High-dose Zoledronic Acid Research Articles

Bone Morphogenetic Protein 2 Promotes Bone Formation in Bone Defects in Which Bone Remodeling Is Suppressed by Long-Term and High-Dose Zoledronic Acid.

The use of long-term and high-dose bisphosphate is associated with severely suppressed bone turnover and the delayed union of fractures. However, therapeutic methods to overcome the negative effects of bisphosphonate use are lacking. Bone morphogenetic proteins (BMPs) are powerful osteoinductive proteins. The development of the delivery system using BMP has been verified to have an excellent effect on fracture healing and the enhancement of osteointegration. We hypothesized that BMPs had similar effects as autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment. Forty rats were divided into the following four groups depending upon the materials implanted into the femoral defect after ten weeks of bisphosphonate (zoledronic acid) injections: Group I: absorbable collagen sponge (control); group II: demineralized freeze-dried bone graft; group III: autogenous bone graft; and group IV: rhBMP-2 with an absorbable collagen sponge. Radiographic union, micro-computed tomography (CT) analysis, manual palpation, and histologic analysis were evaluated. The radiographic union rate, manual union rate, and micro-CT bone volume in groups III and IV were significantly higher than those in groups I and II. Groups III and IV showed similar results to each other. Although the amount of immature bone in the BMP-treated group was large, the effect was similar to that of autografts in the bone defect model in which bone turnover was severely reduced by bisphosphonate treatment. BMP might be a good substitute for autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment.

The Swedish national guidelines on prostate cancer, part 2: recurrent, metastatic and castration resistant disease

Objective There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. Methods This is part 2 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. This part covers recurrence after local treatment and management of metastatic and castration resistant disease. Part 1 covers early detection, diagnostics, staging, patient support and management of non-metastatic disease. Results The 2022 Swedish guidelines include several new recommendations. Among these is a recommendation of a period of observation with repeated PSA tests for patients with approximately 10 years’ life expectancy who experience a BCR more than 2–5 years after radical prostatectomy, to allow for estimating the PSA doubling time before deciding whether to give salvage radiotherapy or not. Recent results from the PEACE-1 trial led to the recommendation of triple-treatment with a GnRH agonist, abiraterone plus prednisolone and 6 cycles of docetaxel for patients with high-volume metastatic disease who are fit for chemotherapy. The Swedish guidelines differ from the European ones by having more restrictive recommendations about genetic testing of and high-dose zoledronic acid or denosumab treatment for men with metastatic prostate cancer, and by recommending considering bicalutamide monotherapy for selected patients with low-volume metastatic disease. Conclusions The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures.

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n = 10) and kinase signaling-associated cluster 2-related (n = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

The investigation of possible beneficial effects of gabapentin on adverse cardiac effects of high dose zoledronic acid: an experimental study

The investigation of possible beneficial effects of gabapentin on adverse cardiac effects of high dose zoledronic acid: an experimental study

Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease

Osteonecrosis of the jaws (ONJ) is a complication of antiresorptive medications, such as denosumab or bisphosphonates, prescribed to patients with bone malignancy or osteoporosis. The most common instigating local factor in ONJ pathogenesis is tooth extraction. However, in adults the great majority of teeth are extracted due to dental disease. Here, we have investigated alveolar bone healing after extraction of healthy teeth or teeth with naturally occurring periradicular disease in mice treated with high dose zoledronic acid (ZA), a potent bisphosphonate, or OPG-Fc, a RANKL inhibitor. C57BL/6 mice were treated for eight weeks and in vivo micro-CT was performed to identify spontaneously occurring periradicular lesions around the roots of maxillary molars. Then, extractions of molars with and without dental disease were performed in all groups. Four weeks later, animals were euthanized and maxillae were dissected and analyzed. Clinically, all vehicle animals with extraction of healthy or diseased teeth, and most OPG-Fc or ZA animals with extraction of healthy teeth showed normal mucosal healing. On the contrary, most animals with OPG-Fc or ZA treatment and extraction of diseased teeth demonstrated impaired healing with visible mucosal defects. Radiographically, bone socket healing was significantly compromised in OPG-Fc and ZA-treated mice with periradicular disease in comparison to other groups. Histologically, all vehicle animals showed normal mucosal healing and socket remodeling. OPG-Fc and ZA animals with extraction of healthy teeth showed normal mucosal healing, woven bone formation in the socket, and decreased remodeling of the original socket confines. OPG-Fc and ZA animals with extraction of diseased teeth showed mucosal defects, persistent prominent inflammatory infiltrate, bone exposure and areas of osteonecrosis. These findings support that dental disease is critical in the pathogenesis of ONJ, not only as the instigating cause for tooth extraction, but also as a compounding factor in ONJ development and pathophysiology.

Effects of zoledronic acid and docetaxel on small GTP-binding proteins in prostate cancer.

Increasingly, in castration-resistant prostate cancer, patients are often treated with docetaxel and the bisphosphonate zoledronic acid concurrently, yet there is still a paucity in the literature regarding the molecular basis of how this drug combination works. The study was performed on the hormone-resistant cell line PC-3. Cells were treated with clinically relevant concentrations of docetaxel and zoledronic acid either as single agents or in sequence and combination. Cell viability and apoptosis were assessed along with the prenylation status of the GTPases Ras and RhoA. Following 1-mM zoledronic acid treatment, inhibition of the prenylation of H-Ras and Rho A was observed along with an increase in the unprenylated form in the cytoplasm. Docetaxel 1 nM and zoledronic acid 1 mM also showed an increase in the unprenylated form of both small GTP-binding proteins in the cytoplasm and a reduction of protein in the membrane fraction. Overall, zoledronic acid followed by docetaxel was the best regimen producing the greatest reduction in cell viability and increase in apoptosis. At the highest concentrations of zoledronic acid and docetaxel, zoledronic acid followed by docetaxel was also the most effective at reducing the prenylation of both H-Ras and RhoA at the membrane. We have demonstrated that clinically achievable concentrations of zoledronic acid and docetaxel cause a reduction in the prenylation of both H-Ras and Rho A and a reduction of protein movement into the membrane. The most effective regimen overall was high-dose zoledronic acid followed by docetaxel, suggesting that this regimen may be of benefit in clinical practice.

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.

Craniofacial consequences of high dose zoledronic acid injections in onco-pediatric patients

Craniofacial consequences of high dose zoledronic acid injections in onco-pediatric patients

Craniofacial consequences of high-dose zoledronic acid injections in onco-pediatric patients

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Periapical Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in Mice

Osteonecrosis of the jaw (ONJ) is a well-recognized complication of antiresorptive medications, such as bisphosphonates (BPs). Although ONJ is most common after tooth extractions in patients receiving high-dose BPs, many patients do not experience oral trauma. Animal models using tooth extractions and high BP doses recapitulate several clinical, radiographic, and histologic findings of ONJ. We and others have reported on rat models of ONJ using experimental dental disease in the absence of tooth extraction. These models emphasize the importance of dental infection/inflammation for ONJ development. Here, we extend our original report in the rat, and present a mouse model of ONJ in the presence of dental disease. Mice were injected with high dose zoledronic acid and pulpal exposure of mandibular molars was performed to induce periapical disease. After 8 weeks, quantitative and qualitative radiographic and histologic analyses of mouse mandibles were done. Periapical lesions were larger in vehicle-treated versus BP-treated mice. Importantly, radiographic features resembling clinical ONJ, including thickening of the lamina dura, periosteal bone deposition, and increased trabecular density, were seen in the drilled site of BP-treated animals. Histologically, osteonecrosis, periosteal thickening, periosteal bone apposition, epithelial migration, and bone exposure were present in the BP-treated animals in the presence of periapical disease. No difference in tartrate-resistant acid phosphatase (TRAP)+ cell numbers was observed, but round, detached, and removed from the bone surface cells were present in BP-treated animals. Although 88% of the BP-treated animals showed areas of osteonecrosis in the dental disease site, only 33% developed bone exposure, suggesting that osteonecrosis precedes bone exposure. Our data further emphasize the importance of dental disease in ONJ development, provide qualitative and quantitative measures of ONJ, and present a novel mouse ONJ model in the absence of tooth extraction that should be useful in further exploring ONJ pathophysiological mechanisms.

Absence of Exposed Bone Following Dental Extraction in Beagle Dogs Treated With 9 Months of High-Dose Zoledronic Acid Combined With Dexamethasone

Factors contributing to osteonecrosis of the jaw with anti-remodeling drug treatment are unclear. Epidemiologic and experimental studies have suggested the combination of bisphosphonates and dexamethasone results in osteonecrosis of the jaw more often than either agent alone. The goal of this study was to assess the combination of these 2 drugs in a large animal model previously shown to be susceptible to exposed bone in the oral cavity when treated with bisphosphonates. Skeletally mature beagle dogs were untreated controls or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL plus DEX. ZOL and DEX were given at doses based on those used in humans. All animals underwent single molar extraction at 7 and 8 months after the start of the study. Extraction sites were obtained at month 9 for assessment of osseous healing using micro-computed tomography and histology. No animals were observed to have exposed bone after dental extraction, yet 1 animal treated with ZOL and 1 treated with ZOL plus DEX had severely disrupted extraction sites as viewed by computed tomography and histology. These 2 animals had an intense periosteal reaction that was less obvious but still present in all ZOL-treated animals and absent from untreated animals. There was no significant difference in bone volume within the socket among groups at 4 or 8 weeks after healing, yet the ratio of surface to volume was significantly higher in animals treated with ZOL plus DEX at 8 weeks compared with control animals. These findings suggest a more complex pathophysiology to osteonecrosis of the jaw than is implied by previous epidemiologic studies and those in rodents and raise questions about the potential role of DEX in its etiology.

High-dose zoledronic acid narrows the periodontal space in rats

The aim of this experiment was to evaluate the histological effects of zoledronic acid on the periodontal space in rats. 40 male Wistar rats were divided into three zoledronic acid groups and a control group. Zoledronic acid was injected subcutaneously at doses of 10, 50, or 500μg/kg once a week for 3 weeks. The rats were killed 1 or 9 weeks after the last injection. Histological examination of the periodontal space around the incisor tooth revealed that zoledronic acid did not inhibit tooth development. In the rats killed 1 week after treatment discontinuation, the periodontal space gradually narrowed in response to increasing zoledronic acid doses, and the changes were statistically significant according to ANOVA but not according to ANOVA with post hoc tests. The changes persisted in the high-dose zoledronic acid group despite zoledronic acid discontinuation, with significant differences identified by ANOVA and ANOVA with post hoc tests. Therefore, although zoledronic acid had an insignificant effect on tooth development, it had a significant effect on the periodontal space when high doses were administered. The results of this experiment may provide useful information for future investigations on the role of zoledronic acid in the osteonecrosis of the jaw.

High-Dose Zoledronic Acid Impacts Bone Remodeling with Effects on Osteoblastic Lineage and Bone Mechanical Properties

The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling. Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays. We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice. High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.

Short-Term Effects of High-Dose Zoledronic Acid Treatment on Bone Mineralization Density Distribution After Orthotopic Liver Transplantation

Patients with "hepatic" bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT), as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n = 18, treatment group ZOL n = 21, the latter treated with i.v. ZOL at doses of 4 mg/month) for how bone at the material level was affected by the "hepatic" disease in general, as well as by OLT and ZOL in particular. (1) BMDD parameters at baseline reflected disturbed bone matrix mineralization in "hepatic" bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (Ca(MEAN) -2.9% and Ca(PEAK) -2.8%, respectively; both P < 0.001), increased heterogeneity of mineralization (Ca(WIDTH) +12.2%, P = 0.01), and increased percentage of bone areas with low mineralization (Ca(LOW) +32.4%, P = 0.02) compared to normal; however, there were no differences compared to cortical bone. (2) Six months after OLT, ZOL-treated trabecular bone displayed reduced Ca(LOW) (-32.0%, P = 0.047), cortical bone increased Ca(MEAN) (+4.2%, P = 0.009), increased Ca(PEAK) (+3.3%, P = 0.040), and decreased Ca(LOW) (-55.7, P = 0.038) compared to CON and increased Ca(MEAN) compared to baseline (+1.9, P = 0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation.

Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats

The effect of cyclosporine A on bone turnover remains unclear. Using adult rats with vascularized bone transplantation, we show that long-term cyclosporine A administration increases bone turnover and zoledronic acid treatment enhances the reconstruction of cyclosporine A-administered skeleton. Bisphosphonates might be efficacious in human bone repair under immunosuppression using cyclosporine A. Bisphosphonate treatment effectively prevents bone loss after transplantation. However, recent evidence from gain- and loss-of-function experiments has indicated that calcineurin inhibitors, such as cyclosporine A (CsA), reduce bone turnover, and severely suppressed bone turnover might delay the union of human fractured bone. The purpose of this study was to investigate the effects of bisphosphonate treatment on the repair of CsA-administered skeleton. After skeletal reconstruction by vascularized tibial grafting, adult recipient rats were treated with intramuscular CsA (10 mg/kg/day) and low-dose (0.2 microg/kg/week) or high-dose (2 microg/kg/week) subcutaneous zoledronic acid alone or in combination for 8 weeks. Biochemical parameters were measured in blood and urine. The reconstructed skeleton was analyzed using soft X-ray, histology, dual energy X-ray absorptiometry, and three-point bending test. CsA induced mild renal dysfunction, hyperparathyroidism and high bone turnover. High-dose zoledronic acid delayed cortical bone union at the distal host-graft junction, but its combination with CsA did not cause such a delay. High-dose zoledronic acid prevented CsA-induced bone loss and bone fragility in the reconstructed skeleton. In this rat model, long-term CsA administration increases bone turnover, at least partly, through hyperparathyroidism and high-dose zoledronic acid treatment does not impair the union of CsA-administered bone.

The beneficial effect of intravenous zoledronic acid therapy following an acute stroke in rats

Purpose Changes of bone metabolism begin from the initial stages of stroke; therefore, early prevention of these changes has become important. The most appropriate target for preventive therapy is to restrict the profound increase in osteoclastic bone resorption that occur soon after stroke. Oral bisphosphonates, which selectively target osteoclasts and their precursors, are appropriate drugs, but dysphagia or drowsiness after acute stroke can make it difficult to easily administer these compounds to stroke patients. The intravenous (IV) administration of bisphosphonates is an alternative method that can overcome these limitations. In order to determine the effect of IV bisphosphonates at the initial stages of stroke for preventing bone loss, an experiment using ischemic stroke rats was conducted. Methods Female Sprague–Dawley rats ( n = 100) were randomly divided into four separate groups; sham surgery and vehicle-treated group (sham-vehicle), stroke and vehicle-treated group (stroke-vehicle), stroke with low-dose zoledronic acid treatment group (stroke-low) and stroke with high-dose zoledronic acid treatment group (stroke-high). Permanent occlusion of the left middle cerebral artery was performed, resulting in right hemiplegia. The bone mineral density (BMD) of the 4th and 5th lumbar vertebrae and the femur on the stroke side were measured in vivo on the day before stroke and on the 10th and 21st day after stroke. The osteocalcin and carboxy-terminal telopeptide blood levels were measured on the 10th and 21st day after stroke. The BMD of the excised proximal tibia and the maximum load of femoral neck were measured on the 21st day after stroke. Results After 21 days of stroke, the BMD of the lumbar vertebrae, femur, and excised tibia and the maximum load of the femoral neck in the sham-vehicle, stroke-low, and stroke-high groups were significantly higher than those in the stroke-vehicle group ( P < 0.05). The carboxy-terminal telopeptide levels in the sham-vehicle and stroke-high groups were significantly lower than those in the stroke-vehicle group ( P < 0.05). Conclusion The results suggest that IV zoledronic acid treatment might prevent bone loss during the initial stages of stroke.