surgeon.