Injection Of Zoledronic Acid Research Articles

Investigation of the Effect of Pentoxifylline and Tocopherol on Osseous Healing Following Tooth Extraction in Bisphosphonate-Administered Rats

Background: The incidence of medication-related osteonecrosis of the jaw has increased with the widespread use of bisphosphonates. Present study aimed to evaluate the effect of pentoxifylline and/or tocopherol alone or in combination, on bisphosphonate-induced osteonecrosis in tooth extracted rat jaw. Methods: 24 rats were randomly assigned to 4 groups and each animal received intraperitoneal zoledronic acid injection 0.06 mg/ kg/week for 3 weeks. Following the zoledronic acid application, the lower right first molars of the rats were extracted on day 22. Starting from the day of tooth extraction animals received intraperitoneal pentoxifylline and/or tocopherol injections. Fourteen days later all rats were sacrificed. RANKL and osteoprotegerin (OPG) in blood were measured, and mandibles were examined histologically. When the inter-group differences were evaluated, the Kruskal Wallis-H Test and the Chi-square analysis were used. Results: Each groups’ serum RANKL, OPG and RANKL/OPG levels did not reveal any statistically significant differences. There were no statistically significant differences in terms of bone necrosis, abscess formation, inflammation, osteoblastic/osteoclastic activity, bone cellularity and epithelial integrity.Conclusions: Pentoxifylline and/or tocopherol injections alone or in combination did not have any statistically significant effecton the jaw following tooth extraction in bisphosphonate-induced rat animal model.

Analysis on application value of Fu's subcutaneous needling for intercostal pain after surgery of osteoporotic thoracic vertebral compression fracture

To observe the effect of Fu's subcutaneous needling therapy on pain degree, quality of life, serum 5-hydroxytryptamine (5-HT) and neuropeptide Y (NPY) in patients with intercostal pain after surgery for osteoporotic thoracic vertebral compression fracture (OVCF) and explore the application value of Fu's subcutaneous needling in treatment of post-operative intercostal pain. A total of 60 patients with intercostal pain after OVCF surgery were divided into a medication group and a Fu's subcutaneous needling therapy group, with 30 cases in each group. In the medication group, zoledronic acid injection, salmon calcitonin injection, calcitonin D tablets and mecobalamin tablets were prescribed. The duration of treatment was 8 weeks. In the Fu's subcutaneous needling therapy group, on the base of treatment as the medicine group, Fu's subcutaneous needling therapy was provided for 2 weeks，once every other day. The needle is inserted 6 cm away from the most painful point. Separately, in 2, 4 and 8 weeks of treatment, as well as in 16 weeks after treatment, the visual analogue scale (VAS) and the generic quality of life inventory-74 (GQOLI-74) were adopted to evaluate intercostal pain and quality of life in the patients of both groups and analyze the incidence of adverse reaction. Radioimmunoassay was used to measure the levels of serum 5-HT and NPY. Compared with the results before treatment, in 2, 4 and 8 weeks of treatment as well as in 16 weeks after treatment, VAS scores of both groups were all reduced (P<0.05), GQOLI-74 scores increased obviously (P<0.05) and the levels of serum 5-HT and NPY increased obviously (P<0.05) in the two groups. In 2, 4 and 8 weeks of treatment as well as in 16 weeks after treatment, VAS score in the Fu's subcutaneous needling therapy group was lower than that in the medication group (P<0.05), GQOLI-74 score and the levels of serum 5-HT and NPY were higher than those in the medication group (P<0.05). During the treatment and in 16 weeks after treatment, the difference was not significant in the incidence of adverse reaction between the two groups (P>0.05). Fu's subcutaneous needling therapy can relieve intercostal pain and improves the quality of life in the patients after surgery for OVCF.

Clinical Efficacy and Safety of Zoledronic Acid Combined with PVP/PKP in the Treatment of Osteoporotic Vertebral Compression Fracture: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective We conducted this meta-analysis to provide better evidence of the efficacy and safety of zoledronic acid (ZA) combined with percutaneous vertebroplasty/kyphoplasty (PVP/PKP) on osteoporotic vertebral compression fracture (OVCF) and proposed a protocol for its application in clinical practice. Methods All randomized controlled trials (RCTs) of ZA combined with PVP or PKP compared to individual PVP/PKP for the management of patients with OVCFs were included in this study. Electronic database searches were conducted from database inception to November 2020, including the Cochrane Library, PubMed, Web of Science, and Embase. The pooled data were analyzed using RevMan 5.3 software. Results Seven RCTs with 929 subjects were finally included. All included studies reported visual analog scores (VAS), and no statistically significant differences were identified at follow-ups of 3 d and 1 w (P > 0.05). In contrast, significant differences were observed at the 1 mo, 3 mo, 6 mo, and 12 mo follow-ups (P < 0.05). Two trials reported the Cobb angle and vertebral body height (VBH), including 182 subjects without significant differences at the 12 mo follow-up (P > 0.05). In addition, significant differences in the bone mineral density (BMD), β-isomerized C-terminal telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I collagen (PINP), and N-terminal molecular fragment (N-MID) levels were observed between the two groups (P < 0.05). All trials reported side effects. Significant differences in recurrent fractures, fever, flu-like symptoms, and arthralgia or myalgia were identified (P < 0.05); however, no significant difference in postoperative leakage was detected (P > 0.05). Conclusion Compared to PVP/PKP alone, an additional ZA injection had advantages of long-term analgesic effects with improved bone metabolism indexes. Moreover, combination therapy significantly prevented complications and drug reactions were well tolerated. Overall, this systematic review revealed that ZA combined with PVP/PKP was an effective, safe, and comprehensive therapy for patients with OVCFs.

Effect and timing of parathyroid hormone analog administration for preventing medication-related osteonecrosis of the jaws in a murine model

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group.In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials.

Potential protective effect of zoledronic acid when switching from long-term therapy of osteoporosis with denosumab

In accordance with the data of the Federal Clinical Recommendations for the Diagnosis, Treatment and Prevention of Osteoporosis, with the latter, antiresorptive drugs (denosumab, bisphosphonates) are used, which mainly suppress bone resorption, and anabolic compounds (teriparatide), which enhance bone formation. The vector of their pharmacological effect helps to prevent BMD loss and significantly reduces the risk of low-energy vertebral fractures and fractures of other localizations. The experience of clinical trials makes it possible to successfully carry out antiresorptive therapy with some drugs (denosumab) for up to 10 years, demonstrating good adherence and tolerance. Bisphosphonates remain in the bone matrix for a long time and are characterized by a period of a certain aftereffect. Denosumab and teriparatide show their effect only during the period of direct use. According to some data, when denosumab therapy is canceled in a situation where the targeted goal is achieved, the incidence of vertebral fractures increases, especially in patients with a history of low-traumatic fractures. The article will present the main provisions of the European Calcified Tissues Society, the European Medical Agency, the Russian Association for Osteoporosis regarding the timing of treatment and an analysis of clinical situations requiring the appointment of alternative antiresorptive therapy. According to the resolution of the Council of Experts of the Russian Association on Osteoporosis, bisphosphonates are recommended for all patients to prevent an increased risk of vertebral fractures 6 months after patients had their last subcutaneous injection of denosumab. Oral bisphosphonates should be taken immediately, and zoledronic acid injection should be delayed for another 65 days following a missed denosumab injection.

STUDY OF INCIDENCE OF OSTEOPOROSIS INDUCED FRACTURES IN THE ELDERLY AFTER ONCE YEARLY ZOLEDRONIC ACID INJECTION

Introduction: In developing countries like India, the various socio-economic factors like anaemia, hypo proteinemia, early menopause, hysterectomy at younger age and loss of teeth at early age are leading causes of osteoporosis. The treatment for all the above problems at community level is difficult job. We advocated IV injections of Zoledronic acid once in a year which is feasible and possible way of preventing the progression of osteoporosis. This is evidenced by decrease in incidence of new fractures in our patients. Patients and Methods: We studied the efficacy of once yearly IV injection of Zoledronic acid -ZOLE to prevent osteoporotic fractures in the 130 elderly patients and compared the incidence of fractures in the placebo group of 150 patients who were not received the ZOLE injection. The age group ranges from 50 to 70 years who attended OP unit of our Orthopaedic department from January 2018 to December 2019 (2 years). These 280 patients presented with common fractures like fracture neck of femur-110, vertebral fractures-85, proximal tibial fractures-15, proximal humoral fractures-15 and distal radial fractures-55. IV Zoledronic acid was given to 130 patients in addition to fracture treatment. The remaining 150 patients who were not willing for IV injections for various reasons were included in the placebo group of our study. Results: We assessed the incidence of new fractures in both the groups patients, ZOLE group who received Zoledronic injection and placebo group who were not received injection for 2 years period. The incidence of new fractures was significantly diminished in ZOLE group compared to placebo group. We observed the incidence of all cumulative fractures were 30 fractures (24%) in the ZOLE group and in the placebo group the incidence was 110 fractures (76%). Bone mineral density (BMD) of Lumbar spine, femoral neck, proximal humerus and distal radius were done for all the patients at the time of starting of the study and at 2 years follow-up. We observed increased BMD in the ZOLE group. There were no adverse effects like osteonecrosis of jaw and others in our study. Conclusion: In rural areas of developing countries, with poor socioeconomic status, early osteoporosis is prevalent and causing the major fractures after trivial injury. Once yearly administration of Zoledronic acid 5 mg IV is safe and effective way of preventing the incidence of Fractures and subsequent morbidity and mortality.

Investigation of Intravenous Zoledronic Acid Therapy on Circulating Lymphocyte Subpopulation in Patients with Primary Osteoporosis: A Pilot Study

BackgroundSeveral studies have investigated the immunomodulating properties of zoledronic acid on T lymphocytes, but the causal relationship between the function of T cells and the efficacy of zoledronic acid has not been elucidatedObjectiveTo investigate the causal relationship between the function of zoledronic acid and T cells.MethodsWe conducted an observational perspective study to observe the effect of intravenous zoledronic acid once yearly for 2 years on lymphocyte subsets in patients with primary osteoporosis through observing the blood cells analysis and the level of lymphocyte subpopulations before and on day 1, 2, and 3 after first and second administration of intravenous zoledronic acid and bone mineral destiny 1 year after a single administration of zoledronic acid.ResultsWhite blood cell count and neutrophils increased, whereas lymphocytes and eosinophils decreased after the first and second zoledronic acid infusion. The count of CD3+T cells, CD3+CD4+T cells, and CD16+CD56+ natural killer lymphocytes decreased from day 1 to day 3 after the first and second zoledronic acid infusion, but the results of second infusion showed no significance.ConclusionsFurther, larger size, more in-depth studies are indicated to examine whether the short-term changes in white blood cells and lymphocyte subtypes noted after 2 once-yearly zoledronic acid injections in this small population of adult patients is associated with the stimulation of immune mechanisms. (Curr Ther Res Clin Exp. 2021; 82:XXX–XXX)

Zoledronic acid re‑sensitises gefitinib‑resistant lung cancer cells by inhibiting the JAK/STAT3 signalling pathway and reversing epithelial‑mesenchymal transition.

Studies have shown that suppression of both the JAK/STAT3 pathway and epithelial-mesenchymal transition (EMT) may overturn the resistance of non-small cell lung cancer (NSCLC) cells to gefitinib. Zoledronic acid (ZA) injection is used to treat and prevent multiple forms of osteoporosis, hypercalcemia and bone metastasis-related complications of malignancy. Clinical research has shown that ZA may exert antitumour effects and delay the progression of NSCLC. In the present study, we investigated whether ZA combined with gefitinib could re-sensitise NSCLC cells to gefitinib in vitro and in vivo through inhibition of the JAK/STAT3 signalling pathway and EMT reversal. The results revealed that ZA potently increased the sensitivity of gefitinib-resistant lung cancer cells to gefitinib. ZA decreased activation of JAK/STAT3 signalling and reversed EMT in the H1975 and HCC827GR cell lines. Furthermore, addition of IL-6 to ZA-pretreated gefitinib-resistant cell lines abrogated the effect of ZA and restored the cellular resistance to tyrosine kinase inhibitors. Finally, ZA-based combinatorial therapy effectively inhibited the growth of xenografts derived from gefitinib-resistant cancer cells, which was correlated with the inhibition of the JAK/STAT3 signalling pathway and EMT reversal. In conclusion, ZA re-sensitised gefitinib-resistant lung cancer cells through inhibition of the JAK/STAT3 signalling pathway and EMT reversal. The combination of ZA and gefitinib may be a promising therapeutic strategy to reverse gefitinib resistance and prolong the survival of patients with NSCLC.

Effects of percutaneous kyphoplasty combined with zoledronic acid injection on osteoporotic vertebral compression fracture and bone metabolism indices.

Osteoporotic vertebral compression fracture (OVCF) is usually treated by percutaneous kyphoplasty (PKP) which has limitations. We aimed to evaluate the effects of PKP combined with zoledronic acid (ZOL) injection on OVCF and bone metabolism indices. A total of 600 OVCF patients admitted from June 2015 to June 2020 were randomly divided into group A (PKP alone), group B (PKP combined with ZOL 1 month later) and group C (PKP concurrently combined with ZOL) (N.=200). Before as well as 1 month (before ZOL treatment in group B) and 1 year after PKP, the pain degree, physical function and self-care ability in daily life were assessed, the height and kyphosis Cobb angle of vertebral body with compression fracture and bone mineral densities (BMDs) at different parts were measured, the clinical efficacy, adverse reactions and recurrence of vertebral fractures during 3 years of follow-up were observed, and the serum levels of BAP, BGP, β-CTx and TP1NP were detected. Compared with groups A and B, group C had significantly reduced visual analogue scale (VAS) and Oswestry disability index (ODI) scores and raised activity of daily living (ADL) score 1 month after PKP (P<0.05). Groups A-C had successively lowered VAS and ODI scores and elevated ADL Score 1 year after PKP (P<0.05). Compared with before PKP, the height of vertebral body with compression fracture significantly increased, and the kyphosis Cobb angle decreased in the three groups 1 month and 1 year after PKP (P<0.05). In group A, the height was lower whereas the angle was larger 1 year after PKP than those 1 month after PKP (P<0.05). One month after PKP, the height was significantly higher and the angle was smaller in group C than those of groups A and B (P<0.05). One year after PKP, the height significantly increased and the angle decreased successively in groups A-C (P<0.05). BMDs at different parts were significantly higher in group C than those of groups A and B 1 month after PKP (P<0.05). One year after PKP, BMDs were highest in group C and lowest in group A (P<0.05). The overall response rate was significantly higher in group C than that in group A (P<0.05). The recurrence rate of fractures was significantly higher in group A than those of groups B and C (P<0.05). The BAP, BGP, β-CTx and TP1NP levels were significantly lower in group C than those of groups A and B 1 month after PKP (P<0.05), and declined successively in groups A-C 1 year after PKP (P<0.05). PKP concurrently combined with ZOL exert the most significant therapeutic effects on OVCF, with the lowest recurrence rate of fractures. It relieves pain and improves the physical function and self-care ability in daily life probably by reducing bone metabolism indices, increasing BMD, and maintaining the height and kyphosis Cobb angle of recovered vertebral body.

Treatment of severely osteoporotic vertebral compression fractures with the vertebral body stent system and percutanous kyphoplasty combined with zoledronic acid

To investigate the clinical efficacy of vertebral body stent (VBS) system and percutanous kyphoplasty (PKP) combined with zoledronic acid for the treatment of severely osteoporotic compression vertebral fractures (OVCFs). The clinical data of 48 patients with osteoporotic thoracolumbar fractures treated from December 2017 to December 2018 were retrospectively analyzed, including 13 males and 35 females, aged 55 to 92 years old with an average (71.2±10.5) years. All patients were treated with VBS system PKP surgery, and zoledronic acid injection was used for anti-osteoporosis treatment after operation. The VAS scores ODI, the height of diseasedvertebral lost were compared before operation, 3 d and half a year after operation, and whether there was re-fracture of diseased or adjacent vertevrae after operation was observed. Before operation, 3 d and half a year after operation, VAS scores were 7.60±0.12, 3.00±0.46, 1.20±0.23, ODI were(82.00±0.32)%, (30.00±1.50) %, (18.00±0.16) %, the height of diseased vertebral lost were (12.00±0.43) mm, (3.00± 0.15) mm, (3.60±0.51) mm respectively. Postoperative VAS score, ODI, the height of diseased vertebral lost were obviously improved (P<0.05), and there was no significant difference between 3 d and half a year after operation (P>0.05). All the 48 patients were followed up with an average time of (6.6±0.5) months. All the incisions healed at grade A after operation, and no re-fracture of diseased vertebrae or adjacent vertebrae was found at the final follow-up. VBS system and PKP combined with zoledronic acid in the treatment of OVCFs not only may effectively relieve the pain in the thoracolumbar back, improve the mobility of the thoracolumbar, but also can restore the height of the vertebral body to the maximum extent, and prevent the re-fracture of the affected vertebrae and adjacent vertebrae, which is worthy to spread in clinic.

Clinical application of zoledronic acid combined with vitamin K2 in percutaneous vertebroplasty for multi-segment osteoporotic vertebral compression fractures

To explore the clinical effect of zoledronic acid combined with vitamin K2 regimen in percutaneous vertebroplasty for multi-segment osteoporotic vertebral compression fractures(OVCFs). This study was a retrospective control study. A total of 364 patients with OVCFs who were admitted to our spinal surgery department from January 2014 to January 2017 were selected as the study subjects. According to whether zoledronic acid combined with vitamin K2 was used to treat osteoporosis after surgery, the patients were divided into control group and experimental group. Among them, 257 patients in the control group were treated with calcium carbonate and vitamin D regimen, while 107 patients in the experimental group were treated with zoledronic acid combined with vitamin K2 regimen on the basis of the control group. Visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were used to evaluate the clinical effect. Pre- and post-operative bone mineral density of lumbar spine and proximal femur, vertebral height ratio of responsible vertebral body and Cobb angle of vertebral body were observed by image data. Serological indicators related to bone metabolism were detected by laboratory. The complications such as fever, dizziness, osteoarthritis, muscular and soft tissue pain and adjacent vertebral re-fracture were compared between two groups. There was no significant difference in general data between the two groups (P<0.05). There was no significant difference in VAS score between experimental group and control group before and 24 hours after operation (P>0.05);VAS score in the experimental group was significantly lower than that in the control group 1 month, 3 months and 1 year after operation(P<0.05). There was no significant difference in ODI between two groups before operation(P>0.05), and at the 24 hours, 3 months, 1 year after operation, the experimental group was significantly lower than the control group (P<0.05). There was no significant difference in the vertebral height ratio of the responsible vertebral body and the Cobb angle before operation between two groups (P>0.05). The vertebral height ratio of the responsible vertebral body in experimental group was significantly higher than that in control group and Cobb angle in experimental group was significantly lower than that in control group at 3 months and 1 year after operation (P<0.05). There was no significant difference in preoperative bone mineral density of lumbar spine and proximal femur between two groups (P>0.05), but at 3 months and 1 year after operation, the bone mineral density of lumbar spine and proximal femur in experimental group was significantly lower than that in control group (P< 0.05). There was no significant difference in preoperative bone metabolic markers such as total type I collagen amino-terminal elongation peptide, β-collagen degradation products and 25-hydroxyvitamin D between two groups (P>0.05). At 1 year after operation the total type I collagen amino-terminal elongation peptide and β-collagen degradation products in experimental group was significantly lower than that in the control group (P<0.05), but the 25-hydroxyvitamin D operation in experimental group was significantly higher than that in control group(P<0.05). The incidence of postoperative complications such as fever, dizziness, osteoarthritis, muscle and soft tissue pain and adjacent vertebral re-fracture in experimental group was significantly lower than that in control group (P<0.05). Zoledronic acid injection combined with vitamin K2 regimen can be used for anti-osteoporosis treatment of OVCFs vertebroplasty. It has a definite curative effect and a high safety factor. It is worth popularizing.

Therapeutic effect of percutaneous kyphoplasty combined with anti-osteoporosis drug on postmenopausal women with osteoporotic vertebral compression fracture and analysis of postoperative bone cement leakage risk factors: a retrospective cohort study

BackgroundThe purpose of this study is to explore the therapeutic effect of percutaneous kyphoplasty (PKP) combined with anti-osteoporosis drug, zoledronic acid, on postmenopausal women with osteoporotic vertebral compression fracture (OVCF) and to perform an analysis of postoperative bone cement leakage risk factors.MethodsA total of 112 OVCF patients, according to therapeutic regimens, were divided into control group (n = 52, treated with PKP) and observation group (n = 60, treated with PKP and zoledronic acid injection).ResultsPostoperative tumor necrosis factor-α and interleukin-6 levels were significantly decreased in the two groups, compared with those before treatment (both P < 0.05); bone mineral density (BMD), serum bone gla protein (BGP), and vertebral height ratio of injured vertebrae were significantly increased, and procollagen type I N-terminal propeptide (PINP), Cobb angle, visual analogue scale/score (VAS), and Oswestry disability index (ODI) were significantly decreased compared with those before treatment (all P < 0.05). There were significantly higher changes in difference value of BMD, PINP, BGP, vertebral height ratio of injured vertebrae, Cobb angle, VAS, and ODI levels and significantly better therapeutic effect in the observation group than those in the control group (all P < 0.05). Multivariate logistic regression analysis showed that the use of zoledronic acid, vertebral height ratio of injured vertebrae, and ODI were independent factors affecting the therapeutic effect, and that the dosage of bone cement, and peripheral vertebrae wall damage were independent risk factors causing postoperative bone cement leakage. There were no significant differences in postoperative bone cement leakage rate between the two groups.ConclusionsPeripheral vertebrae wall damage and the dosage of bone cement are independent risk factors causing bone cement leakage in OVCF patients treated with PKP. PKP combined with zoledronic acid has an improvement effect on the condition of postmenopausal women with OVCF and reduces the inflammation and pain in patients, which is beneficial to clinical treatment.

Synthetic hydroxyapatite: a recruiting platform for biologically active molecules

Background and purpose — Targeted delivery of drugs is important to achieve efficient local concentrations and reduce systemic side effects. We hypothesized that locally implanted synthetic hydroxyapatite (HA) particles can act as a recruiting moiety for systemically administered drugs, leading to targeted drug accretion.Methods — Synthetic HA particles were implanted ectopically in a muscle pouch in rats, and the binding of systemically circulating drugs such as zoledronic acid (ZA), tetracycline and 18F-fluoride (18F) was studied. The local biological effect was verified in an implant integration model in rats, wherein a hollow implant was filled with synthetic HA particles and the animals were given systemic ZA, 2-weeks post-implantation. The effect of HA particle size on drug binding and the possibility of reloading HA particles were also evaluated in the muscle pouch.Results — The systemically administered biomolecules (ZA, tetracycline and 18F) all sought the HA moiety placed in the muscle pouch. Statistically significant higher peri-implant bone volume and peak force were observed in the implant containing HA particles compared with the empty implant. After a single injection of ZA at 2 weeks, micro HA particles showed a tendency to accumulate more 14C-zoledronic acid (14C-ZA) than nano-HA particles in the muscle pouch. HA particles could be reloaded when ZA was given again at 4 weeks, showing increased 14C-ZA accretion by 73% in microparticles and 77% in nanoparticles.Interpretation — We describe a novel method of systemic drug loading resulting in targeted accretion in locally implanted particulate HA, thereby biologically activating the material.

Study on Zoledronic Acid Reducing Acute Bone Loss and Fracture Rates in Elderly Postoperative Patients with Intertrochanteric Fractures.

ObjectiveTo observe the effect of zoledronic acid on the reduction of acute bone loss and fracture rate in elderly postoperative patients with intertrochanteric fracture.MethodsFrom August 2012 to January 2015, a total of 482 patients with senile osteoporotic femoral intertrochanteric fracture, who accepted proximal femoral intramedullary fixation under anesthesia were analysed. The patients were divided into two groups. Treatment group (353 cases) were treated with 100 mL/5 mg of zoledronic acid injection in 1 week after operation, as well as orally taken 600 mg/d of calcium carbonate and active vitamin D3 400 IU/d. Control group (129 cases) were given the same dose of calcium carbonate and active vitamin D3 orally. Efficacy evaluation were conducted during different periods of medicationResultsCompared with pre‐medication, indexes of bone metabolism (TARP‐5b, CTX) in the treatment group were brought down, especially significantly statistically different after 12 months of medication. The treatment group performed superior to control group in alleviating the pain of back and posture changing (P < 0.05), improving bone density (P < 0.05), depressing re‐fracture rate (P < 0.01) after 24 months of medication. In addition, BP, PF and MH dimension scores were demonstrated with statistical significance (P < 0.05).ConclusionsThe application of zoledronic acidin elderly postoperative patients with intertrochanteric fracture can not only relieve acute bone loss, reduce the incidence rate of re‐fracture, alleviate osteoporosis pain and the pain from osteoporotic fracture, but also improve bone metabolism and quality of life, which may offer an acceptable clinical opinion

Evaluation of the Efficacy of EDTA Chelation on Alveolar Bone Healing After Ultrasonic and Conventional Surgery Under Bisphosphonate Medication: A Rat Model

The aims of the present study were 1) to investigate the effects of local ethylenediaminetetraacetic acid (EDTA) chelation on alveolar bone healing after systemic administration of bisphosphonates; and 2) to compare the healing in alveolar defects created with ultrasonic and conventional surgery. A total of 40 male Wistar rats were divided into 4 equal groups of 10 rats each (zoledronate and piezosurgery, zoledronate and bur, placebo and piezosurgery, and placebo and bur). The first 2 groups received weekly intraperitoneal injections of zoledronic acid (0.06mg/kg), and the second 2 groups received saline solution for 4weeks. After the last injections, horizontal defects 4×2×1mm in size were created on the mandibular alveolar bone using piezosurgery or conventional bur surgery. The zoledronate groups received 10minutes of local application of EDTA on 1 side and saline solution on the other side. In the placebo groups, only 1 side was treated (one half of the group with the bur and one half of the group with piezosurgery). All the rats were euthanized at 4 postoperative weeks for comparative histomorphometric evaluation of bone healing in the created defects. Bone formation was found to be the greatest in the placebo groups (P<.05). Although a greater amount of bone formation was observed with piezosurgery and EDTA among the bisphosphonate-treated groups, the difference between the zoledronate groups was not statistically significant (P>.05). Similarly, no statistically significant difference was found between the use of piezosurgery and conventional bur surgery within the placebo groups (P>.05). The findings of the present study revealed improved bone healing with the use of piezosurgery and EDTA chelation, although the difference did not reach statistical significance. Further research should be performed to clearly identify the role of EDTA as a chelating agent and in prevention of medication-related osteonecrosis of the jaws development.

Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats.

Osteonecrosis of the jaw induced by administration of bisphosphonates (BPs), BP-related osteonecrosis (BRONJ), typically develops after tooth extraction and is medically challenging. As BPs inhibit oral mucosal cell growth, we hypothesized that suppression of the wound healing-inhibiting effects could prevent BRONJ onset after tooth extraction. Since basic fibroblast growth factor (bFGF) promotes wound healing, but has a short half-life, we examined whether the initiation of BRONJ could be prevented by applying a bFGF-containing gelatin hydrogel over the extraction sockets of BRONJ model rats. Forty-three rats, received two intravenous injections of zoledronic acid 60 μg/kg, once per week for a period of 2 weeks, underwent extraction of a unilateral lower first molar. The rats here were randomly assigned to the bFGF group (n = 15 rats, gelatin hydrogel sheets with incorporated bFGF applied over the sockets); the phosphate-buffered saline (PBS) group (n = 14 rats, gelatin hydrogel sheets without bFGF applied over the sockets); or the control group (n = 14 rats, nothing applied over the sockets). One rat in the bFGF group was sacrificed immediately after tooth extraction. Twenty-one rats were sacrificed at 3 weeks, and the remaining 21 rats were sacrificed at 8 weeks after tooth extractions. The harvested mandibles were analyzed using micro-computed tomography and sections were evaluated qualitatively for mucosal disruption and osteonecrosis. The incidence of osteonecrosis at 8 weeks after tooth extraction was 0% in the bFGF group, 100% in the PBS group, and 85.7% in the control group. The frequency of complete coverage of the extraction socket by mucosal tissue was significantly greater in the bFGF group than in the other groups. These results suggest that application of bFGF in the extraction socket promoted socket healing, which prevented BRONJ development. The growth-stimulating effects of bFGF may have offset the inhibition of wound healing by BP.

Annual Injection of Zoledronic Acid Improves Bone Status in Children with Cerebral Palsy and Rett Syndrome.

Osteoporosis is a common complication of cerebral palsy and Rett's syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett's syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett's syndrome. 27 children under 18years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1mg/kg (max 4mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. Oneyear after injection of ZA, we observe an increase of Lumbar spine BMD from - 2.99 to - 2.14 SD (p < 0.0001) and femoral BMD from - 4.26 to - 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from - 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.

Effects of Zoledronic Acid and Vitamin E on Surgical- Induced Osteonecrosis of the Femoral Head in Rabbit.

Femoral head osteonecrosis is a progressive disease with disabling outcomes in hip joint if not treated. This study was designed to compare the effects of zoledronic acid plus vitamin E versus zoledronic acid alone in surgical induced femoral head osteonecrosis in rabbits. 26 Japanese white adult normal male rabbits at 28-32 weeks old were undertaken surgical femoral dislocation to devastate the femoral neck vessels; the femoral neck vessels were ligated and the hip was relocated. Next, the first 10 rabbits received zoledronic acid injections at 1st and the 4th weeks; the second group (10 rabbits) received zoledronic acid injections at 1st and the 4th week along with daily oral vitamin E for 12 weeks; and the third group was considered as non-treated control group. Radiographic and postmortem pathological assessments including the Ficat classification, epiphyseal quotient (EQ), new bone formation, and residual necrotic bone (RNB) were performed and compared after week 12. A significant difference was found between the combination therapy group and the control group in Ficat classification at 12th weeks (P=0.048), but, the difference between monotherapy and combination therapy groups at 12th weeks was nonsignificant (P=0.37). Also, both treated groups had significant difference with the control group for RNB (P=0.015). There were no significant differences between the three groups for Ficat classification at the 6th week (P=0.65); EQ at 6th (P=0.59) and 12th week (P=0.64); and NBF (P=0.55). Although zoledronic acid therapy along with vitamin E could improve some radiologic and pathological indices related to femoral head osteonecrosis, vitamin E showed a relative impact. I.

Local delivery of a zoledronate solution improves osseointegration of titanium implants in a rat distal femur model.

This study aimed to determine whether locally applied anti-resorptive agents acetazolamide or zoledronic acid would improve mechanical stability in implant osseointegration when applied as a solution within the medullary canal. Thirty-three rats received titanium-implants bilaterally in their intramedullary femoral canals. Prior to implantation, animals received 0.1 ml saline, 1 mM acetazolamide solution, or 0.7 mM zoledronic acid solution directly into the medullary cavity. The control group only received saline within the medullary canal while the treatment groups only received the respective treatment to which they were randomized. Animals were allowed to heal 4 weeks, at which time they were euthanized and femurs isolated for mechanical and radiographic evaluation. Push-out force to failure increased 152% in the zoledronic acid group relative to the control. There was no significant difference in push-out force with acetazolamide relative to control. Also, zoledronic acid increased metaphyseal bone volume fraction 46% and increased metaphyseal bone-implant contact 58% relative to the control. Recent research exploring local injection of medications to improve implant osseointegration and minimize systemic-effects has failed to quantitatively evaluate implant fixation strength on non-hydroxyapatite coated implants or implants without previous bone compaction. This study demonstrated that a simple injection of zoledronic acid into the medullary canal, rather than coatings or commercial gels, can increase fixation strength of an uncoated titanium-implant. Our findings indicate simple injection of zoledronic acid in saline solution has the potential for improving fixation of uncemented joint implants. Clinical Significance: Intramedullary injection of local bisphosphonate solutions could be implemented to improve osseointegration in cementless arthroplasty. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3294-3298, 2018.

Prevention of ovariectomy-induced osteoporosis in rats

Recently, the use of the pharmacological agents strontium ranelate (SR), parathyroid hormone (1-34, PTH) and zoledronic acid (ZA) has come to prominence for the treatment of osteoporosis due to their ability to prevent bone loss in osteoporotic patients. Although much emphasis has been placed on using pharmacological agents for the prevention of disease, much less attention has been placed on which one is more effective. There is still no direct comparative study on these three drugs. The aim of the present study was to investigate the effect of SR, PTH, ZA on preventing ovariectomy-induced osteoporosis in rats. After bilateral ovariectomy the rats randomly received vehicle, SR (500 mg/kg body weight/day, orally), PTH (20 μg/kg/day, subcutaneously) or asingle injection of ZA (0.1 mg/kg, i.v.) until death at 12weeks. The distal femurs were harvested for evaluation of bone metabolism. The rats treated with ZA demonstrated the highest levels of new bone formation as assessed by microcomputed tomography (CT), biomechanical strength, histological analysis and bone metabolism. Furthermore, PTH and SR showed astronger effect on improving trabecular bone mass at 12weeks. The results from the present study demonstrate that systemic administration of PTH, SR and ZA could prevent bone loss, while asingle dose of ZA has a better effect on preventing ovariectomy-induced osteoporosis than either PTH or SR.