Sclerostin Antibody Research Articles

Sclerostin antibody corrects periodontal disease in type 2 diabetic mice.

Type 2 diabetes (T2D) is on the rise worldwide and is associated with various complications in the oral cavity. Using an adult-onset diabetes preclinical model, we demonstrated profound periodontal alterations in T2D mice, including inflamed gingiva, disintegrated periodontal ligaments (PDLs), marked alveolar bone loss, and unbalanced bone remodeling due to decreased formation and increased resorption. Notably, we observed elevated levels of the Wnt signaling inhibitor sclerostin in the alveolar bone of T2D mice. Motivated by these findings, we investigated whether a sclerostin-neutralizing antibody (Scl-Ab) could rescue the compromised periodontium in T2D mice. Administering Scl-Ab subcutaneously once a week for 4 weeks, starting 4 weeks after T2D induction, led to substantial increases in bone mass. This effect was attributed to the inhibition of osteoclasts and promotion of osteoblasts in both control and T2D mice, effectively reversing the bone loss caused by T2D. Furthermore, Scl-Ab stimulated PDL cell proliferation, partially restored the PDL fibers, and mitigated inflammation in the periodontium. Our study thus established a T2D-induced periodontitis mouse model characterized by inflammation and tissue degeneration. Scl-Ab emerged as a promising intervention to counteract the detrimental effects of T2D on the periodontium, exhibiting limited side effects on other craniofacial hard tissues.

Role of sclerostin deletion in bisphosphonate-induced osteonecrosis of the jaw

PurposeBone resorption inhibitors, such as bisphosphonates (BP) and denosumab, are frequently used for the management of osteoporosis. Although both drugs reduce the risk of osteoporotic fractures, they are associated with a serious side effect known as medication-related osteonecrosis of the jaw (MRONJ). Sclerostin antibodies (romosozumab) increase bone formation and decrease the risk of osteoporotic fractures: however, their anti-resorptive effect increases ONJ. Thus, this study aimed to elucidate the role of sclerostin deletion in the development of MRONJ. MethodsSclerostin knockout (SostΔ26/Δ26) mice were used to confirm the development of ONJ by performing tooth extractions. To confirm the role of sclerostin deficiency in a more ONJ-prone situation, we used the BP-induced ONJ model in combination with severe periodontitis to evaluate the development of ONJ and bone formation in wild-type (WT) and SostΔ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and SostΔ26/Δ26 mice. ResultsONJ was not detected in the extraction socket of SostΔ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the SostΔ26/Δ26 mice treated with BP compared to that of the WT mice. Osteogenic proteins, osteocalcin, and runt-related transcription factor 2, were expressed in the bone surface in SostΔ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in SostΔ26/Δ26 mice than in WT mice. ConclusionSclerostin deficiency did not cause ONJ and reduced the risk of developing BP-induced ONJ. Enhanced bone formation and wound healing were observed in the tooth extraction socket. The use of romosozumab (anti-sclerostin antibody) has proven to be safe for surgical procedures of the jaw.

Anti-sclerostin antibody – A potential therapeutic target for periodontal bone regeneration

Sclerostin is a glycoprotein predominantly released by specialized bone-forming cells (osteocytes). It serves as a principal inhibitor of osteogenesis and plays a key act in modulating the metabolism of alveolar bone. Sclerostin is shown to contribute to the occurrence of periodontitis by regulating the remodeling of the alveolar bone. A monoclonal antibody which antagonizes sclerostin has become extremely useful for osteoanabolic therapies. Romosozumab is an Food and Drug Administration-approved anti-sclerostin antibody that has shown promising results in the treatment of osteoporosis. Research is being conducted on the effect of anti-sclerostin antibody (Scl-Ab) as a therapeutic option in the management of periodontitis, and up till now, the results are promising. A comprehensive review of the literature was done using the PubMed database and Google Scholar. Research articles published before April 2023 with the search terms “sclerostin,” “periodontitis,” and “anti-sclerostin antibody” (Scl-Ab) were included. Most of the studies point toward a definitive association between chronic periodontitis and the levels of sclerostin. Numerous investigations underscore the significance of evaluating sclerostin levels as a diagnostic marker for periodontitis, and the application of anti-sclerostin antibodies as a potential therapeutic option for managing periodontitis and peri-implant diseases. However, further researches are required to delve into the therapeutic effects and possible side effects of Scl-Ab. Sclerostin antibodies show promise as an anabolic drug that enhances bone mass and could potentially become a viable therapeutic alternative for addressing periodontal conditions in future.

AI-based 3D-QSAR model of FDA-approved repurposed drugs for inhibiting sclerostin

BACKGROUND: Wnt activation promotes bone formation and prevents bone loss. The Wnt pathway antagonist sclerostin and additional anti-sclerostin antibodies were discovered as a result of the development of the monoclonal antibody romosozumab. These monoclonal antibodies greatly increase the risk of cardiac arrest. Three-dimensional quantitative structure-activity relationships (3D-QSAR) predicts biological activities of ligands based on their three-dimensional features by employing powerful chemometric investigations such as artificial neural networks (ANNs) and partial least squares (PLS). OBJECTIVE: In this study, ligand-receptor interactions were investigated using 3D-QSAR Comparative molecular field analysis (CoMFA). Estimates of steric and electrostatic characteristics in CoMFA are made using Lennard-Jones and Coulomb potentials. METHODS: To identify the conditions necessary for the activity of these molecules, fifty Food and Drug Administration (FDA)-approved medications were chosen for 3D-QSAR investigations and done by CoMFA. For QSAR analysis, there are numerous tools available. This study employed Open 3D-QSAR for analysis due to its simplicity of use and capacity to produce trustworthy results. Four tools were used for the analysis on this platform: Py-MolEdit, Py-ConfSearch, and Py-CoMFA. RESULTS: Maps that were generated were used to determine the screen’s r2 (Coefficient of Multiple Determinations) value and q2 (correlation coefficient). These numbers must be fewer than 1, suggesting a good, trustworthy model. Cross-validated (q2) 0.532 and conventional (r2) correlation values of 0.969 made the CoMFA model statistically significant. The model showed that hydroxamic acid inhibitors are significantly more sensitive to the steric field than the electrostatic field (70%) (30%). This hypothesis states that steric (43.1%), electrostatic (26.4%), and hydrophobic (20.3%) qualities were important in the design of sclerostin inhibitors. CONCLUSION: With 3D-QSAR and CoMFA, statistically meaningful models were constructed to predict ligand inhibitory effects. The test set demonstrated the model’s robustness. This research may aid in the development of more effective sclerostin inhibitors that are synthesised using FDA-approved medications.

Sclerostin antibody enhances implant osseointegration in bone with Col1a1 mutation

We evaluated the potential of sclerostin antibody (SclAb) therapy to enhance osseointegration of dental and orthopaedic implants in a mouse model (Brtl/+) mimicking moderate to severe Osteogenesis Imperfecta (OI). To address the challenges in achieving stable implant integration in compromised bone conditions, our aim was to determine the effectiveness of sclerostin antibody (SclAb) at improving bone-to-implant contact and implant fixation strength. Utilizing a combination of micro-computed tomography, mechanical push-in testing, immunohistochemistry, and Western blot analysis, we observed that SclAb treatment significantly enhances bone volume fraction (BV/TV) and bone-implant contact (BIC) in Brtl/+ mice, suggesting a normalization of bone structure toward WT levels. Despite variations in implant survival rates between the maxilla and tibia, SclAb treatment consistently improved implant stability and resistance to mechanical forces, highlighting its potential to overcome the inherent challenges of OI in dental and orthopaedic implant integration. These results suggest that SclAb could be a valuable therapeutic approach for enhancing implant success in compromised bone conditions.

Cardiovascular Safety of Romosozumab vs. PTH Analogs for Osteoporosis Treatment: a Propensity Score Matched Cohort Study.

Romosozumab, a monoclonal sclerostin antibody, is a recently approved highly potent anti-osteoporotic agent with osteoanabolic properties. Clinical use of Romosozumab is hindered by the fear of adverse cardiovascular (CV) events raised following the pivotal ARCH-trial. To assess real-world CV safety of romosozumab vs. alternative osteoanabolic therapies used for treatment of severe osteoporosis. Data was obtained from TriNetX, a global federated health research network including real-time electronic medical records from 113 healthcare organizations with a total of 136,460,930 patients across 16 countries at time of analysis. Inclusion criteria were age ≥ 40 years, a diagnosis of osteoporosis and prescription of romosozumab or a PTH analog (teriparatide/abaloparatide) during 8.2019-8.2022. 1:1 propensity score matched cohorts were created using demographic variables, comorbidities, and medications. Kaplan-Meier analysis was used to estimate the probability of the outcomes. Incident 3-point major adverse CV event or death (3P-MACE) during 1-year of follow-up after the initial prescription. 5,626 and 15,986 patients met the criteria for romosozumab and PTH analog cohorts, respectively, with 5,610 patients per group following propensity score matching. 3P-MACE was significantly less frequent in the romosozumab vs. PTH analog cohort (158 vs 211 patients with an outcome, p=0.003) with reductions in the individual components of the composite outcome: myocardial ischemic events (31 vs 58, p=0.003); cerebrovascular events 56 vs 79, p=0.037; deaths (83 vs 104, p=0.099). In a diverse real-world setting, prescription of romosozumab for osteoporosis is associated with less adverse CV events when compared to PTH analog therapy.

Loss of Nmp4 enhances bone gain from sclerostin antibody administration.

Severe osteoporosis is often treated with one of three Food and Drug Administration (FDA)-approved osteoanabolics. These drugs act by (1) parathyroid hormone (PTH) receptor stimulation using analogues to PTH (teriparatide) or PTH-related peptide (abaloparatide) or by (2) monoclonal antibody neutralization of sclerostin, an innate Wnt inhibitor (Scl-mAb, romosozumab-aqqg). The efficacies of both strategies wane over time. The transcription factor Nmp4 (Nuclear Matrix Protein 4) is expressed in all tissues yet mice lacking this gene are healthy and exhibit enhanced PTH-induced bone formation. Conditional deletion of Nmp4 in mesenchymal stem progenitor cells (MSPCs) phenocopies the elevated response to PTH in global Nmp4-/- mice. However, targeted deletion in later osteoblast stages does not replicate this response. In this study we queried whether loss of Nmp4 improves Scl-mAb potency. Experimental cohorts included global Nmp4-/- and Nmp4+/+ littermates and three conditional knockout models. Nmp4-floxed (Nmp4fl/fl) mice were crossed with mice harboring one of three Cre-drivers (i) Prx1Cre+ targeting MSPCs, (ii) BglapCre+ (mature osteocalcin-expressing osteoblasts), and (iii) Dmp1Cre+ (osteocytes). Female mice were treated with Scl-mAb or 0.9% saline vehicle for 4 or 7weeks from 10weeks of age. Skeletal response was assessed using micro-computed tomography, dual-energy X-ray absorptiometry, bone histomorphometry, and serum analysis. Global Nmp4-/- mice exhibited enhanced Scl-mAb-induced increases in trabecular bone in the femur and spine and a heightened increase in whole body areal bone mineral density compared to global Nmp4+/+ controls. This improved Scl-mAb potency was primarily driven by enhanced increases in bone formation. Nmp4fl/fl;PrxCre+ mice showed an exaggerated Scl-mAb-induced increase in femoral bone but not in the spine since Prrx1 is not expressed in vertebra. The Nmp4fl/fl;BglapCre+ and Nmp4fl/fl;Dmp1Cre+ mice did not exhibit an improved Scl-mAb response. We conclude that Nmp4 expression in MSPCs interferes with the bone anabolic response to anti-sclerostin therapy.

Wnt pathway in bone: knowledge structure and hot spots from 1993 to 2022.

Background: The role of the Wnt pathway in bone and its targets in skeletal disease has garnered interest, but the field lacks a systematic analysis of research. This paper presents a bibliometric study of publications related to the Wnt signaling pathway in bone to describe the current state of study and predict future outlooks. Methods: All relevant articles and reviews from 1993 to 2022 were collected from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using CiteSpace 6.1 R3, VOSviewer 1.6.15, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com/). Results: A total of 7,184 papers were retrieved, authored by 28,443 researchers from 89 countries/regions and published in 261 academic journals. The annual publication numbers peaked in 2021. China and United States are the leading countries, with the University of California and Harvard University as the most active institutions. Wang, Yang is the most prolific author. Bone has the most published research, while Proceedings of the National Academy of Sciences of the United States is the most cited journal on average. The main keywords include expression, Wnt, osteoporosis, bone, and osteogenic differentiation. Current and developing research hotspots focus on bone mass, sclerostin antibody, multiple myeloma, and cartilage development. Conclusion: This paper provides new insights for researchers to delve into the mechanisms of Wnt and bone related diseases and translate into clinical studies. It reveals the development and future research trends in Wnt and skeletal-related studies.

A bimolecular modification strategy for developing long-lasting bone anabolic aptamer

The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cut-off threshold of the renal filtration (30-50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized HC and DA, two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25mg/kg. This proposed bimolecular modification strategy could help addressing druggability challenge for aptamers with a short half-life.

Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH)

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg−1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) β-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.

A135 Increased renal mRNA expression of CYP27B1 and improved glucose clearance with sclerostin antibody in ovariectomized mice following Roux-en-Y Gastric Bypass Surgery

A135 Increased renal mRNA expression of CYP27B1 and improved glucose clearance with sclerostin antibody in ovariectomized mice following Roux-en-Y Gastric Bypass Surgery

Recommendations for the Pharmacological Treatment of Osteoporosis – Update 2023 of the German Osteoporosis Guideline

Abstract Aim The German osteoporosis guideline was updated on the basis of a systematic literature review and through a structured consensus process by an interdisciplinary, international (Germany, Austria, Switzerland) expert group representing the 20 member societies of the Joint Osteological Association (DVO) and patient advocacy organizations (BfO). This manuscript summarizes the changes in the German osteoporosis guideline with regard to pharmacological interventions and offers pragmatic pathways for implementation. Method Systematic literature search and structured consensus building according to AWMF regulations. Results The sclerostin antibody romosozumab was adopted into the guideline. In addition, the effectiveness of teriparatide was re-evaluated. For both bone anabolic agents evidence from randomized trials underlined a superiority over oral bisphosphonates with regard to fracture risk reduction. Between the antiresorptive treatments, differences regarding superiority/inferiority could only be shown with respect to surrogate parameters, not with regard to fractures. Data about the duration of treatment of all available drugs is limited. All non-bisphosphonate treatments require follow-up treatment. Conclusion An individualized treatment concept should be developed in a shared decision process, including a bone anabolic-first strategy in high-risk patients. Recommendations on treatment duration, drug holidays and sequential strategies should be considered.

The Effect of Sclerostin and Monoclonal Sclerostin Antibody Romosozumab on Osteogenesis and Osteoclastogenesis Mediated by Periodontal Ligament Fibroblasts.

Sclerostin is a bone formation inhibitor produced by osteocytes. Although sclerostin is mainly expressed in osteocytes, it was also reported in periodontal ligament (PDL) fibroblasts, which are cells that play a role in both osteogenesis and osteoclastogenesis. Here, we assess the role of sclerostin and its clinically used inhibitor, romosozumab, in both processes. For osteogenesis assays, human PDL fibroblasts were cultured under control or mineralizing conditions with increasing concentrations of sclerostin or romosozumab. For analyzing osteogenic capacity and alkaline phosphatase (ALP) activity, alizarin red staining for mineral deposition and qPCR of osteogenic markers were performed. Osteoclast formation was investigated in the presence of sclerostin or romosozumab and, in PDLs, in the presence of fibroblasts co-cultured with peripheral blood mononuclear cells (PBMCs). PDL-PBMC co-cultures stimulated with sclerostin did not affect osteoclast formation. In contrast, the addition of romosozumab slightly reduced the osteoclast formation in PDL-PBMC co-cultures at high concentrations. Neither sclerostin nor romosozumab affected the osteogenic capacity of PDL fibroblasts. qPCR analysis showed that the mineralization medium upregulated the relative expression of osteogenic markers, but this expression was barely affected when romosozumab was added to the cultures. In order to account for the limited effects of sclerostin or romosozumab, we finally compared the expression of SOST and its receptors LRP-4, -5, and -6 to the expression in osteocyte rich-bone. The expression of SOST, LRP-4, and LRP-5 was higher in osteocytes compared to in PDL cells. The limited interaction of sclerostin or romosozumab with PDL fibroblasts may relate to the primary biological function of the periodontal ligament: to primarily resist bone formation and bone degradation to the benefit of an intact ligament that is indented by every chew movement.

Antisclerostin Effect on Osseointegration and Bone Remodeling.

Objective: This study reviewed the literature on local or systemic administration of antisclerostin, presenting results associated with osseointegration of dental/orthopedic implants and stimulation of bone remodeling. Materials and Methods: An extensive electronic search was conducted through MED-LINE/PubMed, PubMed Central, Web of Science databases and specific peer-reviewed journals to identify case reports, case series, randomized controlled trials, clinical trials and animal studies comparing either the systemic or local administration of antisclerostin and its effect in osseointegration and bone remodeling. Articles in English and with no restriction on period were included. Results: Twenty articles were selected for a full-text, and one was excluded. Finally, 19 articles were included in the study (16 animal studies and 3 randomized control trials). These studies were divided into two groups, which evaluated (i) osseointegration and (ii) bone remodeling potential. Initially 4560 humans and 1191 animals were identified. At least 1017 were excluded from the studies (981 humans and 36 animals), totaling 4724 subjects who completed (3579 humans and 1145 animals). (a) Osseointegration: 7 studies described this phenomenon; 4 reported bone-implant contact, which increased in all included studies. Similar results were found for bone mineral density, bone area/volume and bone thickness. (b) Bone remodeling: 13 studies were used for description. The studies reported an increase in BMD with sclerostin antibody treatment. A similar effect was found for bone mineral density/area/volume, trabecular bone and bone formation. Three biomarkers of bone formation were identified: bone-specific alkaline phosphatase (BSAP), osteocalcin and procollagen type 1 N-terminal Pro-peptide (P1NP); and markers for bone resorption were: serum C-telopeptide (sCTX), C-terminal telopeptides of type I collagen (CTX-1), β-isomer of C-terminal telopeptides of type I collagen (β-CTX) and tartrate-resistant acid phosphatase 5b (TRACP-5b). There were limitations: low number of human studies identified; high divergence in the model used (animal or human); the variance in the type of Scl-Ab and doses of administration; and the lack of reference quantitative values in the parameters analyzed by authors' studies (many articles only reported qualitative information). Conclusion: Within the limitations of this review and carefully observing all data, due to the number of articles included and the heterogeneity existing, more studies must be carried out to better evaluate the action of the antisclerostin on the osseointegration of dental implants. Otherwise, these findings can accelerate and stimulate bone remodeling and neoformation.

Targeted postnatal knockout of Sclerostin using a bone-targeted adeno-associated viral vector increases bone anabolism and decreases canalicular density.

The creation of murine gene knockout models to study bone gene functions often requires the resource intensive crossbreeding of Cre transgenic and gene-floxed strains. The developmental versus postnatal roles of genes can be difficult to discern in such models. For example, embryonic deletion of the Sclerostin (Sost) gene establishes a high-bone mass phenotype in neonatal mice that may impact on future bone growth. To generate a postnatal skeletal knockout of Sost in adult mice, this study used a single injection of a bone-targeted recombinant adeno-associated virus (rAAV) vector. 8-week-old Sostflox/flox mice were injected with saline (control) or a single injection containing 5×1011 vg AAV8-Sp7-Cre vector. Ai9 fluorescent Cre reporter mice were dosed in parallel to confirm targeting efficiency. After 6weeks, detailed bone analysis was performed via microCT, biomechanical testing, and bone histology on vertebral and long bone specimens. The AAV8-Sp7-Cre vector induced widespread persistent recombination in the bone compartment. Regional microCT analyses revealed significant increases in bone with vector treatment. In the L3 vertebrae, Sostflox/flox:AAV-Cre showed a 22% increase in bone volume and 21% in trabecular bone fraction compared to controls; this translated to a 17% increase in compressive strength. In the tibiae, Sostflox/flox:AAV-Cre led to small but statistically significant increases in cortical bone volume and thickness. These were consistent with a 25% increase in mineral apposition rate, but this did not translate into increased four-point bending strength. Ploton silver nitrate stain on histological sections revealed an unexpected increase in canalicular density associated with Sost ablation. This report demonstrates a proof-of-concept that the AAV8-Sp7-Cre vector can efficiently produce postnatal skeletal knockout mice using gene-floxed strains. This technology has the potential for broad utility in the bone field with existing conditional lines. These data also confirm an important postnatal role for Sost in regulating bone homeostasis, consistent with prior studies using neutralizing Sclerostin antibodies, and highlights a novel role of Sost in canalicular remodeling.

Is sclerostin antibody an effective agent for alveolar bone regeneration in animal models? A scoping review

Objectives
 The use of Sclerostin Antibody(Scl-Ab) as a bone anabolic agent has shown significant benefit in bone disorders in preclinical animal models and human clinical trials. Currently available evidence on the use of Scl-Ab in alveolar bone regeneration is limited to animal studies and hence this scoping review encompasses the animal studies conducted to ascertain the effectiveness of Scl-Ab on alveolar bone regeneration. 
 Materials and methods
 The search strategy was aimed to locate published animal studies in which the treatment arm includes Sclerostin antibody administration for alveolar bone preservation or regeneration. The search terms used were (((Animal model) OR Rodent) AND Alveolar bone defect) AND Anti sclerostin antibody) OR Sclerostin antibody) AND Alveolar bone regeneration) OR Bone regeneration) AND Bone fill. 
 Results
 Of the 559 results from Medline/PubMed, Scopus, Web of Science, Google scholar and additional articles from the references, six were included in the review. Scl-Ab was found to be effective in improving the bone quality and quantity. It was also observed that Scl-Ab was useful in reduced bone density associated with diseases and conditiona affecting osteoblast activity. 
 Conclusion
 The review concluded that Scl-Ab promotes alveolar bone augmentation and improves bone quality without surgical interventions.

COMBINING SCLEROSTIN AND DKK1 INHIBITORS TO IMPROVE BONE PROPERTIES IN THE AGED SKELETON

Abstract Targeting the secreted Wnt inhibitor sclerostin has been an attractive strategy to improve skeletal health. Sclerostin antibody (romosozumab-aqqg; Evenity) was recently approved by the FDA to treat patients at increased risk of fracture. However, an increased risk of cardiovascular events was reported, resulting in issue a ‘black box warning’ requirement for romosozumab. One potential solution to lower the risk of adverse events is to reduce the medication dose. Previously, we found that dual inhibition of sclerostin and Dkk1 produced extremely potent synergistic bone anabolic effects, in both genetic and pharmacological models. While Dkk1 inhibition alone has no consistent bone-building effects, combining antibodies that target sclerostin (Scl-mAb) and Dkk1 (Dkk1-mAb) at 3:1 ratio resulted in 2-3X more bone gain as Scl-mAb alone. Further, much lower total doses of dual antibody treatment, given at optimized proportions, generated equivalent bone anabolic effects as Scl-mAb alone (at much higher doses), suggesting that a combinational strategy has obvious translational benefits. Finally, we tested whether low-dose combination therapy can maintain the same osteogenic effect as Scl-mAb in adult (6 month) and aged (20 month) mice. Outcome measures derived from radiographic, biomechanical, and histomorphometric assays revealed that a 3:1 ratio of Scl-mAb:Dkk1-mAb at 12.5mg/kg was as efficacious as 25mg/kg of Scl-mAb alone, in both age groups. Moreover, cortical porosity—a significant factor contributing to skeletal fragility in the aged skeleton—was significantly reduced by both Scl-mAb and low-dose combination treatment. In conclusion, our findings suggest that optimized low-dose combinational therapy is viable strategy for improving skeletal fragility.

Osteoporosis and Bone Marrow Adipose Tissue.

This review focuses on the recent findings regarding bone marrow adipose tissue (BMAT) concerning bone health. We summarize the variations in BMAT in relation to age, sex, and skeletal sites, and provide an update on noninvasive imaging techniques to quantify human BMAT. Next, we discuss the role of BMAT in patients with osteoporosis and interventions that affect BMAT. There are wide individual variations with region-specific fluctuation and age- and gender-specific differences in BMAT content and composition. The Bone Marrow Adiposity Society (BMAS) recommendations aim to standardize imaging protocols to increase comparability across studies and sites. Water-fat imaging (WFI) seems an accurate and efficient alternative for spectroscopy (1H-MRS). Most studies indicate that greater BMAT is associated with lower bone mineral density (BMD) and a higher prevalence of vertebral fractures. The proton density fat fraction (PDFF) and changes in lipid composition have been associated with an increased risk of fractures independently of BMD. Therefore, PDFF and lipid composition could potentially be future imaging biomarkers for assessing fracture risk. Evidence of the inhibitory effect of osteoporosis treatments on BMAT is still limited to a few randomized controlled trials. Moreover, results from the FRAME biopsy sub-study highlight contradictory findings on the effect of the sclerostin antibody romosozumab on BMAT. Further understanding of the role(s) of BMAT will provide insight into the pathogenesis of osteoporosis and may lead to targeted preventive and therapeutic strategies.

Sclerostin antibody promotes bone formation through the Wnt/β-catenin signaling pathway in femoral trochlear after patellar instability

ABSTRACT Purpose The molecular mechanism of patellar instability (PI) remains unknown. The purpose of this study was to explore the function of SOST/sclerostin in PI and examine the effect of sclerostin antibody (Scl-Ab). Materials and Methods We randomly divided 60 male 3-week-old C57Bl/6 mice into four groups: sham, PI, Scl-Ab intraperitoneal injection (Scl-Ab IP), Scl-Ab intraarticular injection (Scl-Ab IA). PI was established in the latter three groups. The Scl-Ab IP/IA groups were administered with an intraperitoneal/intraarticular Scl-Ab injection (100 mg/kg, 20 µl), respectively, at 5-day intervals. Distal femurs were collected 30 days after the surgery. The SOST/sclerostin, β-catenin, ALP, OPG and RANKL expression in distal femur were determined. Trochlear morphology and structural parameters of the trabecular and cortical bone compartments were determined by micro-CT. Further sub-regional analysis was performed. HE staining and Masson’s trichrome staining were performed to evaluate cartilage changes. Results PI increased the expression of SOST/sclerostin and RANKL, and decreased β-catenin, ALP and OPG levels, while Scl-Ab IP reversed these changes. Scl-Ab IP brought trochlear morphology closer to normality. Additionally, Scl-Ab IP significantly improved most of the bone parameters. Importantly, both PI and Scl-Ab IP acted mainly on trabecular bone. Histological analysis showed that Scl-Ab IP protected cartilage from degeneration. However, Scl-Ab IA did not protect against bone loss or cartilage degradation. Conclusions SOST/sclerostin plays an important role in PI and systemic Scl-Ab use promotes bone formation through the Wnt/β-catenin signaling pathway in the femoral trochlear after PI.

Sclerostin Concentration and Bone Biomarker Trends in Patients with Spinal Cord Injury: A Prospective Study.

Patients with spinal cord injury (SCI) experience a high osteoporosis incidence, which increases fracture risk. Recently, a sclerostin antibody was introduced as a target biomarker to treat osteoporosis. We aimed to determine the serum concentration of sclerostin and factors affecting its concentration over time. This was a prospective cross-sectional study. The inclusion criteria were (1) SCI patients with a grade 3 modified functional ambulatory category score (FAC—patients requiring firm continuous support) and (2) patients whose injury occurred >1 month ago. The exclusion criterion was a history of osteoporosis medication administration within 6 months. The collected data included bone biomarkers (carboxy-terminal collagen crosslinks (CTX), procollagen type 1 intact N-terminal propeptide, and sclerostin), clinical data (FAC, lower extremity motor score), body mass index, SCI duration, and hip bone mineral density (BMD). This study recruited 62 patients with SCI. Sclerostin levels significantly correlated with age, CTX level, and hip BMD. SCI duration was negatively correlated with sclerostin levels. Lower extremity motor scores were not significantly correlated with sclerostin levels. The acute SCI state showed a higher sclerostin level than the chronic SCI state. Sclerostin showed a significant relationship with CTX. In conclusion, age and BMD affect sclerostin concentration in patients with SCI.