Bone Protection Research Articles

Isolation and Characterization of an Anti-Osteoporotic Compound from Melia toosendan Fructus.

Melia toosendan fructus, traditionally employed in traditional Chinese and Korean herbal medicine, exhibits diverse biological properties encompassing anti-tumor, anti-inflammatory, and anti-viral effects. However, its influence on bone metabolism remains largely unexplored. In this study, we investigated the impact of an ethanolic extract of Melia toosendan fructus (MTE) on osteoclast differentiation and characterized its principal active constituent in osteoclast differentiation and function, as well as its effects on bone protection. Our findings demonstrate that MTE effectively inhibits the differentiation of osteoclast precursors induced by receptor activator of nuclear factor κB ligand (RANKL). Utilizing a bioassay-guided fractionation approach coupled with UHPLC-MS/MS analysis, we isolated and identified the triterpenoid compound toosendanin (TSN) as the active constituent responsible for MTE's anti-osteoclastogenic activity. TSN treatment downregulated the expression of nuclear factor of activated T cells c1, a pivotal osteoclastogenic transcription factor, along with molecules implicated in osteoclast-mediated bone resorption, including tumor necrosis factor receptor-associated factor 6, carbonic anhydrase II, integrin beta-3, and cathepsin K. Furthermore, treatment of mature osteoclasts with TSN impaired actin ring formation, acidification, and resorptive function. Consistent with our in vitro findings, TSN administration mitigated trabecular bone loss and reduced serum levels of the bone resorption marker, C-terminal cross-linked telopeptides of type I collagen, in a mouse bone loss model induced by intraperitoneal injections of RANKL. These results suggest that TSN, as the principal active constituent of MTE with inhibitory effects on osteoclastogenesis, exhibits bone-protective properties by suppressing both osteoclast differentiation and function. These findings imply the potential utility of TSN in the treatment of diseases characterized by excessive bone resorption.

SAT422 Gender Affirming Hormone Therapy in a Non-Binary Individual with Swyer Syndrome

Abstract Disclosure: J.M. Yohannan: None. T. Reisman: None. Background: Swyer syndrome is a rare genetic disorder of sexual development. Patients with Swyer syndrome require physiologic hormone replacement congruent with their gender identity in order to prevent bone loss. It is also important to screen for complications of this condition including osteopenia and dysgerminomas. Clinical Case: A 25 year old individual with a history of Swyer syndrome (46 XY gonadal dysgenesis) presents to clinic to discuss initiation of gender affirming hormone therapy. The patient identifies as non-binary and is interested in starting testosterone for masculinization. The patient was initially diagnosed with Swyer syndrome at age 23 during an evaluation for primary amenorrhea. At that time the patient had a laparoscopic gonadectomy and was found to have a dysgerminoma. Upon diagnosis the patient was started on hormone replacement therapy with norethindrone acetate-ethinyl estradiol 1 - 0.01 mg for bone loss prevention. They had a bone mineral density scan two years prior to presentation that was reportedly normal. To avoid the deleterious effects of hypogonadism they were started on estradiol-norethindrone 0.05 - 0.25 mg patch to provide bone protection. They were also provided testosterone gel for masculinization as part of their gender affirming care. Swyer syndrome is a disorder of sex development in which individuals with XY chromosomes develop phenotypically female Mullerian structures (uterus, fallopian tubes, and vaginal canal). Individuals with Swyer syndrome typically have non-functional “streak gonads” and are diagnosed during evaluation for primary amenorrhea. While some cases may be from a novel mutation, there are case reports showing that the condition can have an autosomal dominant, autosomal recessive, or even X-linked pattern of inheritance depending on the mutated gene. Patients with Swyer syndrome require physiologic doses of hormone replacement for maturation of secondary sex characteristics and bone health. For this patient in particular it is also important to provide appropriate hormone replacement congruent with their gender identity. Additionally, approximately 30% of patients with this condition may develop a gonadal tumor, including dysgerminomas. Because of this, patients frequently have their gonads removed upon diagnosis. Conclusion: Patient’s with Swyer syndrome should be on appropriate hormone replacement as they do not make endogenous sex steroids. Additional consideration of masculinizing hormone replacement should be made for patients that have a gender identity other than cisgender female. It is also important to screen patients for gonadal tumors as there is an increased incidence in this population.

THU449 An Unexpected Case Of Cutaneous Leukocytoclastic Vasculitis Following Zoledronic Acid Infusion

Abstract Disclosure: B. Zahedi: None. Z.S. Wallace: None. M.M. Cote: None. E.W. Yu: Grant Recipient; Self; Amgen Inc. Background: Zoledronic acid is a potent amino-bisphosphonate frequently used in the treatment of osteoporosis. We report a case of small-vessel vasculitis with cutaneous manifestations occurring after zoledronic acid infusion, previously not reported in the literature. Clinical case: A 58-year old woman with a history of sleeve gastrectomy 1.5 years prior was treated for bone protection with an intravenous infusion of zoledronic acid (Zol) 5mg. This was the patient’s first exposure to a bisphosphonate medication. Within minutes of the infusion, she developed a single episode of diffuse watery diarrhea. Although GI symptoms resolved quickly, within a few hours she experienced generalized myalgias and skin tenderness in her abdomen and extremities, for which she took NSAIDs. These symptoms progressed in severity over the next 3-5 days, manifesting as bilateral hand and lower extremity edema and erythema; no fever/chills/sweats, mucocutaneous ulcers, or urinary symptoms were present. By Day 5, she developed palpable purpura without blanching above the ankles and extending to the knees. By Day 7, prednisone 60mg was started. Prior to Zol, labs showed sufficient 25-hydroxyvitamin D, normal calcium, renal and liver function. On Days 10 and 14, labs revealed AST and ALT, twice and thrice the upper limit of normal respectively. Other notable labs included normal UA, Ca, WBC, eGFR, nonelevated ESR/CRP, and a negative work up for an underlying infectious, inflammatory, ANCA-associated, hypocomplementemic or autoimmune process. Cutaneous findings resolved within 3 weeks of Zol, and transaminitis and edema resolved by week 4. In the setting of a negative lab workup and typical palpable purpura, the patient was diagnosed with leukocytoclastic cutaneous vasculitis (LCV), likely induced by Zol (Naranjo score of 5 consistent with probable adverse drug reaction). Although IgA-mediated Henoch-Schonlein Purpura (HSP) cannot be definitively ruled out in absence of a skin biopsy, the patient did not exhibit other clinical features of HSP, and the timeline is highly suggestive of an idiosyncratic drug reaction whereby Zol acted as a hapton to stimulate an immunologic vasculitis response. Up to 50% of patients with LCV have systemic involvement (renal, GI, pulmonary, cardiac or CNS). Cutaneous LCV usually carries a favorable prognosis after treatment with glucocorticoids. On review of the literature, no prior cases of bisphosphonate-induced LCV have been reported, although there are few cases of giant cell arteritis, uveitis and urticarial vasculitis with bisphosphonate therapy. Conclusions: This is the first case demonstrating cutaneous manifestations consistent with leukocytoclastic vasculitis due to zoledronic acid infusion, which was successfully managed with NSAIDs and glucocorticoids. Clinicians should be aware that LCV may be a rare hypersensitivity complication of Zol. Presentation: Thursday, June 15, 2023

Applying data mining techniques to predict vitamin D deficiency in diabetic patients.

Vitamin D is among the vitamins necessary for both adults' and children's health. It plays a significant role in calcium absorption, the immune system, cell proliferation and differentiation, bone protection, skeletal health, rickets, muscle health, heart health, disease pathogenesis and severity, glucose metabolism, glucose intolerance, varying insulin secretion, and diabetes. Because the 25-hydroxyvitamin D (25OHD) test, which is used to measure vitamin D is expensive and may not be covered in healthcare benefits in many countries, this study aims to predict vitamin D deficiency in diabetic patients. The prediction method is based on data mining techniques combined with feature selection by using historical electronic health records. The results were compared with a filter-based feature selection algorithm, namely relief-F. Non-valuable features were eliminated effectively with the relief-F feature selection method without any performance loss in classification. The performances of the methods were evaluated using classification accuracy (ACC), sensitivity, specificity, F1-score, precision, kappa results, and receiver operating characteristic (ROC) curves. The analyses have been conducted on a vitamin D dataset of diabetic patients and the results show that the highest classification accuracy of 97.044% was obtained for the support vector machines (SVM) model using radial kernel that contains 18 features.

Research progress on the clinical application and mechanism of iguratimod in the treatment of autoimmune diseases and rheumatic diseases.

Autoimmune diseases are affected by complex pathophysiology involving multiple cell types, cytokines, antibodies and mimicking factors. Different drugs are used to improve these autoimmune responses, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and small molecule drugs (DMARDs), which are prevalent clinically in the treatment of rheumatoid arthritis (RA), etc. However, low cost-effectiveness, reduced efficacy, adverse effects, and patient non-response are unattractive factors driving the development of new drugs such as iguratimod. As a new disease-modifying antirheumatic drug, iguratimod has pharmacological activities such as regulating autoimmune disorders, inflammatory cytokines, regulating immune cell activation, differentiation and proliferation, improving bone metabolism, and inhibiting fibrosis. In recent years, clinical studies have found that iguratimod is effective in the treatment of RA, SLE, IGG4-RD, Sjogren 's syndrome, ankylosing spondylitis, interstitial lung disease, and other autoimmune diseases and rheumatic diseases. The amount of basic and clinical research on other autoimmune diseases is also increasing. Therefore, this review systematically reviews the latest relevant literature in recent years, reviews the research results in recent years, and summarizes the research progress of iguratimod in the treatment of related diseases. This review highlights the role of iguratimod in the protection of autoimmune and rheumatic bone and related immune diseases. It is believed that iguratimod's unique mode of action and its favorable patient response compared to other DMARDs make it a suitable antirheumatic and bone protective agent in the future.

A Five-Year Retrospective Audit on Bone Protection Prescribing in Patients With Fragility Fractures in Primary Care.

Background Fragility fractures typically occur in the elderly population due to low-energy trauma in the context of underlying osteoporotic bone disease. These fractures are becoming increasingly more common as the population of the United Kingdom ages, representing a significant public health issue. In the community, a joint care approach is adopted between general practitioners and fracture liaison services for the management of patients with fragility fractures. Despite this, preventive care for these patients remains substandard. This project aimed to conduct an audit of patients with a coded diagnosis of a fragility fracture in our primary care practice to ascertain fracture type and the prescription of bone protective agents. When necessary, the appropriate therapy was commenced per best practice guidelines. Methodology A search of patients with the diagnosis of Fragility fracture on our electronic patient database, SystmOne, was conducted for the period of April 2019 to April 2023 inclusive. A retrospective audit of electronic patient records was done to identify patient demographic data, fracture types and dates, osteoporosis prescriptions, vitamin D/calcium supplementation, and bone densitometry scan results (dual-energy X-ray absorptiometry). Results A total of 47 patients were identified with a coded diagnosis of a Fragility fracture, of whom 36 were females and 11 were males. The average age of the patients was 76.89 years with a range of 50 to 97. In total, 49 fractures were identified. More than two-thirds of the fractures identified were either distal forearm or neck of femur fractures (18 and 15, respectively). Of the 47 patients identified, 33 were on bone protection agents. Further, 26 received both bisphosphonates and calcium/vitamin D supplementation. Seven patients were on bisphosphonate monotherapy, and the remaining two patients were on vitamin D/calcium supplementation alone. Of the 47 patients, 12 had neither form of therapy prescribed. Conclusions Despite the joint effort between fracture liaison services and general practitioners, the secondary prevention of fragility fractures within the community remains inadequate. Fragility fractures are associated with significant morbidity, mortality, and re-fracture rates and incur significant costs to the National Health Service. Local practitioners must routinely evaluate their data to identify opportunities to improve patient care. Effective and timely treatment could be key to the prevention of new or second fractures.

56 Audit of assessment, prevalence, and treatment of osteoporosis for patients attending the inflammatory bowel disease Service in Mullingar Regional Hospital

Abstract Background Courses of steroids are common in patients with Inflammatory Bowel Disease (IBD) and are a risk factor for developing osteoporosis. Osteoporosis is a clinically silent entity and osteoporosis-related fractures are associated with chronic pain, disability, and impact quality of life. Screening of high-risk populations is the mainstay of fracture prevention. In this audit, we aimed to assess adherence to international guidelines for osteoporosis risk assessment and bone protection. Methods A retrospective audit was performed with a random sampling of 10% of the patients attending between October 2021 to October 2022 the IBD outpatient clinic in Mullingar Regional Hospital. Data included demographics, IBD diagnosis, FRAX tool components, FRAX score, bone health screening, DEXA results, and use of bone mineral protection. Clinical practice was compared against European Crohn’s and Colitis Organisation (ECCO) recommendations on bone protection in IBD. Results Of 150 charts reviewed, 39 charts were missing essential data and 8 had a diagnosis other than IBD. All 103 patients included in the analysis had received >3 months of systemic steroid use, of which 50 had a diagnosis of Crohn’s disease and 63 with ulcerative colitis. Two (2%) patients had a FRAX risk assessment for osteoporosis, and 22 (21%) had a DEXA ordered, of which 7 (7%) were by the IBD clinic. Two (2%) patients had a previous fragility fracture and 3 (3%) had been diagnosed with osteoporosis. Bone protection was used in 21 (20%) patients receiving steroids, including calcium and vitamin D supplementation (n = 19), and bisphosphonate (n = 2). Conclusion There are low rates of osteoporosis screening for IBD patients attending this service. There was inadequate data in the charts to calculate FRAX scores to assess osteoporosis prevalence. An intervention tool is currently being designed and the audit cycle will be completed with a repeat audit after implementation.

26 Audit of osteoporosis treatment in patients undergoing Orthogeriatric rehabilitation

Abstract Background There was a perceived under-prescribing of osteoporosis treatment in this population. The transition from acute hospital to rehabilitation unit presented an opportunity to check medications and institute change. Methods Retrospective audit of patients’ medication charts. All patients on the rehabilitation ward under the care of an Ortho-geriatrician were included. Data was anonymised and recorded in an excel file. Prescription of calcium and vitamin D (single agent or combination) and targeted osteoporosis medications were recorded. Data collection performed by the specialist registrar on a ward round with the consultant. Interventions included education of Non-Consultant Hospital Doctors (NCHDs) to encourage proactive prescribing and documentation of the bone protection plan on the transfer summary. A re-audit was undertaken at a two month interval using the same methodology. Results 12 medication charts were examined as part of the initial audit. 10/12 had a neck of femur fracture and 2/12 had fragility fractures of the tibia/fibula requiring surgery. Zero patients were prescribed calcium alone, two vitamin D alone and 9/12 were on combination calcium and vitamin D. No patients were prescribed targeted osteoporosis treatment. 1/12 patients had a documented plan regarding bone protection. Re-audit examined 10 medication charts. 9/10 had a neck of femur fracture, 1/10 had a fracture of both the distal femur and the proximal humerus. Zero patients were prescribed calcium alone, three vitamin D alone and 6/10 were on combination calcium and vitamin D. 2/10 were prescribed oral bisphosphonate, 5/10 denosumab and 1/10 intravenous bisphosphonate. The remaining two patients did not yet have osteoporosis treatment prescribed. Conclusion Despite all of the initial patients being >14 days post-operative the majority did not have a plan or prescription for bone protection representing a missed opportunity to prevent further fractures. Re-audit post education demonstrated an 80% improvement in prescription of osteoporosis treatment.

299 Impact of a dedicated fracture liaison service candidate ANP on wait times in a geriatrician-led specialist bone health service

Abstract Background A specialist osteoporosis and bone health service was founded in 2003 in our institution. It sees a range of patients—providing DXA alone to giving specialist opinion on complex cases from all Ireland. Dedicated flow for hip fractures is well established however the advent of the fracture liaison database audit brought challenges providing DXA and reviewing specific acute fractures within the 12 week standard. Fracture liaison services target those who’ve just fractured with the aim of reducing risk of further imminent fracture by screening for osteoporosis and initiating bone protection measures. Methods Wait times for unselected direct review in the nurse led pre-assessment clinic with DXA were compared to the direct identification, review of DXA and subsequent follow up if indicated by a newly appointed candidate ANP (cANP). Results Average wait time for initial review of acute Colles/vertebral/humeral fractures prior to the cANP appointment was 10 months with further waits for consultant led bone clinic. Following the cANP appointment 318 relevant fractures were identified from September 2022 to May 2023. A 3 month lag was applied. Initial DXA took place on average 10 weeks post fracture (range 2–24). After this 169 patients were discharged back to GP with recommendations as scores above −2.0 on DXA as per locally agreed protocol for fractures and osteopenia; 111 seen in FLS by cANP for detailed assessment including bloods and risk factor review under supervision of their clinical mentor. 6 have not attended; the remainder await review. Average time from fracture to review by cANP is already 18 weeks. Conclusion Appointment of a dedicated cANP for fracture liaison has already streamlined bone health assessment for acute fractures attending our hospital as well as freed appointments in the specialist bone service. As the FLS service establishes we expect to reach the 12 week target consistently.

Standardization of global hip fracture audit could facilitate learning, improve quality, and guide evidence-based practice.

National hip fracture registries audit similar aspects of care but there is variation in the actual data collected; these differences restrict international comparison, benchmarking, and research. The Fragility Fracture Network (FFN) published a revised minimum common dataset (MCD) in 2022 to improve consistency and interoperability. Our aim was to assess compatibility of existing registries with the MCD. We compared 17 hip fracture registries covering 20 countries (Argentina; Australia and New Zealand; China; Denmark; England, Wales, and Northern Ireland; Germany; Holland; Ireland; Japan; Mexico; Norway; Pakistan; the Philippines; Scotland; South Korea; Spain; and Sweden), setting each of these against the 20 core and 12 optional fields of the MCD. The highest MCD adherence was demonstrated by the most recently established registries. The first-generation registries in Scandinavia collect data for 60% of MCD fields, second-generation registries (UK, other European, and Australia and New Zealand) collect for 75%, and third-generation registries collect data for 85% of MCD fields. Five of the 20 core fields were collected by all 17 registries (age; sex; surgery date/time of operation; surgery type; and death during acute admission). Two fields were collected by most (16/17; 94%) registries (date/time of presentation and American Society of Anesthesiologists grade), and five more by the majority (15/17; 88%) registries (type, side, and pathological nature of fracture; anaesthetic modality; and discharge destination). Three core fields were each collected by only 11/17 (65%) registries: prefracture mobility/activities of daily living; cognition on admission; and bone protection medication prescription. There is moderate but improving compatibility between existing registries and the FFN MCD, and its introduction in 2022 was associated with an improved level of adherence among the most recently established programmes. Greater interoperability could be facilitated by improving consistency of data collection relating to prefracture function, cognition, bone protection, and follow-up duration, and this could improve international collaborative benchmarking, research, and quality improvement.

366 Vitamin D3 Assessment and Supplementation in Elderly Hip Fracture Patients: A Closed Loop Quality Improvement Project

Abstract Aim to improve the assessment and supplementation of vitamin D3 in elderly hip fracture patients in a trauma unit. Method This is a single-centre quality improvement project utilising the PDSA cycle based in a trauma unit covering the black country within the West Midlands. Data was collected retrospectively using the National Hip Fracture Database and hospital electronic systems such as clinical web portal, ICE, GP records, edischarge and ePMA. Inclusion criteria consisted of patient age greater than 60 with a radiologically confirmed neck of femur fracture, treated operatively with an orthogeriatrics review within 72 hours of admission, and COVID-19 negative PCR. Pre-intervention data included 15 patients from July 2020. We assessed 3 parameters including pre-admission vitamin D3 supplementation, measurement of vitamin D3 during admission and vitamin D3 supplementation on discharge. Interventions placed in February 2021 comprised of a postoperative hip blood profile pathway on ICE and guidelines on how to order bloods were circulated with information posters. In addition, teaching sessions for doctors and nurses with twice weekly orthogeriatric reviews emphasising bone protection. Post-intervention data included 15 patients from April 2021. Results Improvement in vitamin D3 level assessment during admission; 20% to 93.3% however, decline in vitamin D3 supplement prescribed on discharge; 73.3% to 26.7%. Conclusions Interventions showed an improvement in quality of vitamin D3 assessment however, the decline in supplementation on discharge may be due to further planned intravenous bone protection bisphosphonate therapy and miscommunication due to ward doctors rotating every 4-6 months on how to appropriately assess and supplement vitamin D3 levels.

Effect of Compound Supplement on the Bone Health of Rats with Osteoporosis Induced by Ovariectomy

Background: The World Health Organization (WHO) has recognized osteoporosis as the second most serious epidemic in the world. There are many factors in the occurrence of osteoporosis, among which amenorrhea and aging are major causes, therefore the risk of osteoporosis increases with age. Moreover, osteoporosis influences personal health and mobility, and in turn, greatly increases national healthcare expenses. It is known that chicken sternal cartilage (CSC) hydrolysate, salmon nasal cartilage extract, turmeric (Curcuma longa L.) extract, mangosteen (Garcinia mangostana) extract, soybean extract, calcium citrate, vitamin C, and vitamin D have the potential to reduce bone loss and protect bones. However, this novel combination for improving bone loss has not yet been studied or discussed. Objective: This study discussed the effect of a CSC formula containing chicken sternal cartilage hydrolysate, salmon nasal cartilage extract, turmeric extract, mangosteen extract, soybean extract, calcium citrate, vitamin C, and vitamin D on improving the osteoporosis of rats which had received ovariectomy. Their body weight, body length, serum biochemical value, bone tissue, and biomechanics were analyzed. Design: The 10-week-old female Sprague-Dawley (SD) rats used in this study were randomly divided into six groups for the experiment, including the sham group (10 rats) and five ovariectomy (OVX) groups (53 rats). Two weeks after the ovariectomy, the following doses were administered to the corresponding groups respectively every day: carboxymethyl cellulose (CMC) solvent group (represented by OVX+CMC), and CSC 339 mg/kg (represented by OVX+CSC-L), CSC 678 mg/kg (represented by OVX+CSC-M), CSC 1356 mg/kg (represented by OVX+CSC-H). The positive control (alendronate, 2.5 mg/kg represented by OVX+AD) was administered three times weekly. The rats were sacrificed 14-weeks after administration of the experimental materials. Results: According to the experimental results, in comparison to the OVX+CMC group, the OVX+CSC-L group, OVX+CSCM group, and OVX+CSC-H group could significantly reduce the N-terminal telopeptides of type I collagen, the N-telopeptide (NTX) concentration, and the osteocalcin concentration in the serum. According to the micro-computed tomography analysis, in comparison to the OVX+CMC group, the femoral bone mineral density, trabecular area percentage, and trabecular thickness of the OVX+CSC-L, OVX+CSC-M, and OVX+CSC-H groups increased significantly, and the trabecular separation decreased significantly. According to the biomechanical analysis, in comparison to the OVX+CMC group, the OVX+CSC-L, OVX+CSC-M, and OVX+CSC-H groups could increase the maximum load, hardness, absorbed energy, and Young’s modulus of the femur significantly. Conclusion: CSC can increase the bone mineral density, trabecular area percentage, and trabecular thickness significantly; it can reduce the trabecular separation, NTX and osteocalcin (OCN) concentrations in serum significantly, and it can retard the bone loss induced by ovariectomy effectively, as well as protect bones. It can be used as a mild and long-term dietary supplement; however, the result of long-term administration to the human body should be observed in the future.

Clinical evaluation of the three-dimensional printed strut-type prosthesis combined with autograft reconstruction for giant cell tumor of the distal femur.

This study aimed to describe the design and surgical techniques of a three-dimensional (3D) printed strut-type prosthesis with a porous titanium surface for distal femur giant cell tumors of bone (GCTB) and evaluate the short-term clinical outcomes. From June 2018 to January 2021, 9 consecutive patients with grade I or II GCTB in the distal femur underwent extended intralesional curettage followed by 3D-printed strut-type prosthesis combined with autograft reconstruction were retrospectively reviewed to assess their clinical and radiographic outcomes. All patients were followed up for 30.8 ± 7.5 months (18-42 months) after surgery. The mean affected subchondral bone percentage and the mean subchondral bone thickness before surgery was 31.8% ± 9.6% (range, 18.2% ~50.2%) and 2.2 ± 0.8mm (range, 1.2-4.0mm), respectively. At the final follow-up, all the patients were alive without local recurrence; no postoperative complications were observed. Patients had significant improvements in postoperative MSTS-93 score [(26.7 ± 2.4) vs. (18.8 ± 3.7), P < 0.05], and ROM [(122.8° ± 9.1°) vs. (108.3° ± 6.1°), P < 0.05] compared with their preoperative statuses. Furthermore, the mean subchondral bone thickness has increased to 10.9 ± 1.3mm (range, 9.1-12.1mm). 3D-printed strut-type prosthesis combined with autograft reconstruction provides acceptable early functional and radiographic outcomes in patients with grade I or II GCTB in distal femur due to the advantages of the prosthesis such as good biocompatibility, osseointegration capacity, and subchondral bone protection. If our early outcomes can be further validated in studies with more patients and sufficient follow-up, this method may be evaluated as an alternative for the treatment of grade I or II GCTB in the distal femur.

Oral Administration of Protease-Soluble Chicken Type II Collagen Ameliorates Anterior Cruciate Ligament Transection-Induced Osteoarthritis in Rats.

This study investigated whether oral supplementation with protease-soluble chicken type II collagen (PSCC-II) mitigates the progression of anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) in rats. Eight-week-old male Wistar rats were randomly assigned to the following groups: control, sham, ACLT, group A (ACLT + pepsin-soluble collagen type II collagen (C-II) with type I collagen), group B (ACLT + Amano M-soluble C-II with type I collagen), group C (ACLT + high-dose Amano M-soluble C-II with type I collagen), and group D (ACLT + unproteolyzed C-II). Various methods were employed to analyze the knee joint: nociceptive tests, microcomputed tomography, histopathology, and immunohistochemistry. Rats treated with any form of C-II had significant reductions in pain sensitivity and cartilage degradation. Groups that received PSCC-II treatment effectively mitigated the ACLT-induced effects of OA concerning cancellous bone volume, trabecular number, and trabecular separation compared with the ACLT alone group. Furthermore, PSCC-II and unproteolyzed C-II suppressed ACLT-induced effects, such as the downregulation of C-II and upregulation of matrix metalloproteinase-13, tumor necrosis factor-α, and interleukin-1β. These results indicate that PSCC-II treatment retains the protective effects of traditional undenatured C-II and provide superior benefits for OA management. These benefits encompass pain relief, anti-inflammatory effects, and the protection of cartilage and cancellous bone.

The bone-protective benefits of amino-conjugated calcium in an ovariectomized (OVX) rat model

Low bone density, fragility, and microarchitectural disintegration are the symptoms of osteoporosis. An imbalance between bone growth and resorption can lead to osteoporosis. This study evaluated the effects of amino-calcium (AC) on bone protection in ovariectomized control group (NC) rats. Amino-calcium (AC) was characterized using Fourier-transform infrared spectroscopy (FT-IR), energy-dispersive X-ray spectroscopy (EDS), and nuclear magnetic resonance spectroscopy analyses (NMR). After determining the biocompatibility of amino-calcium (AC) with MC3T3-E1 cells, alkaline phosphatase staining revealed significant changes on day 7. Three of the four groups underwent ovariectomy, whereas one group received a placebo. On micro-computed tomography, in vivo, data showed increased bone volume fraction in the femoral head and shaft areas in the amino-calcium (AC) group. Hematoxylin and eosin staining showed a bone mass and architectural protection in the amino-calcium (AC) group compared with the calcium carbonate and OVX control group. RNA sequencing analysis revealed high expression of osteogenesis-related genes in MC3T3-E1 cells. RNA sequencing revealed a significant fold change in the expression of integrin-binding sialoprotein (IBSP), bone gamma-carboxyglutamate proteins 1 and 2(BGLAP1 and BGLAP2), and periostin (POSTN). The study concluded that supplementing the OVX rats with calcium enhanced bone protection.

Antidementia medication acetylcholinesterase inhibitors have therapeutic benefits on osteoporotic bone by attenuating osteoclastogenesis and bone resorption.

This study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate acetylcholine receptors and are used to treat Alzheimer's disease (AD), is associated with osteoporosis protection and inhibition of osteoclast differentiation and function. Firstly, we examined the effects of AChEIs on RANKL-induced osteoclast differentiation and function with osteoclastogenesis and bone resorption assays. Next, we investigated the impacts of AChEIs on RANKL-induced nuclear factor κB and NFATc1 activation and expression of osteoclast marker proteins CA-2, CTSK and NFATc1, and dissected the MAPK signaling in osteoclasts in vitro by using luciferase assay and Western blot. Finally, we assessed the in vivo efficacy of AChEIs using an ovariectomy-induced osteoporosis mouse model, which was analyzed using microcomputed tomography, in vivo osteoclast and osteoblast parameters were assessed using histomorphometry. We found that Donepezil and Rivastigmine inhibited RANKL-induced osteoclastogenesis and impaired osteoclastic bone resorption. Moreover, AChEIs reduced the RANKL-induced transcription of Nfatc1, and expression of osteoclast marker genes to varying degrees (mainly Donepezil and Rivastigmine but not Galantamine). Furthermore, AChEIs variably inhibited RANKL-induced MAPK signaling accompanied by downregulation of AChE transcription. Finally, AChEIs protected against OVX-induced bone loss mainly by inhibiting osteoclast activity. Taken together, AChEIs (mainly Donepezil and Rivastigmine) exerted a positive effect on bone protection by inhibiting osteoclast function through MAPK and NFATc1 signaling pathways through downregulating AChE. Our findings have important clinical implications that elderly patients with dementia who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEI drugs. Our study may influence drug choice in those patients with both AD and osteoporosis.

THE BELFAST TECHNIQUE FOR DEFORMITY CORRECTION OF FEMORAL COXA VARA IN OSTEOGENESIS IMPERFECTA: A NOVEL PLANNING AND SURGICAL TECHNIQUE

IntroductionOsteogenesis imperfect (OI) is a geno- and phenotypically heterogeneous group of congenital collagen disorders characterized by fragility and microfractures resulting in long bone deformities. OI can lead to progressive femoral coxa vara from bone and muscular imbalance and continuous microfracture about the proximal femur. If left untreated, patients develop Trendelenburg gait, leg length discrepancy, further stress fracture and acute fracture at the apex of the deformity, impingement and hip joint degeneration. In the OI patient, femoral coxa vara cannot be treated in isolation and consideration must be given to protecting the whole bone with the primary goal of verticalization and improved biomechanical stability to allow early loading, safe standing, re-orientation of the physis and avoidance of untreated sequelae. Implant constructs should therefore be designed to accommodate and protect the whole bone. The normal paediatric femoral neck shaft angle (FNSA) ranges from 135 to 145 degrees. In OI the progressive pathomechanical changes result in FNSA of significantly less than 120 degrees and decreased Hilgenreiner epiphyseal angles (HEA). Proximal femoral valgus osteotomy is considered the standard surgical treatment for coxa vara and multiple surgical techniques have been described, each with their associated complications. In this paper we present the novel technique of controlling femoral version and coronal alignment using a tubular plate and long bone protection with the use of teleoscoping rods.MethodologyAfter the decision to operate had been made, a CT scan of the femur was performed. A 1:1 scale 3D printed model (AXIAL3D, Belfast, UK) was made from the CT scan to allow for accurate implant templating and osteotomy planning. In all cases a subtrochanteric osteotomy was performed and fixed using a pre-bent 3.5 mm 1/3 tubular plate. The plate was bent to allow one end to be inserted into the proximal femur to act as a blade. A channel into the femoral neck was opened using a flat osteotome. The plate was then tapped into the femoral neck to the predetermined position. The final position needed to allow one of the plate holes to accommodate the growing rod. This had to be determined pre operatively using the 3D printed model and the implants. The femoral canal was reamed, and the growing rod was placed in the femur, passing through the hole in the plate to create a construct that could effectively protect both the femoral neck and the full length of the shaft. The distal part of the plate was then fixed to the shaft using eccentric screws around the nail to complete the construct.ResultsThree children ages 5,8 and 13 underwent the procedure. Five coxa vara femurs have undergone this technique with follow-up out to 62 months (41–85 months) from surgery. Improvements in the femoral neck shaft angle (FNSA) were av. 18o (10–38o) with pre-op coxa vara FNSA av. 99o(range 87–114o) and final FNSA 117o (105–125o). Hilgenreiner's epiphyseal angle was improved by av. 29o (2–58o). However only one hip was restored to &lt;25o. In the initial technique employed for 3 hips, the plates were left short in the neck to avoid damaging the physis. This resulted in 2 of 3 hips fracturing through the femoral neck above the plate at approximately 1 year. There were revisions of the 3 hips to longer plates to prevent intra-capsular stress riser. All osteotomies united and both intracapsular fractures healed. No further fractures have occurred within the protected femurs and no other repeat operations have been required.ConclusionsSurgical correction of the OI coxa vara hip is complex. Bone mineral density, multiplanar deformity, a desire to maintain physeal growth and protection of the whole bone all play a role in the surgeon's decision making process. Following modifications, this technique demonstrates a novel method in planning and control of multiplanar proximal femoral deformity, resulting in restoration of the FNSA to a more appropriate anatomical alignment, preventing long bone fracture and improved femoral verticalization in the medium term follow-up.

A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours.

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or &lt;1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8 mg cohort and 14 in the 16 mg cohort (50% M and 50% F, mean age of 51.4 y). All patients have been discontinued: 16 due to disease progression; 1 due to AEs, 2 developed contra-indication to denosumab &amp; pembrolizumab, 1 withdrawal of consent. PK parameters of ETC-159 in the first cycle were consistent with prior single agent data. TEAEs were reported in all subjects in the study with most events being grade 1/2, with dysgeusia (65%), β-CTX increase (30%), fatigue (25%), constipation (20%), and nausea (20%) being the most common. DLTs were G3 colitis and G3 immune-related enteritis (16 mg, 2 patients), and pneumonitis and erythema with fever (8 mg, 1 patient). Other drug related SAEs were G2 thyroiditis, hematuria, and thrombocytopenia. No fractures or other drug related skeletal SAEs. Of the 15 evaluable patients, 6 (40%) demonstrated clinical benefit (1 PR, 5 SDs) in combination with pembrolizumab (2 ovarian, 1 lung, 1 pancreatic, 1 urachal, 1 MSS CRC patient with RSPO fusion), at the first assessment, in a predominantly MSS population (65% MSS, 25% unknown, 10% MSI). Pharmacodynamics, (hair follicle Axin2 reduction), was detected at both dose levels and was ≥80% from baseline on D15. Conclusions: ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844 .

The Clinical Benefits of Antiresorptive Agents in Patients with Primary Breast Cancer Receiving Adjuvant Endocrine Therapy: A Systematic Review with Pairwise and Network Meta-analysis.

Clinical trials have investigated the role of antiresorptive agents, including bisphosphonates and denosumab, in patients with primary breast cancer receiving adjuvant endocrine therapy, aiming for better bone protection and/or improving survival. To summarize the clinical effects of antiresorptive agents in patients with early breast cancer receiving endocrine therapy. We systematically reviewed and synthesized the clinical benefits and harms of antiresorptive agents in patients with early breast cancer receiving endocrine therapy by calculating the risk ratios (RRs). In the pooled meta-analysis, antiresorptive agents had significant clinical benefits on disease recurrence (RR 0.78, 95% CI 0.67-0.90) and locoregional recurrence (RR 0.69, 95% CI 0.49-0.95) in patients with breast cancer receiving endocrine therapy. Early use of antiresorptive agents has a beneficial effect on secondary endocrine therapy resistance instead of primary resistance. Safety analysis revealed that potential risk for osteonecrosis of the jaw (ONJ, RR 3.29, 95% CI 1.12-9.68) with antiresorptive agents; however, there is an insignificant difference in arthralgia. The subgroup analyses revealed that intervention with bisphosphonates might have profound clinical benefits, but also increased the occurrence of ONJ. A network meta-analysis further supported the clinical effects of early antiresorptive agent use compared with delayed use or placebo. Using antiresorptive agents early in patients with breast cancer receiving adjuvant endocrine therapy may provide additional benefits in risk reduction of recurrence, but there is a potential risk of ONJ.

Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury (S28.001)

<h3>Objective:</h3> We hypothesized that systemically administered N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrugs (P-Dex) will target the brain trauma injury sites, substantially enhance the Glucocorticoid therapy efficacy, and improve its systemic safety. <h3>Background:</h3> Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in children and adults. The pathology of TBI is heterogeneous, resulting from both primary and secondary injury mechanisms, the latter being attributed to the inflammatory response. Use of conventional glucocorticoid formulations (free DEX) leads to limited distribution to the brain, pulsatile brain tissue concentration and systemic side effects, with controversial benefit in being neuroprotective. Dex and prodrugs (P-Dex) passively target inflammation through the leaky vasculature associated with the underlying pathologies. Given the compromised blood brain barrier (BBB) and brain inflammation in the secondary injury phase of the TBI patients, we hypothesized that the systemically administrated P-Dex will passively target the brain trauma injury sites and reduce inflammation with least systemic side effects. <h3>Design/Methods:</h3> 30 mice were randomly assigned into 2 groups: TBI (Cortical impact model) and healthy mice. All mice received Saline, P-Dex or free Dex. They underwent optical imaging, Neurological severity score, Static weight bearing, Immunohistochemistry and Mico-CT analysis. <h3>Results:</h3> We found that P-Dex passively targeted the traumatic brain tissue and had sustained accumulation at the inflamed tissue for over 14 days. Histological evidence demonstrates the P-Dex’s therapeutic effect on the amelioration of neuroinflammation and prevention of neurodegeneration. Behaviorally, the P-Dex treated animals showed better recovery of the imbalance and better neurological severity score post-TBI. Higher bone mineral density and better bone microarchitecture was found in the skeletal tissues from P-Dex treated animals, comparing to the free Dex, and Saline treated animals, confirming the P-Dex bone protection effect. <h3>Conclusions:</h3> P-Dex can be a potential therapy targeting neuro-inflammation and preserving the neurons from death, avoiding bone loss post-TBI. <b>Disclosure:</b> Dr. Wei has nothing to disclose. Dr. Zhao has nothing to disclose. Jia Zhenshan has nothing to disclose. Zhao Zhifeng has nothing to disclose. Dr. Chen has nothing to disclose. Miss Sun has nothing to disclose. Dr. Kelso has received personal compensation for serving as an employee of Agilent Technologies. Dr. Kelso has stock in Agilent Technologies. Dr. Rathore has nothing to disclose. Dr. Wang has nothing to disclose.