Zoledronic Acid Group Research Articles

Can zoledronic acid reduce the risk of cage subsidence after oblique lumbar interbody fusion combined with bilateral pedicle screw fixation in the elderly population? A retrospective study

BackgroundThe objective of this study was to evaluate the potential of zoledronic acid for reducing the incidence of cage subsidence and enhancing interbody fusion rates following oblique lumbar interbody fusion (OLIF) surgery, particularly as the first reported evidence of the role of zoledronic acid combined with OLIF.MethodsA retrospective analysis was conducted on data from 108 elderly patients treated for degenerative lumbar diseases using OLIF combined with bilateral pedicle screw fixation from January 2018 to December 2021. Patients were divided into the zoledronic acid (ZOL) group (43 patients, 67 surgical segments) and the control group (65 patients, 86 surgical segments). A comparative analysis of the radiographic and clinical outcomes between the groups was performed, employing univariate and multivariate regression analyses to explore the relationships between cage subsidence and the independent variables.ResultsRadiographic outcomes, including anterior height, posterior height, disc height, coronal disc angle, foraminal height, and lumbar lordosis, were not significantly different between the two groups. Similarly, no statistically significant differences were noted in the back visual analog scale (VAS) scores and Oswestry Disability Index (ODI) scores between the groups. However, at the 1-year follow-up, the leg VAS score was lower in the ZOL group than in the control group (P = 0.028). The ZOL group demonstrated a notably lower cage subsidence rate (20.9%) than did the control group (43.0%) (P < 0.001). There was no significant difference in the interbody fusion rate between the ZOL group (93.0%) and the control group (90.8%). Non-use of zoledronic acid emerged as an independent risk factor for cage subsidence (OR = 6.047, P = 0.003), along with lower bone mineral density, lower postoperative anterior height, and concave endplate morphology. The model exhibited robust discriminative performance, with an area under the curve (AUC) of 0.872.ConclusionThe administration of zoledronic acid mitigates the risk of cage subsidence following OLIF combined with bilateral pedicle screw fixation in elderly patients; however, it does not improve the interbody fusion rate.

Exploring the Clinical Impact of RANK Pathway Inhibition in Advanced Breast Cancer: Insights From a Retrospective Study on CDK4/6 Inhibitors and Antiresorptive Therapy.

Breast cancer (BC) remains a significant health concern, particularly in advanced stages where the prognosis is poor. The combination of endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has improved outcomes for advanced BC (aBC) patients. However, resistance to CDK4/6i remains a challenge, with no validated biomarkers to predict response. The receptor activator of the nuclear factor-kB (RANK) pathway has emerged as a key player in aBC, particularly in luminal BC. RANK overexpression has been associated with aggressive phenotypes and resistance to therapy. In view of these findings, we proceeded to investigate the potential involvement of the RANK pathway in luminal BC resistance to CDK4/6i. The objective was to evaluate the effectiveness of denosumab in increasing overall survival (OS) and progression-free survival (PFS). In this retrospective analysis, 158 BC patients with bone metastases were included. Patients with human epidermal growth factor receptor-2 (HER2)-negative and hormone receptor-positive BC who received palbociclib or ribociclib in addition to antiresorptive medication were included. Patients received either denosumab or zoledronic acid (ZA) therapy. The primary endpoint was OS, with PFS as a secondary endpoint. Although the PFS and OS of denosumab were better than ZA in this study, it did not show a significant difference between the two drugs. Meanwhile, mOS was not achievable in patients in the denosumab group, while it was 34.1 months in patients in the ZA group. The hazard ratio (HR) showed a significant improvement for the denosumab group in patients under 60 of age (HR: 0.33, p<0.01), patients with a score of 1 HER2 overexpression (HR: 0.09, p=0.01), and patients with resistant endocrine (HR: 0.42, p=0.02) compared to ZA. This study highlights the potential clinical relevance of the RANK pathway in BC treatment, and our findings suggest that denosumab may offer significant benefits in terms of PFS and OS for certain subgroups, particularly those with HER2 scores of 1, patients under 60, and those with endocrine-resistant BC. In conclusion, considering that RANK pathway status may be a predictive biomarker for CDK4/6i treatment and may cause treatment resistance, our results demonstrate the clinical relevance of the combination of CDK4/6i + ET with RANKL inhibition.

Mitigating jaw osteonecrosis: bioactive glass and pericardial membrane combination in a rat model.

Bisphosphonates (BFs) show clinical effectiveness in managing osteoporosis and bone metastases but pose risks of bisphosphonate-related jaw osteonecrosis (BRONJ). With no established gold standard for BRONJ treatment, our focus is on symptom severity reduction. We aimed to assess the preventive effects of bioactive glass and/or pericardial membrane in a preclinical BRONJ model, evaluating their potential to prevent osteonecrosis and bone loss post-tooth extractions in zoledronic acid (ZA)-treated animals. Rats, receiving ZA or saline biweekly for four weeks, underwent 1st and 2nd lower left molar extractions. Pericardial membrane alone or with F18 bioglass was applied post-extractions. Microarchitecture analysis and bone loss assessment utilized computerized microtomography (CT) and positron emission tomography (PET) with 18F-FDG and 18F-NaF tracers. Histological analysis evaluated bone injury. Exclusive alveolar bone loss occurred post-extraction in the continuous ZA group, inducing osteonecrosis, osteolysis, osteomyelitis, and abscess formation. Concurrent pericardial membrane with F18 bioglass application prevented these outcomes. Baseline PET/CT scans showed no discernible uptake differences, but post-extraction 18F-FDG tracer imaging revealed heightened glucose metabolism at the extraction site in the ZA-treated group with membrane, contrasting the control group. These findings suggest pericardial membrane with F18 bioglass effectively prevents BRONJ in the preclinical model.

Beta-adrenergic receptor antagonist propranolol prevents bisphosphonate-related osteonecrosis of the jaw by promoting osteogenesis

Background/purposeBisphosphonate-related osteonecrosis of the jaw (BRONJ), a complication arising from the use of bisphosphonates (BPs), inflicts long-term suffering on patients. Currently, there is still a lack of effective treatments. This study aimed to explore the preventive effects of propranolol (PRO) on BRONJ in vitro and in vivo, given PRO's potential in bone health enhancement. Materials and methodsIn vitro, effect of PRO on zoledronic acid (ZA)-pretreated bone marrow mesenchymal stem cells (BMSCs) was detected by cell counting kit-8, alkaline phosphatase (ALP) staining, alizarin red staining, real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In vivo, forty mice were divided into four groups: control, ZA, PRO, and ZA-PRO. The maxillary extraction sockets sides were analyzed with micro-CT and histomorphometry. Hematoxylin-eosin (H&E), Masson staining, immunofluorescence staining of ALP, bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2) and TUNEL staining were performed. ResultsPRO increased proliferation and osteogenic differentiation of BMSCs. PRO stimulated bone formation and facilitated the healing process in zoledronic acid-induced osteonecrosis of jaw in mouse model. Compared with ZA group, control and PRO group showed more BMP2+, RUNX2+, and ALP+ cells (P < 0.05). However, PRO rescued the decreased expression of ALP, RUNX2, BMP2 due to ZA and decreased the expression of TUNEL (P < 0.05). ConclusionThe findings suggest that propranolol may offer a promising preventive strategy against BRONJ by enhancing bone regeneration. This research contributes to the understanding of the pathogenesis of BRONJ and opens avenues for potential treatments of BRONJ focusing on β-adrenergic signaling.

Effect of Intravenous Zoledronic Acid on Total Knee Replacement in Patients With Symptomatic Knee Osteoarthritis and Without Severe Joint Space Narrowing: A Prespecified Secondary Analysis of a Two-Year, Multicenter, Double-Blind, Placebo-Controlled Clinical Trial.

To determine the effect of zoledronic acid (ZA) on the risk of total knee replacement (TKR) in patients with symptomatic knee osteoarthritis and without severe joint space narrowing (JSN). We included 222 participants (mean age 62 years, 52% female) from the two-year Zoledronic Acid for Osteoarthritis Knee Pain trial (113 received 5 mg of ZA annually and 109 received placebo) conducted between November 2013 and October 2017. Primary TKR were identified until February 22, 2022. The effect of ZA on TKR risk was evaluated using Cox proportional hazard regression models. Because the treatment effect failed the proportional hazards assumption, a time-varying coefficients analysis for treatment was conducted by splitting the study into two periods (ie, within and after two years of randomization). Over a mean follow-up of seven years, 39% and 30% of participants had any TKR in the ZA and placebo groups, and 28% and 18% had TKR in the study knee, respectively. Use of ZA was associated with a higher risk of TKR in any knee (hazard ratio [HR] 4.2, 95% confidence interval [CI] 1.2-14.7) and showed a trend in the study knee (HR 6.8, 95%CI 0.9-53.9) during the trial. In the posttrial period, the risk of TKR was similar in the ZA and the placebo groups for any knee (HR 1.2, 95%CI 0.5-1.8) and the study knee (HR 1.4, 95%CI 0.5-2.2). These results suggest that ZA is not protective against TKR in patients with symptomatic knee osteoarthritis and without severe JSN.

Zoledronic acid enhances tumor growth and metastatic spread in a mouse model of jaw osteosarcoma.

Investigation of the therapeutic effect of zoledronic acid (ZA) in a preclinical model of jaw osteosarcoma (JO). The effect of 100 μg/kg ZA administered twice a week was assessed in a xenogenic mouse model of JO. The clinical (tumor growth, development of lung metastasis), radiological (bone microarchitecture by micro-CT analysis), and molecular and immunohistochemical (TRAP, RANK/RANKL, VEGF, and CD146) parameters were investigated. Animals receiving ZA exhibited an increased tumor volume compared with nontreated animals (71.3 ± 14.3 mm3 vs. 51.9 ± 19.9 mm3 at D14, respectively; p = 0.06) as well as increased numbers of lung metastases (mean 4.88 ± 4.45 vs. 0.50 ± 1.07 metastases, respectively; p = 0.02). ZA protected mandibular bone against tumor osteolysis (mean bone volume of 12.81 ± 0.53 mm3 in the ZA group vs. 11.55 ± 1.18 mm3 in the control group; p = 0.01). ZA induced a nonsignificant decrease in mRNA expression of the osteoclastic marker TRAP and an increase in RANK/RANKL bone remodeling markers. The use of bisphosphonates in the therapeutic strategy for JO should be further explored, as should the role of bone resorption in the pathophysiology of the disease.

Safety and Efficacy of Denosumab in Children With Osteogenesis Imperfecta-the First Prospective Comparative Study.

Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. We aimed to investigate the effects of denosumab on bone mineral density (BMD), spinal morphometry, and safety in children with OI compared with zoledronic acid. In this prospective study, 84 children or adolescents with OI were randomized to receive denosumab subcutaneous injection every 6 months or zoledronic acid intravenous infusion once. Changes of BMD and its Z-score, vertebral shape, serum levels of calcium and bone turnover biomarkers were assessed during the 1-year treatment. After 12 months of treatment, BMD at the lumbar spine, femoral neck, and total hip significantly increased by 29.3%, 27.8%, and 30.2% in the denosumab group, and by 32.2%, 47.1%, and 41.1% in the zoledronic acid group (all P < .001 vs baseline). Vertebral height and projection area significantly increased after denosumab and zoledronic acid treatment. Rebound hypercalcemia was found to be a common and serious side effect of denosumab, of which 14.3% reached hypercalcemic crisis. Rebound hypercalcemia could be alleviated by switching to zoledronic acid treatment. Treatment with denosumab or zoledronic acid is beneficial in increasing BMD and improving the spinal morphometry of children with OI. However, denosumab should be used with caution in pediatric patients with OI because of its common and dangerous side effect of rebound hypercalcemia. The appropriate dosage and dosing interval of denosumab need to be further explored in children with OI.

Efficacy and Safety of Denosumab vs Zoledronic Acid in OI Adults: A Prospective, Open-Label, Randomized Study.

The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established. To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI. This was a prospective, open-label study. Patients were randomized to receive denosumab 60 mg every 6 months or zoledronic acid 5 mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS), and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated. A total of 51 adults with OI (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = .005) and 1.45% (P = .023) in the denosumab group and by 4.92% (P = .006) and 2.02% (P = .016) in the zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of β-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS, and BTMs during the treatment were similar between the 2 groups. Patients with OI with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = .030). During the study period, the denosumab group had fewer adverse events than the zoledronic acid group. Denosumab effectively increases aBMD in adults with OI, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the antifracture efficacy and safety of denosumab in adult patients with OI.

THERMALLY DISINFECTED HUMAN FEMORAL HEAD AS SCAFFOLD FOR OSTEOINDUCTIVE SUBSTANCES

Various approaches have been implemented to enhance bone regeneration, including the utilization of autologous platelet-rich plasma and bone morphogenetic protein-2. The objective of this study was to evaluate the impact of Marburg Bone Bank-derived bone grafts in conjunction with platelet-rich plasma (PRP), recombinant human bone morphogenetic protein-2 (rhBMP-2), and zoledronic acid (ZA) on osteogenesis within rabbit bone defects.MethodologyBone defects (5mm in diameter) were created in the femurs of 96 male rabbits. The animals were allocated into five groups: (1) bone graft + PRP (BG + PRP), (2) bone graft + 5μg rhBMP-2 (BG + rhBMP-2), (3) bone graft + 5μg ZA (BG + ZA), (4) bone graft + 10μg rhBMP-2 + 5μg ZA (BG + rhBMP-2 + ZA), and (5) bone graft (BG). Marburg Bone Bank-processed human femoral head allografts were utilized for bone grafting. The rabbits were euthanized at 14-, 30-, and 60-days post-surgery, and their femurs underwent histopathological and histomorphometric assessments.ResultsHistomorphometric analysis revealed significantly enhanced de novo osteogenesis within the bone allografts in the BG + PRP and BG + rhBMP-2 groups compared to the BG, BG + ZA, and BG + rhBMP-2 + ZA groups at 14 and 30 days (p &lt; 0.05). However, on day 60, the BG + rhBMP-2 group exhibited elevated osteoclastic activity (early resorption). The local co-administration of ZA with thermally treated grafts impeded both bone graft resorption and new bone formation within the bone defect across all time points. The addition of ZA to BG + rhBMP-2 resulted in diminished osteogenic activity compared to the BG + rhBMP-2 group (p &lt; 0.000).ConclusionThe study findings indicated that the combination of PRP and rhBMP-2 with Marburg bone grafts facilitates early-stage osteogenesis in bone defect healing. Incorporating ZA into the thermally treated bone graft hinders both graft resorption and de novo bone formation.

CALCIUM SULFATE/HYDROXYAPATITE-MEDIATED CONTROLLED CO-DELIVERY OF BMP-2 AND ZOLEDRONIC ACID ENHANCES SPINAL FUSION

Although bone morphogenetic protein 2 (BMP-2) has been FDA-approved for spinal fusion for decades, its disadvantages of promoting osteoclast-based bone resorption and suboptimal carrier (absorbable collagen sponge) leading to premature release of the protein limit its clinical applications. Our recent study showed an excellent effect on bone regeneration when BMP-2 and zoledronic acid (ZA) were co-delivered based on a calcium sulphate/hydroxyapatite (CaS/HA) scaffold in a rat critical-size femoral defect model. Therefore, the aim of this study was to evaluate whether local application of BMP-2 and ZA released from a CaS/HA scaffold is favorable for spinal fusion. We hypothesized that CaS/HA mediated controlled co-delivery of rhBMP-2 and ZA could show an improved effect in spinal fusion over BMP-2 alone. 120, 8-week-old male Wistar rats (protocol no. 25-5131/474/38) were randomly divided into six groups in this study (CaS/HA, CaS/HA + BMP-2, CaS/HA + systemic ZA, CaS/HA + local ZA, CaS/HA + BMP-2 + systemic ZA, CaS/HA + BMP-2 + local ZA). A posterolateral spinal fusion at L4 to L5 was performed bilaterally by implanting group-dependent scaffolds. At 3 weeks and 6 weeks, 10 animals per group were euthanized for µCT, histological staining, or mechanical testing. µCT and histological results showed that the CaS/HA + BMP-2 + local ZA group significantly promoted bone regeneration than other treated groups. Biomechanical testing showed breaking force in CaS/HA + BMP + local ZA group was significantly higher than other groups at 6 weeks. In conclusion, the CaS/HA-based biomaterial functionalized with bioactive molecules rhBMP-2 and ZA enhanced bone formation and concomitant spinal fusion outcomeAcknowledgements: Many thanks to Ulrike Heide, Anna-Maria Placht (assistance with surgeries) as well as Suzanne Manthey &amp; Annett Wenke (histology).

Role of Denosumab and Zoledronic Acid in Geriatric Hip Fractures – A Comparative Analysis

Abstract Background: Osteoporotic hip fractures are on the raise in the world. Denosumab and zoledronic acid are among the commonly used current anti-osteoporotic medications to reduce hip fractures. The purpose of the present study was to compare the effectiveness and adverse events of denosumab and zoledronic acid in geriatric patients after a hip fracture. Materials and Methods: A prospective observational study was conducted between February 2020 and May 2021, and a total of 104 patients were included in the study. Fifty-three patients were given subcutaneous (SC) denosumab once in 6 months, and 51 patients were given intravenous (IV) zoledronic acid. The percentage changes in the Bone Mineral Density (BMD) values from the baseline values were compared between both the groups at 0, 12, and 24 months. Results: The percentage increase in lumbar-bone mineral density (L-BMD) was higher significantly in the denosumab group when compared to the zoledronic acid group at 12 months (6.8 ± 0.9 vs. 4.5 ± 0.7; P &lt; 0.01) and 24 months (9.2 ± 0.9 vs. 7.1 ± 0.8; P &lt; 0.001). There was a significant percentage change in the hip-bone mineral density (BMD) in both the groups; however, a higher mean percentage change was noted in the denosumab group when compared to the zoledronic acid group at 12 months and 24 months (P &lt; 0.04 and P &lt; 0.001). Conclusion: We conclude that SC-given denosumab has got a better efficacy on comparison with the IV-given zoledronic acid. Randomized control trials with a large sample size and longer follow-up are required to come to conclusion regarding patient safety, compliance, and persistence.

Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget’s disease of bone

IntroductionPaget’s disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment.MethodsWe randomised 222 individuals at...

Warfarin and bisphosphontes interaction in patients undergoing total knee arthroplasty

BackgroundPatients undergoing knee arthroplasty (TKA) surgery need anticoagulant therapy, mainly warfarin for prevention of venous thromboembolism (VTE). Warfarin is mainly eliminated by renal glomerular filtration where 92 % of warfarin is excreted in urine. Warfarin overdose may lead to significant bleeding and warfarin underdosing may cause VTE and other complications. Thus, international normalized ratio (INR) monitoring is crucial in TKA patients taking warfarin. Great interest has been expressed in bisphosphonate to reduce periprosthetic osteoporosis in patients undergoing total joint arthroplasty. Many human case reports and cohort studies proved bisphosphonates induced impaired renal function. ObjectivesThe main goal of the current study is to examine the pharmacodynamin effect of bisphosphonates on warfarin excretion and clinical effects in patients undergoing TKA surgery. MethodsFifty patients undergoing TKA were recruited in the current study. Twenty five patients were given warfarin and twenty five patients were given warfarin and bisphosphonates starting three days after surgery. INR, major bleeding events and minor bleeding events were followed up in all recruited patients for one month after surgery. Resultswarfarin plus zoledronic acid group had significantly higher percent of post INR greater than 4 (p = 0.022) and significantly higher percent of minor bleeding events (p = 0.041) than warfarin only group. ConclusionConcomitant administration of bisphosphonates may increase warfarin bleeding adverse effects in elderly patient undergoing TKA.

Postoperative Antiosteoporotic Treatment with Zoledronic Acid Improves Rotator Cuff Healing but Does Not Improve Outcomes in Female Patients with Postmenopausal Osteoporosis: A Prospective, Single-Blinded, Randomized Study

To investigate the effect of the antiosteoporotic agent zoledronic acid (ZA) on rotator cuff healing and clinical outcomes in patients with postmenopausal osteoporosis. We prospectively enrolled 138 female patients with postmenopausal osteoporosis who were scheduled to undergo arthroscopic rotator cuff repair (ARCR) from March 2020 to March 2021. Patients were randomly allocated to the ZA group (ARCR followed by intravenous ZA infusions at postoperative Day 1 and 1 year later) and the control group (ARCR alone). All patients were followed up for 24 months. Tendon healing was evaluated by ultrasonography at 6 weeks and 24 months after surgery. The American Shoulder and Elbow Surgeons (ASES) score, Western Ontario Rotator Cuff (WORC) index, and Numeric Rating Scale (NRS) for pain were recorded at each follow-up, and the minimal clinically important difference (MCID) was calculated. A total of 124 patients were included in the final analysis, 61 in the ZA group and 63 in the control group. There was no statistically significant difference in participant characteristics between the 2 groups. The ZA group had a significantly higher tendon healing rate than the control group at 2 years after surgery (odds ratio= 5.0; 95% confidence interval [CI], 1.4-18.7; P= .014). Regarding clinical outcomes, 100% of patients exceeded the MCID in both groups, and no significantdifferences were found at 2 years after surgery between the 2 groups (ASES: 2.5 [95% CI,-2.2 to 7.2; P=.291]; WORC index: 4.5 [95% CI,-0.117 to 9.117; P= .056]; NRS:-0.1 [95% CI,-0.3 to 0.1; P= .394]). Antiosteoporotic treatment with ZA reduced the retear rate but did not significantly influence the clinical outcomes after ARCR in female patients with postmenopausal osteoporosis. Outcomes of ARCR showed good results in both groups and exceeded the MCID. Level I, randomized controlled trial.

The effect of pharmacological treatment in combination with vitamin K on healing in an experimental rat model of osteoporosis.

This study aims to compare the effects of teriparatide, zoledronic acid, and their combination therapy with vitamin K on osteoporotic rats. We divided a total of 50 female Sprague-Dawley rats into five groups: A (the control group), B and D (the teriparatide group), and C and E (the zoledronic acid group). Following ovariectomy and subcutaneous heparin administration at a dose of 2 IU/kg for four weeks, osteoporosis was created. Groups A, B, and C were fed with standard feed, while Groups D and E were fed with vitamin K-rich feed. After four weeks of treatment, sacrification was performed. The right and left femurs were separated for histopathological and biomechanical evaluation, respectively. For histopathological evaluation, the femurs were decalcified, and the sections were stained with hematoxylin-eosin and evaluated under a light microscope. Fracture healing was evaluated using the classification system as described previously. For biomechanical evaluation, the 3-point stress test and torsion stress test were applied to 10 femurs from each group. Groups B-E were histopathologically and biomechanically superior to Group A in fracture healing of osteoporotic rats; however, it was not statistically significant (p>0.05). The group that received additional vitamin K was histopathologically and biomechanically superior to the group which was fed with standard feed, although it was not statistically significant (p>0.05). Our study results indicated that both teriparatide and zoledronic acid had beneficial effects on osteoporotic fractures with comparable histological and biochemical results. Vitamin K promoted teriparatide and zoledronic acid treatment on osteoporotic fracture healing. Based on these findings, combination therapies may yield the most optimal results in biomechanical and histological examinations.

Zoledronic acid affects the process of Porphyromonas gingivalis infecting oral mucosal epithelial barrier: An in-vivo and in-vitro study.

Zoledronic acid (ZA), one of the commonly used bisphosphonates, is mainly used for bone-metabolic diseases. Studies proved that ZA has adverse effects on oral soft tissues. As the first line of innate immunity, the gingival epithelium could be infected by periodontal pathogens, which is a key process of the initiation of periodontal diseases. Yet, how ZA affects the periodontal pathogens infecting the epithelial barrier remains unclear. This study aimed to investigate the influences of ZA on the process of Porphyromonas gingivalis (P. gingivalis) infecting the gingival epithelial barrier via in-vitro and in-vivo experiments. In the in-vitro experiments, under the condition of different concentrations of ZA (0, 1, 10, and 100 μM), P. gingivalis was used to infect human gingival epithelial cells (HGECs). The infections were detected by transmission electron microscope and confocal laser scanning microscope. Besides, the internalization assay was applied to quantify the P. gingivalis, which infected the HGECs, in the different groups. To evaluate the expression levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and IL-8, by infected HGECs, real-time quantitative reverse transcription-polymerase chain reactions were applied. In the in-vivo experiments, rats were given ZA solution (ZA group) or saline (control group) by tail intravenous injection for 8 weeks. Subsequently, we put ligatures around the maxillary second molars of all the rats and inoculated P. gingivalis to the gingiva every other day from day 1 to day 13. The rats were sacrificed on days 3, 7, and 14 for micro-CT and histological analyses. The in-vitro results manifested that the quantity of P. gingivalis that had infected HGECs increased with the ZA concentrations. Pro-inflammatory cytokines expression by HGECs were significantly increased by 100 μM ZA. In the in-vivo study, compared to the control group, more P. gingivalis was detected in the superficial layer of gingival epithelium in the ZA group. Besides, ZA significantly increased the expression level of IL-1β on day 14 and IL-6 on days 7 and 14 in gingival tissues. These findings suggest that the oral epithelial tissues of patients who receive high-dose ZA treatment may be more susceptible to periodontal infections, resulting in severe inflammatory conditions.

Could Local Application of Hypoxia Inducible Factor 1-α Enhancer Deferoxamine Be Promising for Preventing of Medication-Related Osteonecrosis of the Jaw?

This experimental study investigates the prophylactic effect of deferoxamine (DFO) on medication-related osteonecrosis of the jaw (MRONJ). Thirty-six female Sprague Dawley rats received zoledronic acid (ZA) for eight weeks to create an osteonecrosis model. DFO was locally applied into the extraction sockets with gelatin sponge (GS) carriers to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated. Hypoxia-inducible factor 1-alpha (HIF-1α) protein levels in the extraction sockets were quantified. New bone formation rate differed significantly between groups (p = 0.005). Newly formed bone ratios in the extraction sockets did not differ significantly between the control group and the GS (p = 1), GS/DFO (p = 0.749), ZA (p = 0.105), ZA-GS (p = 0.474), and ZA-GS/DFO (p = 1) groups. While newly formed bone rates were higher in the ZA-GS and ZA-GS/DFO groups than in the ZA group, the differences were not significant. HIF-1α levels differed significantly between groups (p < 0.001) and were significantly higher in the DFO and ZA-GS/DFO groups than in the control group (p = 0.001 and p = 0.004, respectively). While HIF-1α levels were higher in the ZA-GS/DFO group than in the ZA group, the difference was not significant. While HIF-1α protein levels and new bone formation rate were elevated in the DFO-treated group, the effect was not significant. Further large-scale studies are needed to understand DFO's preventative effects on MRONJ and the role of HIF-1α in MRONJ pathogenesis.

Abstract P4-07-06: Implementation of A Bone Modifying Agent Pathway at UChicago Medicine for Metastatic Breast Cancer Patients

Abstract Background: In 2019, a quality improvement (QI) research project was conducted at UChicago Medicine (UCM) to evaluate bone modifying agent (BMA) use for skeletal-related event (SRE) prevention in patients with metastatic breast cancer and metastatic castration-resistant prostate cancer. Denosumab was the preferred BMA agent at UCM in this setting. Compared to zoledronic acid (ZA), denosumab was associated with higher drug cost and lower adherence rate mainly due to the difficulty of maintaining the 4-weekly frequency. Studies have shown that ZA can be de-escalated from 4-weekly to 12-weekly for SRE prevention. There is still no convincing evidence to show that this de-escalated schedule can be applied to denosumab. One study evaluated the noninferiority of 12-weekly compared with 4-weekly denosumab suggested that the health-related quality of life was non-inferior (Clemons et al., 2021). However, the study was not powered to evaluate the statistical difference in SRE rates. Based on the results of the 2019 QI project, a BMA pathway was generated at UCM in September 2020 with the purpose of guiding physician prescribing patterns, improving adherence rate, and reducing drug costs. This pathway recommended using ZA as the preferred agent for SRE prevention instead of denosumab. Methods: This was a retrospective study that included 198 patients who had metastatic breast cancer and received at least one dose of ZA or denosumab from UCM outpatient oncology clinic for SRE prevention. All included patients must have bone metastases. 107 patients from the pre-implementation study period (July 1st, 2018 to June 30th, 2019) and 91 patients from the post-implementation study period (November 10th, 2020 to November 10th, 2021) were included. Patients were divided into four groups based on study time (pre- or post-implementation period) and BMA agent (ZA and denosumab). The primary outcome was BMA therapy adherence rate, which was defined by those who received greater than or equal to 80% of appropriately scheduled doses. Secondary outcomes included the percentage of patients on ZA or denosumab, SREs, BMA-associated adverse effects, and BMA cost. Descriptive statistics were used SREs and BMA-associated adverse effects. Results: The percentage of patients on ZA significantly increased from 12% to 64% after BMA pathway implementation (P&amp;lt; 0.0001). Denosumab use decreased from 88% to 36% (P&amp;lt; 0.0001). The overall BMA adherence rate including both ZA and denosumab patients during the post-implementation period was 68%, which was not significantly different compared to the overall adherence rate of 74% during the pre-implementation period (P=0.5461). The adherence rates in denosumab groups (63% in pre and 30% in post) were lower than in ZA groups (100% in pre and 90% in post). The most common reason for the lower adherence rates in denosumab groups was scheduling convenience. During the study period, there were 2, 0, 3, and 3 patients who had SREs in the above four groups respectively. The predominant adverse events among all groups were hypocalcemia and hypophosphatemia. The cost analysis showed using ZA as the primary BMA agent saved 1.1 million dollars of drug costs during the post-implementation study period at UCM. Conclusion: Implementing a BMA pathway encouraged the providers to choose ZA as the preferred agent for SRE prevention in metastatic breast cancer patients with bone metastasis, which dramatically reduced drug costs. The overall BMA adherence rate was not significantly improved with the implementation. The difficulty of maintaining a 4-weekly denosumab frequency continued to exist. Citation Format: Kun Lin, Jordan Baur, Sandeep Parsad, Heng Yang. Implementation of A Bone Modifying Agent Pathway at UChicago Medicine for Metastatic Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-06.

An Evaluation of the Effectiveness of Local Delivery of Zoledronic Acid in Accelerating Bone Healing After the Extraction of Mandibular Third Molars.

Background and objective Zoledronic acid (ZA) has been reported to aid with the formationof new bone, inhibit osteoclastic bone resorption, and improve osteoblast proliferation. This split-mouth randomized clinical research aimed to evaluate the effect of the local application of ZA on bone regeneration after the removal of bilateral mandibular third molars. Methods A randomized, split-mouth study involving 12 patients aged 19-35 yearsrequiring extraction of bilaterally mandibular third molars was conducted. The extraction ofmandibular third molars on both sides was conducted in one session for all patients. In each participant, a gelatin sponge (Gelfoam) soaked with ZA was randomly applied to one cavity of the extraction socket. A gelatin spongesoaked with normal saline wasapplied to the opposite cavity; all patients were blinded asto which socket the drug was applied to. The study was conducted over a period of two months. The changes in bone density (BD) in the socket were assessed through cone-beam CT (CBCT) images; two images were taken for each patient at two different time points: immediately after extraction (T0) and after two months (T1). Results BD values in the socket on both sides of extraction increased from T0 to T1. There were statistically significant differences when comparing the amount of change in radiographic BD from T0 to T1 between the two sides of the extraction (p<0.05); the increase in radial BD between the two different time points was more significant in the ZA group. Conclusions Within the limitation of this study, the local application of ZAradiographically improved bone healingin a statistically significant manner and could be a cost-effective and simple way to activate bone regeneration.

Effect of systemic antiresorptive medication on the histopathological parameters of implant osseointegration in an in vivo rodent study

BackgroundThe purpose of this study was to evaluate the osseointegration of zirconia and titanium implants in the rat maxilla in specimens under systemic antiresorptive therapy.Materials and methodsAfter 4 weeks of systematic medication administration (either zoledronic acid or alendronic acid), 54 rats received one zirconia and one titanium implants that were immediately inserted in the rat maxilla after tooth extraction. Twelve weeks after implant placement, histopathological samples were evaluated for implant osteointegration parameters.ResultsThe bone-implant-contact (BIC) ratio revealed no significant inter-group or inter-material differences. The distance between the implant shoulder to the bone level was significantly greater around the titanium implants of the zoledronic acid group compared to the zirconia implants of the control group (p = 0.0005). On average, signs of new bone formation could be detected in all groups, although often without statistical differences. Signs of bone necrosis were only detected around the zirconia implants of the control group (p < 0.05).ConclusionsAt the 3-month follow-up, no implant material was demonstrably better than the others in terms of osseointegration metrics under systemic antiresorptive therapy. Further studies are necessary to determine whether there are differences in the osseointegration behavior of the different materials.