Alveolar socket healing in 5-lipoxygenase knockout aged female mice treated or not with high dose of zoledronic acid.

This study investigated the role 5-lypoxigenase (5-LO) on alveolar socket healing in aged female mice treated with zoledronic acid (ZL). Forty 129/Sv female mice (64-68 weeks old), 20 wild type (WT) and 20 5-LO knockout (5LOKO) were equally distributed according to ZL treatment: WT Control, WT ZL, 5LOKO Control, and 5LOKO ZL. ZL groups were treated with an intraperitoneal injection of 250 µg/Kg of ZL, while controls were treated with saline. Treatments were administered once a week, starting four weeks before surgery for tooth extraction and until 7 and 21 days post-surgery. Mice were euthanized for a comprehensive microscopic analysis (microCT, histomorphometry and immunohistochemistry). WT ZL mice presented intense inflammatory infiltrate (7 days), delayed bone formation (21 days), reduced collagenous matrix quality, and a deficiency in Runx-2 + , TRAP + , and macrophages as compared to controls. 5LOKO ZL animals presented decreased number of Runx-2 + cells in comparison to 5LOKO Control at 7 days, but no major changes in bone healing as compared to WT or 5LOKO mice at 21 days. The knockout of 5LO favored intramembranous bone healing in aged female mice, with a direct impact on inflammatory response and bone metabolism on the development of ONJ-like lesions.

The effect of high concentration of zoledronic acid on tooth induced movement and its repercussion on root, periodontal ligament and alveolar bone tissues in rats.

Zoledronic acid (ZA) is often prescribed for osteoporosis or resorptive metabolic bone disease. This study aims to evaluate the effect of ZA on orthodontic tooth movement (OTM) and root and bone resorption and its repercussion on root, periodontal ligament and alveolar bone tissues. The experimental group consisted of 72 Wistar rats divided in four subgroups: Naive, Saline and Zoledronic Acid groups at the concentration of 0.2 mg/kg [ZA (0.2)] or 1.0 mg/kg [ZA (1.0)]. The animals were subjected to i.v (dorsal penile vein) administrations of ZA or saline solution, on days 0, 7, 14 and 42. Under anesthesia, NiTi springs were installed in the first left maxillary molar with 50gf allowing the OTM, except for the negative control group (N) for mesial movement of the left first maxillary teeth. The animals were sacrificed and maxillae were removed for macroscopic and histopathological analyzes, scanning electron microscopy, computerized microtomography and confocal microscopy. Treatment with ZA decreased the OTM and the number of osteoclasts and loss of alveolar bone when compared to the naive and saline groups. Reduction of radicular resorption, increased necrotic areas and reduced vascularization in the periodontal ligament were observed in the ZA groups. ZA interferes with OTM and presents anti-resorptive effects on bone and dental tissues associated with a decreased vascularization, without osteonecrosis.

Guideline adherence in bone-targeted treatment of cancer patients with bone metastases in Germany.

PURPOSE: To assess adherence to the current European Society for Medical Oncology (ESMO) clinical practice guideline on bone health in cancer patients and the German guidelines for lung, breast, and prostate cancer among German oncologists in hospitals and office-based physicians and to identify predictors of guideline compliance to assess the needs for dedicated training. METHODS: This was a retrospective sample analysis representing hospitals and office-based physicians in Germany in 2016. Records from lung, breast, and prostate cancer patients who had received a diagnosis of bone metastasis between April 1, 2015, and March 31, 2016, were included. Oncologists at participating centers answered a self-assessment survey on aspects related to their professional life, including guideline adherence and years of clinical experience in medical oncology. Guideline adherence rates were assessed from patient records. Treatment variables and survey data were used to identify predictors of guideline compliance in a Classification and Regression Tree (CART) analysis. RESULTS: Disregarding recommendations for supplementation of calcium and vitamin D, guideline adherence among physicians treating lung, breast, or prostate cancer patients was 62%, 92%, and 83%, respectively. Compliance was 15%, 42%, and 40% if recommendations for dietary supplements were taken into account. Identified predictors of guideline compliance included treatment setting, medical specialty, years of professional experience, and frequency of quality circle attendance. CONCLUSIONS: Compliance with the ESMO and the German guidelines in cancer patients varies between medical specialties. In particular, patients with lung cancer and bone metastases often do not receive the recommended osteoprotective treatment and required supplementation. Discrepancies between guideline recommendations and common practice should be addressed with dedicated training.

Bisphosphonates as a therapeutic choice for multifocal epithelioid hemangioma of bone: A case report.

RATIONALE: Epithelioid hemangioma (EH) of bone is an intermediate vascular tumor that can be locally aggressive. The optimum management of multifocal EH of bone is not well delineated. We described our experience treating one patient with multifocal EH of bone in an effort to document the effect of bisphosphonates in bone EH. PATIENT CONCERNS: In this report, a 53-year old male patient presented with back pain which was initially been diagnosed of multiple bone metastatic carcinoma by 18F-FDG PET/CT scan and bone scintigraphy. DIAGNOSIS: CT-guided bone biopsy of ilium indicated that puncture tissue had irregular hyperplasia of thick and thin-walled blood vessels, immunohistochemistry revealed positive staining for CD31 and CD34, negative for CAMTA-1, PCK and EMA, which confirmed the diagnosis of multiple EH. INTERVENTIONS: The patient was treated with 4 times of intravenous Zometa (zoledronate, 4 mg each time) with average three-month interval. Bone metabolic markers including serum bone specific alkaline phosphatase (BALP) and type I collagen cross-linked C-terminal telopeptide (CTX) levels were closely monitored before and after use of bisphosphonates each time. OUTCOME: BALP and CTX were significantly lowered following intravenous Zometa and the back pain improved with integrated therapy including bone graft fusion internal fixation surgery and vertebroplasty. CONCLUSIONS: EH of multiple bones responded favorably to intravenous Zometa with improvement of bone metabolic markers. After 1 year on follow-up, the patient was doing well with no significant pain. We suggest that bisphosphonates should be considered in the treatment of multifocal osteolytic EH of bone.

Effect of denosumab versus zoledronic acid on calcium levels in cancer patients with bone metastasis: A retrospective cohort study.

OBJECTIVE: To identify the incidence of hypercalcemia and hypocalcemia in zoledronic acid and denosumab groups. Secondary objective was to determine the correlation between calcium supplement and calcium level control. METHODS: An observational retrospective cohort study was conducted by reviewing patient electronic records, laboratory results, and medication charts from 1 August 2015 to 31 July 2016. Adult cancer patients who were diagnosed with bone metastasis secondary to a solid tumor or multiple myeloma and who received either zoledronic acid or denosumab were included. Other indications for bone targeting agents were excluded. Data of bone targeting agents administration encounters were collected, evaluated, and analyzed. RESULTS: A total of 1141 encounters (for 271 patients) were included. The incidence of hypocalcemia was higher in denosumab compared to zoledronic acid group (5.5% vs. 3.1%, OR = 0.55, 95% CI [0.3-1.0]; P = 0.05). Hypercalcemia incidence was also higher in denosumab group (8.5% vs. 3.1%, OR = 2.9, 95% CI [1.68-5.03]; P < 0.0001). Breast cancer was the most common malignancy associated with hypocalcemia (27.3%) followed by ovarian cancer (25%) and multiple myeloma (22.7%). The risk of developing hypocalcemia was reduced by 16% in patients receiving calcium supplementation (RR = 0.84, 95% CI [0.55-1.20]; P = 0.39). CONCLUSION: Denosumab use was associated with higher rates of both hypercalcemia and hypocalcemia compared to zoledronic acid. Adequate supplementation with calcium substantially reduced the risk of hypocalcemia. Our results highlight the importance of taking preventative measures upon bone targeting agents initiation and during treatment including regular monitoring of calcium levels and providing supplements accordingly.

Bone-Targeted Nanoplatform Combining Zoledronate and Photothermal Therapy To Treat Breast Cancer Bone Metastasis.

Bone metastasis, a clinical complication of patients with advanced breast cancer, seriously reduces the quality of life. To avoid destruction of the bone matrix, current treatments focus on inhibiting the cancer cell growth and the osteoclast activity through combination therapy. Therefore, it could be beneficial to develop a bone-targeted drug delivery system to treat bone metastasis. Here, a bone-targeted nanoplatform was developed using gold nanorods enclosed inside mesoporous silica nanoparticles (Au@MSNs) which were then conjugated with zoledronic acid (ZOL). The nanoparticles (Au@MSNs-ZOL) not only showed bone-targeting ability in vivo but also inhibited the formation of osteoclast-like cells and promoted osteoblast differentiation in vitro. The combination of Au@MSNs-ZOL and photothermal therapy (PTT), triggered by near-infrared irradiation, inhibited tumor growth both in vitro and in vivo and relieved pain and bone resorption in vivo by inducing apoptosis in cancer cells and improving the bone microenvironment. This single nanoplatform combines ZOL and PTT to provide an exciting strategy for treating breast cancer bone metastasis.

A Bioactive Coating Enhances Bone Allografts in Rat Models of Bone Formation and Critical Defect Repair.

Bone allografts are inferior to autografts for the repair of critical-sized defects. Prior studies have suggested that bone morphogenetic protein-2 (BMP-2) can be combined with allografts to produce superior healing. We created a bioactive coating on bone allografts using polycondensed deoxyribose isobutyrate ester (PDIB) polymer to deliver BMP-2 ± the bisphosphonate zoledronic acid (ZA) and tested its ability to enhance the functional utility of allografts in preclinical Wistar rat models. One ex vivo and two in vivo proof-of-concept studies were performed. First, PDIB was shown to be able to coat bone grafts (BGs). Second, PDIB was used to coat structural allogenic corticocancellous BG with BMP-2 ± ZA ± hydroxyapatite (HA) microparticles and compared with PDIB-coated grafts in a rat muscle pouch model. Next, a rat critical defect model was performed with treatment groups including (i) empty defect, (ii) BG, (iii) collagen sponge + BMP-2, (iv) BG + PDIB/BMP-2, and (v) BG + PDIB/BMP-2/ZA. Key outcome measures included detection of fluorescent bone labels, microcomputed tomography (CT) quantification of bone, and radiographic healing. In the muscle pouch study, BMP-2 did not increase net bone volume measured by microCT, however, fluorescent labeling showed large amounts of new bone. Addition of ZA increased BV by sevenfold (p < 0.01). In the critical defect model, allografts were insufficient to promote reliable union, however, union was achieved in collagen/BMP-2 and all BG/BMP-2 groups. Statement of clinical significance: These data support the concept that PDIB is a viable delivery method for BMP-2 and ZA delivery to enhance the bone forming potential of allografts. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2278-2286, 2019.

Effects of sequential treatment with intermittent parathyroid hormone and zoledronic acid on particle-induced implant loosening: Evidence from a rat model.

Particle-induced implant loosening is a major challenge to long-term survival of joint prostheses. Administration of intermittent parathyroid hormone (PTH) has shown potential in the treatment of cases of early-stage periprosthetic osteolysis, while sequential administration of intermittent PTH (iPTH) and bisphosphonates (Bps) has achieved significant effects on treatment of postmenopausal osteoporosis. The objective of this study was to determine whether sequential treatment could preserve bone mass and implant fixation during a pathological course of peri-implant osteolysis in a rat model. Ninety male Sprague Dawley rats were randomly divided into nine groups, four of which were used for confirmation of establishment of the peri-implant osteolysis model at two time points, while the other five were used to determine the efficiency of the sequential treatment on peri-implant osteolysis. Implant fixation and peri-implant bone mass were evaluated using biomechanical testing, micro-CT analysis, and histology at 6 and 12 weeks postoperative. The biomechanical test demonstrated that the maximum loading force during a push-out test was significantly elevated in the sequential treatment group compared to the osteolysis group and iPTH withdrawal group at 12 weeks. Peri-implant bone morphology also indicated a robust increase in bone volume in the sequential treatment group. Sequential administration of iPTH and Bps was effective in preventing experimental peri-implant osteolysis, resulting in improved implant fixation and increased peri-implant bone volume. Clinical significance: The innovative application of sequential treatment in peri-implant osteolysis could be used clinically to improve the prognosis of patients with early-stage periprosthetic osteolysis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1489-1497, 2019.

Combination therapy with low-dose teriparatide and zoledronate contributes to fracture healing on rat femoral fracture model.

BACKGROUND: Delay in fracture healing or non-union can be devastating complication. Recent studies have reported that teriparatide (TP) demonstrated effectively on callus formation and mechanical strength and zoledronate (ZA) increased the callus size and resistance at the fracture site in rat fracture model. In this study, the effects of combination therapy with low dose TP and ZA on fracture healing was evaluated. METHODS: From 1 week post-operation, TP (5 times a week administration) and ZA (0.1 mg/kg single administration) were administered by dividing the rats into the following five groups: TP 1 µg group {T(1): TP 1 µg/kg}, ZA group (ZA:0.1 mg/kg), TP1 µg+ZA group {T(1)+ZA: TP 1 µg/kg+ZA}, TP 10 µg+ZA group {T(10)+ZA: TP 10 µg/kg + ZA}, and control group (C: administered saline). Rt femurs were excised 7 weeks after the surgery; bone fusions were evaluated with soft X-ray images on a 4-point scale. And the histopathological examination was performed in demineralized and non-demineralized specimens. Furthermore, the Radiographic Union Scale was conducted in all specimens. RESULTS: About the bone fusions rates, C, T(1), ZA, T(1)+ZA, and T(10)+ZA groups demonstrated 20.0%, 55.6%, 70.0%, 70.0%, and 80.0%, respectively, and with 4-point scale, each group was 0.50, 1.56, 2.00, 2.60, and 2.80 points, respectively. The callus volume was significantly increased to 16.66 mm2 and 17.75 mm2 in the T(1)+ZA and T(10)+ZA groups, respectively, while 10.65 mm2 (p < 0.05) in the C group. Furthermore, the callus area in the T(10)+ZA group was also observed to have significantly increased to 78.78%, compared with 54.63% and 44.11% in the C and T(1)+ZA groups, respectively (p < 0.01). Histopathologically, cartilage tissue and immature callus formation were observed at the bone junction in the C group; however, the osseous bridge formation of mature callus was observed in the ZA, T(1)+ZA, and T(10)+ZA groups. CONCLUSION: It is suggested that administration of low dose TP and ZA in combination may lead to the treatment of delayed union of fracture. We hope the combination treatment may become one of new therapeutic strategy.

Clinical effect of intravenous infusion of zoledronic acid combined with oral medication of cinobufagin in the treatment of metastatic bone tumors.

Aim of the study was to observe and analyze the clinical effect of intravenous infusion of zoledronic acid combined with oral medication of cinobufagin in treating metastatic bone tumors. The 120 patients who have been treated in the hospital for metastatic bone tumor from June 2014 to June 2017 were selected as research objects. They were randomly divided into research group and control group, each containing 60. The research group was treated with intravenous infusion of zoledronic acid combined with oral medication of cinobufagin. In the control group, only zoledronic acid intravenous infusion was administered. The overall treatment effect of the two groups was observed. The pain of two groups was evaluated using numerical rating scale (NRS). The results showed that compared with the control group, the research group achieved better clinical effect and had a higher quality of life, and the intergroup difference was of statistical significance, P<0.05. There was no difference in rate of adverse reactions between the two groups, P>0.05, without statistical significance. The combined therapy of intravenous infusion of zoledronic acid and oral medication of cinobufagin can obtain better therapeutic effect in treating metastatic bone tumors.

Cost-effectiveness of single-dose zoledronic acid for nursing home residents with osteoporosis in the USA.

OBJECTIVE: To evaluate the cost-effectiveness of routine administration of single-dose zoledronic acid for nursing home residents with osteoporosis in the USA. DESIGN: Markov cohort simulation model based on published literature from a healthcare sector perspective over a lifetime horizon. SETTING: Nursing homes. PARTICIPANTS: A hypothetical cohort of nursing home residents aged 85 years with osteoporosis. INTERVENTIONS: Two strategies were compared: (1) a single intravenous dose of zoledronic acid 5 mg and (2) usual care (supplementation of calcium and vitamin D only). PRIMARY AND SECONDARY OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER), as measured by cost per quality-adjusted life year (QALY) gained. RESULTS: Compared with usual care, zoledronic acid had an ICER of $207 400 per QALY gained and was not cost-effective at a conventional willingness-to-pay threshold of $100 000 per QALY gained. The results were robust to a reasonable range of assumptions about incidence, mortality, quality-of-life effects and the cost of hip fracture and the cost of zoledronic acid. Zoledronic acid had a potential to become cost-effective if a fracture risk reduction with zoledronic acid was higher than 23% or if 6-month mortality in nursing home residents was lower than 16%. Probabilistic sensitivity analysis showed that the zoledronic acid would be cost-effective in 14%, 27% and 44% of simulations at willingness-to-pay thresholds of $50 000, $100 000 or $200 000 per QALY gained, respectively. CONCLUSIONS: Routine administration of single-dose zoledronic acid in nursing home residents with osteoporosis is not a cost-effective use of resources in the USA but could be justifiable in those with a favourable life expectancy.

Prevention of breast cancer treatment-induced bone loss in premenopausal women treated with zoledronic acid: Final 5-year results from the randomized, double-blind, placebo-controlled ProBONE II trial.

PURPOSE: Premenopausal women receiving chemotherapy or endocrine treatment for early breast cancer are at increased risk for cancer treatment induced bone loss (CTIBL). The aim of the randomized, double-blind ProBONE II trial was to investigate whether a 2-year adjuvant treatment with 4 mg intravenous zoledronic acid (ZOL) every 3 months versus placebo would prevent CTIBL after a five-year period. METHODS: Thirty-one of the 34 participants in the ZOL arm and thirty-four of the 36 participants in the placebo arm were followed-up to the 5-year visit and completed the study as planned. The changes in Bone Mass Density (BMD) were assessed at baseline and each visit after treatment initiation. RESULTS: After 24 months, BMD at the lumbar spine showed a 2.9% increase in patients treated with ZOL vs. a 7.1% decrease in placebo-treated participants compared to baseline (p < 0.001). Over the 60-month study period, we found a decrease of 2.2% vs. 7.3% in the BMD at the lumbar spine in patients receiving ZOL and placebo respectively (p < 0.001). Over the 60-month study period, BMD in the placebo arm showed a continuous decrease at all sites (p < 0001), whereas patients treated with ZOL reached baseline BMD-values at the femoral neck and total hip. CONCLUSIONS: In ProBone II, a 2-year treatment with ZOL 4 mg intravenous every 3 months prevented cancer treatment induced bone loss in premenopausal women with breast cancer and maintained the BMD up to 3 years post-treatment.