Mechanism exploration of Zoledronic acid combined with PD-1 in the treatment of hepatocellular carcinoma.

How to increase the response of immune checkpoint inhibitors (ICIs) is a challenge. In clinical, we found that Zoledronic acid (ZA) may increase the anti-tumor effect of immunotherapy for hepatocellular carcinoma (HCC). To explore the underlying mechanism, we established a mouse model of HCC by subcutaneously injecting Hepa1-6 cell line. The result showed that the tumor volume in the ZA plus anti-PD-1 monocloning antibody (anti-PD-1 mAb) treatment groups was significantly smaller than that of control group, and the onset time of tumor inhibition was even shorter than that of the anti-PD-1 mAb group. Using flow cytometry (FC) to detect the proportion of major immune cell subsets in tumor tissues of each group of mice, we found that the synergistic anti-tumor effect of ZA and anti-PD-1 mAb may be related to ZA-induced polarization of macrophages toward the M1 phenotype. Next, we performed bulk RNA sequencing on tumor samples from different groups to obtain differentially expressed genes (DEGs), which were then input DEGs into pathway enrichment analysis. Data indicated that ZA participated in the M1-type polarization via ferroptosis-related pathways. Our results revealed how ZA involves in the anti-tumor effect of PD-1 monoclonal antibody and provided a potential therapeutic candidate for patients with HCC.

Mechanism of synergistic inhibitory effect of benzyl isothiocyanate and zoledronic acid combination on breast cancer induction of osteoclast differentiation.

Bone is the most favored site for metastasis for each major subtype of breast cancer. Therapeutic modalities for alleviation of clinical symptoms associated with bone metastasis include surgical resection, radiation, and bone-targeted therapies, including bisphosphonates (e.g., zoledronic acid; ZA) and a humanized antibody against receptor activator of nuclear factor-κB ligand (denosumab). However, the bone-targeted therapies are expensive, and have poor pharmacokinetic attributes and/or serious adverse effects. Therefore, novel strategies are needed for treatment of bone metastasis or to increase effectiveness of existing bone-targeted therapies. We have shown previously that benzyl isothiocyanate (BITC) is a novel inhibitor of osteoclast differentiation in vitro and bone metastasis in vivo. The present study shows that BITC + ZA combination synergistically inhibits osteoclast differentiation induced by addition of conditioned media from breast cancer cells. These effects were associated with a significant increase in levels of several antiosteoclastogenic cytokines, including interferons, interleukin (IL)-3, IL-4, and IL-27. Kyoto Encyclopedia of Genes and Genomes pathway analysis of RNA-seq data from BITC and/or ZA-treated cells revealed downregulation of genes of many pathways (e.g., actin cytoskeleton, Hippo signaling, etc.) by treatment with BITC + ZA combination, but not by BITC alone or ZA alone. Confocal microscopy confirmed severe disruption of actin cytoskeleton upon treatment of MCF-7 and MDA-MB-231 cells with the BITC + ZA combination. This combination also decreased the nuclear level of yes-associated protein, a core component of Hippo signaling. In conclusion, the present study offers a novel combination for prevention or treatment of bone metastasis of breast cancer.

Denosumab vs. bisphosphonates in primary osteoporosis: a meta-analysis of comparative safety in randomized controlled trials.

Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12-24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34-0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03-4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07-2.41), more infections (RR = 1.14; 95% CI 1.02-1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08-2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31-0.93), and less abdominal pain (RR = 0.44;95% CI 0.22-0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results.

Treatment Effect of Zoledronic Acid in Chronic Non-bacterial Osteomyelitis of the Jaw: A Case Series.

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory, osteolytic bone disorder sometimes localized to a unifocal site in the jaw, causing long-term pain and reduced function. The aim of this study was to describe the patients with CNO of the jaw, focusing on treatment with zoledronic acid for pain relief. An analysis of medical records of 24 patients with CNO of the jaw, including treatment with zoledronic acid and effects on pain relief. Descriptive statistics and nonparametric tests were used to describe the population and compare treatment effects, respectively. The average treatment period was 33.4 months (median 23; Q1 11.5; Q3 42.0) with an average of 4.1 infusions (median 3; Q1 2; Q3 5) of zoledronic acid. The average pain VAS score (visual analogue scale) was significantly reduced from 7.7 (median 8; Q1 6.5; Q3 8.5) to 2.5 points (median 2; Q1 0.5; Q3 4.5) (p < 0.001). At final visit, 46% of patients reported no pain and 38% reported a reduction of pain. At least 67% of patients had at least one episode of pain recurrence, and most patients experienced the first recurrence within a year of initial treatment. Four patients (16%) had no pain relief from the treatment. In this group of patients with CNO of the jaw, there was a positive response to treatment with zoledronic acid on pain relief, averaging 5.2 points on a pain VAS score, with 84% of patients treated experiencing either a partial or a total reduction in pain after about 2.5 years.

Effects of Combined Application of Percutaneous Vertebroplasty and Zoledronic Acid on Bone Mineral Density, Bone Metabolism, NPY and PGE2 in Elderly Patients with Osteoporotic Lumbar Vertebral Compression Fracture.

OBJECTIVE: To investigate the effects of the combined application of percutaneous vertebroplasty and zoledronic acid on bone mineral density (BMD), bone metabolism, neuropeptide Y (NPY) and prostaglandin E2 (PGE2) in elderly patients with osteoporotic lumbar vertebral compression fracture (OVCF). METHODS: The medical records of 118 elderly patients with OVCF who received treatment at our hospital from March 2018 to March 2020 were collected and analyzed retrospectively. Vertebral body height, spinal function, pain degree, and lumbar BMD were compared between the two groups upon admission and three years after the operation. Additionally, the levels of bone-specific alkaline phosphatase (BALP), 25-hydroxyvitamin D (25-(OH)D), beta collagen degradation fragments (ß-CTx), neuropeptide Y (NPY), and prostaglandin E2 (PGE2) in the two groups were measured at admission and three years after the operation. Furthermore, complications in the two groups within three years after the operation were documented. RESULTS: After three years post-operation, the combination group showed a significantly greater improvement in vertebral body height compared to the control group (P<0.05). Moreover, the combination group exhibited a significantly lower Oswestry Disability Index (ODI) score compared to the control group (P<0.05). CONCLUSION: In elderly patients with OVCF, the combined use of zoledronic acid and percutaneous vertebroplasty is effective in improving lumbar function, BMD, and bone metabolism indices, while reducing pain and the levels of NPY and PGE2.

Patient preference, efficacy, and compliance with zoledronic acid for glucocorticoid-induced osteoporosis in patients with autoimmune diseases.

PURPOSE: We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. METHODS: We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1 year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1 year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. RESULTS: Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. CONCLUSION: Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.

Dynamic changes in γδT cells and bone resorption markers after zoledronic acid in multiple myeloma: A prospective study.

We conducted a prospective evaluation for the dynamic change of γδT cells in peripheral blood (PB) and N-telopeptide of type I collagen in urine (uNTX) of patients diagnosed with multiple myeloma (MM) who underwent their initial treatment with zoledronic acid (ZOA; Zobonic®, TTY, Taiwan). Between March 2012 and November 2015, a total of 35 patients were enrolled, including 25 newly diagnosed MM (NDMM) patients. The percentage of γδT cells in PB was assessed at 20 days prior to the first ZOA infusion, then at day 8, day 64, and day 85 after the infusion. Simultaneously, uNTX levels were measured as well. Thirty-three patients who had received at least one dose of ZOA were included in subsequent analysis. We identified three dynamic change patterns for γδT cells: fluctuated pattern, continuously increasing pattern, and continuously decreasing pattern. Among NDMM patients, those exhibiting a continuously increasing pattern showed a significantly shorter overall survival compared to those with the other two patterns combined (4.7 months vs. 92.9 months, p = 0.037). For uNTX, which levels significantly decreased following ZOA treatment. In conclusion, our findings reveal three distinct dynamic change patterns for γδT cells after ZOA initiation, with continuously increasing pattern being associated with a poor prognosis. These findings prompt further inquiry into the role of γδT cells in MM patients and support the suppressive nature of γδT cells and their associated tumor microenvironment.

Combined chemotherapy of zoledronic acid and pamidronate in the treatment of bone metastases from nonsmall cell lung cancer and the effects on pain stress and bone metabolic indices.

OBJECTIVE: We conducted this paper to decipher the efficacy of the combined chemotherapy of zoledronic acid and pamidronate in treating bone metastases from nonsmall cell lung cancer (NSCLC) and the effects on pain stress and bone metabolic indices. METHODS: Patients with bone metastases from NSCLC were allocated into Group A and Group B. Patients in the Group A were administrated with pamidronate combined chemotherapy and patients in the Group B were administrated with zoledronic acid combined chemotherapy. The efficacy, pain symptom scores, quality of life scores, serum inflammatory factor, serum bone metabolic indices, serum pain stress indicators, and the occurrence of adverse effects were compared in patients of the two groups. RESULTS: The total effective rate of treatment was higher in the Group B than in the Group A. After treatment, reduced Numerical Rating Scale scores and elevated Karnofsky Performance Score score, reduced serum levels of N-terminal mid-fragment of osteocalcin, N-terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and type I collagen hydroxyl terminal peptide ß special sequence, reduced serum levels of C-reactive protein, procalcitonin, tumor necrosis factor-α, and interleukin-6, as well as decreased levels of bradykinin, substance P, neuropeptide Y, and ß-endorphin were found in the Group B versus the Group A. No notable difference was witnessed in the rate of adverse reactions between the Group A and the Group B. CONCLUSION: Zoledronic acid combined with chemotherapy can effectively treat bone metastases of NSCLC and improve pain stress and bone metabolic status, which has value that can be promoted and applied in clinical treatment.

Zoledronic acid-induced severe lymphopenia.

Although anemia, thrombocytopenia, and mild lymphopenia have been reported in the acute phase response after zoledronic acid, severe lymphopenia has not been reported. This article describes a case of severe lymphopenia following a 5 mg zoledronic acid infusion administered to treat osteoporosis. Zoledronic acid is used to treat osteoporosis, hypercalcemia, Paget's disease, and solid malignancies, including multiple myeloma, breast cancer, and prostate cancer. An acute phase response can be seen in 42% of patients after zoledronic acid treatment. Acute phase response may be accompanied by short-term spontaneously recovered anemia, thrombocytopenia, and severe lymphopenia.

Zoledronic acid after spinal cord injury mitigates losses in proximal femoral strength independent of ambulation ability.

Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI. INTRODUCTION: Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes. METHODS: Participants randomized to either zoledronic acid (n = 29) or placebo (n = 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment. RESULTS: After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (p = 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (p < 0.001) and cortical (p ≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength. CONCLUSION: These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities.

Mitigating the Denosumab-Induced Rebound Phenomenon with Alternating Short- and Long-Acting Anti-resorptive Therapy in a Young Boy with Severe OI Type VI.

Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3-5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.

Comparison of the Efficacy of Zoledronate Acid or Denosumab After Switching from Romosozumab in Japanese Postmenopausal Patients.

We aimed to compare the efficacy of switching from romosozumab (RMAb) to denosumab (DMAb) or zoledronic acid (Zol) with respect to changes in bone mineral density (BMD) and bone metabolism. We also aimed to determine predictors of changes in BMD among patients who received sequential therapy from RMAb. One hundred patients who received RMAb therapy were recruited for this study. A total 49 patients received bisphosphonate (BP) pre-treatment and 51 received active vitamin D3 analog pre-treatment or no treatment. Forty-two patients were switched to Zol (BP-RMAb-Zol; 20 and RMAb-Zol; 22), and 58 patients were switched to DMAb (BP-RMAb-DMAb; 29 and RMAb-DMAb; 29). Longitudinal changes in bone metabolic markers (P1NP and TRACP-5b) and BMD were also evaluated. In the BP-RMAb-Zol group, TRACP-5b increased after administration of Zol, and the mean BMD of the lumbar spine (LS) was significantly lower than those in the BP-RMAb-DMAb, RMAb-Zol and RMAb-DMAb groups at 24 months. The % changes in BMD of the LS after 24 months were associated with TRACP-5b values at baseline and at 12 months in patients who received Zol therapy, and with TRACP-5b value at baseline in patients who received DMAb therapy. The DMAb follow-on regimen could be considered more effective than Zol as a sequential agent for the enhancement of BMD after RMAb in patients with BP pretreatment. TRACP-5b, especially the baseline value, may predict the efficacy of sequential therapy from RMAb, as well as previous treatments.

Bone Microarchitecture and Strength Changes During Teriparatide and Zoledronic Acid Treatment in a Patient with Pregnancy and Lactation-Associated Osteoporosis with Multiple Vertebral Fractures.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis, of which the pathogenesis and best treatment options are unclear. In this report, we describe the case of a 34-year old woman diagnosed with severe osteoporosis and multiple vertebral fractures after her first pregnancy, who was subsequently treated with teriparatide (TPTD) and zoledronic acid (ZA). We describe the clinical features, imaging examination, and genetic analysis. Substantial improvements were observed in areal and volumetric bone mineral density (BMD), microarchitecture, and strength between 7 and 40 months postpartum as assessed by dual-energy X-ray absorptiometry at the total hip and spine and by high-resolution peripheral quantitative CT at the distal radius and tibiae. At the hip, spine, and distal radius, these improvements were mainly enabled by treatment with TPTD and ZA, while at the distal tibiae, physiological recovery and postpartum physiotherapy due to leg pain after stumbling may have played a major role. Additionally, the findings show that, despite the improvements, BMD, microarchitecture, and strength remained severely impaired in comparison with healthy age- and gender-matched controls at 40 months postpartum. Genetic analysis showed no monogenic cause for osteoporosis, and it is suggested that PLO in this woman could have a polygenic origin with possible susceptibility based on familiar occurrence of osteoporosis.

Effect of oral zoledronate administration on bone turnover in older women.

AIM: The aim of this work is to assess the safety and efficacy of two oral zoledronate preparations by determining their effects on bone resorption in healthy postmenopausal women. METHODS: The preparations studied were zoledronic acid in enteric-coated capsules or a microparticle preparation of zoledronic acid in these capsules. Bone resorption was measured as ß-C-telopeptideof type I collagen (CTX) in fasting serum. Separate cohorts, each of five women, were recruited and allocated in sequence to single doses of 20 mg, 40 mg, or 60 mg of oral zoledronate. RESULTS: Zoledronate 20 mg enteric capsules were well tolerated, reduced serum CTX by a median 51% at 1 week, but by only 17% at 1 month. Doses of 40 or 60 mg of this preparation produced APR and/or gastrointestinal symptoms in more than half of participants. With these doses, median CTX reduction at 1 week was >80%, ~70% at 1 month, but only ~30% at 6 months. Enteric capsules containing microparticles of zoledronate 20 mg reduced CTX by a median 53% at 1 week, with offset over 3 months. Two or three of these capsules dosed weekly reduced CTX by ~50% at 1 month, and by ~30% at 3 and 6 months. CONCLUSIONS: Oral zoledronate 20 mg circumvents the problem of APR symptoms but, even with multiple doses, the anti-resorptive effect is smaller and less sustained than with intravenous zoledronate. Probably a viable oral regimen of zoledronate dosing at intervals of weeks to months could be developed, but the advantage of infrequent dosing would be lost.

Safety and effectiveness of once-yearly zoledronic acid in Japanese osteoporosis patients: three-year post-marketing surveillance.

INTRODUCTION: Zoledronic acid (5 mg; ZOL), a once-yearly bisphosphonate, reduces osteoporotic fractures and increases bone mineral density (BMD). This 3-year post-marketing surveillance examined its real-world safety and effectiveness. MATERIALS AND METHODS: This prospective, observational study included patients who started ZOL for osteoporosis. Data were assessed at baseline, 12, 24, and 36 months for safety and effectiveness. Treatment persistence, potentially related factors, and persistence before and after the COVID-19 pandemic started were also investigated. RESULTS: The safety analysis and effectiveness analysis sets included 1406 and 1387 patients, respectively, with mean age of 76.5 years. Adverse reactions (ARs) occurred in 19.35% of patients, with an acute-phase reaction in 10.31, 1.01, and 0.55% after the first, second, and third ZOL infusions. Renal function-related ARs, hypocalcaemia, jaw osteonecrosis, and atypical femoral fracture occurred in 1.71, 0.43, 0.43, and 0.07% of patients, respectively. Three-year cumulative fracture incidences were 4.44% for vertebral, 5.64% for non-vertebral, and 9.56% for clinical fractures. BMD increased by 6.79, 3.14, and 1.78% at the lumbar spine, femoral neck, and total hip, respectively, after 3-year treatment. Bone turnover markers remained within reference ranges. Treatment persistence was 70.34% over 2 years and 51.71% over 3 years. Male, age ≥ 75 years, no previous medicines for osteoporosis, no concomitant medicines for osteoporosis, and inpatient at the first infusion were related to discontinuation. There was no significant difference in the persistence rate between before and after the COVID-19 pandemic (74.7% vs. 69.9%; p = 0.141). CONCLUSION: This 3-year post-marketing surveillance confirmed the real-world safety and effectiveness of ZOL.

Differences between zoledronic acid and denosumab for breast cancer treatment.

Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects include the prevention of osteoporosis induced by cancer-treatment bone loss, treatment and prevention of bone metastasis, and improvement of survival directly or indirectly by maintaining bone health. Interestingly, zoledronic acid and denosumab have different anticancer activities, and they may be associated with the improvement of survival of breast cancer patients under different mechanisms. Zoledronic acid is the most potent bisphosphonate. It provides significant benefits for improving breast cancer mortality in patients with suppressed estrogen level such as in postmenopausal or ovarian suppression condition. Although denosumab's anticancer activity has not been clearly proven compared with zoledronic acid's anticancer activity, denosumab is promising in preventing BRCA1 mutant breast cancer because RANKL is a targetable pathway in BRCA1-associated tumorigenesis. Further studies and more effective clinical use of these agents are anticipated to contribute to the improvement of the clinical outcome of breast cancer patients.

Resveratrol for preventing medication-related osteonecrosis of the jaws in rats.

This study evaluated the effect of resveratrol (RES) on the prevention of medication-related osteonecrosis of the jaws (MRONJ) in ovariectomized (OVX) rats treated with zoledronate (ZOL). Fifty rats were distributed in five groups: SHAM (n = 10): non-ovariectomy + placebo; OVX (n = 10):ovariectomy + placebo; OVX + RES (n = 10):ovariectomy + resveratrol; OVX + ZOL (n = 10):ovariectomy + placebo + zoledronate; and OVX + RES + ZOL (n = 10):ovariectomy + resveratrol + zoledronate. The mandibles left sides were analyzed with micro-CT, histomorphometry, and immunohistochemistry. On the right side, bone markers gene expression was analyzed by qPCR. ZOL increased the percentage of necrotic bone and reduced the neo-formed bone compared to groups not receiving ZOL (p < 0.05). RES impacted the tissue healing pattern in OVX + ZOL + RES, reduced inflammatory cell infiltrate, and improved bone formation in the extraction site. Osteoblasts, alkaline phosphatase (ALP)-, and osteocalcin (OCN)-immunoreactive cells were lower in OVX-ZOL than in SHAM, OVX, and OVX-RES. The OXV-ZOL-RES had fewer osteoblasts and ALP- and OCN-cells than the SHAM and OVX-RES. The tartrate-resistant acid phosphatase (TRAP)-positive cells were reduced in the presence of ZOL (p < 0.05), while the TRAP mRNA levels increased with ZOL treatment, with or without resveratrol, compared with the other groups (p < 0.05). RES alone increased superoxide dismutase levels compared to OVX + ZOL and OVX + ZOL + RES (p < 0.05). In conclusion, resveratrol reduced the tissue impairment severity induced by ZOL; however, it could not prevent the occurrence of MRONJ.

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

BACKGROUND: In 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. METHODS: In 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. RESULTS: Eighteen 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). CONCLUSIONS: We 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 REGISTRATION: This study was registered in IRCT (ID: IRCT20181202041821N1) on 04-05-2019.

Evaluation of denosumab in adult oncology patients for the prevention of skeletal related events across a large academic health system.

INTRODUCTION: Denosumab (Xgeva®) and zoledronic acid (Zometa®) are widely utilized for prevention of skeletal related events (SREs) in oncology patients. Drug costs, renal function, ease and logistics of administration, and adverse effect profile are factors frequently considered by patients and/or providers when selecting an optimal agent. Given the significantly higher drug cost of denosumab compared to zoledronic acid, an evaluation of our institution's denosumab use and investigation into opportunities to shift denosumab administrations to zoledronic acid and/or to lower cost sites-of-care was warranted. METHODS: A single-center, multi-site, retrospective, observational analysis of the electronic medical record (EMR) was conducted for adult oncology patients who received denosumab 120 mg for prevention of SREs from October 1st, 2018 to September 30th, 2019 at three institutions within our health system. Additional information was collected to characterize the patient population based on cancer diagnosis, renal function, and concomitant calcium and vitamin D supplementation. Our primary objective was to evaluate if the use of denosumab met current formulary restrictions of the health system. RESULTS: In total, 304 adult oncology patients received 1411 doses of denosumab for the prevention of SREs. The majority of reviewed patients had a primary oncology diagnosis of breast (35%) or lung (24%) cancer. Of the patients who received denosumab, 278 (93%) met the health system's current formulary restrictions. The majority of patients who did not meet formulary restrictions were those with multiple myeloma (MM) (20/22; 91%). Of the 304 patients reviewed, 70 had the appropriate parameters in the EMR to calculate creatinine clearance (CrCl) using Cockcroft-Gault Equation. Of those 70 patients, 59 (84%) would have been eligible to receive zoledronic acid instead of denosumab given that their CrCl >30 mL/min with no documented intolerance to bisphosphonates. Concurrent use of calcium and vitamin D is recommended when using denosumab. Based on the most recent prior to admission (PTA) medication list obtained from the 304 patients evaluated, 222 (73%) had both calcium and vitamin D listed as "taking". CONCLUSIONS: Within our health system, denosumab is restricted to those who meet formulary restrictions. Additional education is recommended to help limit the use of denosumab, specifically in MM, to reduce drug costs when zoledronic acid is also an appropriate first-line agent.

Adjuvant zoledronic acid therapy for postmenopausal women with early breast cancer in China: a cost-effectiveness analysis.

Combination therapy of zoledronic acid (ZOL) plus aromatase inhibitor (AI) was found to reduce bone metastasis risk and improve overall survival for treatment-naïve postmenopausal women (PMW) with hormone receptor-positive (HR+) early breast cancer (EBC), when compared with AI alone. The objective of this study was to evaluate the cost-effectiveness of adding ZOL to AI in treating PMW with HR+ EBC in China. A 5-state Markov model was constructed to evaluate the cost-effectiveness of adding ZOL to AI for PMW-EBC (HR+) over a lifetime horizon from the perspective of Chinese healthcare provider. Data used were obtained from previous reports and public data. The primary outcomes of this study were direct medical cost, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed to examine the robustness of the presented model. Over a lifetime horizon, adding ZOL to AI was projected to yield a gain of 1.286 LYs and 1.099 QALYs compared with AI monotherapy, which yielded ICER $11 140.75 per QALY with an incremental cost of $12 247.36. The one-way sensitivity analysis indicated that the cost of ZOL was the most influential factor in our study. The probability that adding ZOL to AI was cost-effective at a threshold of $30 425 per QALY in China was 91.1%. ZOL is likely to be cost-effective in reducing bone metastasis risk and improving overall survival for PMW-EBC (HR+) in China.