Differences between zoledronic acid and denosumab for breast cancer treatment.

Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects include the prevention of osteoporosis induced by cancer-treatment bone loss, treatment and prevention of bone metastasis, and improvement of survival directly or indirectly by maintaining bone health. Interestingly, zoledronic acid and denosumab have different anticancer activities, and they may be associated with the improvement of survival of breast cancer patients under different mechanisms. Zoledronic acid is the most potent bisphosphonate. It provides significant benefits for improving breast cancer mortality in patients with suppressed estrogen level such as in postmenopausal or ovarian suppression condition. Although denosumab's anticancer activity has not been clearly proven compared with zoledronic acid's anticancer activity, denosumab is promising in preventing BRCA1 mutant breast cancer because RANKL is a targetable pathway in BRCA1-associated tumorigenesis. Further studies and more effective clinical use of these agents are anticipated to contribute to the improvement of the clinical outcome of breast cancer patients.

Clinical Impact on Dental Implant Survival in Patients Taking Antiresorptive Medications: A Systematic Review and Meta-Analysis.

Dental implants are a predictable option to replace missing teeth. Patients on antiresorptive medications used to treat disorders associated with bone resorption may need dental implants to replace missing teeth. The data on implant failure in patients on antiresorptive medication requiring dental implants, is conflicting and limited. This systematic review aims to investigate if antiresorptive medications have any clinical impact on dental implant survival. Electronic databases were searched until May 2020. The focus question (PICOS): Participants: humans, Interventions: implant placement surgery in patients on antiresorptive medication, Comparisons: patients on antiresorptive medication vs control (patients not on antiresorptive medication), Outcomes: implant survival, and Study design: clinical studies. The protocol of this systematic review was registered in PROSPERO (CRD42020209083). Fourteen nonrandomized studies were selected for data extraction and risk of bias assessment using the ROBINS-1 tool. Only studies with a control were included for the meta-analysis, 8 articles were included in the meta-analysis using implant-level data, and 5 articles were included in the meta-analysis using patient-level data. There was no statistical significance between the 2 groups at the patient level based on 265 patients. However, there was a statistically significant difference at the implant level based on 2697 implants. Therefore, antiresorptive medications, mainly bisphosphonates (BPs), may significantly contribute to implant failure. Antiresorptive medications, especially BPs may reduce implant survival and impair the osseointegration of dental implants. Failed implants in patients on BPs may not lead to osteonecrosis and may be replaced with success.

Evaluating the Effect of Denosumab in Preventing Anchorage Loss: A Split-mouth Randomized Controlled Trial.

AIM: The trial was focused on assessing the effect of Denosumab in preventing anchorage loss during en-masse anterior retraction and evaluating its effect on the retraction. MATERIALS AND METHODS: This was a split-mouth randomized controlled trial. Ten subjects were randomly allocated with equal probability for Denosumab and control interventions in the contralateral quadrants using computer-generated randomization sequence. During the start of retraction, Denosumab (5 mg/0.2 mL) and injectable sterile water were administered locally on the intervention and control sides, respectively. Lateral cephalograms taken during the start of retraction and later in the 3rd and 6th months into retraction were used to evaluate anchorage loss and retraction. Independent sample t-test and Mann-Whitney U test compared anchorage loss and retraction between the two groups in the maxilla and mandible. Paired t-test and Wilcoxon signed-rank test assessed the anchorage loss and retraction during the first and the second 3 months of retraction. RESULTS: In the maxilla, Denosumab was effective in preventing anchorage loss with a p-value of 0.001 whereas it was not effective in the mandible (p-value-0.172). A significant reduction in anchorage loss was observed with Denosumab in the second 3 months of retraction compared to the first 3 months. There was no significant difference in the retraction among both groups. CONCLUSION: Denosumab was effective in minimizing the anchorage loss in the maxilla without affecting the anterior retraction. CLINICAL SIGNIFICANCE: Denosumab can be effectively used for reinforcing anchorage in the maxilla during en-masse anterior retraction.

Denosumab Treatment Does Not Halt Progression of Bone Lesions in Multicentric Carpotarsal Osteolysis Syndrome.

Here we report the use of denosumab, a monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), as monotherapy for multicentric carpotarsal osteolysis syndrome (MCTO) in an 11.5-year-old male with a heterozygous missense mutation in MAFB (c.206C>T; p.Ser69Leu). We treated the subject with 0.5 mg/kg denosumab every 60-90 days for 47 months and monitored bone and mineral metabolism, kidney function, joint range of motion (ROM), and bone and joint morphology. Serum markers of bone turnover reduced rapidly, bone density increased, and renal function remained normal. Nevertheless, MCTO-related osteolysis and joint immobility progressed during denosumab treatment. Symptomatic hypercalcemia and protracted hypercalciuria occurred during weaning and after discontinuation of denosumab and required treatment with zoledronate. When expressed in vitro, the c.206C>T; p.Ser69Leu variant had increased protein stability and produced greater transactivation of a luciferase reporter under the control of the PTH gene promoter than did wild-type MafB. Based on our experience and that of others, denosumab does not appear to be efficacious for MCTO and carries a high risk of rebound hypercalcemia and/or hypercalciuria after drug discontinuation. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Mechanisms of, and Adjuvants for, Bone Pain.

Metastatic bone pain is a complex, poorly understood process. Understanding the unique mechanisms causing cancer-induced bone pain may lead to potential therapeutic targets. This article discusses the effects of osteoclast overstimulation within the tumor microenvironment; the role of inflammatory factors at the tumor-nociceptor interface; the development of structural instability, causing mechanical nerve damage; and, ultimately, the neuroplastic changes in the setting of sustained pain. Several adjuvant therapies are available to attenuate metastatic bone pain. This article discusses the role of pharmacologic therapies, surgery, kyphoplasty, vertebroplasty, and radiofrequency ablation.

Denosumab-Associated Severe Hypocalcemia in a Patient With Chronic Kidney Disease.

Denosumab is a monoclonal antibody directed against the receptor activator of nuclear factor kappa B ligand (RANKL). Denosumab has been shown to reduce the risk of skeletal-related events, including spinal cord compression, pathologic fracture and hypercalcemia of malignancy in patients with bone metastases. Hypocalcemia is a known side effect of denosumab, occurring in an estimated 8-14% of the patients. Here, we present an asymptomatic patient with stage-5 chronic kidney disease and severe hypocalcemia who had received denosumab 1 month earlier.

The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review.

PURPOSE: The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone metastases originating from solid tumors. METHODS: Pubmed, EMBASE and the Cochrane Library were searched. Any type of study design and type and dose of radiotherapy, bisphosphonates and RANKL inhibitors were allowed. RESULTS: 39 articles were identified. Animal studies showed that radiotherapy had similar effects on bone quality and strength as receiving no treatment, whereas adding bisphosphonates to radiotherapy restored bone quality and strength. In patient studies, bone density increased after radiotherapy and radiotherapy combined with bisphosphonates. However, due to the often non-optimal study design and study quality, it was unclear whether this increase could be attributed to these treatments. There was insufficient evidence to assess the additional effect of bisphosphonates or RANKL inhibitors. CONCLUSION: Despite the clinical experience that radiotherapy is an effective treatment for bone metastases, there was no sufficient evidence for a positive effect on bone quality and fracture risk. Animal studies showed that adding bisphosphonates to radiotherapy restored bone quality and strength, whereas this was not proven in patients. There were no studies addressing the adjunct effect of RANKL inhibitors to radiotherapy. Although associated with several methodological, practical and ethical challenges, randomized controlled trials are needed.

Antiresorptive Therapies for the Treatment of Malignant Osteolytic Bone Disease.

Osteolytic bone disease contributes to morbidity and mortality. Antiresorptive therapies reduce the morbidity of metastatic bone disease and alter the natural progression of malignant bone pathophysiology. Several trials showed improvement in quality of life, delay of skeletal-related events, and improvement in bone pain with these agents. Evolving data suggest a role of improvement in morbidity related to other cancer therapies that have potential side effects. Early indication shows they may alter survival in a subset of patients. This article reviews data confirming the efficacy of antiresorptive agents and discusses preliminary data on preventative therapy.

Effect of antiresorptive drugs on bony turnover in the jaw: denosumab compared with bisphosphonates.

Osteonecrosis of the jaw as a result of treatment with receptor activators of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab) is a new type of bony necrosis, the exact pathogenesis of which is unknown. Our aim was to find out whether the turnover of bone in the jaw is increased after denosumab has been given compared with other skeletal sites, and if that turnover might have a role in denosumab-related osteonecrosis of the jaw (DRONJ). Bone scintigraphic images of 45 female patients with breast cancer and bone metastases were analysed retrospectively, and divided into 3 groups: those given denosumab, those given a bisphosphonate, and a control group (n=15 in each). All patients had bone scintigraphy before treatment (T0) and during the course of treatment after 12 (T1) and 24 (T2) months. The data were analysed quantitatively using 6 preset bony regions of interest. There was similar turnover of bone in the mandible compared with other skeletal sites (such as the femur), while the maxilla showed significantly higher turnover. None of the bony regions investigated showed any significant changes after the bisphosphonate had been given. There was a tendency to increase bone turnover in those patients taking denosumab. The bone turnover of the jawbone is not overtly changed either by a bisphosphonate or denosumab, so it seems unlikely that oversuppression of bony turnover in the jawbones plays an important part either in the pathogenesis of DRONJ or in the bisphosphonate-related osteonecrosis of the jaw (BRONJ).