Role Of Bone-modifying Agents Research Articles

The role of bone-modifying agents in myeloma bone disease.

ABSTRACTBone disease is common in patients with multiple myeloma (MM), which manifests as bone pain and skeletal‐related events (SREs) such as pathological fractures and spinal cord compression. Myeloma bone disease (MBD) can adversely affect the quality of life of patients and have negative effects on morbidity and mortality. The pathogenesis of MBD is complex, and several factors are involved in the dysregulation of bone metabolism and uncoupling of bone remodeling, which result in net bone loss and devastating SREs. Broadly speaking, elevated osteoclast activity, suppressed osteoblast activity, and an aberrant marrow microenvironment play a role in MBD. Interaction of MM cells with the main bone cell osteocytes also promote further bone destruction. This review focuses on the role of bone‐modifying agents in the prevention and treatment of MBD. The mainstay of MBD prevention are antiresorptive agents, bisphosphonates and denosumab. However, these agents do not play a direct role in bone formation and repair of existing MBD. Newer agents with anabolic effects such as anti‐sclerostin antibodies, parathyroid hormone, anti‐Dickkopf‐1 antibodies, and others have shown potential in repair of MBD lesions. With the development of several new agents, the treatment landscape of MBD is likely to evolve in the coming years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Role of bone-modifying agents in advanced cancer.

Bone lesions from metastatic solid tumors and multiple myeloma (MM) represent an important source of morbidity in patients with incurable malignancies. Dysregulation of osteoclast and osteoblast activity caused by tumor cells in the bone microenvironment weakens the structural integrity of bone and predisposes to skeletal-related events (SREs), which can include severe bone pain, pathologic fracture, spinal cord compression and hypercalcemia. In order to reduce the risk of these complications, the supportive treatment of patients with bone lesions from advanced cancer typically includes the use of bone-modifying agents (BMAs), specifically bisphosphonates and denosumab. The choice of specific agent, dosing schedule and duration of therapy should be individualized by taking into account disease characteristics, medication side-effect profiles and patient preferences.

Use of Bone-Modifying Agents in Myeloma and Bone Metastases: How Recent Dosing Interval Studies Have Affected Our Practice.

The management of bone lesions from advanced solid tumors and multiple myeloma typically includes use of a bone-modifying agent to reduce the risk of skeletal-related events. Recent data demonstrate that when using zoledronic acid to reduce the risk of skeletal-related events in metastatic breast cancer, metastatic prostate cancer, and multiple myeloma, the dosing interval of zoledronic acid may be extended from every 4 weeks to every 12 weeks. The ASCO guidelines on the role of bone-modifying agents in metastatic breast cancer and multiple myeloma address zoledronic acid dosing intervals. Herein, we discuss how new data on dosing of bone-modifying agents influence our clinical practice.

Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update Summary

Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update Summary

Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update.

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki .

Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update.

Purpose To update, in collaboration with Cancer Care Ontario (CCO), key recommendations of the American Society of Clinical Oncology (ASCO) guideline on the role of bone-modifying agents (BMAs) in metastatic breast cancer. This focused update addressed the new data on intervals between dosing and the role of BMAs in control of bone pain. Methods A joint ASCO-CCO Update Committee conducted targeted systematic literature reviews to identify relevant studies. Results The Update Committee reviewed three phase III noninferiority trials of dosing intervals, one systematic review and meta-analysis of studies of de-escalation of BMAs, and two randomized trials of BMAs in control of pain secondary to bone metastases. Recommendations Patients with breast cancer who have evidence of bone metastases should be treated with BMAs. Options include denosumab, 120 mg subcutaneously, every 4 weeks; pamidronate, 90 mg intravenously, every 3 to 4 weeks; or zoledronic acid, 4 mg intravenously every 12 weeks or every 3 to 4 weeks. The analgesic effects of BMAs are modest, and they should not be used alone for bone pain. The Update Committee recommends that the current standard of care for supportive care and pain management-analgesia, adjunct therapies, radiotherapy, surgery, systemic anticancer therapy, and referral to supportive care and pain management-be applied. Evidence is insufficient to support the use of one BMA over another. Additional information is available at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki .

Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update Summary.

Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update Summary.

WS1–1 - The Role of Bone-Modifying Agents (BMA) in the Treatment of Bone Metastases

Bone metastases result from complex interactions between cancer cells and the bone marrow microenvironment. Disseminated tumour cells (DTC) home to the haematopoietic stem cells niches adjacent to Nestin+ cells in the perivascular space of small arterioles at the bone surface and/or the lining osteoblasts. There, DTC can remain in a dormant state for many years until activation and then either stimulation of osteoclast function resulting in bone metastasis or onward dissemination to other metastatic sites. Bone-targeted treatments such as bisphosphonates (BPs) and denosumab (Dmab) have profound effects on the cellular interactions within the bone marrow microenvironment. Extensive preclinical research led to the hypothesis that BPs and Dmab might influence the course of the disease and led to the design of adjuvant studies in breast cancer and castrate resistant prostate cancer (CRPC). Prostate cancer metastasises almost exclusively to bone and provides an ideal clinical setting for the evaluation of bone-targeted treatments. In CRPC, denosumab significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (HR = 0.85; P = 0.028), and delayed time to symptomatic first bone metastases. In women with early breast cancer, improvements in both disease free (DFS) and overall survival have been demonstrated in large randomised trials. The evidence for this is particularly strong with zoledronic acid but appears to be confined to patients with low levels of reproductive hormones including premenopausal women receiving ovarian suppression therapy and those who have passed through menopause at the time of diagnosis. In these patients, study level meta-analysis has shown an 18% improvement in DFS (hazard ratio [HR] = 0.82; 95%CI 0.74-0.92, 2P = <0.001) with reductions in relapse rates not only in bone but also at extra-skeletal and loco-regional sites. Conversely, in premenopausal women, an increase in extraskeletal relapses was seen that outweighs any reductions in bone metastases with marked heterogeneity of treatment effect according to menopausal status. In patients with metastatic bone disease, BPs and Dmab markedly reduce the frequency and severity of skeletal complications, reduce bone pain, improve quality of life and should be part of routine care across tumour types.

Commentary: Role of Bone-Modifying Agents in Metastatic Breast Cancer

Commentary: Role of Bone-Modifying Agents in Metastatic Breast Cancer

American society of clinical oncology clinical practice guideline update: recommendations on the role of bone-modifying agents in metastatic breast cancer.

Journal of Clinical Oncology recently published ASCO's update to its guideline on the use of bone-modifying agents for patients with bone metastases, the scope of which was narrowed to the use of bone-modifying agents for patients with evidence of bone metastases.

American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer

To update the recommendations on the role of bone-modifying agents in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases. A literature search using MEDLINE and the Cochrane Collaboration Library identified relevant studies published between January 2003 and November 2010. The primary outcomes of interest were SREs and time to SRE. Secondary outcomes included adverse events and pain. An Update Committee reviewed the literature and re-evaluated previous recommendations. Recommendations were modified to include a new agent. A recommendation regarding osteonecrosis of the jaw was added. Bone-modifying agent therapy is only recommended for patients with breast cancer with evidence of bone metastases; denosumab 120 mg subcutaneously every 4 weeks, intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence to demonstrate greater efficacy of one bone-modifying agent over another. In patients with a calculated serum creatinine clearance of more than 60 mg/min, no change in dosage, infusion time, or interval of bisphosphonate administration is required. Serum creatinine should be monitored before each dose. All patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health. Current standards of care for cancer bone pain management should be applied at the onset of pain, in concert with the initiation of bone-modifying agent therapy. The use of biochemical markers to monitor bone-modifying agent use is not recommended.