Zoledronic Acid Group Research Articles

Effect of 5 mg zoledronic acid on bone mineral density in women with postmenopausal osteoporosis

Objective To determine the effects of once yearly zoledronic acid on bone density and falling risk in women with postmenopausal osteoporosis.Methods In this randomized controlled trial,45 patients with postmenopausal osteoporosis were randomly assigned to receive a single 30-minute infusion of zoledronic acid (5 mg) (Group A) and 46 patients were assigned to receive placebo at baseline (Group B).The lumbar spine and hip bone mineral density (BMD) were measured by dual-X-ray absorptiometry (DXA)at 12 months versus baseline.The risk of falling was examined by the balance test (Sunlight Tetrax).New vertebral fracture,hip fracture and other fracture also served as end point.The compliance of patients was evaluated.The adverse events of zoledronic acid were recorded.Results After one year,41 patients in each group had completed the follow-up.In groups A,lumbar spine BMD significantly increased by 5.8％,total hip by 3.9％,and femoral neck by 2.9％.In groups B,lumbar spine BMD significantly increased by 4.4％.The risks of falling significantly reduced in both group,and there was no statistical significance between group A and group B.Patella fracture was found one patient in group A.New vertebral fracture and hip fracture were not found in two groups.The compliance of patients was comparable in two groups.Some adverse events were tolerated in group A.Conclusion A once-yearly infusion of 5 mg zoledronic acid during a 1-year period significantly increased the lumbar spine,total hip,and femoral neck BMD.Zoledronic acid combined with 1,25-dihydroxyvitamin D reduced the risk of falling in postmenopausal women with osteoporosis.The treatment of once-yearly infusion of 5 mg zoledronic acid also increases the compliance of patients.It's a very important for long-time treatment of osteoporosis. Key words: Osteoporosis, postmenopausal; Diphosphonates; Bone density

Additive effect of zoledronic acid on serum prostate‐specific antigen changes for hormone‐sensitive prostate cancer patients with bone metastasis treated by combined androgen blockade

Combined androgen blockade is widely used to treat patients with advanced prostate cancer. Recently, zoledronic acid was proven to be effective in preventing skeletal-related events for prostate cancer patients with bone metastases. Aim of the present study was to assess the effect of adding zoledronic acid to combined androgen blockade in the treatment of hormone-naïve metastatic prostate cancer patients by analyzing the changes of biomarker levels. Patients were treated with either a combination of combined androgen blockade and zoledronic acid (n=23) or combined androgen blockade alone (historical control combined androgen blockade group, n=42). Zoledronic acid was injected intravenously at 4 mg every 4 weeks for 2 years. Prostate-specific antigen and bone turnover markers (alkaline phosphatase and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen) were examined before treatment and at 3, 6, and 12 months after treatment. Sequential changes of prostate-specific antigen, alkaline phosphatase and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen for the two groups versus pretreatment levels were compared. Prostate-specific antigen values in both groups significantly declined at 3, 6 and 12 months compared with pretreatment levels. However, the decline of the prostate-specific antigen was lower in the combined androgen blockade group. Alkaline phosphatase significantly declined at 6 and 12 months in the combination of combined androgen blockade and zoledronic acid group, with no significant changes seen in the combined androgen blockade group. The addition of zoledronic acid to combined androgen blockade showed prostate-specific antigen and bone turnover markers response compared with combined androgen blockade therapy only, suggesting a potential antitumor effect of zoledronic acid in the management of metastatic prostate cancer patients.

Skeletal Remodeling Following Clinically Relevant Radiation-Induced Bone Damage Treated with Zoledronic Acid

Our aim was to determine if zoledronic acid (ZA) changes (45)Ca pharmacokinetics and bone microstructure in irradiated, ovary-intact (I) and irradiated, ovariectomized mice (OVX), two groups with different patterns of skeletal damage. The hind limbs of I and OVX BALB/c mice received a single 16-Gy radiation dose, simulating pre- and postmenopausal female cancer patients undergoing radiation treatment. All I and OVX mice were radiolabeled with 15μCi (45)Ca. Mice were treated with or without a 0.5mg/kg injection of ZA. The time course of bone mineral remodeling was evaluated using a fecal (45)Ca assay, measured by liquid scintillation. A group of nonirradiated, intact mice were used for the longitudinal evaluation of (45)Ca biodistribution. Distal femur bone histomorphometric parameters were measured using microCT at 50days post-ZA intervention. Most (45)Ca was incorporated into the skeleton and eliminated from the soft tissues within 3-5days postirradiation, attaining a steady state of excretion at 25-30days. ZA intervention in both groups resulted in a rapid decrease in fecal (45)Ca excretion. There was a significant difference in (45)Ca excretion in the OVX±ZA (P=0.005) group but not in the I±ZA (P=0.655) group. The rate of excretion of fecal (45)Ca was slower in the OVX+ZA compared to the I+ZA group (P=0.064). (45)Ca assay is useful to monitor the time course of bone mineral remodeling after an antiresorptive intervention in irradiated mice, providing a basis to investigate bone effects of cancer therapy protocols. For equivalent doses of ZA, recovery may depend on the nature and degree of skeletal damage.

Effects of osthole, psoralen, aconitine on breast cancer MDA-MB-231BO cell line inhibition in vitro

To explore the inhibitory effects and to investigate the mechanisms of combined treatment of osthole, psoralen with aconitine on human breast cancer cell line MDA-MB-231BO. The best inhibitory concentration of osthole, psoralen combined with aconitine on MDA-MB-231BO cells was obtained by stepwise regression analysis after adopting a uniform experiment design. The invasive activities were observed by transwell assays, and expressions of transforming growth factor-β1 (TGF-β1), Smad2, Smad3, Smad4, Smad7, nuclear factor-κB (NF-κB) and receptor activator of NF-κB ligand (RANK) mRNAs were analyzed by real-time quantitative polymerase chain reaction. The optimal combination concentrations of osthol, psoralen and aconitine were 6.44, 8.89 and 9.44 μg/mL, respectively. Cell invasion was significantly inhibited after 24 hours of treatment using the combination drugs and zoledronic acid. TGF-β1, Smad2, Smad3, Smad4, Smad7, NF-κB and RANK mRNA expressions of the optimal combination group and zoledronic acid group were significantly reduced compared with the control group (P<0.01). Furthermore, TGF-β1, Smad2, Smad3, Smad4, Smad7, NF-κB and RANK mRNA expressions of the optimal combination group were significantly lower than those of the weak combination group (P<0.01). Combination treatment of osthole, psoralen with aconitine can inhibit cancer cell invasion, which is a result of alteration of the TGF-β/Smad signaling pathway and down-regulation of NF-κB and RANK expressions.

Breast-Cancer Adjuvant Therapy with Zoledronic Acid

Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

Effect of zoledronic acid compared with raloxifene on bone turnover markers in postmenopausal women with low bone density

The aim of this study was to assess the effects of zoledronic acid and raloxifene on bone turnover markers. This multicenter, randomized, double-blind study involved 110 postmenopausal women with low bone mineral density who received either a single intravenous infusion of zoledronic acid 5 mg or 6 months of daily oral raloxifene 60 mg. The primary efficacy variable was change from baseline in the bone resorption marker urine N-telopeptide of type I collagen. The secondary efficacy variable was change from baseline in the bone formation marker serum bone-specific alkaline phosphatase. Analysis time points were at 2, 4, and 6 (primary) months. At 6 months, zoledronic acid produced a significantly greater reduction than did raloxifene in urine N-telopeptide of type I collagen (P < 0.001). Zoledronic acid also yielded significantly greater decreases in urine N-telopeptide of type I collagen at 2 and 4 months and in serum bone-specific alkaline phosphatase at all time points (P < 0.001 vs raloxifene for all comparisons). Both treatments were well tolerated. More adverse events occurred in the zoledronic acid group; these were primarily transient postdose symptoms that occurred within the first 3 days after the infusion. Zoledronic acid demonstrated significantly greater decreases in bone turnover markers than did raloxifene in postmenopausal women with low bone mass.

Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial

SummaryBackgroundBisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events.MethodsPatients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111.Findings1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001).InterpretationThe results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline.FundingMedical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Matrix Metalloproteinase-9 Expression in Alveolar Extraction Sockets of Zoledronic Acid–Treated Rats

The use of nitrogen-containing bisphosphonates (n-bis) is associated with necrosis of the jaws, also known as bisphosphonate-related osteonecrosis of the jaws (BRONJ); however, the pathophysiology is unknown. Matrix metalloproteinase-9 (MMP-9) expression is essential for normal bone healing and is also required for angiogenesis. N-bis alters MMP-9 expression in vitro and in vivo; therefore, we hypothesized that n-bis alters MMP-9 expression during oral wound healing after tooth extraction. A total accumulated dose of 2.25 mg/kg (n = 20) of Zoledronic acid (ZA) Zometa or saline (control, n = 20) was administered to Sprague-Dawley male rats. Next, both groups had maxillary molar teeth extracted. Rats were sacrificed at postoperative day 1, 3, 7, or 21. Western blotting or multiplex ELISA was used to evaluate proteins of interest. Real-time polymerase chain reaction was used to assess the relative quantities of target gene mRNA. MMP-9 enzymatic activity was assessed by zymography. The ZA group showed a statistically significant reduction in bone mineralization rate 21 days after tooth extraction compared with the control group (Student t test, P = .005). Moreover, ZA-treated animals showed a statistically significant increase in MMP-9-specific mRNA at postoperative days 3 (P = .003), 7 (P < .0001), and 21 (P < .0001) and protein on postoperative days 3 (P = .005) and 7 (P < .0001). MMP-9 enzymatic activity was also increased in ZA-treated rats compared with control animals (Student t test, P = .014). We also evaluated the extraction sockets for the presence of tissue inhibitor of MMP-1 (TIMP1), which is an inhibitor of MMP-9 enzymatic activity. TIMP1-specific mRNA and protein were not significantly altered by ZA treatment at the times tested (P > .05). Receptor of NF-κB ligand (RANKL) is known to regulate the expression of MMP-9; we therefore assessed the RANKL expression in our experimental oral wound-healing model. The ZA-treated animals had significantly increased RANKL mRNA at postoperative days 3 (P = .02) and 21 (P = .004), while the protein expression was significantly increased at postoperative days 1 (P < .0001), 7 (P = .02), and 21 (P = .03) compared with the control group. ZA reduced bone mineralization within tooth extraction sockets, suggesting aberrant bone healing. ZA increases the amount and enzymatic activity of MMP-9, while apparently not altering the amount of TIMP1 within extraction sockets. RANKL is increased in ZA-treated rats, which suggests that increased MMP-9 expression is due, in part, to augmented RANKL expression.

Effects of local application of zoledronic acid on bone healing of tooth extraction in rats

To investigate the effect of local application of zoledronic acid (ZA) on the expression of type I collagen and vascular endothelial growth factor (VEGF). Fifty-four male Wistar rats were divided into ZA group, gelatin sponge group, and blank control group after one-side tooth extraction. The expression of type I collagen and VEGF were detected with SP immunohistochemistry method 1, 2 and 4 weeks after operation. The gray value of type I collagen in ZA group (60.00 ± 1.81, 63.47 ± 3.02) was lower than those in gelatin sponge group (68.58 ± 2.90, 71.15 ± 5.57) and blank control group (69.16 ± 9.63, 72.50 ± 4.10, P < 0.05) in the 1 and 2 week. In the ZA and gelatin sponge groups, the gray values of type I collagen were higher in the 4th week than in the 1st and 2nd week (P < 0.05). The expression of VEGF was higher in ZA group (69.93 ± 2.74) than in gelatin sponge group (60.86 ± 4.79) and blank control group (61.52 ± 2.28) in the 1st week (P < 0.05). There was significant difference in VEGF expression between the 2nd week and 1st and 4th week (P < 0.05). Local application of ZA could enhance the expression of type I collagen but inhibit the expression of VEGF in the early stage.

The Effect of Zoledronic Acid on the Clinical Resolution of Charcot Neuroarthropathy

OBJECTIVETo investigate the clinical efficacy of zoledronic acid in patients with diabetes and acute Charcot neuroarthropathy.RESEARCH DESIGN AND METHODSThirty-nine consecutive patients were randomly assigned to placebo or three intravenous infusions of 4 mg zoledronic acid. The primary outcome was clinical resolution of acute Charcot neuroarthropathy determined by total immobilization time (casting plus orthosis).RESULTSAt baseline, there was no significant difference between the randomly assigned groups with respect to Charcot disease activity or other baseline values. In the zoledronic acid group, the median time for total immobilization was 27 weeks (range 10–62), and in the placebo group it was 20 weeks (20–52) (P = 0.02).CONCLUSIONSZoledronic acid had no beneficial effect on the clinical resolution of acute Charcot neuroarthropathy in terms of total immobilization time. It is possible that it may prolong the time to clinical resolution of Charcot neuroarthropathy.

A single infusion of zoledronic acid produces sustained remissions in paget disease: Data to 6.5 years

Two trials have shown that a single 5-mg infusion of zoledronic acid achieves much higher response rates in Paget disease of bone than risedronate. The duration of this effect is unknown. We have conducted an open follow-up of responders from the two trials (152 originally treated with zoledronic acid, 115 with risedronate) out to 6.5 years without further intervention. Endpoints were times to relapse (ie, return of serum total alkaline phosphatase activity to within 20% of the pretreatment value) or loss of response (response = normalization of alkaline phosphatase or 75% or greater reduction in its excess). Bone turnover markers were lower in the zoledronic acid group throughout follow-up, with mean alkaline phosphatase (ALP) remaining within the reference range in these patients, whereas the mean in the risedronate group was above normal from 1 year. Relapse rates were substantially greater in the risedronate group (23 of 115, 20%) than in those treated with zoledronic acid (1 of 152, 0.7%, p < .001), and loss of response occurred in 19 (12.5%) zoledronic acid patients compared with 71 (62%) risedronate patients (p < .0001). Risk ratios for relapse and loss of response in zoledronic acid patients were 0.02 [95% confidence interval (CI) 0.00-0.18] and 0.12 (95% CI 0.07-0.19), respectively. Changes from baseline in quality of life, assessed using SF-36 scores, were more positive in the zoledronic acid group across the follow-up period (p = .01). Bone markers at 6 months were predictive of response duration. These data demonstrate an unprecedented duration of remission of Paget disease following treatment with zoledronic acid, accompanied by an improved quality of life.

Denosumab

Denosumab, a fully human monoclonal antibody, binds to the receptor activator of nuclear factor-κB ligand (RANKL) and thereby inhibits RANKL-mediated bone resorption. In various individual countries, subcutaneous denosumab is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumours (featured indication), and/or for the treatment of postmenopausal osteoporosis and/or of cancer treatment-induced bone loss in prostate or breast cancer patients. In three, pivotal, double-blind, multinational trials in adult patients with cancer-related bone metastases (total n > 5700), including trials in patients with advanced breast or prostate cancer, subcutaneous denosumab (120 mg every 4 weeks) was shown to be noninferior to intravenous zoledronic acid (4 mg every 4 weeks), as determined by the median time to first on-study skeletal-related event (primary endpoint) at the time of the primary analysis (≈34 or 41 months). Denosumab treatment was superior to zoledronic acid in terms of the primary endpoint in two trials in patients with breast cancer or prostate cancer, based on secondary superiority analyses. In a third trial in patients with solid tumours excluding breast or prostate cancer, superiority of denosumab treatment versus zoledronic acid treatment was not demonstrated. The tolerability profile of denosumab was manageable in patients with bone metastases from solid tumours. Osteonecrosis of the jaw occurred in 1.8% and 1.3% of patients in the denosumab and zoledronic acid groups during the primary treatment phase; the incidence after approximately 4 additional months of denosumab treatment was 2.2%.

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09). Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Amgen.

Zoledronic acid does not reduce MRI erosive progression in PsA but may suppress bone oedema: the Zoledronic Acid in Psoriatic Arthritis (ZAPA) Study

BackgroundThe effect of zoledronic acid (ZA) on articular bone in patients with psoriatic arthritis (PsA) was investigated using MRI.MethodsPatients with erosive PsA were randomised to receive 3-monthly infusions of ZA...

The effects of zoledronic acid on neointimal hyperplasia: a rabbit carotid anastomosis model

The aim of the present study was to investigate the effect of zoledronic acid (ZA), as a matrix metalloproteinase inhibitor, on neointimal hyperplasia in rabbit carotid anastomosis model. New Zealand male rabbits were divided into two groups as placebo and treatment groups in this experimental study. After anesthesia, the right carotid artery of each rabbit was end-to-end anastomosed with an 8/0 polypropylene suture. Left carotid artery was kept as control without any operation. Placebo group (n=6) received phosphate buffered saline (PBS) (0.5mL/kg/day/s.c.) for 28 days postoperatively, whereas ZA group (n=6) received ZA (100 µg/kg/day/s.c.) for the same period. After sacrification, the anastomosed and control arteries were isolated. Morphometric and immunohistochemical examinations were performed. Statistical analyses of morphometric and immunohistochemical data were performed using two-way ANOVA and Chi-square test respectively. In PBS group, vascular injury in the anastomosed artery significantly increased the intimal area (anastomosed: 112.51±61.18 µm(2)*1000 vs. control: 22.62±4.26 µm(2)*1000, p<0.01) and intima/media index (anastomosed: 0.347±0.29 vs. control: 0.075±0.01, p<0.05) compared to control artery. ZA significantly reduced the intimal area (39.29±18.21 µm(2)*1000 , p<0.01) and intima/media index (0.112±0.07, p<0.05) compared to PBS group. Additionally, α-smooth muscle actin immunopositivity was found significantly decreased in anastomosed arteries from ZA group (ZA: 2.33±0.52 vs. PBS: 3.50±0.5, p<0.05). Moreover, intensive gelatinase (MMP-2 and MMP-9) immunoreactivities were clearly seen in anastomosed arteries compared to control arteries from PBS group. ZA apparently decreased immunopositivities for gelatinases in anastomosed arteries. ZA might be a promising agent for prevention of neointimal hyperplasia, which is the most significant cause of graft failures in late postoperative period.

Characterization of and Risk Factors for the Acute-Phase Response After Zoledronic Acid

Context: Intravenous aminobisphosphonates often cause an acute-phase response (APR), but the precise components of this, its frequency, and the risk factors for its development have not been systematically studied. Objective: The objective of the study was to characterize the APR and determine its frequency and the risk factors for its development. Design: The study was an analysis of adverse events from a large randomized trial. Setting: This was a multicenter international trial. Patients: Patients included 7765 postmenopausal women with osteoporosis. Intervention: Zoledronic acid 5 mg annually or placebo was the intervention. Main Outcome Measure: Adverse events occurring within 3 d of zoledronic acid infusion were measured. Results: More than 30 adverse events were significantly more common in the zoledronic acid group and were regarded collectively as constituting an APR. These were clustered into five groups: fever; musculoskeletal (pain and joint swelling); gastrointestinal (abdominal pain, vomitin...

Effect of zoledronic acid on bone healing subsequent to mini-implant insertion

To examine remodeling in bone supporting mini-implants by comparing a no drug (ND) group with a group that received a potent intravenous bisphosphonate in a canine model. Twelve skeletally mature (2- to 3-year-old) male dogs were divided into two groups. Seven dogs were administered 0.1 mg/kg/mo of zoledronic acid (ZA) for 16 weeks, while five age-matched dogs received no drug. Two mini-implants (Tomas, Dentaurum, Newton, Pa) were placed unilaterally in the maxilla and mandible (4 mini-implants per animal × 12 = 48). Serial fluorescent bone labels were administered in vivo. Postmortem, the bone blocks containing the mini-implants were harvested and used for histomorphometric analyses at two regions of interest (adjacent: within 1 mm of interface; distant: 1-4 mm from the interface) supporting the mini-implant. Data were analyzed using mixed models. In general, the ZA group had a significantly lower bone formation rate than the ND group (P < .05) for all jaws/regions except for the adjacent region in the maxilla, P = .12. Despite the reduction, mean intracortical remodeling in the ZA group ranged from 35%-42% per year in the implant adjacent bone. This rate is substantially higher than that reported for noninjured sites in the jaw. Bone remodeling is typically elevated in implant supporting bone. After ZA administration, the healing response represented by elevated turnover in implant supporting bone was diminished but was not abolished.

Association between bisphosphonates and jaw osteonecrosis: A study in Wistar rats

This work aimed at determining whether bisphosphonate therapy produces a sufficient condition for jaw osteonecrosis after tooth extraction. Rats were allocated into 3 groups: (1) 11 rats treated with alendronate, (2) 10 rats treated with zoledronic acid, and (3) 10 control rats. The animals were subjected to tooth extractions, and at the end of bisphosphonate therapy, they were humanely killed. Histologic sections of the surgical site were processed and analyzed. The zoledronic acid group showed higher incidences of osteonecrosis, inflammatory infiltrate, and microorganisms. There was no significant difference for epithelial or connective tissue, root fragments, vital bone, and positive staining for vascular endothelial growth factor (VEGF) among the groups. Zoledronic acid is associated with jaw osteonecrosis, whereas alendronate did not produce a condition sufficient for osteonecrosis after tooth extraction. Neither zoledronic acid nor alendronate was associated with a reduced immunohistochemical expression of VEGF in vital bone at the tooth extraction site.

RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162). The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation. A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5). Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

Transient changes in thyroid functions tests after zoledronic acid infusion

Zoledronic acid (ZA) induces an acute phase response in association with elevation of serum cytokines, which possibly alter the 3 types of iodothyronine deiodinase activity. We therefore studied the possible alteration in thyroid function tests by ZA. We investigated the acute changes in serum thyroid hormones, TSH, cortisol, white blood cells, CRP, interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), before (0) and 1, 2 and 3 days after iv infusion of 5 mg ZA in 24 asymptomatic postmenopausal women with osteoporosis (ZA group) in comparison with a placebo group. In the majority of patients the ZA infusion was associated with acute phase response and fever within 24h after infusion which became attenuated on day three. Concurrently with increase in serum cortisol, CRP, IL-6 and TNF-α, on day 1 and 2, total serum T3 (TT3), free T3 (fT3), total T4 (TT4) and fT4 decreased with a nadir on day 2 in association with an increase in the fT4/fT3 ratio and reverse T3 (rT3) levels. All thyroid function changes returned to the baseline levels on day 3, with cytokines still at higher levels, although lower than those on day 2. Serum TSH remained essentially unchanged throughout the study. The changes in thyroid hormones were at least in part explained by the increased TNF-α, but not by IL-6. ZA induces short term changes in thyroid hormones, characteristic of nonthyroidal illness syndrome (NTIS), in association with an increase in TNF-α and IL-6.