RARE DISEASE
High bone mass osteogenesis imperfecta
High bone mass osteogenesis imperfecta
High bone mass osteogenesis imperfecta
Synonyms: High bone mass OI
Synonyms: High bone mass OI
Synonyms: High bone mass OI
Drug discovery
0
drugs
With orphan designations
Overview
High bone mass osteogenesis imperfecta (HBM-OI) is a rare genetic bone dysplasia characterized by increased bone fragility and fractures despite elevated bone mineral density (BMD). Caused by pathogenic variants in COL1A1/A2 or BMP1 affecting collagen processing, it presents with normal/mild short stature, recurrent fractures (often vertebral/peripheral), and typically normal sclerae/dentinogenesis. Diagnosis requires genetic testing and BMD assessment [1][2][11].
Burden
High morbidity: Chronic pain, mobility limitations, and degenerative joint disease (e.g., osteophyte-predominant osteoarthritis) [4][6].
Frequent hospitalizations: Median 3 admissions (12-day stays) per patient, driven by fractures [5][14].
Economic impact: Elevated inpatient costs (median ~$3,163 USD/patient), prolonged disability, and reduced quality of life [5][14].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
73 drug discovery papers about High bone mass osteogenesis imperfecta. Recent publications:
73 drug discovery papers about High bone mass osteogenesis imperfecta. Recent publications:
categories:
Small molecules
proteins
2024-11-13 | Genetics and Bone Mineral Density Predict the Fractures in Adults With Osteogenesis Imperfecta: A Prospective Study.
Osteogenesis imperfecta (OI) is a rare genetic bone disorder characterized by recurrent fractures. In adults, the value of bone mineral density (BMD) in fracture risk is unknown. We prospectively investigated changes in BMD over time and analyzed the determinants of fracture in OI. Among 106 individuals with grade 1 and 4 OI in the Reference Centre of Rare Bone Diseases in Paris, we included those with BMD measurements at 1 or more skeletal sites (hip, lumbar spine, radius) from 2000 to 2022. For 71 individuals with reliable measurements (44 women, 8 postmenopausal; mean age 41.4 ± 13.7 years), baseline BMD was low at the lumbar spine only (mean Z-score -2.3 ± 1.5), affecting mainly men (mean Z-score -3 ± 1.6). Longitudinal changes were assessed for a median follow-up of 5.1 years (interquartile range 3.2-8.8). On adjustment for age, sex, and body mass index, BMD did not significantly change at any site. Logistic regression analysis revealed a high probability of fracture with baseline BMD Z-score <-2 SD vs ≥-2 SD [odds ratio 4.38, 95% confidence interval (CI) 1.10-21.75, P = .048] and harboring splicing, stop codon, and frameshift variants of COL1 gene (odds ratio 29.8, 95% CI 2.56-1503, P = .024). Our OI cohort showed low BMD at the lumbar spine but no significant change at any site after a median of 5.0 years of follow-up. The probability of fracture was associated with baseline BMD Z-score <-2 SD vs ≥-2 SD and harboring COL1 splicing, stop codon, and frameshift variants.
2016-02-02 | ENDOCRINOLOGY AND ADOLESCENCE: Osteoporosis in children: diagnosis and management.
Osteoporosis in children can be primary or secondary due to chronic disease. Awareness among paediatricians is vital to identify patients at risk of developing osteoporosis. Previous fractures and backaches are clinical predictors, and low cortical thickness and low bone density are radiological predictors of fractures. Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary paediatric units with the necessary multidisciplinary expertise. Modern OI management focuses on functional outcomes rather than just improving bone mineral density. While therapy for OI has improved tremendously over the last few decades, this chronic genetic condition has some unpreventable, poorly treatable and disabling complications. In children at risk of secondary osteoporosis, a high degree of suspicion needs to be exercised. In affected children, further weakening of bone should be avoided by minimising exposure to osteotoxic medication and optimising nutrition including calcium and vitamin D. Early intervention is paramount. However, it is important to identify patient groups in whom spontaneous vertebral reshaping and resolution of symptoms occur to avoid unnecessary treatment. Bisphosphonate therapy remains the pharmacological treatment of choice in both primary and secondary osteoporosis in children, despite limited evidence for its use in the latter. The duration and intensity of treatment remain a concern for long-term safety. Various new potent antiresorptive agents are being studied, but more urgently required are studies using anabolic medications that stimulate bone formation. More research is required to bridge the gaps in the evidence for management of paediatric osteoporosis.
2015-01-19 | How tough is brittle bone? Investigating osteogenesis imperfecta in mouse bone.
The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level, we attribute the loss in toughness to a decrease in the stabilizing enzymatic cross-links and an increase in nonenzymatic cross-links, which may break prematurely, inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales.
2014-09-29 | Sc65 is a novel endoplasmic reticulum protein that regulates bone mass homeostasis.
Members of the Leprecan family of proteins include enzymes, prolyl 3-hydroxylase 1 (P3h1), P3h2, and P3h3, and nonenzymatic proteins, Crtap and Sc65. Mutations in CRTAP and LEPRE1 (encoding P3H1) have been associated with human disease such as recessive osteogenesis imperfecta; however, the function of Sc65, which is closely related and highly homologous to Crtap, is unknown. Sc65 has been described as a synaptonemal complex protein, a nucleolar protein, and a cytoplasmic adapter protein. In light of its high sequence similarity with Crtap, an endoplasmic reticulum (ER)-associated protein, and the importance of post-translational modifications such as collagen prolyl 3-hydroxylation in bone metabolism, we hypothesized that Sc65 was an ER-resident protein that would have an important role in bone homeostasis. In this study, we demonstrate that Sc65 is a previously unrecognized ER protein and that it does not localize in the nucleus of somatic cells. Moreover, Sc65 is expressed and functional during skeletal development because loss of Sc65 results in a progressive osteopenia that affects both trabecular and cortical bone. Bone loss is the result of increased bone resorption mediated by a non-cell-autonomous effect on osteoclasts. Therefore, Sc65, like its related family member Crtap, is an important modulator of bone homeostasis, acting as a negative regulator of osteoclastogenesis.
2014-04-07 | Evaluation of teriparatide treatment in adults with osteogenesis imperfecta.
Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength. Trial registration. Clinicaltrials.gov NCT00131469. Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).
cell therapies
2025-01-11 | Orthodontic Management in Pediatric Patients with Rare Diseases: Case Reports.
Background: The orthodontic management of pediatric patients with rare diseases, such as Ectodermal Dysplasia (ED) and Osteogenesis Imperfecta (OI), requires complex protocols due to dental anomalies in both the number and structure of teeth. These conditions necessitate a departure from traditional orthodontic approaches, as skeletal anchoring is often required because of these anomalies. Case Presentation: A patient with ED, characterized by hypodontia and malformed teeth, presented with insufficient natural teeth for anchorage. This challenge was addressed using a Maxillary Skeletal Expander (MSE) with miniscrews. Cone-beam computed tomography (CBCT) and cephalometric radiographs were used to assess bone density, which guided the creation of a customized hybrid device. A second patient with OI, a condition causing fragile bones, had malformed teeth and a high risk of fractures. Skeletal anchoring with MSE and miniscrews was chosen to avoid damaging brittle bones. The fragile nature of the patient's bones required careful planning and close monitoring throughout the treatment process. Both patients were treated at the UOC of Pediatric Dentistry, Sapienza University of Rome, using MSE with miniscrews. Pre- and post-treatment imaging (CBCT and cephalometric radiographs) were used to evaluate bone quality and monitor progress. Skeletal anchoring successfully addressed the unique challenges in both cases, achieving outcomes comparable to those in unaffected patients. Discsussions: despite limited bone volume, MSE successfully achieved maxillary arch expansion and improved occlusion. Post-treatment radiographs showed successful maxillary expansion and alignment without complications. Conclusions: This case series highlighted the effectiveness of MSE with miniscrews in treating patients with rare diseases. It advances orthodontic management by offering reliable solutions for complex cases involving dental anomalies and compromised bone structures.
2004-05-10 | High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta.
Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis imperfecta (OI) are generally identified by having more than one affected child. The mosaic carriers have both normal and mutant cell populations in somatic and germline tissues but are unaffected or minimally affected by the type I collagen mutation that manifests clinically in their heterozygous offspring. We determined the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both carriers had normal height and bone histology; the first carrier had normal lumbar spine measurements (L1-L4), as determined by dual-energy x-ray absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by labeled PCR and single-cell PCR over successive passages, the collagen mutation was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right iliac crest and left patella, respectively, with minimal selection. The second carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and 70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40%-75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data are encouraging for mesenchymal stem-cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.
small molecules
2026-06-16 | Murine model of high bone mass osteogenesis imperfecta exhibits bone matrix hyper-mineralization, misaligned mineral crystals, and altered osteoblast differentiation.
Osteogenesis imperfecta (OI), characterized by bone fragility and low bone mass, is predominantly caused by mutations in type I collagen. High bone mass OI (HBM OI) is a rare form caused by heterozygous missense mutations at the type I procollagen C-propeptide cleavage site. Knock-in HBM OI mice were generated to elucidate the effect of this mutation on cells and bone. HBM OI murine femora contain increased monomeric pro-α1(I)C-propeptide and pC-collagen; their bone collagen fibrils have a "barbed-wire" appearance. Decreased C-propeptide cleavage diminishes bone strength. HBM OI femora are extremely brittle, with thin cortices, decreased BV/TV, and fracture load. The cortical bone has increased mineral content, with thinner, more disorganized mineral particles. Increased expression of ossification genes in both murine and human HBM OI osteoblasts during in vitro differentiation and increased mineral deposition in culture indicate impaired C-propeptide processing affects cellular processes related to mineralization, rather than being a passive matrix process. Gene ontology analysis of RNA-seq data from differentiating HBM OI osteoblasts revealed top upregulated pathways for ossification, mineralization, and osteoblast differentiation (5-25×) while top-downregulated pathways involved cellular adhesion, migration, and angiogenesis (5-10×), all related to cell-matrix interactions. Moreover, the HBM matrix affects osteoblast function. WT osteoblasts plated on HBM OI decellularized matrix in vitro showed less punctate vinculin, increased peripheral actin staining, and the presence of lamellipodia, suggesting a decrease in cellular adhesion. Insights into the mechanism of HBM OI mineralization may lead to improved therapies for HBM OI and low bone mass conditions.
2025-12-11 | Combined treatment with a C-type natriuretic peptide analog and bisphosphonate enhances bone growth in growing mice with osteogenesis imperfecta: a pilot study.
Osteogenesis imperfecta (OI) is a heterogeneous type 1 collagenopathy characterized by recurrent fractures, decreased bone mass, and short stature. Bisphosphonates reduce fracture incidence in children with OI, but do not improve growth velocity. C-type natriuretic peptide (CNP) is produced in the growth plate (also in the brain and heart), and it positively regulates linear bone growth; people with OI have been shown to have reduced serum levels of CNP. This pilot study evaluated whether a CNP analog combined with alendronate (ALN) improves growth and BMD in oim/oim (OIM) mice, a model of moderate-to-severe Type III OI. Two-wk-old OIM and WT mice received weekly ALN and 1 of 3 CNP regimens: 10 μg/kg 3 d/wk (low), 20 μg/kg 3 d/wk (medium), or 20 μg/kg 5 d/wk (high). Controls received saline. Faxitron images were taken at 2, 8, and 14 wk (sacrifice) to assess fracture incidence and measure femoral length and vertebral height. MicroCT was used to assess bone microstructural parameters of the femur ex vivo. The high-dose group had no fractures post-sacrifice, while 1 fracture each was observed in the low and medium dose groups. Femoral length increased in all treated groups, with the high dose-group showing the greatest increase (8.2% and significant) in OIM mice. Vertebral height increased in all treated groups; low and high dose groups had greater and comparable increases than the medium group in OIM mice. All treated groups showed increased trabecular BMD. Cortical tissue mineral density, BMD, and thickness were also elevated in all treated groups compared to the controls. In conclusion, CNP analog adjuvant treatment enhanced linear growth and bone quality without compromising fracture reduction, providing benefits not seen with bisphosphonates alone. These results will inform optimal dosing for future studies. A full murine study is planned to further evaluate the therapeutic potential for translation to humans.
2025-07-20 | Osteoclast-independent osteocyte dendrite defects in mice bearing the osteogenesis imperfecta-causing Sp7 R342C mutation.
Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown. Homozygous human SP7 (c.946 C > T, R316C) mutation results in a recessive form of OI characterized by fragility fractures, low bone mineral density and osteocyte dendrite defects. To better understand how the OI-causing R316C mutation affects the function of SP7, we generated Sp7R342C knock-in mice. Consistent with patient phenotypes, Sp7R342C/R342C mice demonstrate increased cortical porosity and reduced cortical bone mineral density. Sp7R342C/R342C mice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression. Remarkably, these defects in osteocyte function contrast to only mild changes in mature osteoblast function, suggesting that this Sp7 mutation selectively interferes with the function of Sp7 in osteocytes and mature osteoblasts, but not during early stages of osteoblast differentiation. Osteocyte morphology changes in Sp7R342C/R342C mice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intracortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this supports a model in which osteocyte dysfunction can drive OI pathogenesis and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone remodeling.
2025-07-20 | Changes in lean mass and fat mass in children with Osteogenesis Imperfecta.
Deficits in skeletal muscle and function, with resultant abnormal body composition, is a recognised feature of Osteogenesis Imperfecta (OI). Less is known about longitudinal change in body composition in OI. Our objective was to perform a retrospective analysis of longitudinal change in body composition (lean mass and fat mass) in children with OI. Data was collected from 29 children, with a diagnosis of OI, who had at least two dual-energy x-ray absorptiometry (DXA) scans performed between 2015 and 2022. Assessed variables of height, body mass index (BMI), lean mass index (LMI) and fat mass index (FMI), were converted to z scores. Results were reported as median (range). Median age at baseline and follow-up were 10.7 and 14.2 years, respectively. Median height z-score at baseline was -1.10, which was significantly lower than a control population (p<0.001). Median height z-score at latest follow-up was -0.80, which was not significantly different from baseline (p=0.870). Median BMI z-score at baseline was 0.15, which was not significantly different than a control population (p=0.804). Median BMI z-score at latest follow-up was 0.02, which was not significantly different from baseline (p=0.730). At baseline, median LMI z-score was -2.43, which was significantly lower than a control population (p<0.001). Median LMI z-score at follow-up was -1.78, which was not significantly different from baseline (p=0.080). At baseline, median FMI z-score was 0.57 which was significantly higher than a control population (p=0.001). Median FMI z-score at follow-up was 0.62, which was not significantly different from baseline (p=0.540). Children with OI have abnormal body composition throughout childhood typically with low lean mass and relatively high fat mass. These abnormalities in body composition do not change with follow-up. Strategies to improve lean mass, including physical or medical therapies, should be explored in OI given the close relationship between muscle and bone.
2025-04-07 | Viridicatol from the Deep-Sea-Derived Fungus Alleviates Bone Loss by Targeting the Wnt/SHN3 Pathway.
As an enticing bone anabolic target, short-term inhibition of Schnurri-3 (SHN3) resulted in high-bone mass due to augmented osteoblast activity. However, no studies are conducted to identify natural products targeting SHN3 inhibition. Herein, a screening strategy for the discovery of marine compounds that facilitate osteoblast differentiation by targeting SHN3 silencing is presented. One leading quinolinone alkaloid, viridicatol (VDC), isolated from deep-sea-derived fungus, vigorously promotes osteogenic differentiation via the Wnt/SHN3 signaling pathway in osteoblasts, thereby preventing osteoporosis while enhancing bone-fracture healing in a mouse model. Subsequently, the SDSSD (Ser, Asp, Ser, Ser, Asp) is further employed to engineer bone-targeting nanovesicles (BT-NVs) for the optimal delivery of VDC to osteoblasts, which mitigates the bone loss observed in a severe osteogenesis imperfecta model. Hence, these results initially uncover a promising marine natural product, VDC, targeting the Wnt/SHN3 pathway for the treatment of bone loss and highlighting its translational potential in clinical applications.
antibodies
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.
2026-05-21 | The pathogenesis and intersecting mechanisms of monogenic bone mass disorders.
Monogenic disorders of bone mass arise from variants in single genes disrupting the intricate processes of bone formation and resorption. Genes underlying bone mass disorders are involved in various intersecting molecular mechanisms in cells of the mesenchymal and haematopoietic lineages. Signalling pathways, including WNT-β-catenin, TGFβ-BMP and NF-κB, have central roles in bone metabolism, and variants in their regulators or effectors can have opposing effects on bone mass. Defects in osteoblast differentiation, collagen biosynthesis and extracellular matrix mineralization primarily drive the pathogenesis of low bone mass (LBM) conditions, exemplified by various forms of osteogenesis imperfecta. Conversely, impaired osteoclast differentiation and function, or enhanced osteoblastic activity underlie high bone mass (HBM) disorders, such as osteopetrosis and osteosclerosis. A subset of genes have pleiotropic effects, contributing to both LBM and HBM disorders depending on the genetic background. Advances in genetics have not only elucidated pathogenic mechanisms, but also enabled the development of targeted therapies, including anti-sclerostin antibodies and enzyme replacement therapies. However, most LBM and HBM conditions still have no cure. Understanding the shared and divergent mechanisms of bone mass regulation will offer insights into future therapeutic strategies.
2025-07-19 | A Siglec-15 Antibody Promotes High Quality Bone Formation in Adult Female Mice With Osteogenesis Imperfecta.
Osteogenesis imperfecta (OI) is a heterogenous type 1 collagenopathy that results in bone fragility and fractures. There is no standard-of-care treatment to reduce fracture risk for adults with OI. The sialic acid-binding immunoglobulin-like lectin 15 (Siglec 15) immunoreceptor modulates osteoclast development and bone resorption. Prior studies in growing rats demonstrated that Siglec 15 antibodies increased bone mass and improved bone mechanical properties. This study evaluated the safety and efficacy of a Siglec 15 monoclonal antibody, NP159 (NextCure Inc.), in female oim/oim and wildtype (WT) mice. Mice (n = 20/group) were treated from 14 to 26 weeks with either NP159 (10 mg/kg/dose weekly for 4 weeks, then biweekly for 8 weeks), weekly alendronate (ALN, 0.21 mg/kg), or weekly saline (equivalent to NP159). Faxitron images (anterior-posterior and medial-lateral) were taken at enrollment and sacrifice to evaluate fracture incidence and healing. Left femurs were analyzed for length, micro-CT parameters, and biomechanical testing. Right tibias were analyzed by Fourier transform infrared spectroscopy. NP159 reduced fracture incidence in oim/oim, 85% of whom were fracture-free at sacrifice compared to 65% in the ALN group and 55% in the saline group. NP159 treatment enhanced bone strength and structure in oim/oim, with mineral:matrix and carbonate:phosphate content that normalized towards the WT saline group. Unlike ALN, NP159 had a larger increase in bone stiffness(p < 0.05) and enhanced both bone microarchitecture and mineralization without altering Bone Mineral Density. Overall, these findings demonstrate the therapeutic value of NP159 in addressing the presently unmet clinical need for safe and efficacious long-term treatments for adults with OI.
2025-05-13 | Anti-transforming growth factor-β treatment shows increased bone mass and strength in a novel mouse model for osteogenesis imperfecta type I.
Anti-transforming growth factor beta (TGF-β) is a promising approach for the treatment of osteogenesis imperfecta (OI). To date, preclinical and clinical studies for the use of anti-TGF-β therapy have focused on moderate to severe OI caused by qualitative defects in collagen. However, the majority of OI patients are represented by type I OI. Mutations resulting in the haploinsufficiency of type I collagen is the cause of OI type I in the majority of patients. To study the effect of anti-TGF-β therapy in type I OI, we generated a novel mouse model for OI type I. CMV-CRE mice were crossed to mice where Col1a1 was floxed between exon 2 and 5 to create a full body heterozygous deletion of Col1a1. Haploinsufficiency of Col1a1 in the tibia was confirmed by decreased Col1a1 mRNA and protein expression. Comparable to OI patients, we observed reduced bone mass by μCT in these Col1a1+/- mice. Biomechanical measurements showed a decrease in bone strength and an increase in bone brittleness. Histomorphometric analysis showed an increase in osteoclast number and a trend towards increased osteoblast number supporting a high bone turnover phenotype, similar to OI type I patients. Upon treatment with a pan anti-TGF-β antibody, 1D11, Col1a1+/- mice showed increased bone mass and improved ultimate strength, but measures of ductility did not show improvement. Overall, our findings support expanding the study of anti-TGF-β treatment to OI caused by haploinsufficiency of type I collagen.
2025-01-24 | Non-invasive quantification of bone (re)modeling dynamics in adults with osteogenesis imperfecta treated with setrusumab using timelapse high-resolution peripheral-quantitative computed tomography.
Timelapse imaging using high-resolution peripheral quantitative computed tomography has emerged as a non-invasive method to quantify bone (re)modeling. However, there is no consensus on how to perform the procedure. As part of the ASTEROID phase-2b multicenter trial, we used 29 same-day repeated scans from adults with OI to identify a method that minimized measurement error. We evaluated input image type, registration method, segmentation mask, and for grayscale images various values for the voxel density difference considered formed or resorbed, minimum formation/resorption cluster size, and Gaussian smoothing sigma. We verified the accuracy of our method and then used it on longitudinal scans (baseline, 6, 12, 18, and 24 mo) from 78 participants to assess bone formation and resorption induced by an anabolic (setrusumab) and anti-catabolic (zoledronic acid) treatments as part of the ASTEROID trial. Regardless of image registration method, binary input images resulted in large errors ~13% and ~8% for first- and second-generation scanners, respectively. For the grayscale input images, errors were smaller for 3D compared to matched angle registration. For both scanner generations, a density threshold of 200 mgHA/cm3 combined with Gaussian noise reduction resulted in errors <1%. We verified the method was accurate by showing that similar regions of bone formation and resorption were identified when comparing each scan from the same-day repeated scans with a scan from another timepoint. Timelapse analysis revealed a dose-dependent increase in bone formation and resorption with setrusumab treatment. Zoledronic acid altered bone changes in favor of formation, although no changes reached statistical significance. This study identifies a timelapse method that minimizes measurement error, which can be used in future studies to improve the uniformity of results. This non-invasive imaging biomarker revealed dose dependent bone (re)modeling outcomes from 1 year of setrusumab treatment in adults with OI.
other
2025-12-26 | Harnessing Bone-Liver Crosstalk: A Dual-Action LYTAC Approach for Bone-Specific Accumulation and Liver-Specific Protein Degradation in Bone Disorders.
Despite significant progress in extracellular targeted protein degradation (eTPD), existing approaches rarely achieved tissue-specific drug accumulation while maintaining efficient systemic clearance, a critical challenge in treating bone disorders. In this study, we introduced GalNAc-Apc001, a novel aptamer-based lysosome-targeting chimera (LYTAC) that uniquely combined bone-specific retention with hepatocyte-mediated clearance through a spatiotemporally controlled mechanism. By conjugating a tri-N-acetylgalactosamine (GalNAc) moiety to a bone-homing sclerostin aptamer (Apc001), we engineered a bifunctional molecule capable of accumulating in bone via hydroxyapatite binding, capturing circulating sclerostin with high affinity and directing it to hepatocytes for ASGPR-mediated lysosomal degradation. In the absence of ASGPR-positive cells, GalNAc-Apc001 functioned via the conventional aptamer mechanism of binding inhibition, demonstrating efficacy comparable to that of Apc001 but notably lower than that of a sclerostin antibody. However, in ASGPR-positive cell coculture systems, GalNAc-Apc001 achieved a 40% greater activation of the Wnt signaling pathway compared to the sclerostin antibody, effectively reversing sclerostin-mediated inhibition (96 vs 60% recovery). Pharmacologically, GalNAc-Apc001 exhibited superior therapeutic efficacy by mitigating the suppressive effects of sclerostin on Wnt signaling, upregulating bone formation markers, and enhancing bone mass in a Col1a2 +/G610C osteogenesis imperfecta mouse model. These findings provided compelling mechanistic evidence that the spatiotemporal control of protein degradation could resolve the inherent trade-off between tissue targeting and systemic clearance, supporting the clinical potential of GalNAc-Apc001 in bone disorders.
2025-11-21 | Harnessing Bone-LiverCrosstalk: A Dual-Action LYTACApproach for Bone-Specific Accumulation and Liver-Specific ProteinDegradation in Bone Disorders
Despite significant progress in extracellular targeted protein degradation (eTPD), existing approaches rarely achieved tissue-specific drug accumulation while maintaining efficient systemic clearance, a critical challenge in treating bone disorders. In this study, we introduced GalNAc-Apc001, a novel aptamer-based lysosome-targeting chimera (LYTAC) that uniquely combined bone-specific retention with hepatocyte-mediated clearance through a spatiotemporally controlled mechanism. By conjugating a tri-N-acetylgalactosamine (GalNAc) moiety to a bone-homing sclerostin aptamer (Apc001), we engineered a bifunctional molecule capable of accumulating in bone via hydroxyapatite binding, capturing circulating sclerostin with high affinity and directing it to hepatocytes for ASGPR-mediated lysosomal degradation. In the absence of ASGPR-positive cells, GalNAc-Apc001 functioned via the conventional aptamer mechanism of binding inhibition, demonstrating efficacy comparable to that of Apc001 but notably lower than that of a sclerostin antibody. However, in ASGPR-positive cell coculture systems, GalNAc-Apc001 achieved a 40% greater activation of the Wnt signaling pathway compared to the sclerostin antibody, effectively reversing sclerostin-mediated inhibition (96 vs 60% recovery). Pharmacologically, GalNAc-Apc001 exhibited superior therapeutic efficacy by mitigating the suppressive effects of sclerostin on Wnt signaling, upregulating bone formation markers, and enhancing bone mass in a Col1a2+/G610C osteogenesis imperfecta mouse model. These findings provided compelling mechanistic evidence that the spatiotemporal control of protein degradation could resolve the inherent trade-off between tissue targeting and systemic clearance, supporting the clinical potential of GalNAc-Apc001 in bone disorders.
2024-03-29 | Medical Management for Fracture Prevention in Children with Osteogenesis Imperfecta
Abstract There are no licensed treatments for children with osteogenesis imperfecta. Children currently receive off-label treatment with bisphosphonates, without any consistent approach to dose, drug or route of administration. Meta-analyses suggest that anti-fracture efficacy of such interventions is equivocal. New therapies are undergoing clinical trials, and it is likely that one or more will receive marketing authorisation within the next three to five years. The long-term outcome from such interventions will need to be studied carefully well beyond the period over which the clinical trials are conducted, and a consistent approach to the collection of data in this regard will be needed as a major collaborative effort.
proteins
2024-11-13 | Genetics and Bone Mineral Density Predict the Fractures in Adults With Osteogenesis Imperfecta: A Prospective Study.
Osteogenesis imperfecta (OI) is a rare genetic bone disorder characterized by recurrent fractures. In adults, the value of bone mineral density (BMD) in fracture risk is unknown. We prospectively investigated changes in BMD over time and analyzed the determinants of fracture in OI. Among 106 individuals with grade 1 and 4 OI in the Reference Centre of Rare Bone Diseases in Paris, we included those with BMD measurements at 1 or more skeletal sites (hip, lumbar spine, radius) from 2000 to 2022. For 71 individuals with reliable measurements (44 women, 8 postmenopausal; mean age 41.4 ± 13.7 years), baseline BMD was low at the lumbar spine only (mean Z-score -2.3 ± 1.5), affecting mainly men (mean Z-score -3 ± 1.6). Longitudinal changes were assessed for a median follow-up of 5.1 years (interquartile range 3.2-8.8). On adjustment for age, sex, and body mass index, BMD did not significantly change at any site. Logistic regression analysis revealed a high probability of fracture with baseline BMD Z-score <-2 SD vs ≥-2 SD [odds ratio 4.38, 95% confidence interval (CI) 1.10-21.75, P = .048] and harboring splicing, stop codon, and frameshift variants of COL1 gene (odds ratio 29.8, 95% CI 2.56-1503, P = .024). Our OI cohort showed low BMD at the lumbar spine but no significant change at any site after a median of 5.0 years of follow-up. The probability of fracture was associated with baseline BMD Z-score <-2 SD vs ≥-2 SD and harboring COL1 splicing, stop codon, and frameshift variants.
2016-02-02 | ENDOCRINOLOGY AND ADOLESCENCE: Osteoporosis in children: diagnosis and management.
Osteoporosis in children can be primary or secondary due to chronic disease. Awareness among paediatricians is vital to identify patients at risk of developing osteoporosis. Previous fractures and backaches are clinical predictors, and low cortical thickness and low bone density are radiological predictors of fractures. Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary paediatric units with the necessary multidisciplinary expertise. Modern OI management focuses on functional outcomes rather than just improving bone mineral density. While therapy for OI has improved tremendously over the last few decades, this chronic genetic condition has some unpreventable, poorly treatable and disabling complications. In children at risk of secondary osteoporosis, a high degree of suspicion needs to be exercised. In affected children, further weakening of bone should be avoided by minimising exposure to osteotoxic medication and optimising nutrition including calcium and vitamin D. Early intervention is paramount. However, it is important to identify patient groups in whom spontaneous vertebral reshaping and resolution of symptoms occur to avoid unnecessary treatment. Bisphosphonate therapy remains the pharmacological treatment of choice in both primary and secondary osteoporosis in children, despite limited evidence for its use in the latter. The duration and intensity of treatment remain a concern for long-term safety. Various new potent antiresorptive agents are being studied, but more urgently required are studies using anabolic medications that stimulate bone formation. More research is required to bridge the gaps in the evidence for management of paediatric osteoporosis.
2015-01-19 | How tough is brittle bone? Investigating osteogenesis imperfecta in mouse bone.
The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level, we attribute the loss in toughness to a decrease in the stabilizing enzymatic cross-links and an increase in nonenzymatic cross-links, which may break prematurely, inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales.
2014-09-29 | Sc65 is a novel endoplasmic reticulum protein that regulates bone mass homeostasis.
Members of the Leprecan family of proteins include enzymes, prolyl 3-hydroxylase 1 (P3h1), P3h2, and P3h3, and nonenzymatic proteins, Crtap and Sc65. Mutations in CRTAP and LEPRE1 (encoding P3H1) have been associated with human disease such as recessive osteogenesis imperfecta; however, the function of Sc65, which is closely related and highly homologous to Crtap, is unknown. Sc65 has been described as a synaptonemal complex protein, a nucleolar protein, and a cytoplasmic adapter protein. In light of its high sequence similarity with Crtap, an endoplasmic reticulum (ER)-associated protein, and the importance of post-translational modifications such as collagen prolyl 3-hydroxylation in bone metabolism, we hypothesized that Sc65 was an ER-resident protein that would have an important role in bone homeostasis. In this study, we demonstrate that Sc65 is a previously unrecognized ER protein and that it does not localize in the nucleus of somatic cells. Moreover, Sc65 is expressed and functional during skeletal development because loss of Sc65 results in a progressive osteopenia that affects both trabecular and cortical bone. Bone loss is the result of increased bone resorption mediated by a non-cell-autonomous effect on osteoclasts. Therefore, Sc65, like its related family member Crtap, is an important modulator of bone homeostasis, acting as a negative regulator of osteoclastogenesis.
2014-04-07 | Evaluation of teriparatide treatment in adults with osteogenesis imperfecta.
Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength. Trial registration. Clinicaltrials.gov NCT00131469. Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).
cell therapies
2025-01-11 | Orthodontic Management in Pediatric Patients with Rare Diseases: Case Reports.
Background: The orthodontic management of pediatric patients with rare diseases, such as Ectodermal Dysplasia (ED) and Osteogenesis Imperfecta (OI), requires complex protocols due to dental anomalies in both the number and structure of teeth. These conditions necessitate a departure from traditional orthodontic approaches, as skeletal anchoring is often required because of these anomalies. Case Presentation: A patient with ED, characterized by hypodontia and malformed teeth, presented with insufficient natural teeth for anchorage. This challenge was addressed using a Maxillary Skeletal Expander (MSE) with miniscrews. Cone-beam computed tomography (CBCT) and cephalometric radiographs were used to assess bone density, which guided the creation of a customized hybrid device. A second patient with OI, a condition causing fragile bones, had malformed teeth and a high risk of fractures. Skeletal anchoring with MSE and miniscrews was chosen to avoid damaging brittle bones. The fragile nature of the patient's bones required careful planning and close monitoring throughout the treatment process. Both patients were treated at the UOC of Pediatric Dentistry, Sapienza University of Rome, using MSE with miniscrews. Pre- and post-treatment imaging (CBCT and cephalometric radiographs) were used to evaluate bone quality and monitor progress. Skeletal anchoring successfully addressed the unique challenges in both cases, achieving outcomes comparable to those in unaffected patients. Discsussions: despite limited bone volume, MSE successfully achieved maxillary arch expansion and improved occlusion. Post-treatment radiographs showed successful maxillary expansion and alignment without complications. Conclusions: This case series highlighted the effectiveness of MSE with miniscrews in treating patients with rare diseases. It advances orthodontic management by offering reliable solutions for complex cases involving dental anomalies and compromised bone structures.
2004-05-10 | High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta.
Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis imperfecta (OI) are generally identified by having more than one affected child. The mosaic carriers have both normal and mutant cell populations in somatic and germline tissues but are unaffected or minimally affected by the type I collagen mutation that manifests clinically in their heterozygous offspring. We determined the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both carriers had normal height and bone histology; the first carrier had normal lumbar spine measurements (L1-L4), as determined by dual-energy x-ray absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by labeled PCR and single-cell PCR over successive passages, the collagen mutation was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right iliac crest and left patella, respectively, with minimal selection. The second carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and 70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40%-75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data are encouraging for mesenchymal stem-cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.
small molecules
2026-06-16 | Murine model of high bone mass osteogenesis imperfecta exhibits bone matrix hyper-mineralization, misaligned mineral crystals, and altered osteoblast differentiation.
Osteogenesis imperfecta (OI), characterized by bone fragility and low bone mass, is predominantly caused by mutations in type I collagen. High bone mass OI (HBM OI) is a rare form caused by heterozygous missense mutations at the type I procollagen C-propeptide cleavage site. Knock-in HBM OI mice were generated to elucidate the effect of this mutation on cells and bone. HBM OI murine femora contain increased monomeric pro-α1(I)C-propeptide and pC-collagen; their bone collagen fibrils have a "barbed-wire" appearance. Decreased C-propeptide cleavage diminishes bone strength. HBM OI femora are extremely brittle, with thin cortices, decreased BV/TV, and fracture load. The cortical bone has increased mineral content, with thinner, more disorganized mineral particles. Increased expression of ossification genes in both murine and human HBM OI osteoblasts during in vitro differentiation and increased mineral deposition in culture indicate impaired C-propeptide processing affects cellular processes related to mineralization, rather than being a passive matrix process. Gene ontology analysis of RNA-seq data from differentiating HBM OI osteoblasts revealed top upregulated pathways for ossification, mineralization, and osteoblast differentiation (5-25×) while top-downregulated pathways involved cellular adhesion, migration, and angiogenesis (5-10×), all related to cell-matrix interactions. Moreover, the HBM matrix affects osteoblast function. WT osteoblasts plated on HBM OI decellularized matrix in vitro showed less punctate vinculin, increased peripheral actin staining, and the presence of lamellipodia, suggesting a decrease in cellular adhesion. Insights into the mechanism of HBM OI mineralization may lead to improved therapies for HBM OI and low bone mass conditions.
2025-12-11 | Combined treatment with a C-type natriuretic peptide analog and bisphosphonate enhances bone growth in growing mice with osteogenesis imperfecta: a pilot study.
Osteogenesis imperfecta (OI) is a heterogeneous type 1 collagenopathy characterized by recurrent fractures, decreased bone mass, and short stature. Bisphosphonates reduce fracture incidence in children with OI, but do not improve growth velocity. C-type natriuretic peptide (CNP) is produced in the growth plate (also in the brain and heart), and it positively regulates linear bone growth; people with OI have been shown to have reduced serum levels of CNP. This pilot study evaluated whether a CNP analog combined with alendronate (ALN) improves growth and BMD in oim/oim (OIM) mice, a model of moderate-to-severe Type III OI. Two-wk-old OIM and WT mice received weekly ALN and 1 of 3 CNP regimens: 10 μg/kg 3 d/wk (low), 20 μg/kg 3 d/wk (medium), or 20 μg/kg 5 d/wk (high). Controls received saline. Faxitron images were taken at 2, 8, and 14 wk (sacrifice) to assess fracture incidence and measure femoral length and vertebral height. MicroCT was used to assess bone microstructural parameters of the femur ex vivo. The high-dose group had no fractures post-sacrifice, while 1 fracture each was observed in the low and medium dose groups. Femoral length increased in all treated groups, with the high dose-group showing the greatest increase (8.2% and significant) in OIM mice. Vertebral height increased in all treated groups; low and high dose groups had greater and comparable increases than the medium group in OIM mice. All treated groups showed increased trabecular BMD. Cortical tissue mineral density, BMD, and thickness were also elevated in all treated groups compared to the controls. In conclusion, CNP analog adjuvant treatment enhanced linear growth and bone quality without compromising fracture reduction, providing benefits not seen with bisphosphonates alone. These results will inform optimal dosing for future studies. A full murine study is planned to further evaluate the therapeutic potential for translation to humans.
2025-07-20 | Osteoclast-independent osteocyte dendrite defects in mice bearing the osteogenesis imperfecta-causing Sp7 R342C mutation.
Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown. Homozygous human SP7 (c.946 C > T, R316C) mutation results in a recessive form of OI characterized by fragility fractures, low bone mineral density and osteocyte dendrite defects. To better understand how the OI-causing R316C mutation affects the function of SP7, we generated Sp7R342C knock-in mice. Consistent with patient phenotypes, Sp7R342C/R342C mice demonstrate increased cortical porosity and reduced cortical bone mineral density. Sp7R342C/R342C mice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression. Remarkably, these defects in osteocyte function contrast to only mild changes in mature osteoblast function, suggesting that this Sp7 mutation selectively interferes with the function of Sp7 in osteocytes and mature osteoblasts, but not during early stages of osteoblast differentiation. Osteocyte morphology changes in Sp7R342C/R342C mice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intracortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this supports a model in which osteocyte dysfunction can drive OI pathogenesis and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone remodeling.
2025-07-20 | Changes in lean mass and fat mass in children with Osteogenesis Imperfecta.
Deficits in skeletal muscle and function, with resultant abnormal body composition, is a recognised feature of Osteogenesis Imperfecta (OI). Less is known about longitudinal change in body composition in OI. Our objective was to perform a retrospective analysis of longitudinal change in body composition (lean mass and fat mass) in children with OI. Data was collected from 29 children, with a diagnosis of OI, who had at least two dual-energy x-ray absorptiometry (DXA) scans performed between 2015 and 2022. Assessed variables of height, body mass index (BMI), lean mass index (LMI) and fat mass index (FMI), were converted to z scores. Results were reported as median (range). Median age at baseline and follow-up were 10.7 and 14.2 years, respectively. Median height z-score at baseline was -1.10, which was significantly lower than a control population (p<0.001). Median height z-score at latest follow-up was -0.80, which was not significantly different from baseline (p=0.870). Median BMI z-score at baseline was 0.15, which was not significantly different than a control population (p=0.804). Median BMI z-score at latest follow-up was 0.02, which was not significantly different from baseline (p=0.730). At baseline, median LMI z-score was -2.43, which was significantly lower than a control population (p<0.001). Median LMI z-score at follow-up was -1.78, which was not significantly different from baseline (p=0.080). At baseline, median FMI z-score was 0.57 which was significantly higher than a control population (p=0.001). Median FMI z-score at follow-up was 0.62, which was not significantly different from baseline (p=0.540). Children with OI have abnormal body composition throughout childhood typically with low lean mass and relatively high fat mass. These abnormalities in body composition do not change with follow-up. Strategies to improve lean mass, including physical or medical therapies, should be explored in OI given the close relationship between muscle and bone.
2025-04-07 | Viridicatol from the Deep-Sea-Derived Fungus Alleviates Bone Loss by Targeting the Wnt/SHN3 Pathway.
As an enticing bone anabolic target, short-term inhibition of Schnurri-3 (SHN3) resulted in high-bone mass due to augmented osteoblast activity. However, no studies are conducted to identify natural products targeting SHN3 inhibition. Herein, a screening strategy for the discovery of marine compounds that facilitate osteoblast differentiation by targeting SHN3 silencing is presented. One leading quinolinone alkaloid, viridicatol (VDC), isolated from deep-sea-derived fungus, vigorously promotes osteogenic differentiation via the Wnt/SHN3 signaling pathway in osteoblasts, thereby preventing osteoporosis while enhancing bone-fracture healing in a mouse model. Subsequently, the SDSSD (Ser, Asp, Ser, Ser, Asp) is further employed to engineer bone-targeting nanovesicles (BT-NVs) for the optimal delivery of VDC to osteoblasts, which mitigates the bone loss observed in a severe osteogenesis imperfecta model. Hence, these results initially uncover a promising marine natural product, VDC, targeting the Wnt/SHN3 pathway for the treatment of bone loss and highlighting its translational potential in clinical applications.
antibodies
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.
2026-05-21 | The pathogenesis and intersecting mechanisms of monogenic bone mass disorders.
Monogenic disorders of bone mass arise from variants in single genes disrupting the intricate processes of bone formation and resorption. Genes underlying bone mass disorders are involved in various intersecting molecular mechanisms in cells of the mesenchymal and haematopoietic lineages. Signalling pathways, including WNT-β-catenin, TGFβ-BMP and NF-κB, have central roles in bone metabolism, and variants in their regulators or effectors can have opposing effects on bone mass. Defects in osteoblast differentiation, collagen biosynthesis and extracellular matrix mineralization primarily drive the pathogenesis of low bone mass (LBM) conditions, exemplified by various forms of osteogenesis imperfecta. Conversely, impaired osteoclast differentiation and function, or enhanced osteoblastic activity underlie high bone mass (HBM) disorders, such as osteopetrosis and osteosclerosis. A subset of genes have pleiotropic effects, contributing to both LBM and HBM disorders depending on the genetic background. Advances in genetics have not only elucidated pathogenic mechanisms, but also enabled the development of targeted therapies, including anti-sclerostin antibodies and enzyme replacement therapies. However, most LBM and HBM conditions still have no cure. Understanding the shared and divergent mechanisms of bone mass regulation will offer insights into future therapeutic strategies.
2025-07-19 | A Siglec-15 Antibody Promotes High Quality Bone Formation in Adult Female Mice With Osteogenesis Imperfecta.
Osteogenesis imperfecta (OI) is a heterogenous type 1 collagenopathy that results in bone fragility and fractures. There is no standard-of-care treatment to reduce fracture risk for adults with OI. The sialic acid-binding immunoglobulin-like lectin 15 (Siglec 15) immunoreceptor modulates osteoclast development and bone resorption. Prior studies in growing rats demonstrated that Siglec 15 antibodies increased bone mass and improved bone mechanical properties. This study evaluated the safety and efficacy of a Siglec 15 monoclonal antibody, NP159 (NextCure Inc.), in female oim/oim and wildtype (WT) mice. Mice (n = 20/group) were treated from 14 to 26 weeks with either NP159 (10 mg/kg/dose weekly for 4 weeks, then biweekly for 8 weeks), weekly alendronate (ALN, 0.21 mg/kg), or weekly saline (equivalent to NP159). Faxitron images (anterior-posterior and medial-lateral) were taken at enrollment and sacrifice to evaluate fracture incidence and healing. Left femurs were analyzed for length, micro-CT parameters, and biomechanical testing. Right tibias were analyzed by Fourier transform infrared spectroscopy. NP159 reduced fracture incidence in oim/oim, 85% of whom were fracture-free at sacrifice compared to 65% in the ALN group and 55% in the saline group. NP159 treatment enhanced bone strength and structure in oim/oim, with mineral:matrix and carbonate:phosphate content that normalized towards the WT saline group. Unlike ALN, NP159 had a larger increase in bone stiffness(p < 0.05) and enhanced both bone microarchitecture and mineralization without altering Bone Mineral Density. Overall, these findings demonstrate the therapeutic value of NP159 in addressing the presently unmet clinical need for safe and efficacious long-term treatments for adults with OI.
2025-05-13 | Anti-transforming growth factor-β treatment shows increased bone mass and strength in a novel mouse model for osteogenesis imperfecta type I.
Anti-transforming growth factor beta (TGF-β) is a promising approach for the treatment of osteogenesis imperfecta (OI). To date, preclinical and clinical studies for the use of anti-TGF-β therapy have focused on moderate to severe OI caused by qualitative defects in collagen. However, the majority of OI patients are represented by type I OI. Mutations resulting in the haploinsufficiency of type I collagen is the cause of OI type I in the majority of patients. To study the effect of anti-TGF-β therapy in type I OI, we generated a novel mouse model for OI type I. CMV-CRE mice were crossed to mice where Col1a1 was floxed between exon 2 and 5 to create a full body heterozygous deletion of Col1a1. Haploinsufficiency of Col1a1 in the tibia was confirmed by decreased Col1a1 mRNA and protein expression. Comparable to OI patients, we observed reduced bone mass by μCT in these Col1a1+/- mice. Biomechanical measurements showed a decrease in bone strength and an increase in bone brittleness. Histomorphometric analysis showed an increase in osteoclast number and a trend towards increased osteoblast number supporting a high bone turnover phenotype, similar to OI type I patients. Upon treatment with a pan anti-TGF-β antibody, 1D11, Col1a1+/- mice showed increased bone mass and improved ultimate strength, but measures of ductility did not show improvement. Overall, our findings support expanding the study of anti-TGF-β treatment to OI caused by haploinsufficiency of type I collagen.
2025-01-24 | Non-invasive quantification of bone (re)modeling dynamics in adults with osteogenesis imperfecta treated with setrusumab using timelapse high-resolution peripheral-quantitative computed tomography.
Timelapse imaging using high-resolution peripheral quantitative computed tomography has emerged as a non-invasive method to quantify bone (re)modeling. However, there is no consensus on how to perform the procedure. As part of the ASTEROID phase-2b multicenter trial, we used 29 same-day repeated scans from adults with OI to identify a method that minimized measurement error. We evaluated input image type, registration method, segmentation mask, and for grayscale images various values for the voxel density difference considered formed or resorbed, minimum formation/resorption cluster size, and Gaussian smoothing sigma. We verified the accuracy of our method and then used it on longitudinal scans (baseline, 6, 12, 18, and 24 mo) from 78 participants to assess bone formation and resorption induced by an anabolic (setrusumab) and anti-catabolic (zoledronic acid) treatments as part of the ASTEROID trial. Regardless of image registration method, binary input images resulted in large errors ~13% and ~8% for first- and second-generation scanners, respectively. For the grayscale input images, errors were smaller for 3D compared to matched angle registration. For both scanner generations, a density threshold of 200 mgHA/cm3 combined with Gaussian noise reduction resulted in errors <1%. We verified the method was accurate by showing that similar regions of bone formation and resorption were identified when comparing each scan from the same-day repeated scans with a scan from another timepoint. Timelapse analysis revealed a dose-dependent increase in bone formation and resorption with setrusumab treatment. Zoledronic acid altered bone changes in favor of formation, although no changes reached statistical significance. This study identifies a timelapse method that minimizes measurement error, which can be used in future studies to improve the uniformity of results. This non-invasive imaging biomarker revealed dose dependent bone (re)modeling outcomes from 1 year of setrusumab treatment in adults with OI.
other
2025-12-26 | Harnessing Bone-Liver Crosstalk: A Dual-Action LYTAC Approach for Bone-Specific Accumulation and Liver-Specific Protein Degradation in Bone Disorders.
Despite significant progress in extracellular targeted protein degradation (eTPD), existing approaches rarely achieved tissue-specific drug accumulation while maintaining efficient systemic clearance, a critical challenge in treating bone disorders. In this study, we introduced GalNAc-Apc001, a novel aptamer-based lysosome-targeting chimera (LYTAC) that uniquely combined bone-specific retention with hepatocyte-mediated clearance through a spatiotemporally controlled mechanism. By conjugating a tri-N-acetylgalactosamine (GalNAc) moiety to a bone-homing sclerostin aptamer (Apc001), we engineered a bifunctional molecule capable of accumulating in bone via hydroxyapatite binding, capturing circulating sclerostin with high affinity and directing it to hepatocytes for ASGPR-mediated lysosomal degradation. In the absence of ASGPR-positive cells, GalNAc-Apc001 functioned via the conventional aptamer mechanism of binding inhibition, demonstrating efficacy comparable to that of Apc001 but notably lower than that of a sclerostin antibody. However, in ASGPR-positive cell coculture systems, GalNAc-Apc001 achieved a 40% greater activation of the Wnt signaling pathway compared to the sclerostin antibody, effectively reversing sclerostin-mediated inhibition (96 vs 60% recovery). Pharmacologically, GalNAc-Apc001 exhibited superior therapeutic efficacy by mitigating the suppressive effects of sclerostin on Wnt signaling, upregulating bone formation markers, and enhancing bone mass in a Col1a2 +/G610C osteogenesis imperfecta mouse model. These findings provided compelling mechanistic evidence that the spatiotemporal control of protein degradation could resolve the inherent trade-off between tissue targeting and systemic clearance, supporting the clinical potential of GalNAc-Apc001 in bone disorders.
2025-11-21 | Harnessing Bone-LiverCrosstalk: A Dual-Action LYTACApproach for Bone-Specific Accumulation and Liver-Specific ProteinDegradation in Bone Disorders
Despite significant progress in extracellular targeted protein degradation (eTPD), existing approaches rarely achieved tissue-specific drug accumulation while maintaining efficient systemic clearance, a critical challenge in treating bone disorders. In this study, we introduced GalNAc-Apc001, a novel aptamer-based lysosome-targeting chimera (LYTAC) that uniquely combined bone-specific retention with hepatocyte-mediated clearance through a spatiotemporally controlled mechanism. By conjugating a tri-N-acetylgalactosamine (GalNAc) moiety to a bone-homing sclerostin aptamer (Apc001), we engineered a bifunctional molecule capable of accumulating in bone via hydroxyapatite binding, capturing circulating sclerostin with high affinity and directing it to hepatocytes for ASGPR-mediated lysosomal degradation. In the absence of ASGPR-positive cells, GalNAc-Apc001 functioned via the conventional aptamer mechanism of binding inhibition, demonstrating efficacy comparable to that of Apc001 but notably lower than that of a sclerostin antibody. However, in ASGPR-positive cell coculture systems, GalNAc-Apc001 achieved a 40% greater activation of the Wnt signaling pathway compared to the sclerostin antibody, effectively reversing sclerostin-mediated inhibition (96 vs 60% recovery). Pharmacologically, GalNAc-Apc001 exhibited superior therapeutic efficacy by mitigating the suppressive effects of sclerostin on Wnt signaling, upregulating bone formation markers, and enhancing bone mass in a Col1a2+/G610C osteogenesis imperfecta mouse model. These findings provided compelling mechanistic evidence that the spatiotemporal control of protein degradation could resolve the inherent trade-off between tissue targeting and systemic clearance, supporting the clinical potential of GalNAc-Apc001 in bone disorders.
2024-03-29 | Medical Management for Fracture Prevention in Children with Osteogenesis Imperfecta
Abstract There are no licensed treatments for children with osteogenesis imperfecta. Children currently receive off-label treatment with bisphosphonates, without any consistent approach to dose, drug or route of administration. Meta-analyses suggest that anti-fracture efficacy of such interventions is equivocal. New therapies are undergoing clinical trials, and it is likely that one or more will receive marketing authorisation within the next three to five years. The long-term outcome from such interventions will need to be studied carefully well beyond the period over which the clinical trials are conducted, and a consistent approach to the collection of data in this regard will be needed as a major collaborative effort.
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