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Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid.

ABSTRACT: Many patients with advanced genitourinary malignancies develop bone metastases, which can lead to potentially debilitating skeletal complications. Moreover, age-related bone loss and cancer treatments such as hormonal therapy for prostate cancer can weaken bone, placing patients at risk for osteoporotic fractures in addition to skeletal-related events (SREs) from bone metastases. Zoledronic acid, a bisphosphonate, is approved worldwide to reduce the risk of SREs in patients with bone metastases from solid tumors or bone lesions from multiple myeloma. Zoledronic acid, although underutilized in genitourinary malignancies, has long been the mainstay of treatment in patients with bone metastases, and can also help preserve bone during anticancer therapy. Recently, denosumab, a monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand, was approved in the United States and the European Union for reducing the risk of SREs in patients with bone metastases from solid tumors. Denosumab (at a lower dose) is also approved in the European Union and the United States to treat androgen deprivation-induced bone loss in men with prostate cancer. In addition, preclinical rationale and emerging clinical data suggest that bone-modifying agents may be able to delay disease progression in genitourinary cancers, just as newly developed anticancer treatments have produced reductions in SREs, possibly by indirect effects on the disease course. This review article summarizes current data and ongoing studies to preserve bone health in patients with advanced genitourinary cancers.

SUBMITTER: Aapro M

PROVIDER: S-EPMC3317544 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid.

Aapro Matti M Saad Fred F

Therapeutic advances in urology 20120401 2

Many patients with advanced genitourinary malignancies develop bone metastases, which can lead to potentially debilitating skeletal complications. Moreover, age-related bone loss and cancer treatments such as hormonal therapy for prostate cancer can weaken bone, placing patients at risk for osteoporotic fractures in addition to skeletal-related events (SREs) from bone metastases. Zoledronic acid, a bisphosphonate, is approved worldwide to reduce the risk of SREs in patients with bone metastases ...[more]

PMID: 22496711

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Project description:Bone metastases are a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality.The objective of this review is to discuss the incidence, pathophysiology, and management of bone metastases in the most prevalent genitourinary malignancies.We reviewed the relevant medical literature, with a particular emphasis on prospective randomized controlled trials. Much of the relevant clinical trial data focus on prostate cancer (PCa). We provide a nonsystematic review and our perspective on the available data.Clinical manifestations can include pain, hypercalcemia, pathologic fractures, and spinal cord compression. Optimal systemic therapy for skeletal metastases often features a combination of disease-specific therapy and bone-targeted therapy. Some agents, such as the radiopharmaceutical radium-223, blur the line between those categories. Osteoclast inhibition is a validated strategy in the management of selected patients with bone metastases. Zoledronic acid, a bisphosphonate, is approved for the prevention of skeletal events caused by solid tumors metastatic to bone. Denosumab is a fully human monoclonal antibody that inactivates receptor activator of nuclear factor-?B ligand and is approved for the same indication. Beta-emitting radiopharmaceuticals can be effective for the palliation of pain caused by bone metastases, but their use is often limited by marrow suppression. The alpha-emitting radiopharmaceutical radium-223 has recently been shown to improve overall survival and prevent skeletal events in select men with castration-resistant PCa metastatic to bone. Multiple ongoing clinical trials are designed to examine the potential for therapeutic inhibition of additional targets such as Src and hepatocyte growth factor (MET).Bone metastases cause considerable morbidity and mortality among patients with genitourinary malignancies. Optimal management requires consideration of bone-targeted therapy as well as disease-specific therapy. Further research is needed to optimize the use of existing agents and to define the therapeutic potential of novel targets.

Project description:Skeletal metastases are an incurable complication afflicting the majority of patients who die from advanced breast cancer. They are most often osteolytic, characterized by net bone destruction and suppressed new bone formation. Life expectancy from first diagnosis of breast cancer bone metastases is several years, during which time skeletal-related events - including pain, fracture, hypercalcemia, and spinal cord compression - significantly degrade quality of life. The bone marrow niche can also confer hormonal and chemo-resistance. Most treatments for skeletal metastases target bone-destroying osteoclasts and are palliative. Recent results from the Breast cancer trials of Oral Everolimus-2 trial suggest that agents such as the mammalian target of rapamycin inhibitor everolimus may have efficacy against breast cancer bone metastases in part via stimulating osteoblasts as well as by inhibiting tumor growth. Selective estrogen receptor modulators similarly inhibit growth of estrogen receptor-positive breast cancers while having positive effects on the skeleton. This review discusses the future role of bone-anabolic agents for the specific treatment of osteolytic breast cancer metastases. Agents with both anti-tumor and bone-anabolic actions have been tested in the setting of multiple myeloma, a hematological malignancy that causes severe osteolytic bone loss and suppression of osteoblastic new bone formation. Stimulation of osteoblast activity inhibits multiple myeloma growth - a strategy that might decrease breast cancer burden in osteolytic bone metastases. Proteasome inhibitors (bortezomib and carfilzomib) inhibit the growth of myeloma directly and are anabolic for bone. Drugs with limited anti-tumor activity but which are anabolic for bone include intermittent parathyroid hormone and antibodies that neutralize the WNT inhibitors DKK1 and sclerostin, as well as the activin A blocker sotatercept and the osteoporosis drug strontium ranelate. Transforming growth factor-beta inhibitors have little tumor antiproliferative activity but block breast cancer production of osteolytic factors and are also anabolic for bone. Some of these treatments are already in clinical trials. This review provides an overview of agents with bone-anabolic properties, which may have utility in the treatment of breast cancer metastatic to the skeleton.

Project description:ImportanceOsteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown.ObjectiveTo define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm.Design, setting, and participantsThis multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020.Interventions/exposuresCancer treatments, BMAs, and dental care were administered as clinically indicated.Main outcomes and measuresCumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined.ResultsThe SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02).Conclusions and relevanceAs the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.

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Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid.

Publications

Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid.

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