Dysregulation of MicroRNAs in Adult Osteogenesis Imperfecta: The miROI Study.

As epigenetic regulators of gene expression, circulating micro-RiboNucleic Acids (miRNAs) have been described in several bone diseases as potential prognostic markers. The aim of our study was to identify circulating miRNAs potentially associated with the severity of osteogenesis imperfecta (OI) in three steps. We have screened by RNA sequencing for the miRNAs that were differentially expressed in sera of a small group of OI patients versus controls and then conducted a validation phase by RT-qPCR analysis of sera of a larger patient population. In the first phase of miROI, we found 79 miRNAs that were significantly differentially expressed. We therefore selected 19 of them as the most relevant. In the second phase, we were able to validate the significant overexpression of 8 miRNAs in the larger OI group. Finally, we looked for a relationship between the level of variation of the validated miRNAs and the clinical characteristics of OI. We found a significant difference in the expression of two microRNAs in those patients with dentinogenesis imperfecta. After reviewing the literature, we found 6 of the 8 miRNAs already known to have a direct action on bone homeostasis. Furthermore, the use of a miRNA-gene interaction prediction model revealed a 100% probability of interaction between 2 of the 8 confirmed miRNAs and COL1A1 and/or COL1A2. This is the first study to establish the miRNA signature in OI, showing a significant modification of miRNA expression potentially involved in the regulation of genes involved in the physiopathology of OI. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A case of restitution ad integrum in Gorham-Stout disease.

Gorham-Stout disease (or "vanishing bone" disease) is a rare mono or polyostotic disease of unknown etiology, characterized by intraosseous angiomatous proliferation leading to bone resorption. We report the case of a 17-year-old woman presenting with symptomatic osteolytic lesions of the frontal vault. Imaging was suggestive of Gorham-Stout disease without argument for other diagnoses. An unusual evolution of the "vanishing bone" lesions was observed on the scan after one year, with a full recovery of the lytic lesions. This report shows for the first time a spontaneous restitutio ad integrum of bone matrix in Gorham-Stout disease.

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.

Heterozygous FGFR1 mutation may be responsible for an incomplete form of osteoglophonic dysplasia, characterized only by radiolucent bone lesions and teeth retentions.

Non-ossifying fibromas are seen in different disorders recognizable by specific features. Indeed, osteoglophonic dysplasia (OD) is characterized by radiolucent bone lesions associated with severe short stature, dysmorphism and failure of dental eruption. This syndrome is caused by heterozygous activating mutations in the immunoglobulin-like D3 domain of the FGFR1 gene, encoding a tyrosine kinase. Here, we report three patients from the same family presenting with radiolucent bone lesions and teeth retentions. Exome sequencing allowed identification of a novel mutation c.917C > T, p. Pro306Leu in exon 7 of the FGFR1 gene. Our patients present with normal stature and no severe dysmorphism. This report describes a mild form of OD and expands the phenotype related to FGFR1 mutations. These findings emphasize the need to consider FGFR1 variants in the case of multiple non-ossifying bone lesions associated with dental eruption anomalies.

Prognostic Factors From an Epidemiologic Evaluation of Fibrous Dysplasia of Bone in a Modern Cohort: The FRANCEDYS Study.

Fibrous dysplasia of bone (FD) is a rare genetic but sporadic bone disease that can be responsible for bone pain, fracture, and bone deformity. The prognosis may be difficult to establish because of the wide spectrum of disease severity. We have analyzed the data from the French National Reference center for FD. We have established a database from standardized medical records. We have made descriptive statistics of the various forms of FD and examined the prognostic factors by multivariable logistic regression analysis, with a parsimonious stepwise method. The primary outcome was a clinically relevant composite index combining bone pain (visual analogic scale >3) and/or incident fracture. In our modern cohort of 372 patients, the median age at diagnosis was 23 years. The revealing symptom (at a median age of 18 years) was bone pain in 44% of patients and a fracture in 9%, but the diagnosis was fortuitous in 25% of cases. Monostotic forms represented 58% of patients and polyostotic forms 42%. The femur was the most commonly affected bone (44% of patients), followed by the skull (38%). Twelve percent of patients had McCune-Albright syndrome (MAS). With a median duration of follow-up of 7 years among 211 patients, we observed an incidence of fracture of 17% and 51% of patients had no bone pain at the end of follow-up (with or without bisphosphonate therapy). In univariate analysis, younger age at diagnosis, renal phosphate wasting, a polyostotic form, prevalent fracture, and bisphosphonate use were significant predictors. In the multivariate model, the polyostotic form and bisphosphonate use remained significant predictors. In conclusion, in a national referral center for FD, one patient on follow-up out of six had incident fracture. A polyostotic form was the main risk factor of a poorer outcome. © 2016 American Society for Bone and Mineral Research.

Pathophysiology and medical treatment of pain in fibrous dysplasia of bone.

One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The mechanism of bone pain in FD remains uncertain, but by analogy with bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of pain is highly variable and adults reports more pain than children. Bisphosphonates have been shown to reduce bone pain in uncontrolled studies. Their influence on bone strength remains unknown. In a randomized trial testing alendronate, bone pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA.

Influence of blinding sequence of radiographs on the reproducibility and sensitivity to change of joint space width measurement in knee osteoarthritis.

OBJECTIVE: To investigate whether knowledge of the sequence of radiographs impacts inter- and intraobserver reproducibility and sensitivity to change for measuring joint space width (JSW) in patients with knee osteoarthritis (OA). METHODS: A cohort of 70 postmenopausal women with radiologic knee OA was assessed through the measurement of knee radiographs acquired in the semiflexed posteroanterior view, using a positioning frame and fluoroscopy, at baseline and 48 months later. Paired readings of radiographs were made using landmarks at baseline by 2 independent observers unblinded to sequence and blinded to sequence. Intra- and interobserver reproducibility was assessed on JSW measurements at baseline and 4 years later and on the longitudinal difference (joint space narrowing [JSN]), using intraclass correlation coefficient (ICC) and Bland and Altman methods. The sensitivity to change was assessed through standardized response means (SRMs). RESULTS: For JSW and JSN and with both methods, ICCs were high for the intra- and interobserver reproducibility (0.90-0.99 for JSW and 0.77-0.89 for JSN). For the Bland-Altman method, the mean difference was close to 0, with no bias for both observers and methods. The SRMs ranged from 0.38 to 0.48. All of the results were numerically in favor of measuring with knowledge of time sequence, but without a statistically significant difference between the methods. CONCLUSION: Intra- and interobserver reproducibility was high with or without blinding of the radiograph sequence. Reading with knowledge of time sequence using baseline landmarks tended to improve sensitivity. Therefore, in longitudinal studies of OA radiographs can be read unblinded to sequence.

Radiologic assessment of age-related knee joint space changes in women: a 4-year longitudinal study.

OBJECTIVE: To analyze a population-based cohort of women in order to establish normal values of joint space width (JSW) and to evaluate the existence of age-related joint space loss (JSL). METHODS: Knee radiographs were performed 4 years apart in women from the OFELY (Os des Femmes de Lyon) Cohort. Posteroanterior radiographs of both knees were taken in semiflexion with a standardized fluoroscopically assisted protocol. Radiographs were qualitatively evaluated using a scoring system based on the Altman score that assessed joint space narrowing, osteophytes, and sclerosis for each tibiofemoral compartment and each side. For quantitative assessment, radiographs were digitized using a video camera, and specific software was used to measure JSW in every compartment. RESULTS: We evaluated the radiographs of 606 women (ages 39-90 years, mean 62 years) and found that in all subjects, JSW significantly decreased with age in every compartment (r = -0.12 to -0.16, P < 0.001), including in 358 subjects without any radiographic abnormality related to osteoarthritis (OA) at baseline. The longitudinal analysis confirmed a significant loss over 4 years of approximately 0.30 mm (6%) for the medial compartment. Multiple regression analysis did not identify significant predictors of JSL among clinical risk factors and biochemical markers of bone and cartilage turnover. CONCLUSION: In this first longitudinal study of a population-based cohort of women, we have established normal values of JSW and shown that JSW decreases with aging, especially at the medial compartment, even in subjects without any radiographic abnormalities related to OA.