RARE DISEASE
Osteogenesis imperfecta
Osteogenesis imperfecta
Osteogenesis imperfecta
Synonyms: Brittle bone disease, Glass bone disease, Lobstein disease, OI
Synonyms: Brittle bone disease, Glass bone disease, Lobstein disease, OI
Synonyms: Brittle bone disease, Glass bone disease, Lobstein disease, OI
Drug discovery
20
drugs
With orphan designations
Overview
Osteogenesis imperfecta (OI) is a genetic disorder caused by defective collagen production or processing, leading to bone fragility, recurrent fractures, and systemic manifestations like blue sclerae, dentinogenesis imperfecta, hearing loss, and joint hypermobility. Severity ranges from mild (Type I) to perinatal lethality (Type II), with autosomal dominant COL1A1/2 mutations accounting for 90% of cases [1][2][7]. Diagnosis combines clinical evaluation, imaging, and genetic testing [6][14].
Burden
Hospitalization rates are 2.9× higher than the general population, peaking in ages 0–19 (8.4×) [4][9]. Mortality risks include respiratory insufficiency (severe OI) and cardiovascular complications (moderate/mild OI) [4][9]. Families report significant financial strain (29.6% spending >10% income on OI-related costs) [19].
Therapies
Pharmacologic: Bisphosphonates (e.g., zoledronate) to reduce fracture risk [5][13][18]; emerging therapies include anti-RANKL agents (denosumab) and TGF-β inhibitors [18].
Surgical/Rehabilitative: Intramedullary rodding for long-bone stabilization [5][13]; physiotherapy to enhance mobility and prevent deconditioning [3][8][16].
Multidisciplinary care: Dental interventions, hearing aids, and cardiopulmonary monitoring [5][6][14].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
1,889 drug discovery papers about Osteogenesis imperfecta, with 4 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,889 drug discovery papers about Osteogenesis imperfecta, with 4 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-07-31 | Altering host microenvironment is critical for success of cell therapy for osteogenesis imperfecta
Osteogenesis Imperfecta (OI) is a genetic disorder where mutations in Collagen I gene or other genes associated with defective collagen matrix lead to low bone density, bone brittleness with increased fracture risk. Current pharmacological treatments for OI do not address the underlying defect in collagen production. Cellular therapy represents a strategy to form healthy bone in OI, but systemic stem cell delivery approaches have not been successful. By contrast, locally delivered skeletal stem and progenitor cells (SSPCs) can engraft within OI bone, differentiate into matrix-producing osteoblasts, and generate normal collagen. However, without perturbing the marrow environment, endosteal engraftment is low. Irradiation used as preconditioning significantly enhances engraftment of donor progenitor cells. We aimed to determine what alterations in the bone marrow microenvironment influence donor SSPCs engraftment and their differentiation into mature lineages. Several preconditioning treatments and animal models were used to determine optimal conditions for local cell transplantation. Preconditioning with lethal irradiation (IRR) in osteogenesis imperfecta mice (OIM) exhibited high donor cell engraftment on the endosteal surface. Chemical myeloablation using busulfan and cyclophosphamide (BuCy) significantly increased donor cell engraftment, but the effect was less than that of IRR. Interestingly, BuCy caused similar initial changes in T and B cell composition as IRR, but proportions of NK, monocytes/macrophages and neutrophils were not as significant as with IRR. An additional preconditioning strategy involved ablation of recipient OI osteoblasts using OIM/Col2.3ΔTK/ + mice, but was not sufficient for mesenchymal donor cell engraftment. Finally, we investigated whether IRR affects cell therapy success via increasing bone turnover. We found that by reducing bone resorption with zoledronic acid, OIM mice had decreased donor cell engraftment. We separately observed increased engraftment rates in high bone turnover of OIM mice compared to WT. Lethal irradiation remained the most effective pretreatment for SSPCs engraftment and their differentiation into osteoblasts producing healthy matrix in OIM bone. Results indicate that increased bone turnover in OIM mice positively affect engraftment and differentiation into osteoblasts/osteocytes. Future cell transplantation research should include repurposing of existing treatments that can increase bone turnover.
2026-07-01 | Parent and professional experiences of a clinical trial of prenatal and postnatal stem cell therapy for severe osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterised by bone fragility and frequent fractures. While current treatments aim to preserve bone mass, there is no cure. Boost Brittle Bones Before Birth (BOOSTB4) is an international clinical trial investigating postnatal (n = 15) and prenatal plus postnatal (n = 3) infusions of fetal mesenchymal stem cells as a potential treatment for severe OI. Each BOOSTB4 participant received four stem cell doses at four-month intervals. Here we explore the experiences of parents and of healthcare professionals involved in BOOSTB4. In this qualitative study, one or both parents of children participating in BOOSTB4 took part after the second dose (T1: 16 families, 22 participants) and at least 6 months after the final dose (T2: 12 families, 16 participants). Professionals delivering BOOSTB4 participated in one interview (n = 13). Data were analysed using codebook thematic analysis. Decisions to participate in the trial were influenced by the potential for improved prognosis and limited alternative therapies. Parents felt reassurance because they were taking action and gratitude for access to expertise in OI. Balancing hope, expectations and uncertainty around treatment efficacy was challenging. Parents also expressed disappointment and uncertainty about treatment ending. Practical challenges included travel for treatment with a child with OI or late in pregnancy. Professionals noted the difficulty in managing parental expectations and the regulatory and logistical barriers of an international trial. Findings emphasised the need for clear communication before, during and after the trial, transparent information and trial designs that accommodate the needs of individual families.
2026-05-26 | Balancing osteogenesis and adipogenesis in osteogenesis imperfecta: PLIN2 and E2F2 as key targets for mesenchymal stem cell therapy.
Osteogenesis imperfecta (OI) necessitates innovative mesenchymal stem cell (MSC) therapies targeting key molecular pathways to enhance targeted and combination treatments and improve bone health. To investigate the therapeutic mechanisms of various interventions for OI by analyzing relevant datasets, with a focus on lipid metabolism-related genes, particularly PLIN2, in order to determine whether they influence the balance between osteoblast and adipocyte differentiation. This study analyzed datasets from the Gene Expression Omnibus (GEO; GSE157587, GSE214064, GSE186141) and UK Biobank genome-wide association study (GWAS) summary statistics (UKB-b-4657, UKB-b-1096, UKB-b-8875, UKB-b-20124) using bioinformatics tools, including GEO2R, DESeq2, TwoSampleMR, MR-Egger, MR-PRESSO, gwasrapidd, and summary data-based Mendelian randomization (MR), to identify differentially expressed genes (DEGs) and assess causal relationships with heel bone mineral density (BMD). Differentially expressed genes analysis of GSE157587 identified PLIN2 as the most significant gene influenced by MSC therapy in OI (log2 fold change = 0.428, adjusted p = 3.29 × 10-6), whereas GSE186141 revealed 770 DEGs in OI patients, with 7 overlapping with PLIN2-related genes. Notably, TNFRSF19 (log2 fold change = -2.7454, adjusted p = 3.930 × 10-7 in OI; 1.5001, adjusted p = 3.482 × 10-3 in PLIN2 knockdown) and E2F2 (log2 fold change = -2.1428, adjusted p = 8.830 × 10-5 in OI; 1.7207, adjusted p = 1.244 × 10-2 in PLIN2 knockdown) were identified as key genes. Mendelian randomization analysis confirmed a negative association between E2F2 and heel BMD (p = 1.116 × 10-7 to 6.073 × 10-5; effect size -0.0461 to -0.0277). PLIN2 and E2F2 emerge as critical targets for refining MSC therapy in OI, with the potential to improve bone formation and reduce fat accumulation by restoring the osteogenesis-adipogenesis balance. These findings may support the development of combination therapies or engineered MSCs, ultimately improving clinical outcomes for patients with OI.
2026-03-09 | Deciduous pulp stem cell-derived extracellular vesicles stimulate the proliferation of cartilage progenitor cells via extracellular signal-regulated protein kinase 1/2 activation.
The developmental dysfunction of cartilage progenitor cells (CPCs) causes dwarfism. Radical therapies for dwarfism remain underdeveloped. Recently, the therapeutic benefits of extracellular vesicles (EVs) released from human exfoliated deciduous tooth-derived stem cells (SHED) have been investigated for their potential to restore disease-target cells. However, the effects of EVs on human CPCs for the treatment of dwarfism remain unclear. We investigated the impact of EVs on cell proliferation, telomerase activity, telomerase reverse transcriptase (TERT) expression, cell cycle, and extracellular signal-regulated protein kinase 1/2 (ERK1/2) levels in human CPCs and in our established osteogenesis imperfecta (OI)-specific SHED (OI-SHED). EVs enhanced the proliferation and G1/S phase transition of CPCs, which was associated with increased TERT expression and telomerase activity. However, RNase-preconditioned EVs did not attenuate the efficacy of EVs in CPCs. ERK1/2 inhibitor tests demonstrated that CPCs exhibited suppressed proliferation, telomerase activity, and G1/S phase progression. EV-transferring CD29 induced ERK1/2 phosphorylation in CPCs, subsequently activating telomerase activity to induce proliferation. Interestingly, EV stimulation restored the reduction in cell proliferation, cell cycle progression, phosphorylated ERK1/2 levels, and TERT expression in OI-SHED. In conclusion, the present findings provide new insights into ERK1/2-mediated proliferation of human CPCs using EVs.
2026-01-28 | CaO-SiO2-P2O5-B2O3-Based Bioactive Glass (BGS-7) Macrobeads Incorporated in Hydrogels Aid Bone Regeneration: Evaluation in Rabbit Calvarial and Femoral Defect Models.
Bone graft substitutes are extensively investigated for addressing critical-size bone defects; however, their efficacy is limited by inadequate bone regeneration and subpar handling properties. Herein, we compared the bone regenerative capacity of CaO-SiO2-P2O5-B2O3-based bioactive glass (BGS-7) macrobeads with that of β-tricalcium phosphate (β-TCP) beads and evaluated their performance when incorporated into hydrogels to improve their handling properties. BGS-7 macrobeads were fabricated via alginate crosslinking and heat treatment, and their physicochemical properties and microstructures were characterized. In a rabbit calvarial defect model, BGS-7 macrobeads, heat-treated at 600 and 800 °C, exhibited superior bone bridging and degradation than size-matched β-TCP macrobeads. To further evaluate their regenerative potential, critical-size defects (6 mm diameter × 10 mm depth) were created in the rabbit femoral condyle. To enhance clinical applicability, BGS-7 beads were incorporated into cellulose-based hydrogels and implanted into the defects. Radiographic and histomorphometric analyses demonstrated that bone formation and stable fixation achieved with hydrogel formulations containing BGS-7 microbeads and Laponite were more pronounced than those with BGS-7 beads alone. The findings suggest that BGS-7 macrobeads, particularly when combined with microbead- and Laponite-containing hydrogels, represent a promising bone graft substitute with improved regenerative and handling properties compared with using BGS-7 beads alone.
proteins
2026-09-25 | Longitudinal change of bone microarchitecture and fracture risk in adults with osteogenesis imperfecta.
Incident fractures remain the major complications in adults with osteogenesis imperfecta (OI). Cross-sectional studies have shown impaired bone microarchitecture (BM), but the longitudinal changes and their contribution to fracture risk remain unknown. Here, we investigated the changes in BM and their associations with clinical, genetic factors and incident fractures. Fifty-five adults with OI (23 men, 32 women, including 6 postmenopausal; mean age 43 ± 14 years) were followed for a median of 2.7 years (IQR 2.1-4). HR-pQCT was used to measure the cortical (Ct) bone mineral density (vBMD) and thickness and the trabecular (Tb) bone volume (BV/TV), vBMD at the distal radius and tibia. Longitudinal changes adjusted for clinical parameters were analysed with mixed-effects models. We investigated the associations of BM changes and the incident fractures by logistic regression adjusted for age, sex/menopause, genotype and treatment. At the distal radius, Tb.vBMD, Tb.BV/TV and Ct.Pm and were low in premenopausal and postmenopausal women at baseline. Tb.BV/TV declined in men (-0.0030/yr, p < 0.01) and premenopausal women (-0.0027/yr, p < 0.05). Ct.Th decreased also in men (-0.0735 mm/yr) and premenopausal women (-0.0813 mm/yr, p < 0.001). However, Tb.BV/TV increased (+0.0019/yr, p < 0.05) and Ct.Th decreased (-0.0819 mm/yr, p < 0.0001) in postmenopausal women, suggesting trabecularization of cortical bone. Incident fractures during follow-up was similar in the genetic variants (p = 0.179). Neither Tb.BV/TV, Ct.Th nor vBMD changes predicted incident fractures. Bone microarchitecture deteriorates over time in adults with OI and more after menopause. However, longitudinal changes do not predict incident fractures, highlighting the complex determinants of fracture risk in OI.
2026-07-28 | Dose matters: haploinsufficiency in osteogenesis imperfecta.
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.
2026-07-22 | Off-Label Use of Teriparatide for Osteotomy Healing in an Adolescent with Osteogenesis Imperfecta Type VIII: A Case Report.
Osteogenesis imperfecta (OI) type VIII is an autosomal recessive skeletal dysplasia caused by P3H1 variants, resulting in defective collagen post-translational modification and increased bone fragility. Teriparatide (TPTD), a recombinant parathyroid hormone analogue, stimulates osteoblast activity and bone formation and is approved for the treatment of osteoporosis in adults. A 16-year-old male with genetically confirmed OI type VIII presented with delayed union with characterized by the absence of radiographic evidence of healing six months after femoral osteotomy and intramedullary rodding surgery. His prior management included intermittent bisphosphonate therapy which had improved bone mineral density. He had no recent history of fractures. Off-label therapy with TPTD (20 µg/day subcutaneously) was initiated and continued for six months. Although systemic markers of bone formation showed no remarkable changes, except osteocalcin, during therapy, serial radiographs confirmed successful bone union. The treatment was well tolerated, with no reported side effects; however, mild hypercalcemia with hypercalciuria, which persisted after discontinuation of TPTD therapy, was detected. Bisphosphonate therapy was resumed upon completion of TPTD treatment. This case represents the first documented use of TPTD to promote osteotomy healing in an adolescent with OI. The favourable clinical and radiologic outcome suggests a potential role for anabolic therapy in managing complex bone healing challenges in paediatric OI. Further research is warranted to evaluate safety and efficacy in this population.
2026-06-17 | Transcriptional profiling of otic capsule and femur in the oim mouse model of osteogenesis imperfecta.
Hearing loss is a common and debilitating complication of the brittle bone disorder osteogenesis imperfecta (OI). Existing treatments that are designed to address age-related hearing loss in the broader population do not meet the needs of OI patients, who exhibit skeletal fragility and begin to lose their hearing when they are young-adults. The biologic mechanisms responsible for hearing loss in OI are unknown, hindering the development of preventative therapies. To identify potential mechanisms that drive this condition, we performed transcriptome profiling on femoral and otic capsule specimens obtained from the Col1a2oim mouse model at 12- and 25-wk of age. We found that the bulk transcriptomes of femora and otic capsules were markedly different, regardless of mouse genotype. Further, bone formation-associated transcripts were reduced at 25-wk, compared to 12-wk. Mice homozygous for the oim mutation exhibited increased abundance of transcripts associated with osteoblast activity and type I collagen production compared to WT mice in both femoral and otic capsule specimens. The most notable difference between oim and WT mouse otic capsules was the depletion of the transcripts that encode mucin and keratin, suggesting dysregulation of epithelial cells, which has been previously linked to hearing loss. Our data offer new insights into the mechanisms that disrupt the middle ear in OI. Analysis of epithelial cells obtained from OI patients and additional models of OI could suggest novel strategies to prevent and/or treat hearing loss.
2026-06-13 | PTH treatment is effective in the Aga2/+ mouse model of moderate to severe osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by brittle bone and recurrent fractures. The majority of OI is clinically categorized into mild, moderate, severe, and perinatal lethal forms. A clinical study on the use of intermittent parathyroid hormone (PTH) as an anabolic therapy for OI found PTH was effective in mild, but not in individuals with moderate/severe OI. However, this sub-group analysis was relatively small and considered preliminary by the authors. Since then, research on PTH therapy in OI has focused on mild OI and no studies of PTH use in moderate/severe OI patients or animal models have been reported. In this work, we used the Aga2/+ mouse, an established autosomal dominant model of moderate/severe OI, to investigate whether PTH treatment has an effect on bone. In vitro, Aga2/+ osteoblasts were sensitive to PTH and exhibited similar transcriptional changes compared to WT. In vivo, PTH treatment improved lumbar trabecular bone, increased cortical bone area fraction in the mid-femur, and, in females, led to improved biomechanical properties. These results demonstrate the Aga2/+ model responded to PTH and support further investigation into whether PTH is effective in adult individuals with moderate/severe OI who have limited treatment options.
small molecules
2026-09-26 | Heme Oxygenase-1 in Bone Remodeling: Molecular Mechanisms and Therapeutic Implications.
Bone remodeling is a dynamic and tightly regulated process that maintains skeletal homeostasis through a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Disruption of this balance contributes to the development of bone-related disorders, particularly osteopenia, osteoporosis and osteogenesis imperfecta, which weaken, deform, or cause fractures. Increasing evidence indicates that oxidative stress and chronic inflammation impair osteoblast functions while promoting osteoclast differentiation and activity. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with cytoprotective, antioxidant, and anti-inflammatory properties. Besides its primary role in cellular defense against oxidative stress and inflammatory damage, HO-1 has been shown to be involved in both osteoblast differentiation and osteoclastogenesis. Through its interaction with key regulatory systems, including the receptor activator of nuclear factor κB (RANK)-receptor activator of nuclear factor κB ligand (RANKL)-osteoprotegerin axis and redox-sensitive signaling pathways, HO-1 contributes to maintenance of optimal bone remodeling. The enzyme also plays a role in modulating metabolic processes in the bone. This review highlights the role of HO-1 in bone formation, bone resorption, and related pathophysiologic conditions. Furthermore, the therapeutic potential of HO-1 as a target for bone disorders is discussed.
2026-09-20 | The Effect of Bisphosphonate Therapy on Hearing and Middle Ear Dysfunction in Pediatric Osteogenesis Imperfecta.
Osteogenesis imperfecta (OI) is a heterogeneous inherited connective tissue disorder characterized by impaired bone matrix formation. Hearing loss is observed in 28 to 65 percent of patients with OI. Most patients with OI experience conductive hearing loss (CHL); however, mixed and sensorineural (SNHL) hearing loss has also been described. The primary aim of this retrospective study was to characterize the rates of middle ear dysfunction (MED) and hearing loss (HL) with pediatric OI and investigate the efficacy of bisphosphonate therapy in HL. Retrospective chart review of pediatric patients with OI. Pediatric patients with OI treated between January 2000 and January 2021 were included. HL was defined according to pure tone audiometry, while MED was determined by tympanometry at 226 Hz. Patients were categorized by the OI type and considered to be using bisphosphonates if they had been initiated within 1 year prior to testing. No direct intervention was performed. Comparisons between bisphosphate use and no bisphosphonate use were explored. The chi-square test was utilized for categorical data to investigate whether a significant association with two-by-two variables existed. This study included 144 patients. Of these patients, 12.5 percent had HL. Tympanometry revealed that 25 percent had MED. Additionally, 82.6 percent were currently using bisphosphonates. Across all OI types, no association between current bisphosphonates and HL or MED was observed. However, a subanalysis of patients with type I OI indicated that the absence of MED was statistically associated with current bisphosphonate therapy (p = 0.025). Bisphosphonates are associated with the absence of MED in pediatric patients with type I OI. Because of its mild disease course, bisphosphonates are not commonly used for many patients with type I OI. By reducing MED and its associated comorbidities, our results suggest that bisphosphonate use may confer a significant therapeutic benefit. HL is common in individuals with OI. Our study suggests that initiating bisphosphates at an earlier age may delay middle ear changes that contribute to HL.
2026-09-08 | Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.
2026-08-20 | Injury-driven stromal exhaustion disrupts intrinsic regenerative capability.
Bone marrow stromal cells, marked by leptin receptor (Lepr) and C-X-C motif chemokine ligand 12 (Cxcl12), orchestrate osteogenesis and maintain bone homeostasis. Following injury, these stromal cells directly generate reparative bone and subsequently restore the marrow microenvironment, a process widely regarded as a reliable regenerative response. However, it remains unclear whether stromal cells retain full regenerative capacity after prior injury. Here, we show that Lepr+Cxcl12+ stromal cells have limited regenerative capacity and become dysfunctional upon repeated activation, defining a state of stromal exhaustion. Lepr-Cre-labeled stromal cells progressively lose osteogenic potential after repeated injury and instead differentiate into bone marrow adipocytes. Exhausted stromal cells are distinct from aging stromal cells, exhibiting metabolic abnormalities, chronic inflammation associated with stress responses, and impaired regenerative plasticity. Furthermore, β-catenin deletion during injury repair induces adipogenesis through stromal lineage switching, whereas pharmacological and genetic activation of Wnt/β-catenin signaling partially rescues osteogenesis, indicating that dysregulated Wnt/β-catenin signaling drives stromal exhaustion and impaired regeneration. As repeated regenerative activation may occur in recurrent fractures, orthopedic surgeries, osteoporosis, and osteogenesis imperfecta, stromal exhaustion represents a critical barrier to bone regeneration and a potential therapeutic target for restoring stromal plasticity.
2026-08-10 | Favorable aortic remodeling following type B aortic dissection in a patient with osteogenesis imperfecta.
Osteogenesis imperfecta is a heritable type I collagen disorder, with aortic dissection a recognized complication. A 69-year-old man with osteogenesis imperfecta presented with acute uncomplicated type B aortic dissection with a thrombosed false lumen, managed with anti-impulse therapy targeting systolic blood pressure < 120 mm Hg and heart rate < 70 beats/min. Despite an ulcer-like projection and 4.2 cm proximal descending aortic diameter, serial imaging demonstrated complete resolution with optimal medical therapy by 6 months and reduction to 3.2 cm at 12 months. This favorable remodeling is notable given the underlying collagen disorder, where tissue fragility raises concerns about impaired healing and aortic integrity.
gene therapies
2026-09-30 | Pathogenesis and precision management of osteogenesis imperfecta: from genetic mechanisms to novel therapies.
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal dysplasia characterized by systemic bone fragility. Beyond skeletal manifestations, OI is a multisystem condition involving dentinogenesis imperfecta, hearing loss, joint hyperlaxity, and cardiopulmonary complications. The diagnostic paradigm for OI has undergone a revolutionary shift from traditional clinical phenotyping to a molecular etiology-based framework. Driven by advancements in high-throughput sequencing, mutations in over 20 implicated genes have expanded the current OI nosology to at least 23 distinct types. This narrative review was conducted by searching for papers using PubMed/MEDLINE. Relevant publications were identified using single and/or combined keywords including: osteogenesis imperfecta, genes (such as COL1A1 and COL1A2), animal models, phenotypes (such as osteopenia and femoral bowing), and drug therapies (such as bisphosphonate and denosumab), mesenchymal stem cells, gene therapy, and pluripotent stem cells. This review systematically delineates the molecular pathogenesis of OI, categorizing defects into disrupted collagen biosynthesis, impaired post-translational modification, aberrant procollagen trafficking, and dysfunctional osteoblast differentiation or mineralization pathways. Of note, we highlight the unique genetic landscape and clinical characterization of OI within Asian populations. Furthermore, we evaluate the transition towards precision management. Surgical management of OI has been optimized by telescopic rodding and a multidisplinary approach. Bisphosphonates remain a cornerstone of medical therapy, though responses vary with OI genotypes. Emerging targeted biologics include denosumab, romosozumab, setrusumab, and fresolimumab. Finally, we discuss the transformative potential of cell-based therapies, particularly mesenchymal stem cells. Precision gene editing technologies, such as CRISPR-Cas9, offer a strategy in addressing the root genetic causes of OI. Integrating molecular diagnostics with robust genotype-phenotype correlations is essential for advancing personalized care. Future breakthroughs will rely on the translation of gene and cell therapies to ultimately improve the long-term clinical outcomes for patients with OI.
2026-09-27 | In vitro validation of a CRISPR/Cas9 guide RNA targeting COL1A1 gene by cleavage assay.
The CRISPR/Cas9 system has become a widely used tool for genome editing; however, editing efficiency is largely determined by the design and functional activity of the guide RNA (gRNA). Experimental validation prior to cellular applications is particularly important when targeting genes associated with genetic disorders, such as COL1A1, which is frequently mutated in Osteogenesis Imperfecta. This study performed an in vitro functional validation of a CRISPR/Cas9 gRNA designed to target exon 2 of the COL1A1 gene, using a cell-free cleavage assay as a preliminary step before cellular genome editing applications. Three gRNAs targeting distinct COL1A1 exons were designed using bioinformatics tools; the exon 2 candidate was selected for experimental validation based on predicted efficiency, favorable off-target profile, and successful PCR amplification of its target region. The selected gRNA was assembled with recombinant Cas9 protein into a ribonucleoprotein complex, which was incubated with PCR-amplified DNA substrates derived from five distinct human cell lines. Cleavage products were resolved by polyacrylamide gel electrophoresis and quantified by densitometric analysis. The gRNA directed reproducible, specific Cas9-mediated cleavage at the intended COL1A1 exon 2 target site across all cell lines tested, with mean cleavage efficiencies ranging from 58.79% to 68.84%. These results confirm functional validation of the gRNA through in vitro cleavage activity and support its candidate selection for subsequent cellular studies targeting COL1A1, representing an initial step toward future knockout-style cellular models of Osteogenesis Imperfecta.
2026-06-19 | FKBP10 mitigates osteoporosis by restraining the HSPA5-coupled ERS-pyroptosis axis to enhance osteogenic differentiation in BMSCs.
Osteoporosis is characterized by progressive bone deterioration and is closely associated with impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Mutations in FK506-binding protein 10 (FKBP10) are linked to osteogenesis imperfecta. However, the role of FKBP10 in osteoporosis and osteogenic differentiation of BMSCs remains unclear. Serum FKBP10 levels were examined in individuals with different bone mineral density. An ovariectomized (OVX) mouse model was established to mimic osteoporosis, and adeno-associated virus serotype 9 (AAV9) was used to achieve FKBP10 overexpression in vivo. Osteoporotic bone phenotypes were assessed by Micro-CT, hematoxylin and eosin staining, and Masson staining. Loss- and gain-of-function experiments were performed in BMSCs using siRNA and overexpression plasmids. Osteogenic differentiation was assessed by alkaline phosphatase staining and Alizarin red S staining. The underlying mechanism was investigated by RNA sequencing, immunofluorescence, co-immunoprecipitation, and protein degradation assays. FKBP10 levels were reduced in the serum of patients with osteoporosis, as well as in bone tissue and primary BMSCs from OVX mice. AAV9-mediated FKBP10 overexpression attenuated OVX-induced bone loss. FKBP10 knockdown impaired osteogenic differentiation of BMSCs, whereas FKBP10 overexpression enhanced osteogenic differentiation. Mechanistically, FKBP10 knockdown activated Caspase-1-mediated pyroptosis in BMSCs. Further investigation confirmed that FKBP10 directly interacted with heat-shock-protein family A member 5 (HSPA5) and promoted HSPA5 lysosomal degradation, thereby alleviating HSPA5-associated sustained endoplasmic reticulum stress (ERS) and subsequent pyroptosis. Our findings identify FKBP10 as a protective regulator that preserves the osteogenic differentiation capacity of BMSCs and attenuates osteoporosis progression by restraining the HSPA5-associated ERS-pyroptosis pathway.
2026-05-25 | A New Wnt1 Mutant Rat Model of Osteogenesis Imperfecta and Its Application in AAV9-Mediated Gene Therapy.
Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous bone disorder, with more than 20 genes contributing to OI development. Previously, we identified WNT1 c.620G > A (p.Arg207His) mutation among Chinese patients with autosomal recessive OI (AR-OI). This study aims at investigating the causative role of WNT1 deficiency in OI and evaluate whether AAV-based gene therapy could ameliorate bone abnormalities. We generated and analyzed the Wnt1R207H/R207H rat model. The AAV9-Wnt1 virus was delivered via direct intraosseous injection into the femoral marrow cavity of the OI rats to evaluate its therapeutic potential. The homozygous Wnt1R207H/R207H rat recapitulated key features of AR-OI, including fractures, reduced bone mass, growth retardation, decreased survival rate, increased osteoclast numbers, diminished osteoblast function and mineralization capacity, compared with heterozygous and wild-type littermates. In vitro, Wnt1 overexpression in osteoblasts promoted osteoblast activity and bone mineralization. Furthermore, AAV9-Wnt1 treatment in OI rats resulted in significant recovery of bone density and mechanical strength, stimulation of osteoblast activity, suppression of osteoclast activity, and upregulation of Type I collagen expression. Our study demonstrates that WNT1 c.620G > A (p.Arg207His) is pathogenic, and confirms that AAV-mediated Wnt1 gene therapy represents a promising strategy for treating OI caused by WNT1 mutations.
2026-05-13 | Autologous guided bone regeneration: a comprehensive narrative review.
Bone defect is a prevalent and complex challenge in orthopedics and oral-maxillofacial surgery, severely compromising skeletal integrity and functional recovery. Autologous Guided Bone Regeneration (GBR) has emerged as a highly effective therapeutic strategy, demonstrating remarkable efficacy in treating long bone fractures, nonunions, post-tumor resection bone defects, and alveolar bone augmentation for dental implant procedures. This narrative review comprehensively synthesizes the latest research progress, core mechanisms, technical innovations, existing challenges, and future prospects of Autologous GBR through an extensive analysis of domestic and international literature. Its core mechanism relies on selective cell occlusion theory: barrier membranes construct a bone regeneration microenvironment, blocking non-osteoblastic invasion while promoting osteoblast migration and differentiation. Autologous components play key roles: autologous bone (gold standard for grafting) has osteogenic activity, osteoinductivity and osteoconductivity; autologous bone marrow provides mesenchymal stem cells (MSCs) for osteoblast differentiation and microenvironment regulation; autologous growth factors (e.g., Bone Morphogenetic Proteins [BMP], Transforming Growth Factor-β [TGF-β]) regulate bone regeneration via cell signaling pathways. Technical advances include site-specific autologous bone harvesting (ilium, mandible, etc.) and optimized barrier membranes (absorbable Poly Lactic-co-Glycolic Acid [PLGA]/collagen, non-absorbable expanded Polytetrafluoroethylene [ePTFE]). Cell-molecular studies (MSCs differentiation, Wnt pathway) offer theoretical basis. Challenges include surgical infection, potential immune rejection and poor osseointegration. Prospects involve 3D-printed scaffolds, gene therapy-tissue engineering combination, and application in complex diseases like osteogenesis imperfecta. This review provides references for researchers and clinicians.
other
2026-09-24 | Skeletal pathologies caused by PLS3 inactivation are predominantly associated with impaired cortical bone integrity.
The identification of pathogenic PLS3 variants in individuals with X-linked osteoporosis (XLO) has demonstrated the importance of the actin-bundling protein plastin-3 for skeletal integrity. We and others have previously reported that Pls3-deficient mice display a skeletal phenotype that unexpectedly affects only the cortical bone compartment. To better characterize the impact of PLS3 inactivation on bone (micro-)architectural parameters in humans, we retrospectively analyzed skeletal parameters obtained from male XLO patients and compared them to corresponding data from male individuals with genetically diagnosed osteogenesis imperfecta type I (OI-I). We observed no major differences between XLO and OI-I patients in baseline characteristics, laboratory parameters, or bone mineral density measurements by dual-energy X-ray absorptiometry (DXA). However, there was a significant difference between the two groups observed by high resolution peripheral quantitative computed tomography (HRpQCT). More specifically, XLO patients displayed significantly reduced cortical bone parameters, compared to both normal reference ranges and OI-I, especially at the distal radius. We also analyzed female heterozygous carriers of (likely) pathogenic PLS3 alleles, who were less affected compared to male XLO patients. However, two of them displayed osteoporotic fractures at a postmenopausal age, thus treatment with romosozumab, a monoclonal antibody targeting sclerostin, was initiated and appeared to be effective. Since another sclerostin-neutralizing antibody is currently studied for the treatment of OI patients, we crossed Pls3-deficient mice with mice carrying a high bone mass allele of Lrp5 (Lrp5A213V), which serves as a molecular mimic of anti-sclerostin therapy. We found that the presence of the Lrp5A213V allele led to significantly increased cortical and trabecular bone mass not only in wildtype but also in Pls3-deficient mice. Taken together, our data raise the hypothesis that PLS3 inactivation predominantly affects cortical bone parameters in mice and humans and that anti-sclerostin therapy could be effective for the treatment of XLO.
2026-09-07 | Effectiveness and limitations of anti-sclerostin therapy in osteogenesis imperfecta: A systematic review.
Sclerostin inhibition is a potential anabolic therapy for osteogenesis imperfecta (OI). We systematically evaluated whether anti-sclerostin therapy improves bone quantity, bone quality, mechanical performance, and fracture-related outcomes in preclinical and clinical studies of OI. PubMed, Embase, and Web of Science were searched for randomized controlled trials and controlled animal studies investigating sclerostin inhibition in OI. 3 reviewers independently screened studies, extracted data using a standardized template, and assessed methodological quality with Joanna Briggs Institute appraisal tools. 18 studies were included:15 controlled experimental studies in mouse models of OI and 2 clinical trials in adults with OI, plus one ancillary iliac crest biopsy study derived from a trial cohort. Across murine models, anti-sclerostin consistently increased bone quantity (e.g., trabecular bone volume, cortical thickness, bone mineral density), often increased whole-bone strength, and sometimes reduced fracture incidence. However, efficacy varied by genotypes, ages, skeletal sites, or outcome levels. In several collagen-related murine OI models (e.g. Brtl/+, Crtap-deficient and the severe Col1a1Jrt/+ model), tissue-level material properties such as elastic modulus, hardness and mineralization indices remained abnormal despite structural gains. Clinical studies in adults with OI similarly demonstrated increases in areal bone mineral density, whereas microarchitectural and biopsy-based matrix-level outcomes were more variable and frequently failed to normalize. Anti-sclerostin therapy elicits an anabolic response in OI, improving overall bone mass and whole-bone strength. However, it does not consistently restore intrinsic tissue-level material properties. Current clinical evidence supports skeletal responses in adults with COL1A1/COL1A2-related OI types I, III, and IV, without a demonstrated difference between type I and pooled types III/IV; it does not identify a preferentially responsive individual genotype or an optimal pediatric age. Future trials should prespecify molecular and skeletal-maturity strata and prioritize fractures and whole-bone strength, supported by axial DXA, weight-bearing-site HR-pQCT/microFE, and tissue-level bone-quality outcomes.
2026-07-19 | Romosozumab in postmenopausal women with classical Osteogenesis imperfecta.
This study explored whether Romosozumab, an anti-sclerostin antibody, can improve bone quality in women with Osteogenesis imperfecta. After 12 months, spinal areal bone mineral density increased, showing a beneficial treatment effect, although changes in hip bone density and bone structure were less pronounced than in women with severe osteoporosis. Osteogenesis imperfecta (OI) is the most common hereditary bone disorder, characterized by increased bone fragility and impaired bone quality, but pharmacological treatment is limited. Ongoing clinical trials investigate monoclonal anti-sclerostin antibodies for OI patients, offering new hope for reducing bone fragility by increasing bone mass. Postmenopausal women with either OI (n = 5) or severe osteoporosis (OPO, n = 10) receiving Romosozumab monthly (210 mg s.c.) for 12 months were analyzed retrospectively. Clinical assessments were performed at baseline, after 6 months, and after 12 months. Bone mass and structure were evaluated at baseline and after 12 months of treatment. In addition, serum and urine markers of bone turnover were analyzed at each time point. The mean age of the participants was 53.6 ± 8.9 years for OI patients and 57.2 ± 5.8 years for OPO patients (p = 0.444). After 12 months of Romosozumab treatment, spinal aBMD and osteocalcin increased significantly in OI patients, indicating an anabolic response. HR-pQCT analysis revealed no statistically significant microstructural changes in patients with OI, although trends and moderate effect sizes suggested potential improvements. In patients with OPO, we observed a more pronounced response of bone turnover markers with greater aBMD gains at both the spine and femur, as well as significant improvements in bone microstructure, particularly at the tibia. Romosozumab treatment in postmenopausal women with OI resulted in a significant increase in spinal aBMD, though the effect on hip aBMD and peripheral bone microstructure was limited in contrast to postmenopausal osteoporosis.
2026-07-17 | Genetic Bone Diseases: A Scoping Review of Pathology, Symptoms, Diagnosis, Treatment, and New Horizons.
Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.
2026-07-10 | Artificial Intelligence for Evidence Synthesis of Emerging Biologics to Improve Skeletal Health in Osteogenesis Imperfecta: Systematic Review and Meta-Analysis.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and recurrent fractures. Emerging biologics demonstrate promise by targeting bone-remodeling pathways, yet evidence for their efficacy and safety remains fragmented and heterogeneous, and no prior systematic review in OI has incorporated artificial intelligence (AI) to synthesize it. This study aims to systematically evaluate the efficacy and safety of novel biologics in patients with OI using an AI-assisted workflow for evidence synthesis. We conducted a systematic review and meta-analysis of interventional trials of denosumab, setrusumab, teriparatide, romosozumab, and fresolimumab. Data were retrieved from PubMed, Web of Science, Embase, ScienceDirect, the Cochrane Library, and ClinicalTrials.gov up to December 1, 2025. Eligible studies enrolled individuals with OI, reported areal bone mineral density (aBMD) and/or fractures, and were randomized, nonrandomized, or single-arm studies; case series were excluded. As a methodological feature, GPT-4o was integrated into the workflow to perform a parallel 2-stage screening (title/abstract and full text) and to assist with risk of bias assessment using an adapted Cochrane RoB 2 tool. The primary outcome, percentage change in aBMD, was synthesized using a random-effects meta-analysis. GPT-4o was benchmarked against human reviewers using sensitivity, specificity, and weighted Cohen κ. Thirteen trials (n=684) were systematically reviewed, of which 10 (n=333) contributed to meta-analyses. In children, denosumab produced the greatest 12-month increase in lumbar spine aBMD (25.49%, 95% CI 17.14%-33.84%). In adults, setrusumab at 12 months yielded the highest improvement (9.38%, 95% CI 6.5%-12.26%). Across trials, no biologic significantly reduced fracture incidence compared to bisphosphonates. Safety profiles varied: denosumab was associated with a high risk of hypercalcemia in children (30.95%), whereas setrusumab had no treatment-related serious adverse events. AI achieved high sensitivity in abstract (97.4%) and full-text (88.9%) screening, and reduced total screening time by over 95%. Although there was substantial agreement with humans in the quality assessment (Cohen κ=0.778, 95% CI 0.710-0.846), the model exhibited optimism and positional biases due to reliance on probabilistic language patterns rather than structured clinical reasoning. This review is the first to synthesize and quantitatively compare skeletal outcomes across multiple biologics in OI with an AI-assisted review workflow. Denosumab and setrusumab demonstrate promising efficacy in improving lumbar spine aBMD across ages, although current evidence does not support superior fracture reduction over bisphosphonates. GPT-4o can substantially accelerate evidence synthesis but should be deployed with explicit human oversight in tasks requiring contextual understanding and clinical reasoning. These findings should be interpreted cautiously given the small and heterogeneous trial base. Taken together, our workflow presented how evidence synthesis may be scaled and operationalized in real-world rare disease research.
cell therapies
2026-07-31 | Altering host microenvironment is critical for success of cell therapy for osteogenesis imperfecta
Osteogenesis Imperfecta (OI) is a genetic disorder where mutations in Collagen I gene or other genes associated with defective collagen matrix lead to low bone density, bone brittleness with increased fracture risk. Current pharmacological treatments for OI do not address the underlying defect in collagen production. Cellular therapy represents a strategy to form healthy bone in OI, but systemic stem cell delivery approaches have not been successful. By contrast, locally delivered skeletal stem and progenitor cells (SSPCs) can engraft within OI bone, differentiate into matrix-producing osteoblasts, and generate normal collagen. However, without perturbing the marrow environment, endosteal engraftment is low. Irradiation used as preconditioning significantly enhances engraftment of donor progenitor cells. We aimed to determine what alterations in the bone marrow microenvironment influence donor SSPCs engraftment and their differentiation into mature lineages. Several preconditioning treatments and animal models were used to determine optimal conditions for local cell transplantation. Preconditioning with lethal irradiation (IRR) in osteogenesis imperfecta mice (OIM) exhibited high donor cell engraftment on the endosteal surface. Chemical myeloablation using busulfan and cyclophosphamide (BuCy) significantly increased donor cell engraftment, but the effect was less than that of IRR. Interestingly, BuCy caused similar initial changes in T and B cell composition as IRR, but proportions of NK, monocytes/macrophages and neutrophils were not as significant as with IRR. An additional preconditioning strategy involved ablation of recipient OI osteoblasts using OIM/Col2.3ΔTK/ + mice, but was not sufficient for mesenchymal donor cell engraftment. Finally, we investigated whether IRR affects cell therapy success via increasing bone turnover. We found that by reducing bone resorption with zoledronic acid, OIM mice had decreased donor cell engraftment. We separately observed increased engraftment rates in high bone turnover of OIM mice compared to WT. Lethal irradiation remained the most effective pretreatment for SSPCs engraftment and their differentiation into osteoblasts producing healthy matrix in OIM bone. Results indicate that increased bone turnover in OIM mice positively affect engraftment and differentiation into osteoblasts/osteocytes. Future cell transplantation research should include repurposing of existing treatments that can increase bone turnover.
2026-07-01 | Parent and professional experiences of a clinical trial of prenatal and postnatal stem cell therapy for severe osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterised by bone fragility and frequent fractures. While current treatments aim to preserve bone mass, there is no cure. Boost Brittle Bones Before Birth (BOOSTB4) is an international clinical trial investigating postnatal (n = 15) and prenatal plus postnatal (n = 3) infusions of fetal mesenchymal stem cells as a potential treatment for severe OI. Each BOOSTB4 participant received four stem cell doses at four-month intervals. Here we explore the experiences of parents and of healthcare professionals involved in BOOSTB4. In this qualitative study, one or both parents of children participating in BOOSTB4 took part after the second dose (T1: 16 families, 22 participants) and at least 6 months after the final dose (T2: 12 families, 16 participants). Professionals delivering BOOSTB4 participated in one interview (n = 13). Data were analysed using codebook thematic analysis. Decisions to participate in the trial were influenced by the potential for improved prognosis and limited alternative therapies. Parents felt reassurance because they were taking action and gratitude for access to expertise in OI. Balancing hope, expectations and uncertainty around treatment efficacy was challenging. Parents also expressed disappointment and uncertainty about treatment ending. Practical challenges included travel for treatment with a child with OI or late in pregnancy. Professionals noted the difficulty in managing parental expectations and the regulatory and logistical barriers of an international trial. Findings emphasised the need for clear communication before, during and after the trial, transparent information and trial designs that accommodate the needs of individual families.
2026-05-26 | Balancing osteogenesis and adipogenesis in osteogenesis imperfecta: PLIN2 and E2F2 as key targets for mesenchymal stem cell therapy.
Osteogenesis imperfecta (OI) necessitates innovative mesenchymal stem cell (MSC) therapies targeting key molecular pathways to enhance targeted and combination treatments and improve bone health. To investigate the therapeutic mechanisms of various interventions for OI by analyzing relevant datasets, with a focus on lipid metabolism-related genes, particularly PLIN2, in order to determine whether they influence the balance between osteoblast and adipocyte differentiation. This study analyzed datasets from the Gene Expression Omnibus (GEO; GSE157587, GSE214064, GSE186141) and UK Biobank genome-wide association study (GWAS) summary statistics (UKB-b-4657, UKB-b-1096, UKB-b-8875, UKB-b-20124) using bioinformatics tools, including GEO2R, DESeq2, TwoSampleMR, MR-Egger, MR-PRESSO, gwasrapidd, and summary data-based Mendelian randomization (MR), to identify differentially expressed genes (DEGs) and assess causal relationships with heel bone mineral density (BMD). Differentially expressed genes analysis of GSE157587 identified PLIN2 as the most significant gene influenced by MSC therapy in OI (log2 fold change = 0.428, adjusted p = 3.29 × 10-6), whereas GSE186141 revealed 770 DEGs in OI patients, with 7 overlapping with PLIN2-related genes. Notably, TNFRSF19 (log2 fold change = -2.7454, adjusted p = 3.930 × 10-7 in OI; 1.5001, adjusted p = 3.482 × 10-3 in PLIN2 knockdown) and E2F2 (log2 fold change = -2.1428, adjusted p = 8.830 × 10-5 in OI; 1.7207, adjusted p = 1.244 × 10-2 in PLIN2 knockdown) were identified as key genes. Mendelian randomization analysis confirmed a negative association between E2F2 and heel BMD (p = 1.116 × 10-7 to 6.073 × 10-5; effect size -0.0461 to -0.0277). PLIN2 and E2F2 emerge as critical targets for refining MSC therapy in OI, with the potential to improve bone formation and reduce fat accumulation by restoring the osteogenesis-adipogenesis balance. These findings may support the development of combination therapies or engineered MSCs, ultimately improving clinical outcomes for patients with OI.
2026-03-09 | Deciduous pulp stem cell-derived extracellular vesicles stimulate the proliferation of cartilage progenitor cells via extracellular signal-regulated protein kinase 1/2 activation.
The developmental dysfunction of cartilage progenitor cells (CPCs) causes dwarfism. Radical therapies for dwarfism remain underdeveloped. Recently, the therapeutic benefits of extracellular vesicles (EVs) released from human exfoliated deciduous tooth-derived stem cells (SHED) have been investigated for their potential to restore disease-target cells. However, the effects of EVs on human CPCs for the treatment of dwarfism remain unclear. We investigated the impact of EVs on cell proliferation, telomerase activity, telomerase reverse transcriptase (TERT) expression, cell cycle, and extracellular signal-regulated protein kinase 1/2 (ERK1/2) levels in human CPCs and in our established osteogenesis imperfecta (OI)-specific SHED (OI-SHED). EVs enhanced the proliferation and G1/S phase transition of CPCs, which was associated with increased TERT expression and telomerase activity. However, RNase-preconditioned EVs did not attenuate the efficacy of EVs in CPCs. ERK1/2 inhibitor tests demonstrated that CPCs exhibited suppressed proliferation, telomerase activity, and G1/S phase progression. EV-transferring CD29 induced ERK1/2 phosphorylation in CPCs, subsequently activating telomerase activity to induce proliferation. Interestingly, EV stimulation restored the reduction in cell proliferation, cell cycle progression, phosphorylated ERK1/2 levels, and TERT expression in OI-SHED. In conclusion, the present findings provide new insights into ERK1/2-mediated proliferation of human CPCs using EVs.
2026-01-28 | CaO-SiO2-P2O5-B2O3-Based Bioactive Glass (BGS-7) Macrobeads Incorporated in Hydrogels Aid Bone Regeneration: Evaluation in Rabbit Calvarial and Femoral Defect Models.
Bone graft substitutes are extensively investigated for addressing critical-size bone defects; however, their efficacy is limited by inadequate bone regeneration and subpar handling properties. Herein, we compared the bone regenerative capacity of CaO-SiO2-P2O5-B2O3-based bioactive glass (BGS-7) macrobeads with that of β-tricalcium phosphate (β-TCP) beads and evaluated their performance when incorporated into hydrogels to improve their handling properties. BGS-7 macrobeads were fabricated via alginate crosslinking and heat treatment, and their physicochemical properties and microstructures were characterized. In a rabbit calvarial defect model, BGS-7 macrobeads, heat-treated at 600 and 800 °C, exhibited superior bone bridging and degradation than size-matched β-TCP macrobeads. To further evaluate their regenerative potential, critical-size defects (6 mm diameter × 10 mm depth) were created in the rabbit femoral condyle. To enhance clinical applicability, BGS-7 beads were incorporated into cellulose-based hydrogels and implanted into the defects. Radiographic and histomorphometric analyses demonstrated that bone formation and stable fixation achieved with hydrogel formulations containing BGS-7 microbeads and Laponite were more pronounced than those with BGS-7 beads alone. The findings suggest that BGS-7 macrobeads, particularly when combined with microbead- and Laponite-containing hydrogels, represent a promising bone graft substitute with improved regenerative and handling properties compared with using BGS-7 beads alone.
proteins
2026-09-25 | Longitudinal change of bone microarchitecture and fracture risk in adults with osteogenesis imperfecta.
Incident fractures remain the major complications in adults with osteogenesis imperfecta (OI). Cross-sectional studies have shown impaired bone microarchitecture (BM), but the longitudinal changes and their contribution to fracture risk remain unknown. Here, we investigated the changes in BM and their associations with clinical, genetic factors and incident fractures. Fifty-five adults with OI (23 men, 32 women, including 6 postmenopausal; mean age 43 ± 14 years) were followed for a median of 2.7 years (IQR 2.1-4). HR-pQCT was used to measure the cortical (Ct) bone mineral density (vBMD) and thickness and the trabecular (Tb) bone volume (BV/TV), vBMD at the distal radius and tibia. Longitudinal changes adjusted for clinical parameters were analysed with mixed-effects models. We investigated the associations of BM changes and the incident fractures by logistic regression adjusted for age, sex/menopause, genotype and treatment. At the distal radius, Tb.vBMD, Tb.BV/TV and Ct.Pm and were low in premenopausal and postmenopausal women at baseline. Tb.BV/TV declined in men (-0.0030/yr, p < 0.01) and premenopausal women (-0.0027/yr, p < 0.05). Ct.Th decreased also in men (-0.0735 mm/yr) and premenopausal women (-0.0813 mm/yr, p < 0.001). However, Tb.BV/TV increased (+0.0019/yr, p < 0.05) and Ct.Th decreased (-0.0819 mm/yr, p < 0.0001) in postmenopausal women, suggesting trabecularization of cortical bone. Incident fractures during follow-up was similar in the genetic variants (p = 0.179). Neither Tb.BV/TV, Ct.Th nor vBMD changes predicted incident fractures. Bone microarchitecture deteriorates over time in adults with OI and more after menopause. However, longitudinal changes do not predict incident fractures, highlighting the complex determinants of fracture risk in OI.
2026-07-28 | Dose matters: haploinsufficiency in osteogenesis imperfecta.
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.
2026-07-22 | Off-Label Use of Teriparatide for Osteotomy Healing in an Adolescent with Osteogenesis Imperfecta Type VIII: A Case Report.
Osteogenesis imperfecta (OI) type VIII is an autosomal recessive skeletal dysplasia caused by P3H1 variants, resulting in defective collagen post-translational modification and increased bone fragility. Teriparatide (TPTD), a recombinant parathyroid hormone analogue, stimulates osteoblast activity and bone formation and is approved for the treatment of osteoporosis in adults. A 16-year-old male with genetically confirmed OI type VIII presented with delayed union with characterized by the absence of radiographic evidence of healing six months after femoral osteotomy and intramedullary rodding surgery. His prior management included intermittent bisphosphonate therapy which had improved bone mineral density. He had no recent history of fractures. Off-label therapy with TPTD (20 µg/day subcutaneously) was initiated and continued for six months. Although systemic markers of bone formation showed no remarkable changes, except osteocalcin, during therapy, serial radiographs confirmed successful bone union. The treatment was well tolerated, with no reported side effects; however, mild hypercalcemia with hypercalciuria, which persisted after discontinuation of TPTD therapy, was detected. Bisphosphonate therapy was resumed upon completion of TPTD treatment. This case represents the first documented use of TPTD to promote osteotomy healing in an adolescent with OI. The favourable clinical and radiologic outcome suggests a potential role for anabolic therapy in managing complex bone healing challenges in paediatric OI. Further research is warranted to evaluate safety and efficacy in this population.
2026-06-17 | Transcriptional profiling of otic capsule and femur in the oim mouse model of osteogenesis imperfecta.
Hearing loss is a common and debilitating complication of the brittle bone disorder osteogenesis imperfecta (OI). Existing treatments that are designed to address age-related hearing loss in the broader population do not meet the needs of OI patients, who exhibit skeletal fragility and begin to lose their hearing when they are young-adults. The biologic mechanisms responsible for hearing loss in OI are unknown, hindering the development of preventative therapies. To identify potential mechanisms that drive this condition, we performed transcriptome profiling on femoral and otic capsule specimens obtained from the Col1a2oim mouse model at 12- and 25-wk of age. We found that the bulk transcriptomes of femora and otic capsules were markedly different, regardless of mouse genotype. Further, bone formation-associated transcripts were reduced at 25-wk, compared to 12-wk. Mice homozygous for the oim mutation exhibited increased abundance of transcripts associated with osteoblast activity and type I collagen production compared to WT mice in both femoral and otic capsule specimens. The most notable difference between oim and WT mouse otic capsules was the depletion of the transcripts that encode mucin and keratin, suggesting dysregulation of epithelial cells, which has been previously linked to hearing loss. Our data offer new insights into the mechanisms that disrupt the middle ear in OI. Analysis of epithelial cells obtained from OI patients and additional models of OI could suggest novel strategies to prevent and/or treat hearing loss.
2026-06-13 | PTH treatment is effective in the Aga2/+ mouse model of moderate to severe osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by brittle bone and recurrent fractures. The majority of OI is clinically categorized into mild, moderate, severe, and perinatal lethal forms. A clinical study on the use of intermittent parathyroid hormone (PTH) as an anabolic therapy for OI found PTH was effective in mild, but not in individuals with moderate/severe OI. However, this sub-group analysis was relatively small and considered preliminary by the authors. Since then, research on PTH therapy in OI has focused on mild OI and no studies of PTH use in moderate/severe OI patients or animal models have been reported. In this work, we used the Aga2/+ mouse, an established autosomal dominant model of moderate/severe OI, to investigate whether PTH treatment has an effect on bone. In vitro, Aga2/+ osteoblasts were sensitive to PTH and exhibited similar transcriptional changes compared to WT. In vivo, PTH treatment improved lumbar trabecular bone, increased cortical bone area fraction in the mid-femur, and, in females, led to improved biomechanical properties. These results demonstrate the Aga2/+ model responded to PTH and support further investigation into whether PTH is effective in adult individuals with moderate/severe OI who have limited treatment options.
small molecules
2026-09-26 | Heme Oxygenase-1 in Bone Remodeling: Molecular Mechanisms and Therapeutic Implications.
Bone remodeling is a dynamic and tightly regulated process that maintains skeletal homeostasis through a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Disruption of this balance contributes to the development of bone-related disorders, particularly osteopenia, osteoporosis and osteogenesis imperfecta, which weaken, deform, or cause fractures. Increasing evidence indicates that oxidative stress and chronic inflammation impair osteoblast functions while promoting osteoclast differentiation and activity. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with cytoprotective, antioxidant, and anti-inflammatory properties. Besides its primary role in cellular defense against oxidative stress and inflammatory damage, HO-1 has been shown to be involved in both osteoblast differentiation and osteoclastogenesis. Through its interaction with key regulatory systems, including the receptor activator of nuclear factor κB (RANK)-receptor activator of nuclear factor κB ligand (RANKL)-osteoprotegerin axis and redox-sensitive signaling pathways, HO-1 contributes to maintenance of optimal bone remodeling. The enzyme also plays a role in modulating metabolic processes in the bone. This review highlights the role of HO-1 in bone formation, bone resorption, and related pathophysiologic conditions. Furthermore, the therapeutic potential of HO-1 as a target for bone disorders is discussed.
2026-09-20 | The Effect of Bisphosphonate Therapy on Hearing and Middle Ear Dysfunction in Pediatric Osteogenesis Imperfecta.
Osteogenesis imperfecta (OI) is a heterogeneous inherited connective tissue disorder characterized by impaired bone matrix formation. Hearing loss is observed in 28 to 65 percent of patients with OI. Most patients with OI experience conductive hearing loss (CHL); however, mixed and sensorineural (SNHL) hearing loss has also been described. The primary aim of this retrospective study was to characterize the rates of middle ear dysfunction (MED) and hearing loss (HL) with pediatric OI and investigate the efficacy of bisphosphonate therapy in HL. Retrospective chart review of pediatric patients with OI. Pediatric patients with OI treated between January 2000 and January 2021 were included. HL was defined according to pure tone audiometry, while MED was determined by tympanometry at 226 Hz. Patients were categorized by the OI type and considered to be using bisphosphonates if they had been initiated within 1 year prior to testing. No direct intervention was performed. Comparisons between bisphosphate use and no bisphosphonate use were explored. The chi-square test was utilized for categorical data to investigate whether a significant association with two-by-two variables existed. This study included 144 patients. Of these patients, 12.5 percent had HL. Tympanometry revealed that 25 percent had MED. Additionally, 82.6 percent were currently using bisphosphonates. Across all OI types, no association between current bisphosphonates and HL or MED was observed. However, a subanalysis of patients with type I OI indicated that the absence of MED was statistically associated with current bisphosphonate therapy (p = 0.025). Bisphosphonates are associated with the absence of MED in pediatric patients with type I OI. Because of its mild disease course, bisphosphonates are not commonly used for many patients with type I OI. By reducing MED and its associated comorbidities, our results suggest that bisphosphonate use may confer a significant therapeutic benefit. HL is common in individuals with OI. Our study suggests that initiating bisphosphates at an earlier age may delay middle ear changes that contribute to HL.
2026-09-08 | Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.
2026-08-20 | Injury-driven stromal exhaustion disrupts intrinsic regenerative capability.
Bone marrow stromal cells, marked by leptin receptor (Lepr) and C-X-C motif chemokine ligand 12 (Cxcl12), orchestrate osteogenesis and maintain bone homeostasis. Following injury, these stromal cells directly generate reparative bone and subsequently restore the marrow microenvironment, a process widely regarded as a reliable regenerative response. However, it remains unclear whether stromal cells retain full regenerative capacity after prior injury. Here, we show that Lepr+Cxcl12+ stromal cells have limited regenerative capacity and become dysfunctional upon repeated activation, defining a state of stromal exhaustion. Lepr-Cre-labeled stromal cells progressively lose osteogenic potential after repeated injury and instead differentiate into bone marrow adipocytes. Exhausted stromal cells are distinct from aging stromal cells, exhibiting metabolic abnormalities, chronic inflammation associated with stress responses, and impaired regenerative plasticity. Furthermore, β-catenin deletion during injury repair induces adipogenesis through stromal lineage switching, whereas pharmacological and genetic activation of Wnt/β-catenin signaling partially rescues osteogenesis, indicating that dysregulated Wnt/β-catenin signaling drives stromal exhaustion and impaired regeneration. As repeated regenerative activation may occur in recurrent fractures, orthopedic surgeries, osteoporosis, and osteogenesis imperfecta, stromal exhaustion represents a critical barrier to bone regeneration and a potential therapeutic target for restoring stromal plasticity.
2026-08-10 | Favorable aortic remodeling following type B aortic dissection in a patient with osteogenesis imperfecta.
Osteogenesis imperfecta is a heritable type I collagen disorder, with aortic dissection a recognized complication. A 69-year-old man with osteogenesis imperfecta presented with acute uncomplicated type B aortic dissection with a thrombosed false lumen, managed with anti-impulse therapy targeting systolic blood pressure < 120 mm Hg and heart rate < 70 beats/min. Despite an ulcer-like projection and 4.2 cm proximal descending aortic diameter, serial imaging demonstrated complete resolution with optimal medical therapy by 6 months and reduction to 3.2 cm at 12 months. This favorable remodeling is notable given the underlying collagen disorder, where tissue fragility raises concerns about impaired healing and aortic integrity.
gene therapies
2026-09-30 | Pathogenesis and precision management of osteogenesis imperfecta: from genetic mechanisms to novel therapies.
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal dysplasia characterized by systemic bone fragility. Beyond skeletal manifestations, OI is a multisystem condition involving dentinogenesis imperfecta, hearing loss, joint hyperlaxity, and cardiopulmonary complications. The diagnostic paradigm for OI has undergone a revolutionary shift from traditional clinical phenotyping to a molecular etiology-based framework. Driven by advancements in high-throughput sequencing, mutations in over 20 implicated genes have expanded the current OI nosology to at least 23 distinct types. This narrative review was conducted by searching for papers using PubMed/MEDLINE. Relevant publications were identified using single and/or combined keywords including: osteogenesis imperfecta, genes (such as COL1A1 and COL1A2), animal models, phenotypes (such as osteopenia and femoral bowing), and drug therapies (such as bisphosphonate and denosumab), mesenchymal stem cells, gene therapy, and pluripotent stem cells. This review systematically delineates the molecular pathogenesis of OI, categorizing defects into disrupted collagen biosynthesis, impaired post-translational modification, aberrant procollagen trafficking, and dysfunctional osteoblast differentiation or mineralization pathways. Of note, we highlight the unique genetic landscape and clinical characterization of OI within Asian populations. Furthermore, we evaluate the transition towards precision management. Surgical management of OI has been optimized by telescopic rodding and a multidisplinary approach. Bisphosphonates remain a cornerstone of medical therapy, though responses vary with OI genotypes. Emerging targeted biologics include denosumab, romosozumab, setrusumab, and fresolimumab. Finally, we discuss the transformative potential of cell-based therapies, particularly mesenchymal stem cells. Precision gene editing technologies, such as CRISPR-Cas9, offer a strategy in addressing the root genetic causes of OI. Integrating molecular diagnostics with robust genotype-phenotype correlations is essential for advancing personalized care. Future breakthroughs will rely on the translation of gene and cell therapies to ultimately improve the long-term clinical outcomes for patients with OI.
2026-09-27 | In vitro validation of a CRISPR/Cas9 guide RNA targeting COL1A1 gene by cleavage assay.
The CRISPR/Cas9 system has become a widely used tool for genome editing; however, editing efficiency is largely determined by the design and functional activity of the guide RNA (gRNA). Experimental validation prior to cellular applications is particularly important when targeting genes associated with genetic disorders, such as COL1A1, which is frequently mutated in Osteogenesis Imperfecta. This study performed an in vitro functional validation of a CRISPR/Cas9 gRNA designed to target exon 2 of the COL1A1 gene, using a cell-free cleavage assay as a preliminary step before cellular genome editing applications. Three gRNAs targeting distinct COL1A1 exons were designed using bioinformatics tools; the exon 2 candidate was selected for experimental validation based on predicted efficiency, favorable off-target profile, and successful PCR amplification of its target region. The selected gRNA was assembled with recombinant Cas9 protein into a ribonucleoprotein complex, which was incubated with PCR-amplified DNA substrates derived from five distinct human cell lines. Cleavage products were resolved by polyacrylamide gel electrophoresis and quantified by densitometric analysis. The gRNA directed reproducible, specific Cas9-mediated cleavage at the intended COL1A1 exon 2 target site across all cell lines tested, with mean cleavage efficiencies ranging from 58.79% to 68.84%. These results confirm functional validation of the gRNA through in vitro cleavage activity and support its candidate selection for subsequent cellular studies targeting COL1A1, representing an initial step toward future knockout-style cellular models of Osteogenesis Imperfecta.
2026-06-19 | FKBP10 mitigates osteoporosis by restraining the HSPA5-coupled ERS-pyroptosis axis to enhance osteogenic differentiation in BMSCs.
Osteoporosis is characterized by progressive bone deterioration and is closely associated with impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Mutations in FK506-binding protein 10 (FKBP10) are linked to osteogenesis imperfecta. However, the role of FKBP10 in osteoporosis and osteogenic differentiation of BMSCs remains unclear. Serum FKBP10 levels were examined in individuals with different bone mineral density. An ovariectomized (OVX) mouse model was established to mimic osteoporosis, and adeno-associated virus serotype 9 (AAV9) was used to achieve FKBP10 overexpression in vivo. Osteoporotic bone phenotypes were assessed by Micro-CT, hematoxylin and eosin staining, and Masson staining. Loss- and gain-of-function experiments were performed in BMSCs using siRNA and overexpression plasmids. Osteogenic differentiation was assessed by alkaline phosphatase staining and Alizarin red S staining. The underlying mechanism was investigated by RNA sequencing, immunofluorescence, co-immunoprecipitation, and protein degradation assays. FKBP10 levels were reduced in the serum of patients with osteoporosis, as well as in bone tissue and primary BMSCs from OVX mice. AAV9-mediated FKBP10 overexpression attenuated OVX-induced bone loss. FKBP10 knockdown impaired osteogenic differentiation of BMSCs, whereas FKBP10 overexpression enhanced osteogenic differentiation. Mechanistically, FKBP10 knockdown activated Caspase-1-mediated pyroptosis in BMSCs. Further investigation confirmed that FKBP10 directly interacted with heat-shock-protein family A member 5 (HSPA5) and promoted HSPA5 lysosomal degradation, thereby alleviating HSPA5-associated sustained endoplasmic reticulum stress (ERS) and subsequent pyroptosis. Our findings identify FKBP10 as a protective regulator that preserves the osteogenic differentiation capacity of BMSCs and attenuates osteoporosis progression by restraining the HSPA5-associated ERS-pyroptosis pathway.
2026-05-25 | A New Wnt1 Mutant Rat Model of Osteogenesis Imperfecta and Its Application in AAV9-Mediated Gene Therapy.
Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous bone disorder, with more than 20 genes contributing to OI development. Previously, we identified WNT1 c.620G > A (p.Arg207His) mutation among Chinese patients with autosomal recessive OI (AR-OI). This study aims at investigating the causative role of WNT1 deficiency in OI and evaluate whether AAV-based gene therapy could ameliorate bone abnormalities. We generated and analyzed the Wnt1R207H/R207H rat model. The AAV9-Wnt1 virus was delivered via direct intraosseous injection into the femoral marrow cavity of the OI rats to evaluate its therapeutic potential. The homozygous Wnt1R207H/R207H rat recapitulated key features of AR-OI, including fractures, reduced bone mass, growth retardation, decreased survival rate, increased osteoclast numbers, diminished osteoblast function and mineralization capacity, compared with heterozygous and wild-type littermates. In vitro, Wnt1 overexpression in osteoblasts promoted osteoblast activity and bone mineralization. Furthermore, AAV9-Wnt1 treatment in OI rats resulted in significant recovery of bone density and mechanical strength, stimulation of osteoblast activity, suppression of osteoclast activity, and upregulation of Type I collagen expression. Our study demonstrates that WNT1 c.620G > A (p.Arg207His) is pathogenic, and confirms that AAV-mediated Wnt1 gene therapy represents a promising strategy for treating OI caused by WNT1 mutations.
2026-05-13 | Autologous guided bone regeneration: a comprehensive narrative review.
Bone defect is a prevalent and complex challenge in orthopedics and oral-maxillofacial surgery, severely compromising skeletal integrity and functional recovery. Autologous Guided Bone Regeneration (GBR) has emerged as a highly effective therapeutic strategy, demonstrating remarkable efficacy in treating long bone fractures, nonunions, post-tumor resection bone defects, and alveolar bone augmentation for dental implant procedures. This narrative review comprehensively synthesizes the latest research progress, core mechanisms, technical innovations, existing challenges, and future prospects of Autologous GBR through an extensive analysis of domestic and international literature. Its core mechanism relies on selective cell occlusion theory: barrier membranes construct a bone regeneration microenvironment, blocking non-osteoblastic invasion while promoting osteoblast migration and differentiation. Autologous components play key roles: autologous bone (gold standard for grafting) has osteogenic activity, osteoinductivity and osteoconductivity; autologous bone marrow provides mesenchymal stem cells (MSCs) for osteoblast differentiation and microenvironment regulation; autologous growth factors (e.g., Bone Morphogenetic Proteins [BMP], Transforming Growth Factor-β [TGF-β]) regulate bone regeneration via cell signaling pathways. Technical advances include site-specific autologous bone harvesting (ilium, mandible, etc.) and optimized barrier membranes (absorbable Poly Lactic-co-Glycolic Acid [PLGA]/collagen, non-absorbable expanded Polytetrafluoroethylene [ePTFE]). Cell-molecular studies (MSCs differentiation, Wnt pathway) offer theoretical basis. Challenges include surgical infection, potential immune rejection and poor osseointegration. Prospects involve 3D-printed scaffolds, gene therapy-tissue engineering combination, and application in complex diseases like osteogenesis imperfecta. This review provides references for researchers and clinicians.
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2026-09-24 | Skeletal pathologies caused by PLS3 inactivation are predominantly associated with impaired cortical bone integrity.
The identification of pathogenic PLS3 variants in individuals with X-linked osteoporosis (XLO) has demonstrated the importance of the actin-bundling protein plastin-3 for skeletal integrity. We and others have previously reported that Pls3-deficient mice display a skeletal phenotype that unexpectedly affects only the cortical bone compartment. To better characterize the impact of PLS3 inactivation on bone (micro-)architectural parameters in humans, we retrospectively analyzed skeletal parameters obtained from male XLO patients and compared them to corresponding data from male individuals with genetically diagnosed osteogenesis imperfecta type I (OI-I). We observed no major differences between XLO and OI-I patients in baseline characteristics, laboratory parameters, or bone mineral density measurements by dual-energy X-ray absorptiometry (DXA). However, there was a significant difference between the two groups observed by high resolution peripheral quantitative computed tomography (HRpQCT). More specifically, XLO patients displayed significantly reduced cortical bone parameters, compared to both normal reference ranges and OI-I, especially at the distal radius. We also analyzed female heterozygous carriers of (likely) pathogenic PLS3 alleles, who were less affected compared to male XLO patients. However, two of them displayed osteoporotic fractures at a postmenopausal age, thus treatment with romosozumab, a monoclonal antibody targeting sclerostin, was initiated and appeared to be effective. Since another sclerostin-neutralizing antibody is currently studied for the treatment of OI patients, we crossed Pls3-deficient mice with mice carrying a high bone mass allele of Lrp5 (Lrp5A213V), which serves as a molecular mimic of anti-sclerostin therapy. We found that the presence of the Lrp5A213V allele led to significantly increased cortical and trabecular bone mass not only in wildtype but also in Pls3-deficient mice. Taken together, our data raise the hypothesis that PLS3 inactivation predominantly affects cortical bone parameters in mice and humans and that anti-sclerostin therapy could be effective for the treatment of XLO.
2026-09-07 | Effectiveness and limitations of anti-sclerostin therapy in osteogenesis imperfecta: A systematic review.
Sclerostin inhibition is a potential anabolic therapy for osteogenesis imperfecta (OI). We systematically evaluated whether anti-sclerostin therapy improves bone quantity, bone quality, mechanical performance, and fracture-related outcomes in preclinical and clinical studies of OI. PubMed, Embase, and Web of Science were searched for randomized controlled trials and controlled animal studies investigating sclerostin inhibition in OI. 3 reviewers independently screened studies, extracted data using a standardized template, and assessed methodological quality with Joanna Briggs Institute appraisal tools. 18 studies were included:15 controlled experimental studies in mouse models of OI and 2 clinical trials in adults with OI, plus one ancillary iliac crest biopsy study derived from a trial cohort. Across murine models, anti-sclerostin consistently increased bone quantity (e.g., trabecular bone volume, cortical thickness, bone mineral density), often increased whole-bone strength, and sometimes reduced fracture incidence. However, efficacy varied by genotypes, ages, skeletal sites, or outcome levels. In several collagen-related murine OI models (e.g. Brtl/+, Crtap-deficient and the severe Col1a1Jrt/+ model), tissue-level material properties such as elastic modulus, hardness and mineralization indices remained abnormal despite structural gains. Clinical studies in adults with OI similarly demonstrated increases in areal bone mineral density, whereas microarchitectural and biopsy-based matrix-level outcomes were more variable and frequently failed to normalize. Anti-sclerostin therapy elicits an anabolic response in OI, improving overall bone mass and whole-bone strength. However, it does not consistently restore intrinsic tissue-level material properties. Current clinical evidence supports skeletal responses in adults with COL1A1/COL1A2-related OI types I, III, and IV, without a demonstrated difference between type I and pooled types III/IV; it does not identify a preferentially responsive individual genotype or an optimal pediatric age. Future trials should prespecify molecular and skeletal-maturity strata and prioritize fractures and whole-bone strength, supported by axial DXA, weight-bearing-site HR-pQCT/microFE, and tissue-level bone-quality outcomes.
2026-07-19 | Romosozumab in postmenopausal women with classical Osteogenesis imperfecta.
This study explored whether Romosozumab, an anti-sclerostin antibody, can improve bone quality in women with Osteogenesis imperfecta. After 12 months, spinal areal bone mineral density increased, showing a beneficial treatment effect, although changes in hip bone density and bone structure were less pronounced than in women with severe osteoporosis. Osteogenesis imperfecta (OI) is the most common hereditary bone disorder, characterized by increased bone fragility and impaired bone quality, but pharmacological treatment is limited. Ongoing clinical trials investigate monoclonal anti-sclerostin antibodies for OI patients, offering new hope for reducing bone fragility by increasing bone mass. Postmenopausal women with either OI (n = 5) or severe osteoporosis (OPO, n = 10) receiving Romosozumab monthly (210 mg s.c.) for 12 months were analyzed retrospectively. Clinical assessments were performed at baseline, after 6 months, and after 12 months. Bone mass and structure were evaluated at baseline and after 12 months of treatment. In addition, serum and urine markers of bone turnover were analyzed at each time point. The mean age of the participants was 53.6 ± 8.9 years for OI patients and 57.2 ± 5.8 years for OPO patients (p = 0.444). After 12 months of Romosozumab treatment, spinal aBMD and osteocalcin increased significantly in OI patients, indicating an anabolic response. HR-pQCT analysis revealed no statistically significant microstructural changes in patients with OI, although trends and moderate effect sizes suggested potential improvements. In patients with OPO, we observed a more pronounced response of bone turnover markers with greater aBMD gains at both the spine and femur, as well as significant improvements in bone microstructure, particularly at the tibia. Romosozumab treatment in postmenopausal women with OI resulted in a significant increase in spinal aBMD, though the effect on hip aBMD and peripheral bone microstructure was limited in contrast to postmenopausal osteoporosis.
2026-07-17 | Genetic Bone Diseases: A Scoping Review of Pathology, Symptoms, Diagnosis, Treatment, and New Horizons.
Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.
2026-07-10 | Artificial Intelligence for Evidence Synthesis of Emerging Biologics to Improve Skeletal Health in Osteogenesis Imperfecta: Systematic Review and Meta-Analysis.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and recurrent fractures. Emerging biologics demonstrate promise by targeting bone-remodeling pathways, yet evidence for their efficacy and safety remains fragmented and heterogeneous, and no prior systematic review in OI has incorporated artificial intelligence (AI) to synthesize it. This study aims to systematically evaluate the efficacy and safety of novel biologics in patients with OI using an AI-assisted workflow for evidence synthesis. We conducted a systematic review and meta-analysis of interventional trials of denosumab, setrusumab, teriparatide, romosozumab, and fresolimumab. Data were retrieved from PubMed, Web of Science, Embase, ScienceDirect, the Cochrane Library, and ClinicalTrials.gov up to December 1, 2025. Eligible studies enrolled individuals with OI, reported areal bone mineral density (aBMD) and/or fractures, and were randomized, nonrandomized, or single-arm studies; case series were excluded. As a methodological feature, GPT-4o was integrated into the workflow to perform a parallel 2-stage screening (title/abstract and full text) and to assist with risk of bias assessment using an adapted Cochrane RoB 2 tool. The primary outcome, percentage change in aBMD, was synthesized using a random-effects meta-analysis. GPT-4o was benchmarked against human reviewers using sensitivity, specificity, and weighted Cohen κ. Thirteen trials (n=684) were systematically reviewed, of which 10 (n=333) contributed to meta-analyses. In children, denosumab produced the greatest 12-month increase in lumbar spine aBMD (25.49%, 95% CI 17.14%-33.84%). In adults, setrusumab at 12 months yielded the highest improvement (9.38%, 95% CI 6.5%-12.26%). Across trials, no biologic significantly reduced fracture incidence compared to bisphosphonates. Safety profiles varied: denosumab was associated with a high risk of hypercalcemia in children (30.95%), whereas setrusumab had no treatment-related serious adverse events. AI achieved high sensitivity in abstract (97.4%) and full-text (88.9%) screening, and reduced total screening time by over 95%. Although there was substantial agreement with humans in the quality assessment (Cohen κ=0.778, 95% CI 0.710-0.846), the model exhibited optimism and positional biases due to reliance on probabilistic language patterns rather than structured clinical reasoning. This review is the first to synthesize and quantitatively compare skeletal outcomes across multiple biologics in OI with an AI-assisted review workflow. Denosumab and setrusumab demonstrate promising efficacy in improving lumbar spine aBMD across ages, although current evidence does not support superior fracture reduction over bisphosphonates. GPT-4o can substantially accelerate evidence synthesis but should be deployed with explicit human oversight in tasks requiring contextual understanding and clinical reasoning. These findings should be interpreted cautiously given the small and heterogeneous trial base. Taken together, our workflow presented how evidence synthesis may be scaled and operationalized in real-world rare disease research.
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Drug Discovery Landscape
20 orphan drug designations for Osteogenesis imperfecta.
20 orphan drug designations for Osteogenesis imperfecta.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
4-(2-Methylanilidocarbamoyl)-phenylacetyl-L-Citrullyl-L-Glutamyl-L-Seryl-L-Valyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-[N-(19-carboxy-1-oxononadecyl)-L-gamma-glutamyl]-L-Lysyl amide | peptides | FDA | — | Zhongshan LaiBo RuiChen BioMedicine Co., Ltd.(RabPharma) |
Cisatracurium besilate | other | EMA | — | Fundacion Vasca De Innovacion E Investigacion Sanitarias |
N-[(2S)-1-[(3aS,6R,6aR)-6-Ethynyl-3-oxohexahydro-2H-furo[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide hydrochloride | small molecules | FDA | — | OsteoCat Therapeutics AB |
Humanised IgG4 bispecific monoclonal antibody against sclerostin and dickkopf-related protein 1 | antibodies | EMA | Worldwide Clinical Trials | |
anti-Siglec-15 monoclonal antibody on a human IgG1-Fc-silenced backbone | antibodies | FDA | — | NextCure, Inc. |
DNA, (Cm-Gm-Gm-Gm-G-T-G-T-G-G-G-T-T-C-G-T-C-G-T-T-A-G-C-T-T-G-A-T-T-T-G-G-C-A-G-C-Um-Gm-Cm-Cm-(5'->3')-dT), 5'-ester with (29S)-29-(tert-butoxycarbonyl)-1-((hydroxyphosphoryl)oxy)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraazaoctatetracontan-48-oic acid | oligonucleotides | FDA | Aptacure Therapeutics Limited | |
A Humanized Bispecific Antibody Neutralizing Both Sclerostin and Dickkopf-1 | antibodies | FDA | Angitia Biopharmaceuticals Guangzhou Limited | |
anti-human transforming growth factor beta (TGF-Beta) monoclonal antibody (mAb), based on the amino acid sequence of the human monoclonal antibody fresolimumab (GC1008) with the exception of one serine to proline substitution | antibodies | FDA | Sanofi Genzyme, A Sanofi Company | |
Losartan | small molecules | EMA | 3R Pharma Consulting GmbH | |
allogenic fetal mesenchymal stem cells | cell therapies | FDA | BOOST Pharma Aps | |
Allogeneic fetal mesenchymal stem cells | cell therapies | EMA | Boost Pharma ApS | |
romosozumab | antibodies | FDA | Amgen Inc. | |
denosumab | antibodies | FDA | Amgen Inc. | |
DNA, (Cm-Gm-Gm-Gm-G-T-G-T-G-G-G-T-T-C-G-T-C-G-T-T-A-G-C-T-T-G-A-T-T-T-G-G-C-A-G-C-Um-Gm-Cm-Cm-(3'¿3')-dT), 5'-ester with [[5-(phosphoonoxy) pentyl] amino] carbonyl-oxy-1, 2-ethanediyl, sodium salt | oligonucleotides | FDA | — | Aptacure Therapeutics Limited |
Recombinant humanised monoclonal IgG2 lambda antibody against human sclerostin | antibodies | EMA | Mereo BioPharma Europe B.V. | |
human monoclonal antibody targeting human sclerostin | antibodies | FDA | Ultragenyx Pharmaceutical, Inc. | |
human allogeneic bone marrow derived osteoblastic cells | cell therapies | FDA | — | Biosenic SA |
Human allogeneic bone-marrow-derived osteoblastic cells | cell therapies | EMA | — | BioSenic |
risedronate sodium | small molecules | FDA | Warner Chilcott Pharmaceuticals | |
alendronate | small molecules | FDA | — | Merck, Sharpe & Dohme Corp. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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