Skeletal Effects Research Articles

Osteogenesis and Embryogenesis in Zebrafish Embryo Is Differentially Modulated by Solvents and Prednisolone

Several molecules and extracts are known to have bone-specific effects. For example, the long-term use of glucocorticoids like prednisolone causes several negative effects including a loss of bone mass. Molecules like prednisolone are usually dissolved in organic solvent which are known to be toxic for zebrafish embryo in certain concentrations. Nevertheless, solvents like dimethyl sulfoxide (DMSO), ethanol and methanol have never been tested for specific skeletal effects during development in dose-dependency. Vitality assay, live fluorescence and bone-specific staining were used to evaluate solvents effects compared to prednisolone. DMSO, ethanol and methanol perturb osteogenesis starting from 1%, 1.5% and 3% respectively, concentrations in which vasculature, length and survival rate appear unaffected. This effect may be due to high sensitivity of the osteogenesis process to external chemical stimuli, especially in the trunk. On the contrary, the negative effect of prednisolone on skeletal development appears more specific since it is found at very low concentrations, far from any other developmental defects. The recommended solvent concentration to be used in zebrafish embryos osteogenesis assay was established in 0.5% for DMSO, 2% for methanol and 0.5% for ethanol. We recommend analyzing both head and trunk mineralization in zebrafish embryo osteogenesis assay.

Anchorage In Primary Vs. Permanent Teeth For Rapid Maxillary Expansion In Children: Systematic Review And Meta-Analysis

Background: Rapid maxillary expansion (RME) is a widely used orthodontic technique to correct transverse maxillary deficiencies. Both primary and permanent teeth are commonly used as anchorage for this procedure. However, there is limited evidence regarding differences in skeletal and dental effects or buccal alveolar bone preservation between these anchorage types. Materials and Methods: A systematic review was conducted to compare the skeletal and dental effects of RME using primary or permanent teeth as anchorage. Searches were performed in the following databases: PubMed, Web of Science, Scopus, LILACS, and OpenGrey. The risk of bias was assessed using the Rob 2.0 and Robins I tools. The certainty of evidence was evaluated according to the GRADE system, and meta-analysis was performed with R software. Results: Eight studies were included in the qualitative analysis and five in the quantitative analysis. The risk of bias was low in two studies, moderate in five studies, and high in one study. The certainty of evidence was very low. It was not possible to perform a meta-analysis for the outcome "buccal alveolar bone thickness" due to the lack of available studies, which was limited to only one study. The intermolar width was greater when the anchorage used permanent teeth SMD= -1.24; 95% CI (-2.14; -0.33); p<0.01]. However, this difference may not be clinically relevant. Conclusion: The evidence does not support a clear recommendation for the use of primary or permanent teeth as anchorage in RME, as no clinically relevant differences were observed in skeletal or dental effects. Primary teeth may be preferred when buccal alveolar bone preservation is a priority. Further studies are required to enhance evidence and support clinical decisions.

Skeletal effects of sleeve gastrectomy, by sex and menopausal status and compared to Roux-en-Y gastric bypass surgery.

Roux-en-Y gastric bypass (RYGB) has deleterious effects on bone mass, microarchitecture, and strength. The skeletal effects of sleeve gastrectomy (SG), now the most commonly performed bariatric surgical procedure, are incompletely understood. We examined changes in bone turnover, areal and volumetric bone mineral density (aBMD, vBMD), and appendicular bone microarchitecture and estimated strength after SG. We compared the results to those previously reported after RYGB, hypothesizing lesser effects after SG than RYGB. Prospective observational cohort study of 54 adults with obesity undergoing SG at an academic center. Skeletal characterization with biochemical markers of bone turnover, dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) was performed preoperatively and 6- and 12-months postoperatively. Over 12 months, mean percentage weight loss was 28.8%. Bone turnover marker levels increased, and total hip aBMD decreased -8.0% (95% CI -9.1%, -6.7%, p<0.01). Spinal aBMD and vBMD declines were larger in postmenopausal women than men. Tibial and radial trabecular and cortical microstructure worsened, as did tibial estimated strength, particularly in postmenopausal women. When compared to data from a RYGB cohort with identical design and measurements, some SG biochemical, vBMD, and radial microstructural changes were smaller, while other changes were not. Bone mass, microstructure, and strength decrease after SG. Some skeletal parameters change less after SG than after RYGB, while for others, we find no evidence for smaller effects after SG. Postmenopausal women may be at highest risk of skeletal consequences after SG.

Integrating Endocrine, Genomic, and Extra-Skeletal Benefits of Vitamin D into National and Regional Clinical Guidelines.

Vitamin D is essential for bone health, immune function, and overall well-being. Numerous ecological, observational, and prospective studies, including randomized controlled clinical trials (RCTs), report an inverse association between higher serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels in various conditions, including cardiovascular disease, metabolic disorders such as diabetes and obesity, susceptibility to infection-related complications, autoimmune diseases, and all-cause mortality. Vitamin D operates through two distinct systems. The endocrine system comprises the renal tubular cell-derived circulatory calcitriol, which primarily regulates calcium homeostasis and muscular functions. In contrast, intracellularly generated calcitriol in peripheral target cells is responsible for intracrine/paracrine system signaling and calcitriol-vitamin D receptor-mediated genomic effects. Government-appointed committees and health organizations have developed various clinical practice guidelines for vitamin D supplementation and management. However, these guidelines heavily relied on the 2011 Institute of Medicine (IoM) report, which focused solely on the skeletal effects of vitamin D, ignoring other body systems. Thus, they do not represent maintaining good overall health and aspects of disease prevention. Additionally, the IoM report was intended as a public health recommendation for the government and is not a clinical guideline. New country- and regional-specific guidelines must focus on healthy nations through disease prevention and reducing healthcare costs. They should not be restricted to bone effect and must encompass all extra-skeletal benefits. Nevertheless, due to misunderstandings, medical societies and other governments have used faulty IoM report as a foundation for creating vitamin D guidelines. Consequently, they placed disproportionate emphasis on bone health while largely overlooking its benefits for other bodily systems, making current guidelines, including 2024, the Endocrine Society less applicable to the public. As a result, the utility of published guidelines has been significantly reduced for clinical practice and RCTs that designed on bone-centric are generate misleading information and remain suboptimal for public health and disease prevention. This review and its recommendations address the gaps in current vitamin D clinical practice guidelines and propose a framework for developing more effective, country and region-specific recommendations that capture the extra-skeletal benefits of vitamin D to prevent multiple diseases and enhance public health.

Evaluation of pain intensity and airway changes in non-growing patients treated by MARPE with and without micro-osteoperforation: a randomized clinical trial

Trial designParallel.ObjectivesTo assess the effect of mini-screw assisted rapid palatal expansion (MARPE) with/without micro-osteoperforation (MOP) on the airway and pain intensity in non-growing patients with maxillary transverse deficiency.MethodTwo equal groups of twenty-four individuals aged ≥ 19 years old with maxillary transverse deficit were randomly assigned. MOP-facilitated MARPE was used to treat one group (MMG), and the other group was treated with MARPE without MOP (NMG). For airway evaluation, CBCT images were obtained 2 months before starting the palatal expansion and 3 months after finishing the expansion in 28 days. The Visual Analogue Scale (VAS) was used to measure the pain level.ResultsSignificant suture opening was observed in both groups. All linear measurements of the nasal cavity and volumetric measurements of the nasal passage and oropharyngeal airway increased significantly in both groups, with no significant difference between them. Moderate pain was experienced in the first two weeks of expansion in MMG (5.11 ± 0.30), while more significant pain was recorded in NMG (6.87 ± 0.40). Pain decreased significantly in the following two weeks in MMG (2.77 ± 0.39) and in NMG (5.11 ± 0.32), with a significant difference between the two groups throughout the entire duration of expansion.ConclusionTransverse maxillary deficit was successfully treated with both expansion methods, with and without MOP, with comparable skeletal effects at the nasal levels and airway volumetric improvement. So, MOP did not provide any further advantage in improving the airway volume after maxillary expansion. However, it significantly reduced pain intensity throughout the entire duration of expansion.Trial registrationThe protocol registration and results system (PRS) of ClinicalTrials.gov has this RCT registered under the number NCT06502041 on 13/07/2024.

Analyses of Off-Target Effects on Cardiac and Skeletal Muscles by Berberine, a Drug Used to Treat Cancers and Induce Weight Loss.

Previous reports from our laboratory describing the formation of myofibrils in cultured embryonic cardiac and skeletal muscle cells have proposed that myofibrillogenesis occurs in three steps of increasing protein organization: beginning with premyofibrils, followed by nascent myofibrils, and ending in mature myofibrils. Inhibitors of the ubiquitin proteasome system (UPS) prevented nascent myofibrils from progressing directly to mature myofibrils in cultured cardiac and skeletal muscle cells, supporting a three-step model of assembly in which some of the proteins in nascent myofibrils are proteolyzed to allow the assembly of mature myofibrils. Application of UPS inhibitors on cultured muscle cells suggests possible explanations for the off-target cardiac and skeletal muscle adverse effects of UPS drugs, which are used on cancer patients. Berberine, a plant derivative, has been used to treat various cancers, including multiple myelomas. In contrast to the use of UPS drugs, success was reported with Berberine in multiple myeloma patients with no off-target effects on their hearts. We have exposed cultured cardiac and skeletal muscle cells to Berberine, a ligase inhibitor of UHRF1 (ubiquitin-like with PHD and RING finger domains). Berberine inhibited myofibril assembly at the nascent myofibril stage in embryonic skeletal muscle cells but had no effect in the assembly of mature myofibrils in embryonic heart cells. RT-PCR experiments demonstrated Berberine inhibition of mRNA for muscle myosin II heavy chains but not for muscle actin mRNA in skeletal muscle cells. Berberine is also being used as a popular weight losing compound, because it is much cheaper and available without a prescription than the semaglutide containing weight losing drugs (Wegovy and Ozempic). In contrast to Berberine, semaglutide had no effects on myofibril assembly in culture assays for both cardiac and skeletal muscle cells. We postulate that analyses of cultured embryonic cardiac and skeletal muscle cells will provide a preclinical assay for the testing of novel cancer drugs with improved outcomes for patients, an important goal for cancer therapeutics.

Skeletal and dental effects of skeletally anchored forsus fatigue resistant devices during class II malocclusion treatment: A meta-analysis and systematic review

OBJECTIVE: To evaluate and compare the skeletal and dental treatment effects of Class II malocclusion cases using skeletally anchored Forsus (miniscrew-anchored FRD or miniplate-anchored FRD), with conventional Forsus FRD. MATERIALS AND METHODS: Unrestricted electronic search of six databases and additional manual searches were performed up to July 2023. Randomized controlled trials having one treatment arm with skeletal anchored Forsus FRD in treatment of Class II malocclusion and another matched treatment group treated with conventional Forsus FRD were included in this review. Risk of bias assessment was performed using Cochrane’s Risk of Bias Tool. No restrictions were set concerning treatment duration, or the cephalometric analysis used. Skeletal and dentoalveolar outcomes data were extracted by two authors independently. RESULTS: Three studies using miniscrews as means of skeletal anchorage were evaluated and qualified for the final review and meta-analysis. Three other studies using miniplates were considered in the systematic review but were not qualified for a meta-analysis. The data gathered from the miniscrews anchored FRD papers included a total of 93 Class II patients (46 treated with miniscrew-anchored Forsus FRD, 47 treated with conventional Forsus FRD). The meta-analysis showed a statistically significant reduction in the SNA angle in favor of miniscrew-anchored Forsus FRD (mean difference: −0.26, CI: −0.50 to −0.02), a nonsignificant difference in the SNB (mean difference: 0.17, CI: -0.06 to 0.39), a statistically significant increase in the SN–MP angle in favor of miniscrew-anchored Forsus FRD (mean difference: 0.53, CI: 0.06–1.00)—a statistically significant reduction in the L1-MP angle in favor of miniscrew-anchored Forsus FRD (mean difference: −2.12, CI: −4.96 to −2.12). Data from miniplate-anchored FRD included 31 Class II patients treated with mini plate anchored FRD. Although meta-analysis was not applicable to these studies, lower incisor inclination was observed to be less. CONCLUSIONS: Based on the existing evidence, the use of skeletal anchorage could not enhance forward mandibular growth. However, miniscrew-anchored Forsus FRD could minimize mandibular incisor protrusion while miniplates could even retract the mandibular incisor position with a headgear effect on the maxilla.

Exploring Antidepressant and Skeletal Muscle Relaxant Effects of the Hydroalcholic Extract of the Sedum lineare Thunb

Exploring Antidepressant and Skeletal Muscle Relaxant Effects of the Hydroalcholic Extract of the Sedum lineare Thunb

The effect of biocide chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) mixture on C2C12 muscle cell damage attributed to mitochondrial reactive oxygen species overproduction and autophagy activation

ABSTRACT The mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT) is a biocide widely used as a preservative in various commercial products. This biocide has also been used as an active ingredient in humidifier disinfectants in South Korea, resulting in serious health effects among users. Recent evidence suggests that the underlying mechanism of CMIT/MIT-initiated toxicity might be associated with defects in mitochondrial functions. The aim of this study was to utilize the C2C12 skeletal muscle model to investigate the effects of CMIT/MIT on mitochondrial function and relevant molecular pathways associated with skeletal muscle dysfunction. Data demonstrated that exposure to CMIT/MIT during myogenic differentiation induced significant mitochondrial excess production of reactive oxygen species (ROS) and a decrease in intracellular ATP levels. Notably, CMIT/MIT significantly inhibited mitochondrial oxidative phosphorylation (Oxphos) and reduced mitochondrial mass at a lower concentration than the biocide amount, which diminished the viability of myotubes. CMIT/MIT induced activation of autophagy flux and decreased protein expression levels of myosin heavy chain (MHC). Taken together, CMIT/MIT exposure produced damage in C2C12 myotubes by impairing mitochondrial bioenergetics and activating autophagy. Our findings contribute to an increased understanding of the underlying mechanisms associated with CMIT/MIT-induced adverse skeletal muscle health effects.

Miniscrew-Assisted Rapid Palatal Expansion: A Scoping Review of Influencing Factors, Side Effects, and Soft Tissue Alterations.

Background: Miniscrew-assisted rapid palatal expansion (MARPE) has gained attention as an effective alternative to traditional rapid palatal expansion, particularly in adult patients. This scoping review synthesizes recent evidence to assess the clinical efficacy and safety of MARPE, addressing a gap in comprehensive, up-to-date analyses in this area. Objective: To present the recent assessments concerning MARPE influencing factors, side effects, soft tissue alterations, and airway changes, focusing on comparisons with conventional devices. Methods: Using PRISMA guidelines, we conducted a search of the literature published in 2018-2023 using Medline, Scopus, and Embase databases. This review focused on randomized controlled trials, cohort studies, and other reviews that evaluated the outcomes of MARPE. Results: Our analysis included 75 studies and revealed that MARPE significantly improves suture expansion with fewer dental and skeletal side effects compared to traditional methods. The technique shows high efficacy in subjects up to 25 years of age, with reduced incidence of complications and improved stability of expansion. Conclusions: The results support MARPE as a viable and superior alternative for maxillary expansion in late adolescents and adults. Given its advantages over traditional methods, MARPE should be considered a standard procedure in orthodontic treatment plans. Future research should focus on long-term outcomes and optimization of patient-specific treatment protocols.

Bone health in childhood cancer survivors, is there really a problem? Pitfalls of assessment, calculating risk, and suggested surveillance and management for osteonecrosis and low and very low bone mineral density.

Childhood cancer survivors are at increased risk of developing (long-term) skeletal adverse effects, such as osteonecrosis, impaired bone mineral density, and fractures. This paper provides an overview of the current understanding of bone health in these survivors, examining whether it represents a significant concern. It focusses on the challenges of assessing and managing bone health in childhood cancer survivors, highlighting diagnostic pitfalls, methods for accurately identifying those at high risk, and suggested strategies for the surveillance and management of osteonecrosis and impaired bone mineral density. The need for improved surveillance strategies, particularly for high-risk survivors, alongside potential prevention and management options, including pharmacological and lifestyle interventions, is emphasised. Given the lack of consensus on optimal prevention and treatment strategies, the paper emphasises the need for further research to optimise care and improve long-term outcomes for childhood cancer survivors with bone health impairments.

Effect of Anchorage Modifications on the Efficacy of Miniscrew-Assisted Rapid Palatal Expansion: A Systematic Review and Meta-Analysis.

Mini-implant-assisted rapid palatal expansion (MARPE) offers a non-surgical alternative for expanding the basal bone, increasing skeletal effects while minimizing undesirable dental side effects. This systematic review and meta-analysis evaluatethe effectiveness of MARPE in terms of transverse skeletal development, dentoalveolar changes, and periodontal effects, with consideration of appliance design. A review was conducted across multiple databases, including PubMed, MEDLINE, Embase, Scopus, and Springer, covering studies published between 2005 and 2024. Randomized controlled trialsinvolving MARPE, with specific attention to design variations (e.g., miniscrew type, number, diameter, length, position, and activation protocol), were selected. Transverse skeletal expansion, assessed via changes in the nasal width, was reported in six of seven studies, with an average increase ranging from 0.31 mm to 2.90 mm for MARPE, compared to 0.11 mm to 2.46 mm for conventional Hyrax expanders. Maxillary width expansion ranged from 2.89 mm to 9.08 mm with MARPE and from 2.59 mm to 8.51 mm with Hyrax. Periodontal changes were reported in six studies, although details were generally unclear. The use of four self-drilling miniscrews with once-daily activation over an extended period produced greater nasal width expansion, greater average skeletal expansion of the maxilla, and less dental inclination and dentoalveolar expansion compared to Hyrax. No significant differences were observed between short and long miniscrews, although wider miniscrews resulted in improved outcomes. The MARPE technique, especially when using a design with four self-drilling miniscrews and daily activation until the targeted expansion is reached, offers notable benefits compared to the conventional Hyrax appliance. This method improves both nasal and maxillary skeletal expansion, lessens dental inclination, and reduces negative effects relative to traditional approaches.

Dentofacial and skeletal effects of two orthodontic maxillary protraction protocols: bone anchors versus facemask

BackgroundMaxillary retrognathia and/or mandibular prognathia are resulting in class III malocclusion. Regarding orthodontic class III malocclusion treatment, the literature reports several treatment approaches. This comparative clinical study investigated two maxillary protraction protocols including bone anchors and Delaire type facemask.MethodsCephalometric radiographs of n = 31 patients were used for data acquisition. The patients were divided into two groups according to their treatment protocol: bone anchored protraction (n = 12, 8 female, 4 male; mean age 11.00 ± 1.76 years; average application: 13.50 ± 5.87 months) and facemask protraction (n = 19, 11 female, 8 male; mean age 6.74 ± 1.15 years; average application: 9.95 ± 4.17 months). The evaluation included established procedures for measurements of the maxilla, mandibula, incisor inclination and soft tissue. Statistics included Shapiro-Wilk- and T-Tests for the radiographs. The level of significance was set at p < 0.05.ResultsThe cephalometric analysis showed differences among the two groups. SNA angle showed significant improvements during protraction with bone anchors (2.30 ± 1.18°) with increase in the Wits appraisal of 2.01 ± 2.65 mm. SNA angle improved also during protraction with facemask (1.22 ± 2.28°) with increase in the Wits appraisal of 1.85 ± 4.09 mm. Proclination of maxillary incisors was larger in patients with facemask (3.35 ± 6.18°) and ML-SN angle increased more (1.05 ± 1.51°) than in patients with bone anchors. Loosening rate of bone anchors was 14.58%.ConclusionsBoth treatment protocols led to correction of a class III malocclusion. However, this study was obtained immediately after protraction treatment and longitudinal observations after growth spurt will be needed to verify the treatment effects over a longer period. The use of skeletal anchorage for maxillary protraction reduces unwanted side effects and increases skeletal effects needed for class III correction.

Skeletal muscle fibre type-dependent effects of atorvastatin on the PI3K/Akt/mTOR signalling pathway and atrophy-related genes in rats

BackgroundOne of the probable causes of statin myotoxicity is an imbalance between protein synthesis and degradation. These processes are regulated by the PI3K/Akt/mTOR pathway and the ubiquitin‒proteasome system (UPS). The aim of this study was to assess whether the effects of atorvastatin on PI3K/Akt/mTOR pathway downstream proteins, the FoxO3a transcription factor and the UPS genes, i.e., MuRF-1 and MAFbx, depend on muscle fibre type.Methods and resultsAtorvastatin (50 mg/kg) was administered to Wistar rats. The levels of selected PI3K/Akt/mTOR pathway proteins were assayed via Western blotting, whereas MuRF-1, MAFbx and FoxO3a mRNA levels were measured using reverse transcription quantitative polymerase chain reaction (RT‒qPCR). Gomöri trichrome staining was performed to assess skeletal muscle pathology. A decrease in the P-Akt/Akt ratio was observed in the gastrocnemius muscle (MG), whereas an increase in the P-Akt/Akt ratio was observed in the soleus muscle (SOL). FoxO3a gene expression increased in the SOL and extensor digitorum longus (EDL) muscles. MuRF-1 gene expression increased in the MG, and MAFbx expression increased in the EDL. No histopathological changes were observed in any of the tested muscles.ConclusionsIn the absence of overt muscle damage, atorvastatin decreased the P-Akt/Akt ratio in the MG, indicating an increase in inactive Akt. Consistent with the decrease in Akt activation, rpS6 phosphorylation decreased. In SOL, atorvastatin increased the P-Akt/Akt ratio, indicating Akt activation. P-FoxO3a and the P-FoxO3a/FoxO3a ratio increased, suggesting that FoxO3a inactivation occurred. Moreover, in the SOL, atorvastatin did not affect the expression of atrophy-related genes. These findings indicate that atorvastatin has no adverse effect on the Akt pathway in the SOL. Our results showed that the effects of atorvastatin on the Akt signalling pathway and atrophy-related gene expression depend on muscle type.

Favourable dentoalveolar changes after lower premolar extractions for Class III camouflage with completely customized lingual appliances

BackgroundThe aim of the investigation was to evaluate if the inclination of the lower anterior teeth can be controlled reliably after lower premolar extraction for Class III camouflage treatment with completely customized lingual appliances (CCLAs). Treatment outcome was tested against the null hypothesis that lower premolar extractions for non-surgical camouflage treatment of a Class III malocclusion will lead to further compensation by retroclining mandibular incisors during CCLA treatment.MethodsThis retrospective study included 25 patients (f/m 12/13; mean age 20.7 years, SD 9.5 years) with uni- or bilateral Class III molar relationship and a Wits value of ≤ -2 mm. In all consecutively debonded patients, lower premolars were extracted to correct the sagittal relationship with a non-surgical camouflage approach. Lateral head films prior to (T1) and at the end of lingual orthodontic treatment (T2) were used to evaluate skeletal and dentoalveolar effects. A paired t-test with alpha = 5% was used to define differences between the endpoints. The linear correlation between the inclination of the mandibular incisors at T1 and the achieved correction was measured with the Pearson correlation coefficient (PCC). A Schuirmann’s TOST equivalence test was used to check if the final lower incisor inclination was within the defined norms.ResultsThe null hypothesis was rejected as the mean lower incisor inclination was improved by 1.8° despite lower premolar extractions (T1: 86.8°/ T2: 88.6°). There was a strong correlation (-0.75) between the lower incisor inclination at T1 and the achieved correction indicating a controlled correction towards the norm regardless of the initial incisor position. At T2, the interincisal angle as well as the lower incisor inclination were within the norm.ConclusionLower premolar extractions for non-surgical camouflage treatment of a Class III malocclusion will not lead to undesired retroclining of mandibular incisors during CCLA treatment even in severe cases.

The Androgen Deprivation Therapy Landscape in 2024 – Co-navigating the Available Options with Prostate Cancer Patients

This symposium convened during the 2024 European Association of Urology (EAU) Congress in Paris, France, focusing on the multifaceted aspects of prostate cancer (PCa) treatment from the patient’s perspective. The session delved into the nuanced needs, expectations, and treatment experiences encountered by individuals diagnosed with this condition. A pivotal aspect of the discussion centred on the imperative of ensuring patient awareness and informed consent, particularly concerning androgen deprivation therapy (ADT), given its array of potential side effects. ADT, a cornerstone in advanced PCa management, encompasses a spectrum of side effects including both physical and psychological dimensions. These include, but are not limited to, body hair loss, weight fluctuations, mood alterations, decreased libido, cognitive impairments, muscle atrophy, and bone density loss. Effective management of these side effects requires comprehensive support to be provided to patients to mitigate complications and optimise quality of life. The options for ADT were discussed, with their comparative strengths and challenges. ADT strategies take effect over different time periods (from 12 hours up to 4 weeks), exert varying effects on testosterone levels, and carry different side effect profiles. Selecting the optimal course of treatment for localised or locally advanced PCa requires consideration of whether the patient is at intermediate-, high-, or very high-risk of biochemical recurrence, and whether the intermediate-risk disease is classified as favourable intermediate-risk (FIR) or unfavourable intermediate-risk (UIR). While continuous ADT is the standard of care, intermittent ADT has been associated with significantly better quality of life scores for hot flushes, desire for sexual activity, and urinary symptoms, with a trend toward improvement in the level of fatigue. Furthermore, the interplay between PCa, ADT, and cardiovascular disease (CVD) was discussed to underscore the imperative for clinicians to assess the cardiovascular risks associated with ADT, particularly in patients with heightened cardiovascular vulnerability. Mitigating the adverse skeletal effects of ADT mandates a multifaceted approach encompassing nutritional supplementation, exercise regimens, and lifestyle modifications including alcohol cessation and smoking cessation. Integrating a prehabilitation checklist into clinical practice emerges as a pragmatic strategy to facilitate informed discussions regarding the potential adverse effects of ADT, enabling proactive support provision to optimise patient outcomes.

8749 Skeletal effects among pre and postmenopausal women with hypoparathyroidism (HypoPT); data from the Canadian National Hypoparathyroidism Registry (CNHR)

Abstract Disclosure: H. AbuAlrob: None. S. Hussein: None. H. Afifi: None. D.S. Ali: None. A. Almoulia: None. D. Bole: None. M. Braga: None. P. Chandra: None. A. Cheng: None. R. Cheung: None. J.E. Young: None. J. Hetal: None. S. Khan: None. T.S. Khan: None. J. Malhem: None. H. Malik: None. S. Mehmood: None. A. Millar: None. E. Morgante: None. F. Naveed: None. H. Niazi: None. T.L. Paul: None. A. Prebtani: None. Z. Punthakee: None. J.A. Shaban: None. R. Shah: None. M. Shrayyef: None. M. Shaikh: None. C. Tagra: None. S.R. Teschke: None. I.T. Tauqir: None. S. Van Uum: None. W. Robert: None. M. Ovize: Employee; Self; Amolyt. A.A. Khan: Research Investigator; Self; Amolyt, Ascend Therapeutics (A Besins Healthcare company), Takeda. Introduction: the CNHR registry was established in 2014 with the objectives of identifying the etiology, presentation, natural history and current treatment of hypoPT[1]. Methods: 101 patients with hypoPT were included in this prospective study. Patients completed baseline assessments including 3 site bone mineral density (BMD), trabecular bone score (TBS), fracture risk assessments, and bone biomarkers. Baseline data is presented. Results: A total of 101 participants were enrolled, 83 (82%) were female, and 18 (18%) were male. There were 35 (42%) premenopausal females and 48 (58%) postmenopausal females (PMF). Only PMF were on antiresorptive therapy. Seven (7/8) were on bisphosphonate therapy (i.e., alendronate), and 3 females were on denosumab. Among premenopausal females the average corrected calcium (Ca) was 2.03 mmol/L (SD=0.26), calcium phosphate product (Ca PO4) was 2.75 (SD=0.62), and the eGFR 94.63 mL/min (SD=18.08). The average bone turnover markers among premenopausal women for the Telopeptide-C (CTX) was 242.4 ng/L (SD=209.4) (CTX within the reference range (WRR) 136-689 ng/L) while the Propeptide 1 Collagen (P1NP) was 37.6 ug/L (SD=39.2) (P1NP WRR 19-83 ug/L). Among PMF, the average corrected Ca was 2.22 mmol/L (SD=0.18), Ca PO4 was 2.14 (SD=0.17), and the eGFR 73.9 mL/min (SD=23.0). The average bone turnover markers among PMF for CTX was 346.1 ng/L (SD=488.4) (WRR 177-1015 ng/L) while P1NP was 47.1 ug/L (SD=33.1) (WRR 16-98 ug/L). Among premenopausal women (n=35), the mean total hip Z-score was 0.87 (SD=1.29), L1-L4 Z-score 0.98 (SD=1.19), FN Z-score 0.59(SD=1.17), and 1/3R Z-score -0.04 (SD=0.77). Among PMF (n=48) the mean total hip T-score was -0.20 (SD=1.65), L1-L4 T-score -0.24 (SD=1.88), FN T-score -0.43(SD=1.59), and 1/3R T-score -0.94(SD=1.23).TBS scores in premenopausal women were normal (TBS=1.41 (SD=0.10)) however the TBS was partially degraded among PMF (TBS= 1.28(SD=0.15)). Fracture data has previously been reported3. Conclusion: The effects of hypoPT on bone strength needs further study2. Our data suggests that bone quality maybe impaired in PMF with hypoPT as noted by the presence of degraded TBS scores and the presence of fragility fracture in this population. Reference 1.Khan AA et al Canadian national hypoparathyroidism registry: an overview of hypoparathyroidism in Canada. Endocrine 2021. 2.Khan AA et al JBMR 2022 Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop3.Hussein S et al. Skeletal effects of hypoparathyroidism (HypoPT); data from the Canadian National Hypoparathyroidism Registry (CNHR). Available here: https://amolytpharma.com/wp-content/uploads/2023/10/ASBMR-CNHR_FINAL.pdf Presentation: 6/2/2024

9267 Targeting IGF-I to Growth Plate Cartilage Augments Therapeutic Effects on Skeletal Growth and Reduces Hypoglycemic Effects in Mice

Abstract Disclosure: K. Tailor: None. T. Stowe: None. J. Ree: None. B. Ventura: None. J. Deursen: None. R. O'Brien: None. J. Baron: None. J. Lui: None. Recombinant human growth hormone (GH) is commonly used to treat short stature in children but has limited efficacy in severe, non-GH-deficient conditions, such as skeletal dysplasias, and has adverse off-target effects. Because short stature is the result of reduced growth plate chondrogenesis, we hypothesized that targeting chondrogenic growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing adverse effects on non-target tissues. Toward this end, we previously developed fusion proteins conjugating insulin-like growth factor-1 (IGF-1) with a single-chain human monoclonal antibody fragment (ScFv) targeting matrillin-3 (1), a protein specifically expressed in cartilage matrix, and demonstrated increased on-target therapeutic efficacy at the growth plate and decreased off-target effects in a GH-deficient (lit) mouse model (2). In the current study, we established a second GH-deficiency model by administration of a GH antagonist, pegvisomant (PEG), in C57BL/6 wild-type male mice. Alternate-day injection of pegvisomant at 40 mg/kg for 7 days reduced body weight, serum IGF-1 levels, and growth plate height in mice. Using this model, we found that once-daily SQ administration of cartilage-targeted IGF-I (named CV1574-1) for five days increased body weight and growth plate height greater than an equimolar dose of IGF-I itself administered twice daily. Hypoglycemia is an adverse effect of recombinant IGF-1 treatment. Therefore, we also monitored blood glucose levels after a single SQ injection of CV1574-1 and found that this fusion protein showed a reduced hypoglycemic effect compared to injection of IGF-I itself. Lastly, to gain mechanistic insight into the role of matrillin-3 targeting on therapeutic efficacy, we assessed the ability of CV1574-1 to induce pAKT signaling in vitro. Transient exposure to CV1574-1 caused more prolonged induction of pAKT signal in wild-type rat chondrosarcoma (RCS) cells compared to matrillin-3-knockout RCS cells, suggesting that matrillin-3 targeting extends the duration of IGF-1 receptor activation. To summarize, the current findings demonstrate that CV1574-1, a fusion protein that targets IGF-1 to cartilage, improves efficacy at the growth plate, reduces hypoglycemic effects, and, in vitro, prolongs receptor activation. Our study provides further evidence that cartilage-targeted therapy has the potential to provide new pharmacological approaches for the treatment of childhood linear growth disorders, including skeletal dysplasias and growth failure due to systemic disease. Reference:(1) Cheung et al. Pharma Res 2015, 32(7):2439-49.(2) Lui et al. Molecular Therapy 2019, 27(3):673-680 Presentation: 6/3/2024

7237 Targeting IGF-I to Growth Plate Cartilage Augments Therapeutic Effects on Skeletal Growth and Reduces Hypoglycemic Effects in Mice

Abstract Disclosure: K. Tailor: None. T. Stowe: None. J. Ree: None. B. Ventura: None. J. Deursen: None. R. O'Brien: None. J. Baron: None. J. Lui: None. Recombinant human growth hormone (GH) is commonly used to treat short stature in children but has limited efficacy in severe, non-GH-deficient conditions, such as skeletal dysplasias, and has adverse off-target effects. Because short stature is the result of reduced growth plate chondrogenesis, we hypothesized that targeting chondrogenic growth factors specifically to the growth plate might augment the therapeutic skeletal effect while diminishing adverse effects on non-target tissues. Toward this end, we previously developed fusion proteins conjugating insulin-like growth factor-1 (IGF-1) with a single-chain human monoclonal antibody fragment (ScFv) targeting matrillin-3 (1), a protein specifically expressed in cartilage matrix, and demonstrated increased on-target therapeutic efficacy at the growth plate and decreased off-target effects in a GH-deficient (lit) mouse model (2). In the current study, we established a second GH-deficiency model by administration of a GH antagonist, pegvisomant (PEG), in C57BL/6 wild-type male mice. Alternate-day injection of pegvisomant at 40 mg/kg for 7 days reduced body weight, serum IGF-1 levels, and growth plate height in mice. Using this model, we found that once-daily SQ administration of cartilage-targeted IGF-I (named CV1574-1) for five days increased body weight and growth plate height greater than an equimolar dose of IGF-I itself administered twice daily. Hypoglycemia is an adverse effect of recombinant IGF-1 treatment. Therefore, we also monitored blood glucose levels after a single SQ injection of CV1574-1 and found that this fusion protein showed a reduced hypoglycemic effect compared to injection of IGF-I itself. Lastly, to gain mechanistic insight into the role of matrillin-3 targeting on therapeutic efficacy, we assessed the ability of CV1574-1 to induce pAKT signaling in vitro. Transient exposure to CV1574-1 caused more prolonged induction of pAKT signal in wild-type rat chondrosarcoma (RCS) cells compared to matrillin-3-knockout RCS cells, suggesting that matrillin-3 targeting extends the duration of IGF-1 receptor activation. To summarize, the current findings demonstrate that CV1574-1, a fusion protein that targets IGF-1 to cartilage, improves efficacy at the growth plate, reduces hypoglycemic effects, and, in vitro, prolongs receptor activation. Our study provides further evidence that cartilage-targeted therapy has the potential to provide new pharmacological approaches for the treatment of childhood linear growth disorders, including skeletal dysplasias and growth failure due to systemic disease. Reference:(1) Cheung et al. Pharma Res 2015, 32(7):2439-49.(2) Lui et al. Molecular Therapy 2019, 27(3):673-680 Presentation: 6/3/2024

Epidural Steroid Injections and Fracture Incidence Among Older Individuals with Radiculopathy.

Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.