Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate.

Purpose: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial. Methods: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing. Results: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD. Conclusion: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies.

[Analysis of the efficacy and safety of bone disease treatment in patients with newly diagnosed multiple myeloma treated with denosumab or zoledronic acid].

Objective: This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma. Methods: The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) . Results: Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration (P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum ß-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups (P>0.05), and the median PFS and OS time were not reached (P>0.05) . Conclusions: In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

Effects of the Application Local Zoledronic Acid On Different Dental Implants in Rats On Osseointegration.

Objective: Recently, a lot of research has been done around the world to popularize the osseointegration of dental implants. In this study, it was investigated the effect of local zoledronic acid application on implants with machined (MAC), resorbable blast materials (RBM), sandblasted and acid-etched (SLA) surface implants integrated in rat tibias. Methodology: A total of 60 female Wistar rats weighing between 270 and 300 g were used in the study. The rats were passing divided into six classes: controls; MAC (n = 10), RBM (n = 10), SLA (n = 10), and local zoledronic acid (LZA) applied groups; LZA-MAC (n = 10), LZA-RBM (n=10) and LZA-SLA (n = 10) and implants were surgically placement into rat tibias in general anesthesia. After a four-week experimental period, the biomechanical bone implant connection level was determined with reverse torque analysis. Results: Osseointegration levels were detected highly in SLA and RBM surface compared with the machined surfaced implants in both control and treatment groups (p < 0.05). Additionally, local application of zoledronic acid in both three groups; implants increased the biomechanic osseointegration level compared with the controls (p < 0.05). Conclusion: In this research, we observe that the local application of the zoledronic acid could increase the osseointegration, and RBM and SLA surface could be better than machined surfaced implants in terms of bone implant connection. In addition, local application of zoledronic acid may be a safer method than systemic application.

[A retrospective cohort study of the effect of zolendronic acid on mandibular bone optical density in cancer patients]. / Issledovanie vliyaniya zolendronovoi kisloty na plotnost' nizhnei chelyusti u onkologicheskikh patsientov.

THE AIM THE STUDY: To analyze the density of the mandible in cancer patients during treatment with zoledronic acid. MATERIALS AND METHODS: A retrospective cohort study included 45 patients with cancer aged 26-81 years (average age 55±12.88 years), of whom 14 patients had bone metastases (n=14) and took 4 mg of zolendronic acid once every 28 days. The patients underwent standard PET-CT examinations in the «whole body¼ mode, and the density of the mandible was examined on CT. Radiation therapy was performed by intracavitary administration of strontium 89 chloride; remote radiation therapy with cisplatin radiomodification. In the presence of bone metastases, patients received complex supportive therapy with zolendronic acid. The effect of zolendronic acid on the density of the mandible in the frontal and lateral sections was studied by multidimensional dispersion analysis. RESULTS: Statistically significant differences (p=0.002) were revealed for density indicators according to CT scans of the mandible in the frontal region against the background of zolendronic acid therapy. We attribute the absence of statistically significant differences for the density of the mandible in the lateral sections (p=0.101 and p=0.082) against the background of zolendronic acid therapy to a measurement bias. We attribute the absence of statistically significant differences in density indices against the background of hormonal, radiation, targeted and chemotherapy to the design of the study. CONCLUSION: Density measurement based on CT examination data can be recommended for use as an additional tool in assessing the effect of zolendronic acid on the density of the mandible. However, the method of measuring the density of the mandible in the lateral sections requires improvement to prevent measurement bias.

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.

BACKGROUND: The 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. METHODS: A 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. RESULTS: Radiographic 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. CONCLUSION: The 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.

Cinobufotalin Capsule Combined with Zoledronic Acid in the Treatment of Pain Symptoms and Clinical Efficacy in Prostate Cancer Patients with Bone Metastases: A Retrospective Study.

OBJECTIVE: To retrospectively analyse the effects of cinobufotalin capsule combined with zoledronic acid on pain symptoms and clinical efficacy of prostate cancer patients with bone metastases. METHODS: Patients with prostate cancer with bone metastasis admitted to our hospital from January 2021 to December 2022 were selected as study subjects. They were divided into the control group (treated with zoledronic acid) and the combined group (cinobufotalin capsules were added on the control group basis) according to different recorded treatment methods. The efficacies of the two groups after matching, lumbar L1-4 bone mineral density (BMD), serum calcium, serum phosphorus, visual analogue scale (VAS) score and Karnofsky performance status (KPS) score before and after treatment were compared, and adverse reactions were statistically analysed. RESULTS: A total of 102 patients were included in the study, encompassing 52 patients in the combined group and 50 patients in the control group. After 1:1 preference score matching, 64 patients were included in the two groups. No significant difference in baseline data was found between the two groups (p > 0.05). The total effective rate of the combination group was higher than that of the control group (p < 0.05). No significant differences in L1-4 bone mineral density, serum calcium and phosphorus, VAS score and KPS score were observed between the two groups prior to treatment (p > 0.05). After treatment, the L1-4 bone mineral density (BMD) and KPS score of the combined group decreased to less than those of the control group, the VAS score was lower than that of the control group, and the serum calcium and phosphorus level increased but less than that of the control group (p < 0.05). No significant difference in adverse reactions was found between the two groups (p > 0.05). CONCLUSIONS: Cinobufotalin capsule combined with zoledronic acid had ideal efficacy in the treatment of prostate cancer in patients with bone metastasis. This approach could improve their bone density and quality of life, improve their calcium and phosphorus metabolism, reduce their pain symptoms and provide increased safety. It may have an important guiding role in formulating future clinical treatment plans for patients with prostate cancer and bone metastasis.

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.

OBJECTIVE: 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). METHODS: 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). RESULTS: 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). CONCLUSION: These results suggest that ZA is not protective against TKR in patients with symptomatic knee osteoarthritis and without severe JSN.

Differential effects of teriparatide, denosumab and zoledronate on hip structural and mechanical parameters in osteoporosis; a real-life study.

PURPOSE: The aim of this study was to evaluate changes in hip geometry parameters following treatment with teriparatide (TPD), denosumab (Dmab) and zoledronate (ZOL) in real-life setting. METHODS: We studied 249 patients with osteoporosis (OP) with mean [SD] age of 71.5 [11.1] years divided into 3 treatment groups; Group A received TPD; n = 55, Group B (Dmab); n = 116 and Group C (ZOL); n = 78 attending a routine metabolic bone clinic. Bone mineral density (BMD) was measured by DXA at the lumbar spine (LS), total hip (TH) and femoral neck (FN) prior to treatment and after 2 years (Group A), after a mean treatment duration of 3.3 [1.3] years (Group B) and after 1, 2 and 3 doses of ZOL (Group C) to assess treatment response. Hip structural analysis (HSA) was carried out retrospectively from DXA-acquired femur images at the narrow neck (NN), the intertrochanter (IT) and femoral shaft (FS). RESULTS: Changes in parameters of hip geometry and mechanical strength were seen in the following treatment. Percentage change in cross-sectional area (CSA): 3.56[1.6] % p = 0.01 and cross-sectional moment of inertia (CSMI): 4.1[1.8] % p = 0.029 increased at the NN only in Group A. Improvement in HSA parameters at the IT were seen in group B: CSA: 3.3[0.67]% p < 0.001, cortical thickness (Co Th): 2.8[0.78]% p = 0.001, CSMI: 5.9[1.3]% p < 0.001, section modulus (Z):6.2[1.1]% p < 0.001 and buckling ratio (BR): - 3.0[0.86]% p = 0.001 with small changes at the FS: CSA: 1.2[0.4]% p = 0.005, Z:1.6 [0.76]%, p = 0.04. Changes at the IT were also seen in Group C (after 2 doses): CSA: 2.5[0.77]% p = 0.017, Co Th: 2.4[0.84]% p = 0.012, CSMI: 3.9[1.3]% p = 0.017, Z:5.2[1.16]% p < 0.001 and BR: - 3.1[0.88]% p = 0.001 and at the NN (following 3 doses): outer diameter (OD): 4.0[1.4]% p = 0.0005, endocortical diameter(ED): 4.3[1.67% p = 0.009, CSA:5.2[1.8]% p = 0.003, CSMI: 9.3[3.8]% p = 0.019. CONCLUSIONS: Analysis of the effect of OP therapies on hip geometry is useful in understanding the mechanisms of their anti-fracture effect and may provide additional information on their efficacy.

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

CONTEXT: The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established. OBJECTIVE: To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI. METHODS: 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. RESULTS: 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 ß-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. CONCLUSION: 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.

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

CONTEXT: Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Call to action: a five nations consensus on the use of intravenous zoledronate after hip fracture.

Currently in the UK and Ireland, after a hip fracture most patients do not receive bone protection medication to reduce the risk of refracture. Yet randomised controlled trial data specifically examining patients with hip fracture have shown that intravenous zoledronate reduces refracture risk by a third. Despite this evidence, use of intravenous zoledronate is highly variable following a hip fracture; many hospitals are providing this treatment, whilst most are currently not. A range of clinical uncertainties, doubts over the evidence base and practical concerns are cited as reasons. This paper discusses these concerns and provides guidance from expert consensus, aiming to assist orthogeriatricians, pharmacists and health services managers establish local protocols to deliver this highly clinically and cost-effective treatment to patients before they leave hospital, in order to reduce costly re-fractures in this frail population.

Esclerosis bilateral de huesos largos: enfermedad de Erdheim-Chester. Reporte de un caso / Bilateral long bone sclerosis: Erdheim-Chester disease. Case report

La enfermedad de Erdheim-Chester (EEC) es una patología poco frecuente, caracterizada por presentar infiltración xantogranulomatosa sistémica, con afección de diversos sistemas incluido el óseo. La EEC se encuentra descripta dentro de las enfermedades osteocon-densantes (EO), las cuales se reconocen por presentar aumento de la masa ósea y compromiso tanto de huesos largos como planos. La presentación clínica de la EEC es variada: puede presentar desde un curso indolente hasta manifestaciones multisistémicas. Las características radiológicas son de gran importancia para establecer su diagnóstico. Presentamos una paciente con EEC, con esclerosis bilateral de huesos largos, que exhibe algunas características diferenciales con relación a otros casos reportados: a) afectación exclusivamente ósea a 10 años de evolución, b) compromiso bilateral y simétrico de distinta magnitud, c) esclerosis cortical endóstica y perióstica, d) signos radiológicos sugestivos de periostitis, d) ausencia de compromiso metafisario, e) ausencia de actividad metabólica de las lesiones en las imágenes de 18F-FDG PET/CT.Conclusión: la presencia de lesiones osteocondensantes bilaterales exclusivamente en huesos largos deben hacer sospechar EEC. La ausencia de compromiso metafisario y de actividad metabólica en 18F-FDG PET/CT ha sido raramente descripta. (AU)

Erdheim - Chester disease (ECD) is a rare disease, characterized by systemic xanthogranulomatous infiltration, with involvement of various organs including bone. ECD is described within the sclerosing bone disorders, which are recognized for presenting increased bone mass and involvement of both long and flat bones. The clinical presentation of ECD is diverse, ranging from an asymptomatic course to multisystemic manifestations. Radiological features are of great importance to establish the diagnosis. We describe here a patient with ECD, with bilateral sclerosis of long bones that presents some differential characteristics in relation to other reported cases: a) exclusively bone involvement at 10 years of evolution, b) bilateral and symmetric involvement of different magnitude, c) endosteal and periosteal cortical sclerosis d) radiological signs suggestive of periostitis, d) absence of metaphyseal involvement, e) absence of metabolic activity of the lesions in 18F-FDG PET/CT.Conclusion: the presence of bilateral osteosclerosis exclusively in long bones should lead to suspect ECD. The absence of metaphyseal involvement and metabolic activity in 18F-FDG PET/CT have been rarely described. (AU)

Does Local Zoledronate Applied to Pasteurized Bone Autografts Improve the Likelihood of Union of Graft-Host Junctions after Limb-sparing Surgery?

BACKGROUND: Pasteurized bone autograft is a recycling biological reconstruction method for limb-sparing surgery when an allograft or other reconstruction technique is unavailable. Since the application of a local bisphosphonate to morselized allografts can reduce graft resorption and enhance bone formation without systemic complications, adding the local bisphosphonate to pasteurized bone autografts should reduce the graft resorption and improve the graft incorporation to host bone. However, no study that we know of has described the outcomes of local bisphosphonate application to massive allografts or pasteurized bone autografts. Thus, this study compared the outcomes of pasteurized bone autografts with and without local zoledronate. QUESTIONS/PURPOSES: (1) What is the survival of pasteurized bone autografts and what complications lead to graft removal? (2) Does treatment of pasteurized bone autografts with zoledronate alter the survival of pasteurized bone autografts compared with grafts without treatment? (3) Does the local application of zoledronate reduce the proportion of patients with fractures because of metaphyseal graft resorption? (4) Does local application of zoledronate improve union at the graft-host bone junction compared with untreated grafts? METHODS: Between July 2011 and December 2019, we performed 538 musculoskeletal bone tumor resections. Of these, 101 patients underwent reconstruction with pasteurized bone autografts. Other reconstructions included tumor prostheses (150 patients), allografts (70 patients), reconstruction using a bone cement-plate construct (62 patients), and resection only (155 patients). We generally used pasteurized bone autograft when tumors showed an osteoblastic pattern, had less than one-third cortical destruction, and less than half of metaphyseal bone destruction. Six percent (6 of 101) were lost to follow-up, 6% (6 of 101) had incomplete clinical data, and 16% (16 of 101) had a follow-up period less than 2 years without an event, leaving 73 patients for evaluation. The median (interquartile range) age of the patients was 18 years (15 to 26). Ninety-seven percent (71 of 73) had a diagnosis of bone sarcoma. The median follow-up time was 46 months (33 to 75). From 2011 to 2014, 21 pasteurized bone autografts were prepared without local zoledronate, and from 2014 to 2019, 52 pasteurized bone autografts were prepared with local zoledronate because we thought it might improve union and reduce resorption of the graft. From our tumor registry database, we obtained age, sex, use of chemotherapy, graft length and location, pasteurized bone graft type, fixation methods, the use of local zoledronate, osteotomy gap, complications, proportion of grafts that united by 2 years, and local recurrences. Curves for graft survival were determined using the Kaplan-Meier method with the endpoint of autograft removal and metaphyseal fracture from graft resorption. The probabilities of graft removal were estimated by cumulative incidences using the competing risk analysis, where death was considered as the competing event. Intergroup differences in survival and multivariable analyses were performed using the log-rank test and a Cox regression analysis. A logistic regression model was used to evaluate the association between graft-host osseous union by 2 years and other baseline factors. Union was defined when a callus was seen to bridge the osteotomy line for at least three cortices in both the AP and mediolateral planes. RESULTS: The 5-year survival rate of all 73 pasteurized grafts was 85% (95% confidence interval 74% to 92%). With the numbers available, we found no difference in the 5-year survival rates between grafts with and without local zoledronate (90% [95% CI 78% to 96%] versus 74% [95% CI 48% to 89%]; p = 0.30). Eleven percent (8 of 73) of patients had metaphyseal fractures because of graft resorption, primarily associated with osteoarticular grafts (5-year fracture-free survival 56% [95% CI 20 to 80]) rather than pasteurized graft-prosthesis composites (94% [95% CI 78% to 98%]) and intercalary grafts (91% [95% CI 50 to 99]; p = 0.001); there was no association with the use of local zoledronate (13%; 7 of 52) compared with those without local zoledronate (5%; 1 of 21) (odds ratio 3.1 [95% CI 0.4 to 27]; p = 0.43). Of the 84 graft-host bone junctions, 85% (71) of the grafts unified within 2 years, 7% (6) unified after 2 years, and 8% (7) of grafts showed nonunion. Union within 2 years was associated with fixation using plate compared with those with stem and with both stem and plate (odds ratio 6.6 [95% CI 1.4 to 31]; p = 0.02) and grafts treated with local zoledronate compared with those without treatment (OR 5.9 [95% CI 1.3 to 28]; p = 0.02). CONCLUSION: The application of local zoledronate to pasteurized bone autografts for limb-sparing surgery improved the likelihood of graft union compared with untreated grafts, especially when the osteotomy junctions were fixed using plate osteosynthesis, but it did not appear to alter the proportion of patients who experience metaphyseal fracture of the grafts because of graft resorption. Although this is a small study, it suggests that the treatment of pasteurized bone autografts and perhaps bone allografts should be studied further to determine whether bisphosphonates or other adjuncts can improve the union time and return to function in patients undergoing bone tumor resections using these reconstruction types. LEVEL OF EVIDENCE: Level III, therapeutic study.

The Effect of Daily Teriparatide versus One-Time Annually Zoledronic Acid Administration After Transforaminal Lumbar Interbody Fusion in Osteoporotic Patients.

PURPOSE: The research aimed to compare the therapeutic effect of teriparatide (TPTD) and zoledronic acid (ZOL) therapy on bone formation and spinal fusion in patients with osteoporosis (OP) who underwent transforaminal lumbar interbody fusion (TLIF). METHODS: On the basis of different anti-OP treatment options, the TPTD group was treated daily with TPTD (20 µg. ih. qd) for at least 6 months, while the ZOL group was treated with a single dose of ZOL (5 mg. ivgtt. st) postoperatively. The visual analogue scale (VAS), Oswestry Disability Index (ODI), bone mineral density (BMD), and concentration of bone turnover markers before, 6, and 12 months after surgery were evaluated. X-ray and three-dimensional computed tomography scans were performed at 6 and 12 months postoperatively to assess interbody fusion. RESULTS: The number of patients in the TPTD and ZOL groups was 29 and 38 patients, respectively. The VAS and ODI scores in both groups were significantly reduced at 6 and 12 months after TLIF. Compared with that of baseline, the lumbar spine BMD of TPTD patients increased significantly from 0.716±0.137 g/cm2 to 0.745±0.124 g/cm2 and 0.795±0.123 g/cm2 at 6 and 12 months, respectively, and was significantly higher than that of the ZOL group at 12 months (0.720±0.128 g/cm2). The bone formation marker, P1NP, in the TPTD group increased significantly (145.48±66.64 ng/mL and 119.55±88.27 ng/mL) compared with baseline (44.67±25.15 ng/mL) and in the ZOL group (28.82±19.76 ng/mL and 29.94±20.67 ng/mL) at 6 and 12 months, respectively. The fusion rates in the TPTD and ZOL groups were 57% and 45% at 6 months, without statistical significance. However, TPTD had a more statistically significant positive influence on fusion rate than ZOL at 12 months (86% vs 70%). CONCLUSION: TPTD was more efficient than ZOL in bone formation and spinal fusion in OP patients who underwent TLIF.

Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages.

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.

Oestradiol Contributes to Differential Antitumour Effects of Adjuvant Zoledronic Acid Observed Between Pre- and Post-Menopausal Women.

Clinical trials have demonstrated that adding zoledronic acid (Zol) to (neo)adjuvant standard of care has differential antitumour effects in pre- and post-menopausal women: Both benefit from reduced recurrence in bone; however, while postmenopausal women also incur survival benefit, none is seen in premenopausal women treated with adjuvant bisphosphonates. In the current study, we have used mouse models to investigate the role of oestradiol in modulating potential antitumour effects of Zol. Pre-, peri-, and post-menopausal concentrations of oestradiol were modelled in BALB/c wild-type, BALB/c nude, and C57BL/6 mice by ovariectomy followed by supplementation with oestradiol. Mice also received 40 mg/kg/day goserelin to prevent ovariectomy-induced increases in follicle-stimulating hormone (FSH). Metastasis was modelled following injection of MDA-MB-231, 4T1, or E0771 cells after ovariectomy and saline or 100 µg/kg Zol administered weekly. Supplementing ovariectomised mice with 12.5 mg/ml, 1.38 mg/ml, and 0 ng/ml oestradiol, in the presence of goserelin, resulted in serum concentrations of 153.16 ± 18.10 pg/ml, 48.64 ± 18.44 pg/ml, and 1.00 ± 0.27 pg/ml oestradiol, which are equivalent to concentrations found in pre-, peri-, and post-menopausal humans. Osteoclast activity was increased 1.5-1.8-fold with peri- and post-menopausal compared with premenopausal oestradiol, resulting in a 1.34-1.69-fold reduction in trabecular bone. Zol increased trabecular bone in all groups but did not restore bone to volumes observed under premenopausal conditions. In tumour-bearing mice, Zol reduced bone metastases in BALB/c (wild-type and nude), with greatest effects seen under pre- and post-menopausal concentrations of oestradiol. Zol did not affect soft tissue metastases in immunocompetent BALB/c mice but increased metastases 3.95-fold in C57BL/6 mice under premenopausal concentrations of oestradiol. In contrast, Zol significantly reduced soft tissue metastases 2.07 and 4.69-fold in immunocompetent BALB/c and C57BL/6 mice under postmenopausal oestradiol, mirroring the results of the clinical trials of (neo)adjuvant bisphosphonates. No effects on soft tissue metastases were observed in immunocompromised mice, and differences in antitumour response did not correlate with musculoaponeurotic fibrosarcoma (MAF), macrophage capping protein (CAPG), or PDZ domain containing protein GIPC1 (GIPC1) expression. In conclusion, oestradiol contributes to altered antitumour effects of Zol observed between pre- and post-menopausal women. However, other immunological/microenvironmental factors are also likely to contribute to this phenomenon.

Alveolar socket healing in 5-lipoxygenase knockout aged female mice treated or not with high dose of zoledronic acid.

This study investigated the role 5-lypoxigenase (5-LO) on alveolar socket healing in aged female mice treated with zoledronic acid (ZL). Forty 129/Sv female mice (64-68 weeks old), 20 wild type (WT) and 20 5-LO knockout (5LOKO) were equally distributed according to ZL treatment: WT Control, WT ZL, 5LOKO Control, and 5LOKO ZL. ZL groups were treated with an intraperitoneal injection of 250 µg/Kg of ZL, while controls were treated with saline. Treatments were administered once a week, starting four weeks before surgery for tooth extraction and until 7 and 21 days post-surgery. Mice were euthanized for a comprehensive microscopic analysis (microCT, histomorphometry and immunohistochemistry). WT ZL mice presented intense inflammatory infiltrate (7 days), delayed bone formation (21 days), reduced collagenous matrix quality, and a deficiency in Runx-2 + , TRAP + , and macrophages as compared to controls. 5LOKO ZL animals presented decreased number of Runx-2 + cells in comparison to 5LOKO Control at 7 days, but no major changes in bone healing as compared to WT or 5LOKO mice at 21 days. The knockout of 5LO favored intramembranous bone healing in aged female mice, with a direct impact on inflammatory response and bone metabolism on the development of ONJ-like lesions.

CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer.

Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic regulators on two patient-derived colon CSC-enriched spheroids. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells yielded therapeutic candidates. We unraveled 44 essential genes for colon CSC-enriched spheroids propagation, including key cholesterol biosynthetic genes (HMGCR, FDPS, and GGPS1). Cholesterol biosynthesis was induced in colon cancer tissues, especially CSC-enriched spheroids. The genetic and pharmacological inhibition of HMGCR/FDPS impaired self-renewal capacity and tumorigenic potential of the spheroid models in vitro and in vivo. Mechanistically, HMGCR or FDPS depletion impaired cancer stemness characteristics by activating TGF-ß signaling, which in turn downregulated expression of inhibitors of differentiation (ID) proteins, key regulators of cancer stemness. Cholesterol and geranylgeranyl diphosphate (GGPP) rescued the growth inhibitory and signaling effect of HMGCR/FDPS blockade, implying a direct role of these metabolites in modulating stemness. Finally, cholesterol biosynthesis inhibitors and 5-FU demonstrated antitumor synergy in colon CSC-enriched spheroids, tumor organoids, and xenografts. Taken together, our study unravels novel genetic vulnerabilities of colon CSC-enriched spheroids and suggests cholesterol biosynthesis as a potential target in conjunction with traditional chemotherapy for colon cancer treatment.

Core Decompression with Local Administration of Zoledronate and Enriched Bone Marrow Mononuclear Cells for Treatment of Non-Traumatic Osteonecrosis of Femoral Head.

OBJECTIVE: To investigate the efficacy and safety of core decompression (CD) with local administration of zoledronate and enriched bone marrow mononuclear cells (BMMCS) for the treatment of non-traumatic osteonecrosis of femoral head (ONFH). METHODS: A total of 17 patients (30 hips) diagnosed with stage II and III ONFH according to the 2019 revised Association for Research on Osseous Circulation (ARCO) staging criteria from 2012 to 2014 were retrospectively reviewed. The patients received the following therapy: the BMMCs and zoledronate were injected into the necrotic zone, respectively, along with CD. The mean age of the patients was 36.8 years; 14 were men and three were women. All patients included had non-traumatic ONFH and a minimum follow-up of 5 years, which ended when total hip arthroplasty (THA) was performed. Imaging modalities, including plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were taken pre- and postoperatively. Harris hip score (HHS) was used to evaluate the functional outcomes of femoral head necrosis. Kaplan-Meier analysis was adopted to determine the probability of survivorship with THA as the end point in this series of patients. The correlation between radiological progression or THA and related risk factors were further analyzed. All complications were recorded. RESULTS: With THA as the follow-up endpoint, All patients were followed up for an average of 69.1 ± 20.5 months (range, 18-95 months). Preoperative imaging found six hips (20%) at ARCO stage II, 14 hips (46.7%) at stage IIIA, 10 hips (33.3%) at stage IIIB. Fourteen hips (46.7%) shown progression radiologically, while six hips (20%) underwent TKA among these patients with hip preservation. The cumulative survival was 80% (95% CI, 0.608-905) at 5 years with THA as the end point. HHS improved from 63.3 ± 8.7 preoperatively to 74.6 ± 20.6 postoperatively (P = 0.000). Radiological progression was found to be associated with ARCO stage, Japanese Investigation Committee (JIC) type, and corticosteroid exposure (P = 0.047; P = 0.012; P = 0.031). However, no correlation was found between conversion to THA and the known risk factors. No major complication was reported, with only four patients complaining about general weakness and muscle soreness, and all disappeared within 2-3 days. CONCLUSIONS: The novel treatment modality could relieve pain, delay the progression of collapse, which might be an effective and safe method for hip preservation of early and mid-term ONFH. However, the effect of this method may be related to ARCO stage, JIC type, and corticosteroid exposure.

Zoledronic acid-loaded lipidic nanoparticles enhance apoptosis and attenuate invasiveness by inhibiting epithelial to mesenchymal transition (EMT) in HepG2 cancer cells.

The aim of this study was to evaluate the potential of zoledronic acid (ZOL)-loaded lipidic nanoparticles (ZOL-NLCs) in enhancing the efficiency of paclitaxel (Pac) in the context of cytotoxicity, apoptosis, and invasiveness of HepG2 hepatocellular carcinoma cells. ZOL-NLCs were characterized in terms of zeta potential, particle size, and scanning electron microscope (SEM) as well as cell internalization. To measure the anti-proliferative effects of ZOL-NLCs, annexin-V/PI and MTT assays were employed. Real-time PCR and western blot analysis were performed to identify the molecular mechanisms underlying the apoptosis in response to the studied conditions. Furthermore, the transwell migration assay was applied to clarify the role of applied formulations on the invasiveness of HepG2 cells. Our results demonstrated that the optimized ZOL had an average particle size of 105 ± 6 nm with a nearly narrow size distribution. The IC50 values for ZOL and ZOL-NLCs were 90 ± 3.1 and 54.6 ± 2.4 µM, respectively. The population of apoptotic cells was increased from 17 ± 2% to 27 ± 4% (p < 0.05) in response to treatment with ZOL-NLCs. ZOL-loaded nanoparticles triggered the mRNA expression of Bax as pro-apoptotic marker and E-cadherin as epithelial one along with a decrease in mesenchymal marker, N-cadherin, and Bcl-xl as an anti-apoptotic marker in HepG2 cells. These outcomes were consistent with western blot analysis of protein expressions. Besides, ZOL-incorporated lipidic nanoparticles reduced the migration of HepG2 cells significantly. Our data suggest that the formulation of ZOL into lipidic nanoparticles can be considered a potential therapeutic approach that can enhance the efficacy of Pac chemotherapy.