Osteogenesis imperfecta is a common genetic disorder of syndromic bone fragility manifesting in types with variable skeletal and extraskeletal severity. Over the past decades, the deforming types have almost exclusively received all scientific attention, leaving large knowledge gaps about the prevalent osteogenesis imperfecta type 1. However, studies within the past 5 years reveal serious unrecognized aspects of disease burden in this large patient population that contrast with osteogenesis imperfecta type 1's widely adopted classification as mild osteogenesis imperfecta. These patients present distinct clinical and molecular features, necessitating personalized clinical approaches and dedicated research. To our knowledge, this Review addresses this distinct patient group by recognizing the diverse facets of clinical burden, genetic landscape, bone pathophysiology, disease models and emerging treatment options. Owing to their later diagnosis, disease invisibility, increased mobility and uncharted clinical course compared with patients who have other types of osteogenesis imperfecta, these patients and their treating physicians face distinct healthcare and diagnostic challenges. In contrast to other patients with osteogenesis imperfecta with broader genetic causes, they are primarily characterized by molecular uniformity in the form of collagen type I deficiency. The scarcity of animal and cell models has also contributed to the lack of initiatives to explore osteogenesis imperfecta type 1. This Review aims to break this vicious cycle of osteogenesis imperfecta type 1 obscurity by defining knowledge gaps that future investigations of this disease should aim to address.

Rare bone and mineral conditions (RBMCs) are diverse disorders involving skeletal fragility, altered bone metabolism, and multisystemic complications. Improved pediatric care has increased survival, creating a growing population of adolescents and young adults requiring specialized support. Yet, transition from pediatric to adult services remains fragmented and underdeveloped across RBMCs. This review aimed to map existing literature on transition care for young people with RBMCs and to identify priorities, barriers, and gaps to guide future research and practice. Within the ERN BOND framework, a scoping review was conducted following PRISMA-ScR guidelines. MEDLINE, EMBASE, and SCOPUS were searched (July–August 2025) for studies addressing transition from pediatric to adult care in RBMCs. All study designs were eligible. Screening and data extraction were performed by multiple reviewers using Covidence, and findings were summarized descriptively. Of 1706 records identified, 34 met inclusion criteria. Most studies originated from Europe and North America and focused on osteogenesis imperfecta or X-linked hypophosphatemia. Expert opinion and consensus papers dominated the evidence base, while empirical research remained limited. Across RBMCs, transition processes were consistently described as suboptimal, with poor coordination, limited adult multidisciplinary expertise, unclear pathways, and inadequate patient preparation. Patients, parents, and healthcare professionals highlighted priorities such as continuity of care, structured planning, patient empowerment, psychosocial support, and improved communication between pediatric and adult teams. Barriers included scarcity of adult specialists, organizational fragmentation, and insufficient training. Recommendations emphasized early planning, readiness assessment, multidisciplinary collaboration, and support for self-management. Evidence on transition care in RBMCs is sparse, largely expert-driven, and concentrated in a few conditions. Nonetheless, consistent themes underscore the need for structured, coordinated, and patient-centered transition pathways. Strengthening adult expertise, ensuring continuity of care, and enhancing psychosocial support are essential to improve outcomes. Further longitudinal and implementation research is urgently needed to inform evidence-based transitional care models for RBMCs.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility due to reduced bone quality, often accompanied by low bone mass, recurrent fractures, hearing loss, skeletal abnormalities, and short stature. Pathogenic variants in over 20 genes lead to clinical and genetic variability in OI, resulting in diverse symptoms and severity. Current management involves a multidisciplinary approach, including antiresorptive medications, physiotherapy, occupational therapy, and orthopedic surgery, which provide symptomatic relief but no cure. Advancements in gene therapy technologies and stem cell therapies offer promising prospects for long-lasting or permanent solutions. This review provides a comprehensive overview of OI's classification, pathogenesis, and current treatment options. It also explores emerging biotechnologies for stem cells and gene-targeted therapies in OI. The potential of these innovative therapies and their clinical implementation challenges are evaluated, focusing on their imminent success in treating bone disorders.

Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are inherited connective tissue disorders caused by diverse genetic defects, many of which affect collagen biosynthesis. However, the identified genetic variants do not always fully explain the clinical heterogeneity observed in patients, highlighting the need for advanced models and imaging techniques to assess collagen structure and fibroblast behavior at the microscopic level. In this study, we employed 5-week three-dimensional (3D) dermal fibroblast cultures derived from patients with haploinsufficient (HI) and dominant-negative (DN) OI, EDS, and healthy controls. Using label-free higher harmonic generation microscopy (HHGM), we visualized and quantified secreted collagen fibers and fibroblast morphology in situ. We analyzed fibroblast 3D orientation, collagen fiber diameter, collagen amount per cell, and the spatial alignment between fibroblasts and collagen fibers. HI OI fibroblasts secreted significantly less collagen than both control and EDS-derived cells, while EDS samples exhibited thinner collagen fibers compared to controls. Across all groups, collagen fiber orientation was strongly correlated with fibroblast alignment, in line with the role of fibroblasts in matrix organization. In healthy controls and HI OI samples, we observed a depth-dependent, counterclockwise rotation in fibroblast orientation from the culture bottom to the surface-a pattern that was less prominent in DN OI and EDS samples, potentially reflecting altered matrix guidance in diseased tissues. Overall, the quantity and quality of collagen, as well as fibroblast morphology and organization, were markedly altered in the OI and EDS model systems. These alterations may mirror tissue-level manifestations of the diseases, demonstrating the physiological relevance of patient-derived 3D fibroblast models for OI and EDS, as well as the power of harmonic generation microscopy in probing the cellular and extracellular consequences of disease-related gene defects in collagen or its biosynthetic pathways. Extensions of this methodological approach provide a way towards deeper understanding of tissue-level manifestations of collagen dysregulation in connective tissue disorders.

INTRODUCTION:Palovarotene is a retinoic acid receptor gamma agonist that was studied in phase-2 and phase-3 clinical trials for the inhibition of new heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP). Despite numerous setbacks and regulatory delays, palovarotene is now the first approved FOP treatment in the U.S.A., Canada and Australia but remains unapproved in Europe where concerns surrounding the drug and its path to regional market authorization persist. AREAS COVERED:The developmental history of palovarotene and an overview of the clinical trials and the regulatory approval journey are discussed by global FOP experts. EXPERT OPINION:While post hoc analyses indicate that palovarotene may have modest benefits for the inhibition of new HO formation in FOP, a number of limitations and concerns remain about its generalized use. Although the long-term risks and benefits of treatment with palovarotene remain unknown, the regional approval of palovarotene marks a milestone for the FOP community at the very beginning of a new era of clinical trials.

Osteogenesis imperfecta (OI), a rare genetic connective tissue disorder, primarily arises from pathogenic variants affecting the production or structure of collagen type I. In addition to skeletal fragility, individuals with OI may face an increased risk of developing ophthalmic diseases. This association is believed to stem from the widespread presence of collagen type I throughout various parts of the eye. However, the precise consequences of abnormal collagen type I on different ocular tissues remain unknown. Of particular significance is the sclera, where collagen type I is abundant and crucial for maintaining the structural integrity of the eye. Recent research on healthy individuals has uncovered a unique organizational pattern of collagen fibers within the sclera, characterized by fiber arrangement in both circular and radial layers around the optic nerve head. While the precise function of this organizational pattern remains unclear, it is hypothesized to play a role in providing mechanical support to the optic nerve. The objective of this study is to investigate the impact of abnormal collagen type I on the sclera by assessing the fiber organization near the optic nerve head in individuals with OI and comparing them to healthy individuals. Collagen fiber orientation of the sclera was measured using polarization-sensitive optical coherence tomography (PS-OCT), an extension of the conventional OCT that is sensitive to materials that exhibit birefringence (axial changes in light refraction). Birefringence was quantified and used as imaging contrast to extract collagen fiber orientation as well as the thickness of the radially oriented scleral layer. Three individuals with OI, exhibiting different degrees of disease severity, were assessed and analyzed, along with seventeen healthy individuals. Mean values obtained from individuals with OI were descriptively compared to those of the healthy participant group. PS-OCT revealed a similar orientation pattern of scleral collagen fibers around the optic nerve head between OI individuals and healthy individuals. However, two OI participants exhibited reduced mean birefringence of the radially oriented scleral layer compared to the healthy participant group (OI participant 1 oculus dexter et sinister (ODS): 0.34 °/μm, OI participant 2: ODS 0.26 °/μm, OI participant 3: OD: 0.29 °/μm, OS: 0.28 °/μm, healthy participants: ODS 0.38 ± 0.05 °/μm).The radially oriented scleral layer was thinner in all OI participants although within ±2 standard deviations of the mean observed in healthy individuals (OI participant 1 OD: 101 μm, OS 104 μm, OI participant 2: OD 97 μm, OS 98 μm, OI participant 3: OD: 94 μm, OS 120 μm, healthy participants: OD 122.8 ± 13.6 μm, OS 120.8 ± 15.1 μm). These findings imply abnormalities in collagen organization or composition, underscoring the necessity for additional research to comprehend the ocular phenotype in OI.

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients’ fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1, Nos1ap, and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism.

Eagle syndrome is a bone disease where elongation of the styloid process leads to throat and neck pain, and in severe cases neurovascular symptoms such as syncope and neuralgia. The pathophysiology of Eagle syndrome is poorly understood with various theories having been proposed how this elongation is caused. To better understand the pathophysiology, we performed a work-up in 6 patients presenting with Eagle syndrome. Patients mainly presented with pain on turning the neck (100%), foreign body sensation (67%), tension in the neck (67%), and dysphagia (50%). The typical length of the styloid process ranges from 25 to 30 mm; however, [18F]NaF (sodium fluoride) PET/CT showed elongated styloid processes with an average length of 52.1 +/- 15.6 mm (mean +/- SD) with increased turnover at the base of one of the styloid processes. The removed styloid processes were further examined by histology, micro-CT, quantitative backscatter electron imaging (qBEI), Fourier transform infrared spectroscopy (FTIR), and circularly polarized light imaging. Histology revealed one case of a fractured styloid process healing through callus formation and one case of pseudarthrosis. Bone mineral density and mineralization was similar in the styloid processes when compared to cortical bone samples derived from the mandibular bone of different patients. Circular polarized light microscopy showed a collagen orientation in the styloid process comparable to the cortical bone samples with a distinct separation of collagen structure between the mineralized structure and the surrounding soft tissue with FTIR analysis demonstrating a typical composition of bone. This altogether suggests that the elongated styloid processes in Eagle syndrome are mature bone, capable of endochondral repair, possibly growing from the base of the process through endochondral ossification, rather than being a form of secondary calcification of the stylohyoid ligament as previously postulated.

[18F]NaF PET has become an increasingly important tool in clinical practice toward understanding and evaluating diseases and conditions in which bone metabolism is disrupted. Full kinetic analysis using nonlinear regression (NLR) with a two-tissue compartment model to determine the net rate of influx (Ki) of [18F]NaF is considered the gold standard for quantification of [18F]NaF uptake. However, dynamic scanning often is impractical in a clinical setting, leading to the development of simplified semi-quantitative parameters. This systematic review investigated which uptake parameters have been used to evaluate bone disorders and how they have been validated to measure disease activity. A literature search (in PubMed, Embase.com, and Clarivate Analytics/Web of Science Core Collection) was performed up to 28th November 2023, in collaboration with an information specialist. Each database was searched for relevant literature regarding the use of [18F]NAF PET/CT to measure disease activity in bone-related disorders. The main aim was to explore whether the reported semi-quantitative uptake values were validated against full kinetic analysis. A second aim was to investigate whether the chosen uptake parameter correlated with a disease-specific outcome or marker, validating its use as a clinical outcome or disease marker. The initial search included 1636 articles leading to 92 studies spanning 29 different bone-related conditions in which [18F]NaF PET was used to quantify [18F]NaF uptake. In 12 bone-related disorders, kinetic analysis was performed and compared with simplified uptake parameters. SUVmean (standardized uptake value) and SUVmax were used most frequently, though normalization of these values varied greatly between studies. In some disorders, various studies were performed evaluating [18F]NaF uptake as a marker of bone metabolism, but unfortunately, not all studies used this same approach, making it difficult to compare results between those studies. When using [18F]NaF PET to evaluate disease activity or treatment response in various bone-related disorders, it is essential to detail scanning protocols and analytical procedures. The most accurate outcome parameter can only be obtained through kinetic analysis and is better suited for research. Simplified uptake parameters are better suited for routine clinical practice and repeated measurements.

INTRODUCTION:Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility. While skeletal manifestations are well documented, few studies have explored the effect of OI on the fetal heart. This retrospective case series investigates cardiac pathology in OI type II fetuses, aiming to address this gap. METHODS:Medical records and autopsy reports of 6 genetically confirmed OI type II cases were examined. Fetuses had pathogenic variants in COL1A1 or PPIB, inducing structural defects in collagen type I. In addition to hematoxylin and eosin and Elastic van Gieson staining, the expression of collagen type I, COL1A1 and COL1A2 chains was examined by immunohistochemistry. RESULTS:Immunohistochemistry confirmed robust expression of collagen type I throughout the heart. Five fetuses had normal heart weight, while 1 had a low heart weight in the context of generalized growth retardation. None displayed structural heart anomalies. CONCLUSION:This study reveals robust collagen type I expression in the hearts of OI type II fetuses without structural anomalies. We hypothesize that collagen type I abnormalities may not be causative factors for heart anomalies during early embryonic development. Instead, their impact may be conceivably related to an increased susceptibility to degenerative changes later in life.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by fragile bones and skeletal deformities. Individuals with OI may have dental abnormalities such as dentinogenesis imperfecta (DI) type I, malocclusions, and unerupted or missing teeth. This review comprehensively examines these dental abnormalities to assess their prevalence among the OI population and explore potential differences across different clinical types of OI and pathogenic variants. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, and Web of Science was conducted that included articles up to June 2024. Out of 672 articles screened, 34 were included. The included studies confirmed that dental abnormalities are prevalent in OI, with DI prevalence ranging from approximately 20 to 48

(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2, NANOG, and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR, TFAP2A, and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73, CD105, and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells.

BackgroundFibrodysplasia Ossificans Progressiva (FOP) is a rare, genetic disease in which heterotopic bone is formed in muscles, tendons and ligaments throughout the body. Disease progression is variable over time and between individuals. 18F-fluoride uptake in newly formed bone can be evaluated using [18F]NaF (i.e., sodiumfluoride) PET/CT, identifying active areas of bone formation in FOP. The purpose of this study was to assess the performance of various semi-quantitative methods with full kinetic analysis.ResultsSeven patients (age range: 20–31 years) with FOP underwent dynamic [18F]NaF scans at baseline and after one year. [18F]NaF uptake was measured in aorta descendens, vertebrae, heterotopic bone lesions and metabolically active regions on PET, and quantified using nonlinear regression (NLR) analysis together with standardized uptake value (SUV) and target-to-blood ratio (TBR). SUV was on measured the 40–45 min frame of the dynamic sequence (SUV40–45) and on the subsequent static sweep (SUVStatic). Correlations between and SUV40–45 and NLR-derived Ki were comparable when normalized to body weight (r = 0.81, 95% CI 0.64–0.90), lean body mass (r = 0.79, 95% CI 0.61–0.89) and body surface area (r = 0.84, 95% CI 0.70–0.92). Correlation between TBR40–45 and NLR-derived Ki (r = 0.92, 95% CI 0.85–0.96) was higher than for SUV40–45. Correlation between TBR40–45 and NLR-derived Ki was similar at baseline and after one year (r = 0.93 and 0.94). The change in TBR40–45 between baseline measurement and after one year correlated best with the change in NLR-derived Ki in the PET-active lesions (r = 0.87).ConclusionThe present data supports the use of TBR for assessing fluoride uptake in PET-active lesions in FOP.Clinical trial registrationSub-study of the Lumina-1 trial (clinicaltrials.gov, NCT03188666, registered 13-06-2017).

Osteogenesis Imperfecta (OI), known as “brittle bone disease,” presents a rare genetic disorder characterized by bone fragility, often accompanied by skeletal deformities and extraskeletal complications. OI is primarily associated with collagen type I defects, responsible for the syndromic nature of the disease affecting a broad range of tissues. As such, its multisystemic complexity necessitates multidisciplinary care approaches in all patient life stages. OI treatment remains largely supportive, commonly including bisphosphonates and orthopedic surgeries, which show promise in children. Although rehabilitation programs for children exist, guidelines for adult care and especially the transition from pediatric to adult care, are lagging behind in OI care and research. The current systematic review summarizes the literature on OI patient pediatric to adult care transition experiences and compares OI transition approaches to other chronic diseases. The review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were conducted across multiple databases. Search terms encompassed synonyms and closely related phrases relevant to “OI” and “Transition to adult care”. The initial screening involved the evaluation of article titles, followed by a thorough review of abstracts to assess relevance for the purpose of the current review. Programs aimed at easing the transition from pediatric to adult OI care necessitate a multifaceted approach. Collaborative efforts between different medical disciplines including pediatricians, endocrinologists, orthopedics, cardiology, pulmonology, ophthalmology, otolaryngologists, maxillofacial specialists, psychologists and medical genetics, are crucial for addressing the diverse needs of OI patients during this critical life phase. Comprehensive education, readiness assessments, personalized transition plans, and further follow-up are essential components of a structured transition framework. Further research is warranted to evaluate the feasibility and efficacy of sequential stepwise transition systems tailored to individuals with OI.

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)

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.