ZOL Group Research Articles

Bis‑enoxacin blocks alveolar bone resorption in rats with ovariectomy‑induced osteoporosis.

Postmenopausal osteoporosis is a common systemic skeletal disease that is associated with estrogen‑deficiency. Bone loss associated with bisphosphonates therapy can increase the risk of developing oral osteonecrosis. Recent studies have indicated that enoxacin may inhibit osteoclast formation and bone resorption via a different mechanism from that of bisphosphonates. Therefore, the authors hypothesized that the use of an enoxacin such as bis‑enoxacin (BE) in association with bisphosphonates may be effective in the treatment of postmenopausal osteoporosis‑associated alveolar bone resorption and reduce the risk of oral osteonecrosis by allowing the dose of bisphosphonates to be reduced. A total of 30 6‑month‑old female Sprague‑Dawley rats were randomly assigned to five groups: The Sham, Vehicle, zoledronic acid (ZOL), low concentrations of BE (BE‑L) and high concentrations of BE (BE‑H) groups. The results demonstrated that the ZOL, BE‑L and BE‑H groups had an increased bone volume/tissue volume, trabecular thickness, mineral apposition rate, mineralizing surface/bone surface and a decreased trabecular separation when compared with the Vehicle group. The microscopic evaluation of histological sections clearly supported the results of the micro‑computed tomography. The number of tartrate‑resistant acid phosphatase‑positive osteoclasts was markedly decreased in the ZOL, BE‑L and BE‑H groups, indicating that BE may inhibit osteoclast formation. The anti‑resorptive effect in the BE‑H group was close to or better than that exhibited by the ZOL group; however, this effect was poorer in the BE‑L group. In conclusion, BE has the potential to block alveolar bone resorption resulting from ovariectomy‑induced osteoporosis in rats in a dose‑dependent manner.

Protective effect of zoledronic acid on articular cartilage and subchondral bone of rabbits with experimental knee osteoarthritis.

Subchondral bone reabsorption and remodeling are responsible for the initiation and progression of osteoarthritis (OA). Zoledronic acid (ZOL), a third-generation bisphosphonate (BIS), is an inhibitor of bone reabsorption. However, the intervention effect of ZOL on OA has not been fully characterized and remains to be directly demonstrated in animal experiments. The present study examined the microscopic and macroscopic changes in the anterior cruciate ligament transection (ACLT) model of OA in rabbits and evaluated the effects of ZOL on cartilage degeneration and subchondral bone loss. A total of 32 New Zealand white rabbits were randomly divided into four groups: High-, medium- and low-dose ZOL groups, which received an intravenous injection of 250, 50 and 10 µg/kg ZOL, respectively, after modeling, as well as an untreated group. The bone mineral density (BMD) of the knee joint was evaluated by dual-energy X-ray absorptiometry scanning immediately after modeling and at 4 and 8 weeks. At week 8, quantitative measurement of cartilage was performed by a specialized magnetic resonance imaging (MRI) technique, including three-dimensional fat-suppressed spoil gradient-recalled sequence and T2 mapping. The rabbits were sacrificed by air embolism after anesthesia and both knee joints were harvested and evaluated by general and histological observation. Toluidine blue and hematoxylin and eosin staining were used to assess histological changes in the articular cartilage. Quantitative analysis of cartilage histopathology was performed according to the Mankin scoring system. The BMD of ACLT joints dropped after modeling, which was effectively suppressed by ZOL at the high and medium dose but not the low dose. MRI scans demonstrated that in the untreated group, articular cartilages on ACLT knees were thinner than those on normal knees. The high dose of ZOL preserved the cartilage tissue thickness more efficiently than the medium and low doses. Observation of specimens and pathological slices revealed that the articular cartilage degeneration in the high-dose ZOL group was lightest, while that in the medium- and low-dose ZOL group was moderate, and the untreated group exhibited the most severe defect. The untreated group had the highest Mankin score, whereas the high-dose ZOL group had the lowest score. In conclusion, ZOL increased the subchondral bone density, improved the microstructure and reduced the degeneration of articular cartilage in OA according to morphological as well as quantitative observation. ZOL exerted significant chondroprotective effects in a dose-dependent manner. A favorable chondroprotective effect was induced at the dose of 250 µg/kg. ZOL may represent a novel promising drug to complement the treatment of OA.

Evaluation of Mandibular Bone After Dental Extraction in Rats Treated With Antiresorptive Drugs

Zoledronic acid (ZOL) and denosumab (Dmab) are commonly used to treat bone pathologies. Because these drugs suppress bone metabolism, this study sought to compare their effect on bone repair after tooth extraction. Four-week-old male Wistar rats were randomly assigned to 1 of 3 groups: ZOL 0.125mg/kg, Dmab 0.25mg/kg, or saline solution 10mL/kg (control). After 1week of treatment, the first left molar was extracted; the rats were euthanized at 28days. The jaws were removed and photographed for macroscopic analysis of wound healing and then subjected to tomographic and histologic analyses. Immunohistochemistry was carried out against the receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG). No difference in wound healing, presence of inflammatory infiltrate and bone sequestration, or osteocyte expression of RANKL and OPG was found among groups. Tomographic analysis showed that the ZOL group had less alveolar resorption and more complete alveolar repair compared with the other groups. There was a statistically significant difference in the OPG marker in the control (P=.008) and ZOL (P=.05) groups when comparing the extracted and non-extracted sides. Systemic use of ZOL can improve alveolar bone healing; however, the potential risk for the development of osteonecrosis should be considered. Higher expression of OPG seems to be associated with the control of osteoclastogenesis during bone repair.

Radiodensitometric study for evaluation of bone mineral density around dental implants after zoledronic acid treatment in ovariectomized rats

BackgroundThe purpose of this study was to evaluate the effects of intravenous zoledronic acid applied systemically on osseointegration of dental implants and the surrounding bone mineral density (BMD) in the ovariectomized rats.Material and Methods36 rats were divided into three groups: control (CTRL), ovariectomy (OVX), and ovariectomy-zoledronic acid (OVX/ZOL). The rats in the CTRL group underwent sham surgery, while rats in OVX and OVX / ZOL group underwent ovariectomy. After 12 weeks, rats from OVX / ZOL were injected with 0.04 mg/kg ZOL intravenously once a week for 6 weeks. The rats from CTRL and OVX groups were injected with 0.9% NaCl. Implants were placed in the left tibia. After 8 weeks, rats were sacrificed and tibia bones were removed for radiodensitometric examination. Digital radiographs of bones’ lateral surface were taken. The BMD was measured by using radiographic analysis software.ResultsStatistically significant differences were found between all groups (p<0.05). While highest mean BMD values were observed in the CTRL group, the lowest were in the OVX group.ConclusionsThe systemic use of ZOL has increased the bone density around the implants inserted osteoporotic rat tibia. Key words:Bisphosphonate, bone density, dental implants, osteoporosis.

The Clinical Characteristics and Efficacy of Bisphosphonates in Audlt Patients with Osteogenesis Impergecta

Osteogenesis imperfecta (OI) is characterized by low bone mass and recurrent fractures. Adults with OI are often treated with oral or intravenous bisphosphonates (BPs). We investigated the clinical phenotypes of adult OI patients and prospectively compared the efficacy of oral alendronate (ALN) with intravenous zoledronic acid (ZOL) in OI patients. This 24-month, observational, randomized clinical study included 60 adult patients with OI. We compared the differences in bone mineral density (BMD) and bone turnover biomarkers between OI adults and healthy subjects. Thereafter, OI patients were randomized at a 2:1 ratio to receive either weekly oral ALN 70 mg or once-yearly infusion of ZOL 5 mg. The efficacy outcomes were changes in BMD, bone turnover biomarkers, and fracture incidence. Adult OI patients had significantly lower BMD and significantly higher cross-linked C-telopeptide of type I collagen (β-CTX) levels than age-/sex-/BMI-matched healthy subjects. A total of 52 patients completed the 24-month clinical study. BMD at lumbar spine, femoral neck, and total hip were equivalently elevated in the ALN (10.5, 13.2, and 14.7%, respectively) and ZOL (11.3, 13.7, and 11.7%, respectively; all P>.05) groups. Serum alkaline phosphatase decreased by 30.3% in the ALN group and 37.3% in the ZOL group (P = .12), and β-CTX decreased by 58.0% in the ALN group and 63.6% in the ZOL group (P = .48). Compared to the prior fracture rates, clinical fracture incidences were decreased in the ALN and ZOL groups (both P<.05). Adults with OI present significantly lower bone mass and higher bone resorption biomarkers than healthy populations. Oral ALN and intravenous ZOL are equally effective at increasing BMD and inhibiting bone turnover in adults with OI. The treatment may reduce fractures in this study, but further efforts are still needed to demonstrate the anti-fracture efficacy of BPs. 25OHD = 25-hydroxyvitamin D ALN = alendronate ALP = alkaline phosphatase BMD = bone mineral density BMI = body mass index BP = bisphosphonate β-CTX = cross-linked C-telopeptide of type I collagen FN = femoral neck LS = lumbar spine OI = osteogenesis imperfecta RCT = randomized controlled trial TH = total hip ZOL = zoledronic acid.

Efficacy and safety of once-yearly zoledronic acid in Japanese patients with primary osteoporosis: two-year results from a randomized placebo-controlled double-blind study (ZOledroNate treatment in Efficacy to osteoporosis; ZONE study)

SummaryIn a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures.IntroductionThe purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis.MethodsThis was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months.ResultsThe 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group (p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17–0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip (t test: p < 0.0001). No new adverse events or osteonecrosis of the jaw were observed in this study.ConclusionsOnce-yearly administration of ZOL 5 mg to Japanese patients with primary osteoporosis reduced the risk of new morphometric vertebral fractures and was found to be safe.

Differential Effects of Teriparatide and Zoledronic Acid on Bone Mineralization Density Distribution at 6 and 24 Months in the SHOTZ Study

The Skeletal Histomorphometry in Patients on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study assessed the progressive effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone remodeling and material properties in postmenopausal women with osteoporosis. Previously, we reported that biochemical and histomorphometric bone formation indices were significantly higher in patients receiving TPTD versus ZOL. Here we report bone mineralization density distribution (BMDD) results based on quantitative backscattered electron imaging (qBEI). The 12-month primary study was randomized and double blind until the month 6 biopsy, then open label. Patients (TPTD, n = 28; ZOL, n = 31) were then eligible to enter a 12-month open-label extension with their original treatment: TPTD 20 μg/d (subcutaneous injection) or ZOL 5 mg/yr (intravenous infusion). A second biopsy was collected from the contralateral side at month 24 (TPTD, n = 10; ZOL, n = 10). In cancellous bone, ZOL treatment was associated at 6 and 24 months with significantly higher average degree of mineralization (CaMEAN, +2.2%, p = 0.018; +3.9%, p = 0.009, respectively) and with lower percentage of low mineralized areas (CaLOW , -34.6%, p = 0.029; -33.7%, p = 0.025, respectively) and heterogeneity of mineralization CaWIDTH (-12.3%, p = 0.003; -9.9%, p = 0.012, respectively), indicating higher mineralization density and more homogeneous mineral content versus TPTD. Within the ZOL group, significant changes were found in all parameters from month 6 to 24, indicating a progressive increase in mineralization density. In sharp contrast, mineralization density did not increase over time with TPTD, reflecting ongoing deposition of new bone. Similar results were observed in cortical bone. In this study, TPTD stimulated new bone formation, producing a mineralized bone matrix that remained relatively heterogeneous with a stable mean mineral content. ZOL slowed bone turnover and prolonged secondary mineralization, producing a progressively more homogeneous and highly mineralized bone matrix. Although both TPTD and ZOL increase clinical measures of bone mineral density (BMD), this study shows that the underlying mechanisms of the BMD increases are fundamentally different. © 2016 American Society for Bone and Mineral Research.

Abstract P5-15-04: Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients

Abstract Background: Bisphosphonates can delay the onset and reduce the risk of skeletal related events in patients with bone metastatic breast cancer; it can prevent and controlcancer treatment-induced bone loss. Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease free survival. The aim of the study is to evaluate the benefits of ZOL combined with adjuvant therapy in premenopausal early breast cancer patients. Patients and methods: Patients were premenopausal females who had undergone primary surgery for stage I, II ER +ve and/or PR +ve breast cancer with &amp;lt; 10 positive lymph nodes. All 300 patients were scheduled for standard tamoxifen 20mg/day for five years plus goserelin 3.6 mg every 28 days and were randomized to ZOL 4mg every 6 months for 3 years (group A) and without ZOL (group B). The primary end points were toxicity and disease-free survival (DFS), while overall survival (OS) was the secondary end point. Results: Between April 2005 and March 2012, 300 patients were enrolled, the median follow up duration was 98.4 months (range 14-120 months), adding ZOL to endocrine therapy strongly suggests improved DFS versus endocrine therapy alone (90% versus 85% for an absolute increase of 5%). There were fewer disease recurrences in the ZOL group versus no ZOL group (12% vs. 16%) with the greatest reductions in the loco-regional recurrence (3% vs. 5%), distant metastasis (6% vs. 7%) and bone metastasis (3% vs. 5%). Conclusion: ZOL with adjuvant endocrine therapy were generally well tolerated with no reports of renal failure or osteonecrosis of the jaw. So, a twice yearly ZOL enhanced the efficacy of adjuvant endocrine treatment, and this benefit is maintained for long time. Citation Format: El-Ibrashi MM, El-Sadda WM, Abdel-Halim II, Elashri MS. Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-15-04.

Anti-proliferation effect of zoledronic acid on human colon cancer line SW480.

To investigate the anti-proliferation effect and mechanism of zoledronic acid (ZOL) on human colon cancer line SW480. SW480cells were treated with 0, 12.5, 25, 50, 100 and 200μmoL/L of ZOL for 48h, and CCK-8 assay was employed to obtain the survival rate of SW480cells. SW480 cells were treated with 25μmoL/L of ZOL for 0, 12, 24, 48 and 72h, and then the survival rate was obtained. SW480 cells of the ZOL group were treated with 25μmoL/L of ZOL for 48h, while cells of the CsA+ZOL group were pretreated with 10μmoL/L of CsA for 0.5h and then treated with 25μmoL/L of ZOL for 48h. Then the survival rates of SW480cells of the control group, ZOL group and CsA+ZOL group were determined. Flow cytometry was employed to detect the apoptosis rate and the mitochondrial transmembrane potential (△Ψm) of the three groups and Western blot was used to detect the expressions of cyt C in the cytosol of the three groups. ZOL inhibited the proliferation of SW480cells, and the inhibition rate positively correlated with the concentration of ZOL and the action time (P<0.01). The cell survival rate and the △Ψm of the ZOL group were greatly lower than those of the control group, while the apoptosis rate and the expression of cyt C in the cytosol were obviously higher than those of the control group. All the differences showed distinctly statistical significances (P<0.01). The cell survival rate and the △Ψm of the CsA+ZOL group were all lower than those of the control group, but substantially higher than those of the ZOL group; while the apoptosis rate and the expression of cyt C in the cytosol were higher than those of the control group, but distinctly lower than those of the ZOL group. All the differences were statistically significant (P<0.01). ZOL can induce the apoptosis in human colon cancer line SW480 and then inhibit the proliferation of SW480cells directly by opening the mitochondrial permeability transition pore abnormally, decreasing △Ψm, and releasing the cyt C into the cytosol. And the effect enhances with the increases of the concentration of ZOL and the action time.

Effect of a local, one time, low-dose injection of zoledronic acid on titanium implant osseointegration in ovariectomized rats

IntroductionLocal application of bisphosphonates has been proven to be safer than systemic administration to promote implant fixation. The objective of this study was to introduce such a simple, convenient and efficient method to enhance titanium (Ti) implant osseointegration in ovariectomized (OVX) rats.Material and methodsTwenty female Sprague-Dawley rats sequentially underwent bilateral ovariectomy and tibia implantation, and injection of 30 µg/implant zoledronic acid (ZOL) at the site of implantation was performed. At the end of the study, the tibiae, mandibles, femurs and vertebrae were harvested for dual energy X-ray absorptiometry, histology and micro-computed tomography examination.ResultsOvariectomized rats showed poor bone density, bone mass and trabecular microstructure. OVX + ZOL rats were characterized by significantly improved peri-implant bone area (1.72-fold), bone contact (2.30-fold), bone mineral density (1.57-fold) and bone mineral content (1.67-fold), as well as moderately increased bone volume to total volume ratio (1.34-fold), percentage osteointegration (1.54-fold), connectivity density (1.45-fold), and trabecular number (1.43-fold), but decreased trabecular separation (57.69%) when compared with the control levels (p < 0.05). No histological signs of jaw osteonecrosis were observed in the rats treated with ZOL, and there was no significant difference between the OVX group and OVX + ZOL group in the bone mass of the mandible, femur and 5th lumbar vertebra (p > 0.05). In addition, the overproduction of osteoporosis-induced advanced glycation end-products (AGEs) was completely prevented by local treatment with 30 µg/implant ZOL.ConclusionsA local, one time, low-dose injection of ZOL at the site of implantation is able to promote the osseointegration of Ti implants following postmenopausal osteoporosis, and this action may be partly mediated by inhibition of the osteoporosis-induced AGE overproduction in the bone marrow.

The Effect of Interferon-γ and Zoledronate Treatment on Alpha-Tricalcium Phosphate/Collagen Sponge-Mediated Bone-Tissue Engineering.

Inflammatory responses are frequently associated with the expression of inflammatory cytokines and severe osteoclastogenesis, which significantly affect the efficacy of biomaterials. Recent findings have suggested that interferon (IFN)-γ and zoledronate (Zol) are effective inhibitors of osteoclastogenesis. However, little is known regarding the utility of IFN-γ and Zol in bone tissue engineering. In this study, we generated rat models by generating critically sized defects in calvarias implanted with an alpha-tricalcium phosphate/collagen sponge (α-TCP/CS). At four weeks post-implantation, the rats were divided into IFN-γ, Zol, and control (no treatment) groups. Compared with the control group, the IFN-γ and Zol groups showed remarkable attenuation of severe osteoclastogenesis, leading to a significant enhancement in bone mass. Histomorphometric data and mRNA expression patterns in IFN-γ and Zol-injected rats reflected high bone-turnover with increased bone formation, a reduction in osteoclast numbers, and tumor necrosis factor-α expression. Our results demonstrated that the administration of IFN-γ and Zol enhanced bone regeneration of α-TCP/CS implants by enhancing bone formation, while hampering excess bone resorption.

Effect of zoledronic acid on vertebral marrow adiposity in postmenopausal osteoporosis assessed by MR spectroscopy.

Zoledronic acid (ZOL) has a suppressive effect on marrow adiposity in ovariectomized rats. Currently, however, data on the effect of ZOL on marrow fat in humans are unavailable. The purpose of this work was to determine the in vivo effect of ZOL on bone remodeling and marrow adipogenesis in postmenopausal osteoporosis. In a 12-month, randomized, double-blind, placebo-controlled trial, we studied 100 postmenopausal women with osteoporosis who were randomly given either a single dose of intravenous infusion of ZOL (5 mg) or placebo. All subjects received adequate dietary calcium and vitamin D3. Main outcome measures included bone mineral density by dual-energy X-ray absorptiometry, vertebral marrow fat content by proton MR spectroscopy, serum markers of bone turnover by biochemical analysis. Ninety percent of the participants completed the 12-month follow-up. With respect to baselines, marrow fat content reduced by 8.1% in the ZOL-treated women and increased by 3.0% in the controls (all p < 0.05). In addition, there were significant increases of bone mineral density by 2.8, 2.0, and 1.7% in the lumbar spine, femoral neck, and total hip, respectively, in the ZOL group compared with the placebo group. Serum levels of bone resorption marker CTX and bone formation marker BALP decreased by 33 and 18% in postmenopausal women receiving ZOL. In postmenopausal women with osteoporosis, a single dose of ZOL therapy significantly reduced marrow adiposity. MR spectroscopy of vertebral marrow fat may therefore serve as a novel tool for BMD-independent efficacy assessment.

Chondroprotective effect of high-dose zoledronic acid: An experimental study in a rabbit model of osteoarthritis.

To address the need to impact the subchondral bone-articular cartilage interaction for the treatment of degenerative osteoarthritis (OA), bisphosphonates may be used as a means to inhibit the subchondral bone resorption. The purpose of the present study is to evaluate the chondroprotective effect of zoledronic acid (ZOL) in a model of OA. Eighteen adult male rabbits underwent an anterior cruciate ligament transection and were separated into two groups: ZOL group (n=10) received 0.6 mg/kg intravenous injection of ZOL on day 1, 15, and 29 and placebo group (n=8) received saline. The animals were euthanized at 8 weeks. Macroscopically, the ZOL group had significantly milder ulcerations, cartilage softening and fibrillation compared to the placebo group. Microscopically, morphology of the articular cartilage was better in the ZOL treated group compared with the placebo group, without complete disorganization in any section of the ZOL group. Furthermore, the chondrocytes in the ZOL treated group were mainly cloning, indicating cartilage repairing and regeneration process, while in the placebo group hypocellularity predominated. Additionally, subchondral necrosis was evident in some specimens of the placebo group. Zoledronic acid, in a high-dose regimen, proved to be chondroprotective in a well-established animal model of OA.

Zoledronic acid infusion for lumbar interbody fusion in osteoporosis

BackgroundClinical outcomes of intravenous (IV) infusion of zoledronic acid (ZOL) for lumbar interbody fusion surgery (LIFS) remain unknown. We investigated the efficacy of IV ZOL on clinical outcome and bone fusion after LIFS. Materials and methodsWe retrospectively analyzed 64 patients with both degenerative lumbar spondylolisthesis and osteoporosis who underwent LIFS from January 2007 to April 2010. All patients were followed up for 2 y. Thirty-two were treated with an IV infusion of ZOL 3 d after surgery and a second injection 1 y later, and the other 32 patients did not receive ZOL. Preoperatively and every 3 mo postoperatively, oswestry disability index questionnaire and visual analog scale (VAS) scores for back and leg were compared. Preoperative and final postoperative follow-up to evaluate for subsequent compression fractures were also performed. Pedicle screw loosening, cage subsidence, and fusion rate were documented 2 y after surgery. ResultsAt 2-y follow-up, a solid fusion was achieved in 75% of the ZOL group and only 56% of the control group. At final follow up, the incidence of final subsequent vertebral compression fractures (19% of the ZOL group and 51% of the control group, P = 0.006), pedicle screw loosening (18% of the ZOL group and 45% of the control group, P = 0.03), and cage subsidence >2 mm (28% of the ZOL group and only 54% of the control group, P = 0.04) were significantly lower in the ZOL group than in the control group. The ZOL group demonstrated improvement in VAS (for leg pain VAS, 2/10 for the ZOL group and 5/10 for the control group; for back pain VAS, 2/10 for the ZOL group and 6/10 for the control group) and oswestry disability index scores (7/25 for the ZOL group and 16/25 for the control group). ConclusionsZOL treatment has beneficial effects on instrumented LIFS both radiographic and clinically. Thus, ZOL treatment can be recommended for osteoporosis patients undergoing LIFS.

Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results

Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21-28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5.9-year median follow-up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5.2% vs. CLO 5.8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3.7% vs. CLO 0.5%; P < 0.0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23.7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date.

Early tissue responses to zoledronate, locally delivered by bone screw, into a compromised cancellous bone site: a pilot study

BackgroundIn fracture treatment, adequate fixation of implants is crucial to long-term clinical performance. Bisphosphonates (BP), potent inhibitors of osteoclastic bone resorption, are known to increase peri-implant bone mass and accelerate primary fixation. However, adverse effects are associated with systemic use of BPs. Thus, Zoledronic acid (ZOL) a potent BP was loaded on bone screws and evaluated in a local delivery model. Whilst mid- to long-term effects are already reported, early cellular events occurring at the implant/bone interface are not well described. The present study investigated early tissue responses to ZOL locally delivered, by bone screw, into a compromised cancellous bone site.MethodsZOL was immobilized on fibrinogen coated titanium screws. Using a bilateral approach, ZOL loaded test and non-loaded control screws were implanted into femoral condyle bone defects, created by an overdrilling technique. Histological analyses of the local tissue effects such as new bone formation and osteointegration were performed at days 1, 5 and 10.ResultsHistological evaluation of the five day ZOL group, demonstrated a higher osseous differentiation trend. At ten days an early influx of mesenchymal and osteoprogenitor cells was seen and a higher level of cellular proliferation and differentiation (p < 5%). In the ZOL group bone-to-screw contact and bone volume values within the defect tended to increase. Local drug release did not induce any adverse cellular effects.ConclusionThis study indicates that local ZOL delivery into a compromised cancellous bone site actively supports peri-implant osteogenesis, positively affecting mesenchymal cells, at earlier time points than previously reported in the literature.

Effect of adjuvant endocrine therapy on hormonal levels in premenopausal women with breast cancer: the ProBONE II study

Endocrine therapy (ET) is a key treatment modality in hormone receptor positive (HR+) early breast cancer (BC) patients. Although the anticancer activity of adjuvant ET + zoledronic acid (ZOL) has been investigated, the potential effects of ET ± ZOL on endocrine hormones in premenopausal women with HR+ early BC are not well understood. ProBONE II was prospective, double-blind, randomized controlled trial. Premenopausal patients with histologically confirmed invasive BC with no evidence of metastases and a T score >-2.5 received ET ± ZOL 4 mg every 3 months for 2 years. Serum levels of estradiol (E2), follicle-stimulating hormone, anti-muellerian hormone (AMH), inhibins A and B, sex hormone-binding globulin, parathyroid hormone, total testosterone, and vitamin D were evaluated at baseline and at every scheduled visit. Of 71 women enrolled, 70 were evaluable (n = 34, ZOL; n = 36, placebo). No statistically significant differences were observed in hormone levels, except E2 and AMH, which showed minor differences. These included decreases in serum E2 levels, which reached a nadir after 3 and 9 months in placebo and ZOL groups, respectively, and decrease in serum AMH levels throughout the study with ZOL, but remained constant with placebo after 6 months. Adverse events in ZOL-treated group were influenza-like illness (32.4 %), bone pain (32.4 %), chills (20.6 %), and nausea (23.5 %). ET ± ZOL was well tolerated. This study showed no influence of ZOL on hormonal level changes that accompany ET, supporting inclusion of ZOL in adjuvant therapy for premenopausal women with HR + BC.

Molecular mechanism of synergistic antitumor activity and induced apoptosis of zoledronic acid and paclitaxel

Objective: This study aimed to investigate the inhibitory effect of zoledronic acid(ZOL) alone or the combined treatment of ZOL and paclitaxel(PTX) on the cell growth of lung cancer cell line in vitro. Methods: The effects of different concentrations of ZOL alone, 2 nM PTX, and combined treatment of ZOL and PTX on the growth of A-549 cell line were determined using methyl thiazolyl tetrazolium(MTT) method. The mechanism of the curative effect was analyzed by flow cytometry on the basis of apoptotic rate. AKT, phospho-AKT, ERK, phospho-ERK, and Bcl-2 expressions were determined by western blot analysis. AKT and ERK gene expressions were determined by RT-PCR. Results: MTT results showed that ZOL alone could inhibit the growth of lung cancer cell line A-549 in a dose-dependent manner. The combined therapy of ZOL and PTX could inhibit cell growth. This combined treatment is more effective than the single treatment with either ZOL or PTX alone. The synergistic inhibition rate is dependent on drug sequencing. Furthermore, maximum inhibition was induced by sequence order, i.e., initial treatment with PTX and then with ZOL. RT-PCR results demonstrated that the mRNA of ERK and AKT of the group treated with PTX and then ZOL were lower than that in other treatment groups. Western blot analysis results demonstrated that the ERK and AKT levels of the treated groups were parallel in the cell line. However, the lowest phospho-ERK, phospho-AKT, and Bcl-2 levels were observed in the PTX then ZOL group. The cell lines treated with PTX alone and ZOL alone ranked second and third among the lowest results, respectively. The highest level was observed in the control group. Conclusion: The combined ZOL and PTX treatment induced the downregulation of phospho-ERK, phospho-AKT, and Bcl-2 protein expressions in RAF/MEK/ERK and PI3K/AKT signaling pathway. This pathway could be one of the synergistic antitumor mechanisms of the two drugs.

Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial

BackgroundThe presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068).MethodsPatients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated.Results86 patients could be included into survival analysis (median follow-up: 88 months, range: 8–108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011).ConclusionsBisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC.Trial registrationClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].

Study on the role of zoledronic acid in treatment of postmenopausal osteoporosis women.

We aimed to assess the role of zoledronic acid (ZOL) on the risk of fracture and bone mineral density (BMD) in women with osteoporosis. A double-blind and placebo-controlled design was taken in our study. 327 patients who received an intravenous 5-mg infusion zoledronic acid at day 0, at 12 months were enrolled in treatment group, and the remaining 333 patients who received placebo at the same time of the treatment group were included as control group. The incidence of fracture and BMD in the femoral neck and total hip were assessed. ZOL group had lower incidence of fracture at any clinical fracture, clinical vertebral fracture, non-vertebral fracture and hip fracture compared with placebo group at the time of one year and three years. We found that the BMD were significantly increased at femoral neck and total hip in ZOL group at the time of one year and three years follow-up when compared with placebo group (P<0.05). The adverse events in the ZOL within three days of drug infusion were significantly higher than the control group, but we did not find significant difference in the serious adverse effect between the two groups. Zoledronic acid (ZOL) could be used as a safe and effective method for female with osteoporosis.