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Jackie07 05-31-2011 08:19 PM

Bone modifying agents - Denosumab now added
The Use of Bone-Modifying Agents

Treatment-related bone loss and the subsequent increase in fracture risk is an increasingly important concern for patients with metastatic breast cancer (MBC) receiving hormonal agents or chemotherapy. In postmenopausal women, the natural and progressive loss of bone mineral density associated with aging can be accelerated by the administration of an aromatase inhibitor (AI).[Eastell 2008; McCloskey 2007; LÝnning 2005; Coombes 2004]

Recently updated results of the landmark ATAC trial demonstrated an annual fracture rate of 2.93% in postmenopausal women receiving an AI for 5 years.[ATAC Trialistsí] Although this trial was performed in the adjuvant setting, the results show a substantial degree of bone loss that could also be seen in the metastatic setting among patients on prolonged AI therapy. In premenopausal patients with breast cancer, chemotherapy-induced premature ovarian failure or treatments aimed at ovarian function inhibition can lead to sudden and substantial bone density loss.[Shapiro 2001]

Medical oncologists treating breast cancer patients have therefore recently taken a more proactive role in the evaluation and management of treatment-related bone loss in these women. In addition to the impact of treatments on bone health, the skeleton is one of the main sites of metastasis for women with MBC that may lead to pain and pathological fractures.[Coleman 2001]
Bisphosphonates are bone-modifying agents that prevent the loss of bone mass. There is an expanding role for bisphosphonates in the therapy of breast cancer patients. Traditionally, these agents were administered for the prevention of skeletal events in patients with osseous metastases; however, recently they have been evaluated as part of the management strategy to prevent further bone loss, particularly in the adjuvant setting.

Results from the ABCSG-12 bone density subprotocol and the Z-FAST trial clearly demonstrated the effectiveness of the bisphosphonate zoledronic acid in preserving bone mineral density in pre- and postmenopausal women on hormonal manipulation, respectively.[Gnant 2008; Brufsky 2009b] Although both trials focus on women receiving adjuvant treatments, it is reasonable to expect bisphosphonates to also reduce bone loss in patients with MBC; however, this has not been tested prospectively. Although not yet confirmed, there is a growing body of data that suggest that bisphosphonates also improve breast cancer outcomes when given in combination with adjuvant endocrine therapy in both premenopausal and postmenopausal women.[Gnant 2009]

It is still unclear what the optimal bisphosphonate for preventing bone loss should be considering that both oral and intravenous agents have been tested in different doses and schedules. Trials have evaluated both short- and long-term therapy, raising uncertainty about the most advantageous duration of treatment as well. Evidence also suggests that some bone loss is recoverable after cessation of hormonal manipulation or chemotherapy, raising the question of the best time to institute these agents.

Denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), was approved by the US Food and Drug Administration in November 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors. This approval was based on 3 pivotal studies of denosumab vs zoledronic acid. In these studies, denosumab showed superior efficacy when compared head to head with zoledronic acid in breast cancer and castrate-resistant prostate cancer and was noninferior (trend toward superiority) for preventing/delaying skeletal-related events in solid tumors.[Stopeck 2009; Fizazi 2011; Henry 2009] Subsequently, the National Comprehensive Cancer Network added denosumab to the list of agents recommended (along with zoledronic acid and pamidronate) to help prevent skeletal-related events in selected patients with bone metastases.[NCCN 2011]

In February 2011, the American Society of Clinical Oncology updated the 2003 version of its Clinical Practice Guideline for the use of bone-modifying agents.[Van Poznak 2011]In patients with metastatic breast cancer who have evidence of bone metastases, denosumab is now listed as a recommended bone-modifying agent to be administered at a dose of 120 mg subcutaneously every 4 weeks. The guideline recommends careful monitoring for hypocalcemia in patients with creatinine clearance < 30 mg/mL or in those patients receiving dialysis. The package insert of zoledronic acid now provides guidance for dosing when a patientís baseline serum creatinine clearance is ≥ 30 and < 60 mg/mL. The updated guideline also recommends that before receiving a bone-modifying agent, a patient should have a dental examination and/or any necessary preventive dentistry.

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