Cancer: Update on bone-modifying agents in metastatic breast cancer


Abbreviations: DKK1, dickkopf-related protein 1; HSC, hematopoietic stem cell; NMB, nonmetastatic melanoma protein B; RANKL, receptor activator of nuclear factor κ-B ligand. The growth of disseminated tumor cells is a major cause of mortality in patients with breast cancer.1 Since the introduction of the bisphosphonate pamidronate for the treatment of skeletal-related events (SREs) in patients with breast cancer and bone metastases,2 the beneficial effects of bonemodifying agents in this group of patients have been recognized.3 The first American Society of Clinical Oncology evidence-based clinical practice guidelines for the use of bisphosphonates in patients with breast cancer were published in 2000 and updated in 2003.4,5 Here, we comment on the 2011 guideline update, which covers metastatic breast cancer and uses the term bonemodifying agents instead of bisphos phonates in recognition of the emergence of new types of treatments.6 At first glance, the updated guidelines may serve only to reinforce what we already recognize clinically; namely, that patients with Stage IV breast cancer and bone metastases benefit from treatment with bonemodifying agents. How ever, new to the guidelines are recommen dations regarding the use of a new bone-modifying agent, denosumab, as well as recommendations related to osteonecrosis of the jaw. The guidelines, therefore, provide patients and their physicians with an appropriate and timely review of the new evidence from high-quality clinical trials. The guidelines state that therapy with bone-modifying agents is only recommended for patients with metastatic breast cancer and evidence of bone meta stases. In relation to treatment with denosumab, the guidelines recommend 120 mg subcutaneously every 4 weeks and encourage health-care providers to be proactive in the reporting of any postmarketing safety concerns. Denosumab and other new bone-modifying agents in clinical development for the treatment of metastatic breast cancer to the bone are outlined in Table 1. Guidelines on renal safety suggest careful monitoring of the creatinine clearance of patients treated with bone-modifying agents. In patients with a creatinine clearance <30 ml per min (or on dialysis) who are treated with denosumab, close monitoring for hypo calcemia is recommended. Similarly, in patients with a creatinine clearance >60 ml per min, close monitoring of the creatinine level is suggested following each intra venous dose of bisphosphonates. In terms of which bone-modifying agent to use, the guideline states that the current evidence is insufficient to recommend one bone-modifying agent over another; however, this advice is not in line with published data that demonstrate the superiority of denosumab over the nitrogen-containing bisphosphonates, such as zoledronic acid.7 Furthermore, denosumab was shown to be associated with fewer adverse events than zoledronic acid.7 However, admittedly, the clinical superiority of denosumab over zoledronic acid in delaying or preventing SREs was assessed only as a secondary end point. The suppression of bone resorption by bone-modifying agents, as assessed by bone turnover markers, is associated with a significant reduction in the risk of vertebral, hip and nonvertebral fractures in postmenopausal women with osteoporosis.8 Reduc tions in markers of bone resorption have also been found to be associated with an increased survival and decreased SREs in women with metastatic breast cancer to the bone.3 The new guidelines do not recommend the use of biochemical markers to monitor the effect of bone-modifying agents as no studies have directly measured these markers as primary end points. Indeed, how to integrate bone turnover markers into treatment decisions is not clear. Specific trials of the effect of bone-modifying agents in patients with breast cancer and bone metastases that measure serum bio chemical markers as a primary end point may help resolve this issue. The growing safety concerns related to osteo necrosis of the jaw are addressed with a new recommendation in the guideline update. Osteonecrosis of the jaw is defined as an area of exposed bone in the maxillofacial or mandibular region that does not heal within the 8 weeks after clinical identification, in a patient treated with bisphosphonates. Appropriately, the guideline committee also concluded that the direct evidence for the best approach to minimize the risk of osteonecrosis of the jaw in

DOI: 10.1038/nrendo.2011.129
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@article{Suva2011CancerUO, title={Cancer: Update on bone-modifying agents in metastatic breast cancer}, author={Larry J. Suva and Brooke E. Brander and Issam Makhoul}, journal={Nature Reviews Endocrinology}, year={2011}, volume={7}, pages={380-381} }