Zoledronic Acid Administration Research Articles

Systemically administered zoledronic acid activates locally implanted synthetic hydroxyapatite particles enhancing peri-implant bone formation: A regenerative medicine approach to improve fracture fixation

Fracture fixation in an ageing population is challenging and fixation failure increases mortality and societal costs. We report a novel fracture fixation treatment by applying a hydroxyapatite (HA) based biomaterial at the bone-implant interface and biologically activating the biomaterial by systemic administration of a bisphosphonate (zoledronic acid, ZA). We first used an animal model of implant integration and applied a calcium sulphate (CaS)/HA biomaterial around a metallic screw in the tibia of osteoporotic rats. Using systemic ZA administration at 2-weeks post-surgery, we demonstrated that the implant surrounded by HA particles showed significantly higher peri‑implant bone formation compared to the unaugmented implants at 6-weeks. We then evaluated the optimal timing (day 1, 3, 7 and 14) of ZA administration to achieve a robust effect on peri‑implant bone formation. Using fluorescent ZA, we demonstrated that the uptake of ZA in the CaS/HA material was the highest at 3- and 7-days post-implantation and the uptake kinetics had a profound effect on the eventual peri‑implant bone formation. We furthered our concept in a feasibility study on trochanteric fracture patients randomized to either CaS/HA augmentation or no augmentation followed by systemic ZA treatment. Radiographically, the CaS/HA group showed signs of increased peri‑implant bone formation compared with the controls. Finally, apart from HA, we demonstrated that the concept of biologically activating a ceramic material by ZA could also be applied to β-tricalcium phosphate. This novel approach for fracture treatment that enhances immediate and long-term fracture fixation in osteoporotic bone could potentially reduce reoperations, morbidity and mortality. Statement of significance• Fracture fixation in an ageing population is challenging. Biomaterial-based augmentation of fracture fixation devices has been attempted but lack of satisfactory biological response limits their widespread use. • We report the biological activation of locally implanted microparticulate hydroxyapatite (HA) particles placed around an implant by systemic administration of the bisphosphonate zoledronic acid (ZA). The biological activation of HA by ZA enhances peri‑implant bone formation. •Timing of ZA administration after HA implantation is critical for optimal ZA uptake and consequently determines the extent of peri‑implant bone formation. • We translate the developed concept from small animal models of implant integration to a proof-of-concept clinical study on osteoporotic trochanteric fracture patients. • ZA based biological activation can also be applied to other calcium phosphate biomaterials.

Influence of zoledronic acid and pamidronate on tooth eruption in children with osteogenesis imperfecta

IntroductionOsteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children. MethodsAn ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption. ResultsThe age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration. ConclusionPatients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.

1912 Reviewing the effect of COVID pandemic on changing clinical practice of administrating Zoledronic Acid to hip fracture patients

Abstract Introduction Reduction in outpatient appointments during the COVID-19 pandemic and patient concern surrounding risk of contracting COVID-19 by attending day-case settings, resulted in delayed or cancelled medical treatments including Zoledronic Acid infusions as management for Osteoporosis. This, alongside recent research concluding that these treatments can be given safely as early as 1-2 weeks post-fracture, lead to the adaptation of protocol at Hull University Teaching Hospitals Trust in 2021, to provide rapid loading of Cholecalciferol over 6 days, prior to administration of Zoledronic Acid on day 7. However, some concerns remain surrounding the potential interference with bone remodelling and healing. This completed audit cycle evaluates the logistics and safety of this new protocol. Methods All patients over 60, admitted with neck of femur fracture who received Zoledronic Acid infusion as inpatient or outpatient in 2019 and 2021 were included in the initial and repeat audit respectively. Electronic records for the following 12 months were analysed evaluating for further fragility fracture and mortality rate. Results There was an increase in patients receiving Zoledronic Acid as an inpatient treatment from 21% in the initial audit to 97% in the repeat audit. There was a slight increase in mortality rate at one year from 14% to 19%. The percentage of a further fragility fracture within one year, remained stable at 7%. Conclusion The increase in inpatient infusions suggests more patients with significant frailty who would otherwise not have been able to attend outpatient settings, have been able to receive treatment. The mortality results reflect this frailer audit population. The absence of a substantial increase in the rate of further fragility fracture at one year; supports the earlier administration of Zoledronic Acid as a management protocol.

Impact of Bone Modifying Agent Initiation Time, Frequency, and Duration on Skeletal-Related Events in Patients with Multiple Myeloma

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values &amp;gt;0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

The effect of zoledronic acid on hip geometry in renal transplant recipients: a double-blind placebo-controlled randomized study

BackgroundIn renal transplant patients, bisphosphonates may prevent bone loss, but little is known about their effects on bone microarchitecture and geometrical hip parameters, as the key factors of bone stability. This study aimed to analyze the effect of zoledronic acid on the mentioned parameters in kidney transplant patients.MethodsIn this double-blind, randomized trial, 33 patients were followed for six months after administering either 4mg of zoledronic acid or a placebo. Bone mineral density (BMD) measurement of the spine, hip, radius, and whole body was obtained, and trabecular bone score (TBS) was evaluated using the software. Geometric assessment at the proximal femur was performed by the HSA program.ResultsEighteen patients in the intervention group and 15 in the control group completed the study. The mean percentages of the changes in the BMD at the lumbar spine and whole body were significantly different between the placebo and intervention groups (-0.23% vs. 4.91% and -2.03% vs. 1.23%) (P < 0.05). Zoledronic acid appeared to enhance the subperiosteal diameter, endocortical diameter, and cross-sectional moment of inertia (CSMI) at the narrow neck in comparison with placebo (P < 0.05); however, no difference in TBS was observed between both groups (P > 0.05).ConclusionsWe concluded that a single administration of zoledronic acid might ameliorate bone loss at the lumbar spine and the whole body and maintain the subperiosteal diameter, endocortical diameter, and CSMI as parameters of bone strength at the narrow neck of the proximal femur after six months in renal-transplant recipients.Trial registrationThis study was registered in IRCT (ID: IRCT20181202041821N1) on 04–05-2019.

SAT253 A Rare Case Of Osteolytic Hypercalcemia Of Malignancy In Acute Myeloid Leukemia

Abstract Disclosure: S. Elahi: None. S. Baim: None. Introduction: Acute myeloid leukemia (AML) and other leukemias do not commonly induce hypercalcemia of malignancy (HCM). Limited previous reports of AML-related HCM have largely attributed cases to inflammatory-cytokine-mediated osteoclast activation, with rare reports of calcitriol-mediated HCM and ectopic parathyroid hormone (PTH) production. We describe an unusual case of AML-induced HCM caused by direct leukemic bone invasion, which responded to bisphosphonate therapy. Case Presentation: A 59-year-old female presented with spontaneous bruising and severe leukocytosis concerning for AML. The diagnosis was confirmed by flow cytometry and bone marrow biopsy. Imaging did not reveal any gross destructive bone lesions, but showed soft tissue nodules in the lumbar region which biopsy revealed to be myeloid sarcoma. Prior to initiation of chemotherapy, the patient developed severe hypercalcemia that was treated with aggressive intravenous hydration and zoledronic acid. Intrathecal chemotherapy and high-dose glucocorticoid therapy were initiated thereafter with normalization of serum calcium levels. PTH levels were suppressed. Calcitriol and PTHrP were below normal and undetectable, respectively. Bone turnover markers (C-telopeptide and bone-specific alkaline phosphatase) were significantly elevated prior to administration of zoledronic acid and normalized post-therapy. Calcium levels did not rebound after several interruptions in chemotherapy. Bone marrow biopsy showed focal areas of erosion in trabecular bone consistent with diffuse microscopic osteolytic disease. The patient developed bisphosphonate-induced hypocalcemia following treatment with zoledronic acid, which normalized with treatment with oral calcium carbonate. Discussion: Hypercalcemia of malignancy is a very unusual consequence of AML. No currently-published reports of this phenomenon have described biopsy-proven diffuse microscopic bone erosion associated with AML. We attribute our patient’s severe HCM to large-scale focal bone erosion by AML, independent of and/or associated with concurrent bone resorption mediated by inflammatory cytokines. A single dose of zoledronic acid, a potent suppressor of bone remodeling, achieved long term control of calcium for our patient despite interruption of chemotherapy. Bisphosphonate therapy should be considered an early treatment of HCM in patients with AML due to several potential mechanisms that result in direct calcium release from the skeleton. Presentation: Saturday, June 17, 2023

Effectiveness of fracture liaison services in osteoporosis.

In response to the gradual decline in the number of prescriptions for anti-osteoporosis medication (AOM) following fragility fractures, fracture liaison services (FLSs) have been set up around the world with the aim of filling this treatment gap. Several studies have already reported the benefits of such organizations, particularly in reducing fracture risk, mortality rates and healthcare costs, and literature on FLSs has increased at a steady pace over time. A narrative review was conducted on the latest available findings on the effectiveness of FLSs. Various approaches to implementing an effective FLS program are discussed. FLS programs have enhanced the management of osteoporosis-related fractures. However, several studies have highlighted that not all FLSs are necessarily effective in reducing subsequent fracture risk and mortality. Long-term AOM persistence and monitoring are another critical issue in FLS programs. A few studies have reported that FLSs are associated with an improvement in AOM persistence, regardless of the type of AOM. Practitioners in the FLS setting need to be aware of the impact of recency of fracture and fracture recurrence rates, and the need for timely interventions. The administration of zoledronic acid in an in-patient setting may improve AOM treatment rates in patients, who often encounter obstacles to outpatient follow-up. Introducing 'vertebral fracture identification services' in FLS programs is also an option. However, doing so leads to an increase in workload and this would need to be considered by any FLS that is considering introducing such a service. Evidence suggests that digital technologies can support (i) multidisciplinary teams in providing the best possible patient care based on current evidence, and (ii) patient self-management. However, as the methodological quality of many of the studies evaluating these technologies was poor, their validity of their results is limited. Further research should focus on the optimal implementation of post-fracture care using automated systems, and standardized reporting of patient's characteristics and outcome measures using key performance indicators.

Menaquinone-4 prevents medication-related osteonecrosis of the jaw through the SIRT1 signaling-mediated inhibition of cellular metabolic stresses-induced osteoblast apoptosis.

Long-term usage of bisphosphonates, especially zoledronic acid (ZA), induces osteogenesis disorders and medication-related osteonecrosis of the jaw (MRONJ) in patients, thereby contributing to the destruction of bone remodeling and the continuous progression of osteonecrosis. Menaquinone-4 (MK-4), a specific vitamin K2 isoform converted by the mevalonate (MVA) pathway in vivo, exerts the promotion of bone formation, whereas ZA administration suppresses this pathway and results in endogenous MK-4 deficiency. However, no study has evaluated whether exogenous MK-4 supplementation can prevent ZA-induced MRONJ. Here we showed that MK-4 pretreatment partially ameliorated mucosal nonunion and bone sequestration among ZA-treated MRONJ mouse models. Moreover, MK-4 promoted bone regeneration and inhibited osteoblast apoptosis in vivo. Consistently, MK-4 downregulated ZA-induced osteoblast apoptosis in MC3T3-E1 cells and suppressed the levels of cellular metabolic stresses, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and DNA damage, which were accompanied by elevated sirtuin 1 (SIRT1) expression. Notably, EX527, an inhibitor of the SIRT1 signaling pathway, abolished the inhibitory effects of MK-4 on ZA-induced cell metabolic stresses and osteoblast damage. Combined with experimental evidences from MRONJ mouse models and MC3T3-E1 cells, our findings suggested that MK-4 prevents ZA-induced MRONJ by inhibiting osteoblast apoptosis through suppression of cellular metabolic stresses in a SIRT1-dependent manner. The results provide a novel translational direction for the clinical application of MK-4 for preventing MRONJ.

Targeting Melanoma-Associated Fibroblasts (MAFs) with Activated γδ (Vδ2) T Cells: An In Vitro Cytotoxicity Model.

The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), a subpopulation of which is labeled as γδ T cells. Since the current anti-cancer therapies using γδ T cells in various cancers have exhibited mixed treatment responses, to better understand the γδ T cell biology in melanoma, our research group aimed to investigate whether activated γδ T cells are capable of killing MAFs. To answer this question, we set up an in vitro platform using freshly isolated Vδ2-type γδ T cells and cultured MAFs that were biobanked from our melanoma patients. This study proved that the addition of zoledronic acid (1-2.5 µM) to the γδ T cells was necessary to drive MAFs into apoptosis. The MAF cytotoxicity of γδ T cells was further enhanced by using the stimulatory clone 20.1 of anti-BTN3A1 antibody but was reduced when anti-TCR γδ or anti-BTN2A1 antibodies were used. Since the administration of zoledronic acid is safe and tolerable in humans, our results provide further data for future clinical studies on the treatment of melanoma.

Hypocalcemia in Children with Osteogenesis Imperfecta Treated with Intravenous Zoledronic Acid

Background: Bisphosphonates (Pamidronate and Zoledronic acid) mainly used for the treatment of childhood osteoporosis such as osteogenesis imperfecta have been associated with adverse effects ranging from acute phase response, hypocalcemia, musculoskeletal pain and up to serious side effects such as osteonecrosis of the jaw. In this report, we describe the prevalence of hypocalcemia among Saudi children treated with Zoledronic acid. Method: The biochemical profile of 13 Saudi children with osteogenesis imperfecta treated with Zoledronic acid was reviewed. The bone profile including calcium and phosphorus levels were monitored before and 4-24 hours after Zoledronic acid administration. The annual total Zoledronic acid dose was 0.1 mg/kg/year. Results: Post therapy, 46% of the treated children had mild hypocalcemia and 15% had mild hypophosphatemia. None of the children had hypocalcemic or hypophosphatemic signs or symptoms. No reports of seizure or tetany or muscle spasm. Conclusion: Hypocalcemia associated with Zoledronic acid administration is common, however mild. Close monitoring and calcium supplementation might be needed.

Delayed versus immediate use of zoledronic acid for postmenopausal patients with ER/PR positive early breast cancer who are using adjuvant letrozole.

8 Background: Aromatase inhibitors are the standard adjuvant therapy for postmenopausal women with hormone receptor (HR) positive early breast cancer (EBC). In such patients, a significant reduction in bone density was observed. To stop bone loss, bisphosphonates have a powerful effect on reducing bone resorption and improving the survival of patients with EBC. This study compared potential bone-protection of immediate versus delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. Methods: In a prospective two-arm comparative study, 65 postmenopausal patients with HR+ EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years), we included either (45) immediate ZOL treatment or (20) delayed ZOL treatment (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for fracture or increased bone pain or developed bone mineral density (BMD)T score = or &lt; -2.0. We aimed to assess the change in lumber spine BMD every 3 months for 24 months for both immediate and delayed arm patients, in addition to evaluating bone pain deterioration and the disease-free survival (DFS). Results: Analysis of data showed significant differences between immediate and delayed arms in the first three BMD measurements with mean values were -1.55± 0.4 vs. -1.9± 0.2, -1.56± 0.3 vs. -2.5± 0.3, and -1.4±0.3 vs. -3.5± 0.3 with p&lt;0.002, 0.001, 0.0001 respectively. Despite ZOL administration in delayed arm patients was initiated 6 months later than immediate arm patients, improvement of BMD was detected in delayed arm later on. The median DFS for immediate and delayed arms were 39± 0.6 months and 21± 0.4 months respectively with p&lt;0.001 in both. Although, in pre-ZOL bone pain scoring, most patients of delayed arm (75%) were found to have a score of 3 compared to 51.1% of immediate arm, significant improvement in bone pain scores in both arms separately after ZOL administration was noted with p-values 0.031, and 0.025 respectively. Conclusions: Immediate ZOL administration prevented bone loss, improved bone pain, and ameliorate DFS in postmenopausal women with HR+ EBC receiving adjuvant letrozole. Clinical trial information: PACTR202112813934276.

Radiological Features of Zoledronic Acid Therapy in Saudi Children with Osteogenesis Imperfecta

Background: The majority of osteogenesis imperfecta (OI) cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. Patients with OI may have blue sclerae, dentinogenesis imperfecta, and growth deficiency. Zoledronic acid is a third-generation bisphosphonate which was reported to inhibit osteoclast-mediated bone resorption, improve bone density, and reduce incidence of fractures. Aim: To describe the radiographic features of cyclic Zoledronic acid administration on the growing skeleton in children with OI and to report the efficacy of Zoledronic acid on bone mineral density. Methods: We retrospectively reviewed the radiographs of 11 children treated with Zoledronic acid. The age of these children ranged from one to 13 years. Zoledronic acid was administrated intravenously at 6 months intervals at the Pediatric Endocrinology Day Medical Unit, King Faisal Specialist Hospital and Research Centre, and Security Forces Hospital, Riyadh, Kingdom of Saudi Arabia for 2 years. Results: During the course of treatment, a gradual increase in bone density was observed. The baseline mean lumbar BMDz score was -4.9SD + 1.3, which improved to a mean score of -2.7SD + 1.1, and a mean whole body BMDz score was -2SD +1.2 and improved to a mean score of -1.1SD + 1.3 by the end of therapy. Post treatment, there were multiple sclerotic metaphyseal bands seen in all children in the long bones paralleling to the growth plates and corresponding to the number of treatment cycles. Conclusion: Intravenous Zoledronic acid in children with osteogenesis imperfecta improved the bone mineral density and resulted in permanent sclerotic metaphyseal bands.

Phase 1 study of WNT pathway Porcupine inhibitor CGX1321 and phase 1b study of CGX1321 + pembrolizumab (pembro) in patients (pts) with advanced gastrointestinal (GI) tumors.

3514 Background: Despite the fundamental role of WNT signaling in GI cancers, especially colorectal cancer (CRC), no drug targeting WNT signaling has been successfully developed. CGX1321, a highly-potent and selective inhibitor of O-acyltransferase Porcupine, blocks WNT ligand secretion. Preclinical studies show that CGX1321 inhibits WNT signaling and growth of tumors with RSPO fusions or inactivating RNF43 mutations. Activation of WNT signaling has been associated with cancer immune-suppression and resistance to immunotherapy. Methods: The first-in-human trials (NCT02675946 in U.S., NCT03507998 in China) include phase 1 CGX1321 dose escalation (3 – 18 mg, once daily) and dose expansion (18 mg), and phase 1b CGX1321 + pembro combination (Keynote 596). The primary objectives were safety, tolerability and identification of recommended doses and schedules for further evaluation. Secondary objectives were characterization of the PK profile and PD response and anti-tumor activity. CGX1321 was dosed once daily, orally, for 21 days out of 28-day cycles as single-agent, or for 14 days out of 21-day cycles in combination with pembro. Results: As of January 1, 2023, 77 pts were enrolled, including 38 pts with solid tumors in the CGX1321 dose escalation, 17 pts with CRC or small bowel cancer (SBC) carrying RSPO or RNF43 alterations in the CGX1321 expansion, 17 pts with microsatellite stable (MSS) CRC in the CGX1321 + pembro dose escalation and 5 pts with MSS CRC in the CGX1321 + pembro expansion. Six of the 17 pts with MSS CRC or SBC from the CGX1321 single-agent expansion were rolled over to CGX1321 + pembro upon disease progression. Across all cohorts, treatment was well tolerated with the majority of AEs being Grade 1/2 and not related to CGX1321, while Grade &gt; 3 AEs related to CGX1321 were infrequent (~6%). Dysgeusia, a common AE observed with other WNT inhibitors, was mild (mostly Grade 1). Bone resorption, the main on-target AE, was manageable and preventable by prophylactic administration of denosumab or zoledronic acid. PK and PD analyses showed adequate drug exposure and significant inhibition of WNT signaling as measured by reduced hair follicle axin2 expression from 12 mg dose. Twelve of 17 pts (71%) with confirmed tumor genetic alterations in RSPO or RNF43 had SD with median time to progression of 112 days (range: 56 – 392). Of the 6 pts in the roll-over cohort, 3 pts with RSPO3 fusion tumors achieved PR during CGX1321 + pembro combination therapy. Conclusions: CGX1321 has demonstrated potent inhibition of the WNT pathway with manageable side effects. Promising efficacy signals have been observed in pts whose tumors harbor RSPO fusion, supporting further development of CGX1321 monotherapy and CGX1321 + anti-PD-1/L1 in a defined patient population that is historically known to be refractory to standard therapies and immune checkpoint inhibitors. Clinical trial information: NCT02675946 , NCT03507998 .

Correlation between Bone Mineral Density and Progression of Hip Osteoarthritis in Adult Men and Women in Bulgaria—Results from a 7-Year Study

Changes in clinical presentation, radiographic progression (RP), bone mineral density (BMD), bone turnover (BT), and cartilage turnover (CT) markers were compared in two groups of patients with hip osteoarthritis (HOA) over a period of 7 years. Each group consisted of 150 patients, including a control group on standard-of-care therapy (SC) with simple analgesics and physical exercises, and a study group (SG) on standard-of-care therapy supplemented by vitamin D3 and intravenous administration of zoledronic acid (5 mg) yearly for 3 consecutive years. Patient groups were homogenized regarding the following: (1) radiographic grade (RG), including 75 patients with hip OA RG II according to the Kellgren-Lawrence grading system (K/L), and 75 with RG III on K/L; (2) radiographic model (RM), as each of the K/L grades was subdivided into three subgroups consisting of 25 patients of different RMs: atrophic ('A'), intermediate ('I'), and hypertrophic ('H'); (3) gender-equal ratio of men and women in each subgroup (Female/Male = 15/10). The following parameters were assessed: (1) clinical parameters (CP), pain at walking (WP-VAS 100 mm), functional ability (WOMAC-C), and time to total hip replacement (tTHR); (2) radiographic indicators(RI)-joint space width (JSW) and speed of joint space narrowing (JSN), changes in BMD (DXA), including proximal femur (PF-BMD), lumbar spine (LS-BMD), and total body (TB-BMD); (3) laboratory parameters (LP)-vitamin D3 levels and levels of BT/CT markers. RV were assessed every 12 months, whereas CV/LV were assessed every 6 months. Results: Cross-sectional analysis (CsA) at baseline showed statistically significant differences (SSD) at p < 0.05 in CP (WP, WOMAC-C); BMD of all sites and levels of CT/BT markers between the 'A' and 'H' RM groups in all patients. Longitudinal analysis (LtA) showed SSD (p < 0.05) between CG and SG in all CP (WP, WOMAC-C, tTHR) parameters of RP (mJSW, JSN), BMD of all sites, and levels of CT/BT markers for all 'A' models and in 30% of 'I'-RMs (those with elevated markers for BT/CT at baseline and during the observation period). Conclusion: The presence of SSD at baseline ('A' vs. 'H') supported the thesis that at least two different subgroups of HOA exist: one associated with 'A' and the other with 'H' models. D3 supplementation and the intravenous administration of bisphosphonate were the treatment strategies that slowed down RP and postponed tTHR by over 12 months in the 'A' and 'I' RM with elevated BT/CT markers.

Zoledronic Acid Does Not Retard Bone Union: A Randomized Controlled Trial in Fragility Intertrochanteric Femur Fractures.

Fragility hip fracture is a leading cause of death in the elderly and is common in postmenopausal women and elderly people. In the treatment of osteoporosis, bisphosphonates (BPs) are often considered first-line medications.Zoledronic acid is the most potent and long-acting BP in clinical use and is administered as an intravenous infusion. In the context of acute fractures, the use of BPs has been controversial due to conflicting reports of their positive and negative effects on fracture healing. The purpose of this study was to determine the effect of zoledronic acid on fracture healing in intertrochanteric (IT) fragility fractures. The study was conducted in a tertiary healthcare center after receiving scientific and ethical approval. The study included 136 patients of either gender over the age of 50 who presented with an IT femur fracture after minor trauma between November 2020 and November 2022. The total number of patients had been classified into two groups, and grouping involved random sampling: Group T (test group, n = 68; zoledronic acid injections were given on postoperative day 3) and Group C (control group, n = 68; interventions were given after fracture healing). Patients were evaluated using the Radiographic Union Score for Hip (RUSH) and SinghIndex for radiological outcomes and the Harris Hip Score (HHS) for functional outcomes. The patients were followed for six months. The overall mean age was 73.25 years; in Group T, it was 72.5± 11.9 years, and in Group C, it was 73.7± 11.8 years. Of 136 patients, 69 (51%) were males and 67 (49%) were females. The average fracture healing time in Group T was 12.2 ± 3.6 weeks, while it was 13.0 ± 2.8 weeks in Group C. Functional outcomes, including HHS, were found to be better in Group T than in Group C (p < 0.005). No significant difference was observed between the two groups with respect to the radiological union, the RUSHscore, or Singh Index, implying no negative effect of zoledronic acid. This study demonstrates that postoperative intravenous zoledronic acid therapy does not retard fracture healing. Osteoporosis management is frequently neglected because of a surgeon's fear of ZOL retarding fracture healing and a lack of awareness among patients, resulting in low compliance.Thus, opportunistic administration of zoledronic acid postoperatively can be beneficial and will increase compliance for osteoporosis management and fracture prevention to 100%.

Zoledronic acid targets chemo-resistant polyploid giant cancer cells

Although polyploid giant cancer cells (PGCCs) are known as a key source of failure of current therapies, sufficient drugs to target these cells are not yet introduced. Considering the similarities of polyploid cells in regeneration and cancer, we hypothesized that zoledronic acid (ZA), an osteoclast-targeting agent, might be used to eliminate PGCCs. The 5637-bladder cancer cell line was treated with various doses of cisplatin to enrich polyploid cells and the efficacy of different concentrations of ZA in reducing this population was assessed. The metabolic profile of PGCCs was investigated with gas chromatography-mass spectrometry. Lipid profiles, mitochondrial density, and ROS content were also measured to assess the response of the cells to ZA. Cancer cells surviving after three days of exposure with 6 μM cisplatin were mainly polyploid. These cells demonstrated special morphological features such as fusion with diploid or other polyploid cells and originated in daughter cells through budding. ZA could substantially eradicate PGCCs with the maximal effect observed with 50 μM which resulted in the drop of PGCC fraction from 60 ± 7.5 to 19 ± 1.7%. Enriched PGCCs after cisplatin-treatment demonstrated a drastic metabolic shift compared to untreated cancer cells with an augmentation of lipids. Further assays confirmed the high content of lipid droplets and cholesterol in these cells which were reduced after ZA administration. Additionally, the mitochondrial density and ROS increased in PGCCs both of which declined in response to ZA. Taken together, we propose that ZA is a potent inhibitor of PGCCs which alters the metabolism of PGCCs. Although this drug has been successfully exploited as adjuvant therapy for some malignancies, the current evidence on its effects on PGCCs justifies further trials to assess its potency for improving the success of current therapies for tackling tumor resistance and relapse.

Parathyroid carcinoma with pancreatitis causing hypercalcaemic emergency treated with extracorporeal membrane oxygenation-assisted parathyroid resection.

Emergencies due to malignancies usually have a severe clinical course and require urgent treatment. These scenarios are dubbed 'oncologic emergencies'. Parathyroid tumours often cause hypercalcaemia but not oncologic emergencies. We present a case of parathyroid carcinoma with severe hypercalcaemia and pancreatitis, resolved by surgical resection of the tumour assisted by extracorporeal membrane oxygenation (ECMO). A 66-year-old woman presented to our hospital because of haematuria. Laboratory findings were as follows: white blood cell count: 30 000, C-reactive protein: 17.7, calcium: 21.9, creatine kinase: 316, creatine kinase-myoglobin binding: 20, troponin I: 1415.8, amylase: 1046, lipase: 499, blood urea nitrogen: 57, and creatinine: 2.42. ECG was unremarkable. CT revealed a 4-cm low-density irregular tumour in the left lobe of the thyroid gland and severe pancreatitis. We diagnosed hypercalcaemia and pancreatitis due to parathyroid carcinoma. Volume expansion with isotonic saline was started immediately. Calcitonin, followed by denosumab, calcimimetic agents, and continuous hemodiafiltration were administered. The patient's general condition worsened due to uncontrolled hypercalcaemia. Urgent tumour resection was planned, assisted with ECMO for cardiopulmonary support and surgical field venous pressure reduction. Tumour histology was suggestive of parathyroid carcinoma. Hypercalcaemia and the patient's general condition improved gradually postoperatively. Hypercalcaemia is one of the oncologic emergency symptoms, commonly occurring because of lytic bone metastasis. However, reports about parathyroid carcinoma-causing life-threatening hypercalcaemia and pancreatitis are scarce; the fatality of this condition is estimated to be 30-70%. We report a case of survival of hypercalcaemia of malignancy. Parathyroid carcinoma is relatively rare and sometimes causes emergent conditions such as hypercalcaemia and severe pancreatitis. General therapy for hypercalcaemia including aggressive saline dehydration, administration of furosemide, calcitonin, zoledronic acid, and evocalcet, and dialysis is sometimes ineffective for parathyroid carcinoma. Therefore, careful planning of therapy in case of exacerbation is important. During an emergency, rapid surgical treatment despite high calcium level is the best potential therapeutic strategy.

Zoledronic acid sequential to teriparatide may promote greater inhibition of bone resorption than zoledronic acid alone.

Teriparatide (TPTD) should be followed by an antiresorptive to maximize bone mineral density gain and anti-fracture protection. Infrequent zoledronic acid (ZOL) administration has demonstrated effectiveness. The duration of ZOL effect following TPTD is unknown. To evaluate the effect of ZOL on bone resorption marker in a post-TPTD versus ZOL-alone scenario in osteoporotic patients. Retrospective cohort study. Patients treated with TPTD followed by ZOL (TPTD-ZOL) or with a single ZOL infusion were identified in the database of a tertiary referral center. Clinical and laboratory data, including C-terminal telopeptide of type I collagen (CTX) following ZOL treatment, were compared. Twenty-six patients (93% women) treated with TPTD-ZOL and 41 with ZOL were comparable in age (median 70.1 versus 69.6 years, p = 0.6) and sex. Timing of CTX measurement post-ZOL was the same, median 1.0 year. CTX was lower following TPTD-ZOL (median 142.1 versus 184.2 pg/mL, p = 0.005). In a multivariable regression model (controlled for baseline characteristics), pretreatment with TPTD strongly predicted CTX <150 pg/mL, 1 year following ZOL (odds ratio = 7.5, 95% CI 1.3-58.1, p = 0.03). In a subgroup with sequential CTX measurements following one ZOL, significantly lower levels persisted in the TPTD-ZOL group for a median of 4.4 years follow-up. ZOL-administered sequential to TPTD yielded deeper and more prolonged bone resorption suppression than ZOL alone. Prospective data are needed to confirm whether in a sequential treatment scenario, subsequent ZOL dosing interval should be less frequent.

Clinical Outcomes of Switching from Zoledronic Acid to Denosumab for the Management of Severe Bone Metastasis from Hepatocellular Carcinoma: A Single-Center, Open-Label, Prospective Intervention Trial.

Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma. This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration. Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol · Cre (P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L (P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch. Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited.

Lessons learned from long-term side effects after zoledronic acid infusion following denosumab treatment: a case report and review of the literature

BackgroundZoledronic acid is an intravenous, highly potent aminobisphosphonate for use in patients with primary or secondary osteoporosis. Zoledronic acid-induced prolonged side-effects are well known and quite common. However, severe side-effects can be a threat to life. We report a case of severe side-effects induced by zoledronic acid infusion, and its positive effect on long-term back pain.Case presentationIn 2012, a 62-year-old white native Finnish woman was operated on for an estrogen and progesterone receptor-positive breast cancer. After radiotherapy, an aromatase inhibitor (letrozole) was started. Nine months after the operation, the patient suffered a low-energy compression fracture of Th XII. She received denosumab to prevent fragility fractures and to improve bone mineral density. Letrozole was discontinued after 5.5 years, and the last denosumab injection was given after 7 years. Six months later, at the age of 71 years, the patient received a single intravenous zoledronic acid infusion. Suddenly, at 10 hours from the infusion, she complained of severe trismus, muscle twitching, spasms, and tingling, matching hypocalcemia and several other symptoms. Her serum 25-hydroxyvitamin D concentration was high (163 nmol/L), the concentration of serum calcium and calcium-ion was normal (2.32 mmol/L and 1.23 mmol/L, respectively). However, the neutrophil to lymphocyte ratio (NLR) was low (1.6). A complete recovery took 2 months. Zoledronic acid infusion also had a positive effect: for many years, the patient had suffered low back pain and strain, which came to an end after this single infusion.ConclusionIt is important that the potential patients receive sufficient information about the possibility of side-effects following the administration of intravenous zoledronic acid. To ensure that a zoledronic acid infusion is given as safely as possible, the safety information should include that the patient should not be left without monitoring for a minimum 24 hours after the infusion. Being alone and experiencing serious side-effects may lead to acute cardiac problems. Furthermore, the chronic low back pain and strain that our patient suffered for many years has clearly reduced for 16 months after infusion, so far. We conclude that this is a positive effect of zoledronic acid.