Zoledronic Acid Treatment Research Articles

Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries.

This observational safety study used national registers to compare the real world cardiovascular and skeletal safety of zoledronic acid (ZA) against oral bisphosphonates (oBP) and untreated population controls. Propensity score matched cohort study in Sweden and Denmark. Matched cohort 1 included 8739 ZA users and 25,577 oBP users while matched cohort 2 included 8731 ZA users and 25,924 untreated subjects. In comparison to oBP users, heart failure risk was higher in ZA users, with an adjusted HR (adj) (95%CI) of 1.17 (1.04;1.32) and a higher all-cause mortality (adj HR 1.24 (1.15; 1.34)), however, there was no increased risk of cardiovascular mortality. In the comparison to untreated subjects, ZA users showed a higher risk of atrial fibrillation, adj HR 1.18 (1.05;1.32), arrhythmias adj HR 1.18 (1.06;1.31), and heart failure, adj HR 1.38 (1.24;1.54). Cardiovascular mortality was lower in ZA users (adj HR 0.87 (0.77; 0.98)) and risk of adverse skeletal outcomes was significantly higher, reflecting more severe osteoporosis in these patients. There was no association of cardiovascular risk with increasing exposure time. Sensitivity analyses produced similar findings with no substantial changes in event rates. We noted an increased risk of heart failure, fractures and death among ZA users compared with oral BP. The risk of cardiovascular and skeletal outcomes was higher in ZA users than in matched population controls, but there was no increase in cardiovascular mortality in ZA users compared to oral BP or untreated controls. Despite propensity score matching, it is not possible to determine with certainty whether the increased risk of cardiovascular outcomes is consistent with a true drug effect or higher baseline risk in patients who begin ZA treatment.

Osteoporosis Treatments Affect Bone Matrix Maturation in a Rat Model of Induced Cortical Remodeling.

ABSTRACTTo test how osteoporosis drugs affect bone matrix maturation during cortical bone remodeling, 72 pregnant rats were switched from a 0.4% to a 0.01% calcium diet at parturition for a 23‐day lactation period. At weaning, eight dams were sacrificed to establish baseline values, while the remaining dams were returned to 0.4% calcium and treated with vehicle (saline), sodium fluoride (NaF), zoledronic acid (ZA), or sclerostin antibody (Scl‐Ab) for either 7 or 28 days (eight animals per group per time point). Femora were examined by μCT, dynamic histomorphometry, Fourier transform infrared imaging, and three‐point bending of notched specimens. Cortical porosity decreased in all groups from baseline to day 28. Intracortical mineralizing surface (MS/BS) and mineral apposition rate (MAR), as well as the mineral‐to‐matrix ratio were unaffected by treatment, but intracortical crystallinity was increased in the ZA group at day 10 compared with vehicle. Cortical area increased in all groups over 28 days mainly because of an addition of bone at the endocortical surface. Endocortical MS/BS did not vary among the groups, but endocortical MAR was suppressed in the NaF group at day 2 and elevated in the Scl‐Ab group at day 4 compared with vehicle. Endocortical mineral‐to‐matrix ratio was increased at days 5 and 10 following NaF treatment and endocortical crystallinity was increased at day 5 following ZA treatment compared with vehicle. Fracture toughness did not differ among the groups. Thus, the treatments affected matrix maturation more strongly at the endocortical then intracortical envelope. In this model of induced remodeling, the bone formation phase is synchronized at multiple sites, facilitating study of the effects of drugs or other bone‐targeting agents on matrix maturation independent of their effects on the initiation of remodeling. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Zoledronic acid accelerates osteogenesis of bone marrow mesenchymal stem cells by attenuating oxidative stress via the SIRT3/SOD2 pathway and thus alleviates osteoporosis.

The aim of this study was to clarify the potential effect of zoledronic acid on alleviating oxidative stress and promoting bone marrow mesenchymal stem cells (BMSCs) osteogenesis through the SIRT3/SOD2 pathway, thus alleviating the progression of osteoporosis. Relative expression levels of osteogenesis-related genes (ALP, RUNX2, and Bglap) were determined. Meanwhile, ALP activity and capacity of mineralization in BMSCs treated with different doses of zoledronic acid were measured. Subsequently, viability and ROS level in H2O2-induced BMSCs influenced by zoledronic acid treatment were assessed. The regulatory effect of zoledronic acid on the SIRT3/SOD2 pathway was detected by Western blot. Furthermore, the involvement of the SIRT3/SOD2 pathway in zoledronic acid-mediated BMSCs osteogenesis was evaluated. Zoledronic acid treatment significantly up-regulated the levels of ALP, RUNX2, and Bglap. Meanwhile, it improved ALP activity and capacity of mineralization in BMSCs dose-dependently. H2O2 induction markedly suppressed viability and enhanced ROS level in BMSCs, which were reversed by zoledronic acid treatment. Besides, zoledronic acid protected H2O2-induced SIRT3 down-regulation and AC-SOD2/SOD2 up-regulation in BMSCs. In addition, silence of SIRT3 reversed the protective effects of zoledronic acid on osteogenesis of BMSCs. Zoledronic acid alleviates the progression of osteoporosis. Meanwhile, it accelerates BMSCs osteogenesis by inhibiting oxidative stress via the SIRT3/SOD2 pathway.

Next Generation Lipophilic Bisphosphonate Shows Antitumor Effect in Colorectal Cancer In Vitro and In Vivo.

Bisphosphonates, despite proven antitumor effect in vitro in many tumor types, are currently used only for treatment of osteoporosis and bone metastasis. Colorectal cancer is the third most commonly diagnosed type of cancer and lacks targeted therapy for RAS or RAF mutation carrying cases. A new lipophilic bisphosphonate showed promising results in lung cancer models, but their effect on colorectal cancer cells was not investigated excessively. Antitumor effects and impact on RAS-related signalization of zoledronic acid (ZA) and a lipophilic bisphosphonate (BPH1222) were investigated on 7 human colorectal cancer cell lines in vitro and in vivo. Furthermore, mutant KRAS dependent effect of prenylation inhibition was investigated using isogeneic cell lines. Both bisphosphonates reduced cell viability in vitro in a dose-dependent manner. Both compounds changed cell cycle distribution similarly by increasing the proportion of cells either in the S or in the subG1 phase or both. However, BPH1222 exerted higher inhibitory effect on spheroid growth than ZA. Interestingly, we found profound alterations in phosphorylation level of Erk and S6 proteins upon ZA or BPH1222 treatment. Furthermore, investigation of a mutant KRAS isogeneic model system suggests that the drugs interfere also with the mutant KRAS proteins. In vivo experiments with KRAS mutant xenograft model also revealed growth inhibitory potential of bisphosphonate treatment. Our results show that lipophilic bisphosphonates might extend the therapeutic spectrum of bisphosphonate drugs and could be considered as additional treatment approaches in colorectal cancer.

WITHDRAWN

The document associated with this DOI has been withdrawn.

Zoledronic Acid Inhibits the RhoA-mediated Amoeboid Motility of Prostate Cancer Cells.

The bisphosphonate Zoledronic acid (ZA) is a potent osteoclast inhibitor currently used in the clinic to reduce osteoporosis and cancer-induced osteolysis. Moreover, ZA exerts an anti-tumor effect in several tumors. Despite this evidence, the relevance of ZA in prostate cancer (PCa) is not completely understood. To investigate the effect of ZA administration on the invasive properties of PC3 cells, which are characterised by RhoA-dependent amoeboid motility. The effect of ZA administration on the in vitro invasive properties of PC3 cells was evaluated by cell migration in 3D collagen matrices, immunofluorescence and Boyden assays or transendothelial migration. Lung retention and colonization assays were performed to assess the efficacy of ZA administration in vivo. PC3 cells are characterised by RhoA-dependent amoeboid motility. We now report a clear inhibition of in vitro PC3 cell invasion and RhoA activity upon ZA treatment. Moreover, to confirm a specific role of ZA in the inhibition of amoeboid motility of PC3 cells, we demonstrate that ZA interferes only partially with PC3 cells showing a mesenchymal phenotype due to both treatment with conditioned medium of cancer associated fibroblasts or to the acquisition of chemoresistance. Furthermore, we demonstrate that ZA impairs adhesion to endothelial cells and the trans-endothelial cell migration, two essential properties characterising amoeboid motility and PC3 metastatic dissemination. In vivo experiments prove the ability of ZA to inhibit the metastatic process of PC3 cells as shown by the decrease in lung colonization. This study demonstrates that ZA inhibits Rho-dependent amoeboid motility of PC3 cells, thus suggesting ZA as a potential therapy to impede the metastatic dissemination of PC3 cells.

Skeletal Site-Specific Response of Jawbones and Long Bones to Surgical Interventions in Rats Treated with Zoledronic Acid.

Bisphosphonates (BPs) have been extensively used for management of bone diseases with pathologically high resorption. Despite the great clinical benefits, a severe complication known as medication-related osteonecrosis of the jaw (MRONJ) has been reported. It is found that most of the reported MRONJ cases were limited in the jawbones/craniofacial bones instead of long bones. The present study aims to investigate the differential bone response to surgical procedures between jawbones and long bones exposed to BPs. Forty-eight skeletal mature Sprague Dawley female rats were administered oncologic dose of zoledronic acid (ZA) or normal saline for 4 weeks and then subjected to tooth extraction on the mandible and maxilla, and a bone defect creation on the femur. After surgical procedures, ZA or saline treatment were continued until sacrifice at week 2, week 4, and week 8, post-operatively. The samples were subjected to micro-computerized tomography (micro-CT) and histological assessment. Osteonecrosis was only found in jawbones in ZA-treated rats. ZA-treated rats showed significantly higher bone mineral density with greater bone volume in all surgical sites than that in the controls. The length of exposure of ZA did not seem to affect trabecular microstructure, and it only showed higher bone volume and BMD with longer healing time which is expected in the healing process.

Efficacy of zoledronic acid in older prostate cancer patients undergoing androgen deprivation therapy

ObjectivesThe purpose of this study is to evaluate the efficacy of annual zoledronic acid treatment in Japanese patients with nonmetastatic prostate cancer during androgen deprivation therapy (ADT). MethodsThis is a single institution 12-month study. Between 2016 and 2019, patients aged 70 years or older on ADT for nonmetastatic prostate cancer had bone mineral density (BMD) measured and 10-year probability of fracture calculated using fracture risk assessment tool (FRAX). Patients who showed osteopenia or had a 10-year hip fracture risk ≥ 3% or a 10-year probability of major osteoporotic fracture ≥ 20% were offered treatment with zoledronic acid 5 mg intravenously (ZA group). The patients who did not receive treatment were set as the control group. Lumbar and hip BMD were measured 6 and 12 months after treatment in the ZA group and 12 months after baseline in the control group. The yearly BMD change of both groups was compared. ResultsThe mean ages of the ZA group (n = 26) and control group (n = 12) were 80.5 ± 9.1 and 76.1 ± 6.7 years, respectively. In the ZA group, lumbar and hip BMD changes at 12 months were +2.1% and +0.8%, respectively. In the control group, lumbar and hip BMD changes were −0.9% and −4.9%, respectively. There were statistically significant differences between the 2 groups in BMD percent changes (P < 0.05). ConclusionsWithout intervention, BMD tends to continue to decrease during ADT. Our findings suggest that administration of zoledronic acid enables maintenance of BMD in the older adults.

Contribution of Inflammation and Bone Destruction to Pain in Arthritis: A Study in Murine Glucose-6-Phosphate Isomerase-Induced Arthritis.

Arthritis is often characterized by inflammation and bone destruction. This study was undertaken to investigate the contribution of inflammation and bone destruction to pain. Inflammation, bone resorption, pain-related behaviors, and molecular markers (activating transcription factor 3 [ATF-3], p-CREB, and transient receptor potential vanilloid channel 1) in sensory neurons were measured in murine glucose-6-phosphate isomerase (G6PI)-induced arthritis, a model of rheumatoid arthritis. Depletion of Treg cells before immunization changed self-limiting arthritis into nonremitting arthritis with pronounced bone destruction. Zoledronic acid (ZA) was administered to reduce bone resorption. Compared to nondepleted mice, Treg cell-depleted mice exhibited arthritis with more severe bone destruction and higher guarding scores (P < 0.05; n = 10 mice per group) as well as more persistent thermal hyperalgesia (P < 0.05), but displayed similar mechanical hyperalgesia at the hindpaws (n = 18-26 mice per group). These pain-related behaviors, as well as an up-regulation of the neuronal injury marker ATF-3 in sensory neurons (studied in 39 mice), appeared before the clinical score (inflammation) became positive and persisted in Treg cell-depleted and nondepleted mice. In the late stage of arthritis, Treg cell-depleted mice treated with ZA showed less bone resorption (<50%; P < 0.01) and less thermal hyperalgesia (P < 0.01) than Treg cell-depleted mice without ZA treatment (n = 15 mice per group), but ZA treatment did not reduce the clinical score and local mechanical hyperalgesia. Pain-related behaviors precede and outlast self-limiting arthritis. In nonremitting arthritis with enhanced bone destruction, mainly local thermal, but not local mechanical, hyperalgesia was aggravated. The up-regulation of ATF-3 indicates an early and persisting affection of sensory neurons by G6PI-induced arthritis.

Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review

BackgroundWhile denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy.MethodsTo analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions.ResultsThe study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF.ConclusionsWe found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Risk factors for developing osteonecrosis of jaw in advanced cancer patients underwent zoledronic acid treatment.

Aim: To investigate the risk factors for developing osteonecrosis of jaw (ONJ) in advanced cancer patients with bone metastases underwent zoledronic acid (ZA) treatment. Materials & methods: Univariate and multivariate logistic regression analyses were performed to investigate factors associated with developing ONJ in advanced cancer patients. Results: A total of 2214 advanced cancer patients were included. Univariate and multivariate logistic regression analyses for risk factors associated with ONJ were older age (≥66 years, hazards ratio [HR]: 3.21; p = 0.007), anemia (HR: 3.29; p = 0.006) and duration of ZA exposure (between 1 and 2 years, HR: 3.91, p = 0.01; ≥2 years, HR: 8.07, p < 0.001), respectively. Conclusion: Patients with older age, anemia and/or more than 1 year of ZA treatment are at high risk of developing ONJ.

P732Maternal high-fat diet promotes the expansion of abdominal aortic aneurysm in adult offspring by enhancing osteoclast-like macrophage differentiation

Abstract Background and objective Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) formation. Methods and results Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating and received during pregnancy and lactation. In eight-week-old offspring of both genders, AAA was induced with the application of 0.5M calcium chloride (CaCl2) on the infrarenal aorta. Male offspring of HFD-fed dams (O-HFD) showed a significant increase in maximum outer diameter of AAA at 1, 4 and 8 weeks after surgery compared with offspring of ND-fed dams (O-ND) (P&lt;0.05). The lengths of outer circumference assessed by histological analysis were increased in O-HFD (P&lt;0.05). Likewise, female O-HFD showed a greater length of outer circumference than female O-ND (P&lt;0.05). While the number of F4/80-positive cells at 1 wk after surgery was comparable between the male O-HFD and O-ND, the percentage of MMP-9/F4/80 double-positive cells was significantly increased in male O-HFD. Consistently, fluorescent image of abdominal aorta taken by IVIS at 1 wk after surgery revealed a 2-fold increase in MMP activity (P&lt;0.01). Intriguingly, F4/80-positive cells in male O-HFD showed a 2.5-fold increase in co-staining with tartrate-resistant acid phosphate (TRAP), typical marker of osteoclast-like macrophages which abundantly secrete proteases than classically activated macrophages (M1), while the percentage of TNF-α/F4/80 double-positive cells was comparable between the 2 groups. Pharmacological inhibition of osteoclastogenesis by zoledronic acid (ZA) (100μg/kg) completely abolished the exaggerated AAA development in male O-HFD to a similar extent of that in male O-ND, while AAA development in male O-ND mice did not change even after ZA treatment. Furthermore, in vitro TNF-α-induced osteoclast differentiation of bone marrow-derived macrophages (BMDMs) showed a significantly higher number of TRAP-positive cells, accompanied by increased calcitonin receptor mRNA expression. Western blotting analysis showed that protein expression level of NFATc1, master regulator of osteoclastogenesis, was significantly higher in BMDM of O-HFD than O-ND. Conclusion Our findings demonstrate that maternal HFD accelerates CaCl2-induced AAA expansion, accompanied by the exaggerated accumulation of osteoclast-like macrophages and augmented activity of MMPs. Inhibition of macrophages skewing toward osteoclast-like cells could be a potential therapeutic target for preventing AAA development.

Zoledronik asit osteoporozlu β-talasemi hastalarında kemik mineral yoğunluğunu arttırır: Bir vaka kontrol çalışması

Purpose: This study addresses the efficacy of zoledronic acid treatment in osteoporotic patients with β-thalassemia.Materials and Methods: Thirty-nine thalassemic patients were enrolled in this study. Bone mineral density was measured using Dual energy x-ray absorbtiometry (DEXA), and biochemical markers of osteoporosis in serum and urine were measured at 0, 6, and 12 months of treatment. Patients with thalassemia were randomly received either zoledronic acid 4 mg IV once every six months or calcitriol 0.25 mcg / day for 12 months. A subgroup analysis was also performed according to gonadal status. Results: There were 21 males and 18 females, mean age of 23.1 ± 1.3 and bone age of 16.3±0.35 years. At the end of 12 months, bone mineral densities of the lumbar vertebra and femoral neck significantly increased in the zoledronic acid group. In patients with hypogonadism who received hormone replacement therapy, t-scores significantly increased. Serum NTX levels indicated significant increase in both treatment groups compared with the control group at the end of the treatment. A significant increase was obtained in urinary NTX level in hypogonadal patients who received zoledronic acid, and in serum NTX and IGF-1 levels in normogonadal patients who received calcitriol. Conclusion: In our study, zoledronic acid resulted in significant improvement in bone mineral density and t-scores. This improvement was in correlation with IGF-1 levels.

Addition of zoledronic acid to neoadjuvant chemotherapy is not beneficial in patients with HER2-negative stage II/III breast cancer: 5-year survival analysis of the NEOZOTAC trial (BOOG 2010-01)

BackgroundAdjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS).Patients and methodsPatients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes.ResultsTwo hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226–0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371–1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176–1.222, P = 0.120; HR 0.539, 95% CI 0.228–1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369–1.725, P = 0.565; HR 0.456, 95% CI 0.156–1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005–1.045, P = 0.014).ConclusionsOur results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival.Trial registrationClinicalTrials.gov, NCT01099436, April 2010.

May zoledronic acid have negative effects on cognition and muscle performance?

We aimed to investigate the effects of zoledronic acid treatment on daily living activities, cognitive functions, depression, muscle strength, and performance. The study was conducted retrospectively. Bone mineral densitometry (BMD) values, Katz activities of daily living (ADL), Lawton-Brody instrumental activities of daily living (IADL), mini mental state examination (MMSE), geriatric depression scale (GDS), mini nutritional assessment (MNA), grip strength, and gait speed scores before and 6months after zoledronic acid administration were compared. A total of 115 patients were included in the study. There was a significant increase in lumbar total (p < .001), femoral neck (p = .002), and femur total (p = .001) BMD values after zoledronic acid treatment. Significant decrease was found in MMSE (p = .016) and gait speed scores (p = .008) after zoledronic acid treatment, but no significant difference was found in terms of Katz ADL, Lawton-Brody IADL, MNA, GDS, and grip strength (p > .05). Our study indicated that zoledronic acid did not affect daily living activities, depression, and muscle strength. Although we have concluded that cognitive and muscle performance may be adversely affected by zoledronic acid treatment.

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20–30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92–133 days], and the median number of ZA administrations was 4 (range, 2–41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156–264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.

Longitudinal changes in bone mineral density and trabecular bone score following yearly zoledronic acid infusion in postmenopausal osteoporosis-a retrospective-prospective study from southern India.

There is limited information available with regard to the impact of zoledronic acid treatment on bone mineral density (BMD) and trabecular bone score (TBS) in Indian postmenopausal women with osteoporosis. We studied the changes in BMD at femoral neck (FN), hip and lumbar spine (LS), and in TBS following yearly administration of zoledronic acid (ZA) in subjects with postmenopausal osteoporosis. This was a prospective-retrospective study which included subjects on follow-up after administration of yearly zoledronic acid, over the past 6years. Postmenopausal women with a T score of ≤ - 2.5 at any site, assessed by dual energy X-ray absorptiometry (DXA), were included. A total of 620 subjects had received ZA during the study period, 197 postmenopausal women were eligible, and follow-up data were available in 164 and 103 at 1st and 2nd follow-up yearly visits respectively. The mean (SD) age and BMI of the women were 63.2 (8.5) years and 25.6 (4.5)kg/m2 respectively. There was significant increment in LS BMD from baseline to the 1st and 2nd follow-up visits, respectively (mean (SD), 0.718 (0.116), 0.734 (0.104), 0.762 (0.127)g/cm2, p = 0.024). No decline in the BMD at FN and hip at first and second follow visit was found. The TBS scores (n = 90) on baseline and follow-up visits were 1.260 (±0.11), 1.256 (± 0.15), and 1.242 (± 0.17) (p value = 0.71). Lumbar spine BMD showed significant improvement with zoledronic acid treatment. No decline was noted in femoral neck BMD and TBS with treatment.

METASTATIC NEUROENDOCRINE PROSTATE CANCER, AN AGGRESSIVE PROSTATE MALIGNANCY: A REPORT OF TWO CASES WITH ORAL MANIFESTATIONS

Objectives Neuroendocrine prostate cancer (NEPC) is a lethal prostate malignancy with a median survival of less than 1 year from time of detection. NEPC can occur de novo or more commonly as a treatment emergent phenomenon (t-NEPC). t-NEPC occurs in a subset of patients with metastatic-castration resistant prostate cancer. Two cases of t-NEPC with oral manifestations are presented highlighting the pathologic features and the varied clinical context in which these lesions presented. Patients and Methods Case 1) A 79 year-old man with a history of prostate adenocarcinoma undergoing hormone treatment presented with a fungating mass of the right maxilla and palate, clinically suspicious for squamous cell carcinoma. Biopsy revealed a high grade neuroendocrine carcinoma. Case 2) A 76 year-old man with a history of metastatic prostate adenocarcinoma receiving zoledronic acid and denosumab treatment for bony metastases, presented with mandibular fracture. A segmental resection without reconstruction with debridement was performed with a clinical diagnosis of medication-related osteonecrosis of the jaw (MRONJ). The pathology revealed a high grade neuroendocrine cell tumor. Both cases were positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, and stained negative for prostate specific antigen (PSA) and prostate specific acid phosphatase (PSAP). Both tumors demonstrated a proliferative index (Ki-67) of 60-70%. An extended panel of immunostains appeared to eliminate other entities from consideration. Conclusions Awareness of t-NECP is of importance to correctly diagnosis the entity, recognizing that tumor markers such as PSA and PSAP are negative, and standard serum markers for prostate carcinoma may be stable or show no increase with progression of disease. Neuroendocrine carcinoma in the setting of medication related osteonecrosis of the jaw in a patient with prostate carcinoma needs to be included in the differential diagnosis.

Automated Bone Scan Index as an Imaging Biomarker to Predict Overall Survival in the Zometa European Study/SPCG11

BackgroundOwing to the large variation in treatment response among patients with high-risk prostate cancer, it would be of value to use objective tools to monitor the status of bone metastases during clinical trials. Automated Bone Scan Index (aBSI) based on artificial intelligence has been proposed as an imaging biomarker for the quantification of skeletal metastases from bone scintigraphy. ObjectiveTo investigate how an increase in aBSI during treatment may predict clinical outcome in a randomised controlled clinical trial including patients with high-risk prostate cancer. Design, setting, and participantsWe retrospectively selected all patients from the Zometa European Study (ZEUS)/SPCG11 study with image data of sufficient quality to allow for aBSI assessment at baseline and at 48-mo follow-up. Data on aBSI were obtained using EXINIboneBSI software, blinded for clinical data and randomisation of zoledronic acid treatment. Data on age, overall survival (OS), and prostate-specific antigen (PSA) at baseline and upon follow-up were available from the study database. Outcome measurements and statistical analysisAssociation between clinical parameters and aBSI increase during treatment was evaluated using Cox proportional-hazards regression models, Kaplan-Meier estimates, and log-rank test. Discrimination between prognostic variables was assessed using the concordance index (C-index). Results and limitationsIn this cohort, 176 patients with bone metastases and a change in aBSI from baseline to follow-up of ≤0.3 had a significantly longer median survival time than patients with an aBSI change of >0.3 (p<0.0001). The increase in aBSI was significantly associated with OS (p<0.01 and C-index=0.65), while age and PSA change were not. ConclusionsThe aBSI used as an objective imaging biomarker predicted outcome in prostate cancer patients in the ZEUS/SPCG11 study. An analysis of the change in aBSI from baseline to 48-mo follow-up represents a valuable tool for prognostication and monitoring of prostate cancer patients with bone metastases. Patient summaryThe increase in the burden of skeletal metastases, as measured by the automated Bone Scan Index (aBSI), during treatment was associated with overall survival in patients from the Zometa European Study/SPCG11 study. The aBSI may be a useful tool also in monitoring prostate cancer patients with newly developed bone metastases.

Effects of zoledronic acid on bone mineral density around prostheses and bone metabolism markers after primary total hip arthroplasty in females with postmenopausal osteoporosis.

To investigate the effect of zoledronic acid on periprosthetic bone mineral density (BMD) and bone metabolism markers after primary total hip arthroplasty in females with postmenopausal osteoporosis. From November 2015 to April 2016, 40 female patients who met the inclusion criteria were randomized into two groups: a control group (calcium + calcitriol) and a zoledronic acid group (calcium + calcitriol + zoledronic acid). At 1week and 3, 6, and 12months after operation, BMD was obtained through dual-energy X-ray absorptiometry (DEXA). At pre-operation and at 3, 6, and 12months after the operation, levels of bone metabolism markers were obtained by serum examination. Loss of BMD was significantly more pronounced in the control group than in the ZOL group in zones 1, 4, 6, and 7 at 6months and in zones 1, 2, 4, 6, and 7 at 12months after the operation. The levels of bone-resorption marker (β-CTX) were significantly lower in the ZOL group than in the control group at 3, 6, and 12months after operation. The levels of bone-formation marker (TP1NP) performed statistically differences only at 12months after the operation in these two groups. Receiving an intravenous infusion of 5mg zoledronic acid after THA can effectively reduce periprosthetic BMD loss and improve bone remodeling in females with postmenopausal osteoporosis. Zoledronic acid significantly inhibited bone mass loss in zones 1, 2, 4, 6, and 7 after THA and inhibited bone-resorption marker (β-CTX) to improve bone remodeling. Zoledronic acid treatment is potentially important for patients with osteoporosis after THA.