Compliance in Metastatic Bone Disease Treatment Explored

Bone metastases commonly occur with advanced cancers, including cancers of the breast and prostate. Bone-targeted agents may help to minimize complications associated with osseous metastases, such as skeletal-related events (SREs), but ongoing compliance and adherence to these therapies are important to ensure they provide the desired benefit.^1-3

Adherence and persistence with bone-targeted therapy have been observed to be suboptimal when patients self-administer, both in osteoporosis prevention and in the treatment of bone metastases.^2,3Although oral bisphosphonate therapy may be considered, for example, in patients with cancer who do not require regular hospital visits, inconvenience and complexity of the oral dosing regimen, as well as issues such as GI adverse events and low rates of absorption, can make other administration routes preferable.²

Intravenous (IV) administration, on the other hand, may be combined with monitoring and/or administration of chemotherapy in a single patient visit, and can help ensure ongoing adherence and compliance with bone-targeted therapy for metastases.^2,3Also, IV therapy may be considered for patients who are unable to tolerate oral therapies.⁴A drawback of this approach is the need for lengthy administration times, which can be disruptive to patient schedules. With both oral and IV administration routes, the need for more frequent dosing in patients with metastatic bone disease (relative to osteoporosis treatment) can add to the compliance problem.⁵

Available options for the treatment of bone metastases in patients with advanced cancers include zoledronic acid, an IV-administered bisphosphonate, and, more recently, denosumab, which is administered as a subcutaneous injection^6,7and is a monoclonal antibody directed against the receptor activated nuclear factor-κB ligand (RANKL). Zoledronic acid may be limited by the need for IV access and administration, the potential for first-dose acute-phase reactions, and the need to monitor renal function and adjust dosing in patients with renal impairment.^6,8Both agents need to be administered with appropriate calcium and vitamin D supplementation.^6,7

As with other solid tumors, patients with advanced prostate cancer are already at risk for bone loss from systemic treatments such as androgen deprivation therapy, and those with bone metastases are at risk for debilitating SREs.¹Thus, the prevention of SREs such as pathologic fractures and spinal cord compression, and the need for radiotherapy or surgery for bone metastases, has been the principal endpoint to evaluate bone-targeted therapies for the past 2 decades.⁸A benefit of both zoledronic acid and denosumab in preventing SREs has been demonstrated in men with castration-resistant metastatic prostate cancer, as well as in other cancers.¹Allan Lipton, MD, a medical oncologist at Pennsylvania State University and the Milton S. Hershey Medical Center, in Hershey, Pennsylvania, cited 3 randomized, controlled trials that compared denosumab with zoledronic acid for the prevention of SREs in patients with advanced cancers.

Results from these studies in castration-resistant prostate cancer,⁸advanced breast cancer,⁹and advanced solid tumors (exclusive of breast or prostate) or multiple myeloma¹⁰demonstrated the efficacy of denosumab over zoledronic acid for preventing SREs in patients with bone metastases. In an integrated analysis of all 3 pivotal trials, denosumab was associated with a 17% relative reduction in the risk of first SRE.¹¹Across these 3 studies, denosumab was associated with more (mainly asymptomatic) hypocalcemia, but a similar rate of osteonecrosis of the jaw (ONJ) versus zoledronic acid.¹¹

Findings of these studies also showed that, unlike zoledronic acid, denosumab was not associated with renal toxicity and acute-phase reactions, and did not require dose adjustment in patients with renal impairment.^8-11

The studies were not designed to assess patient preference for either therapy, or any potential difference in ease of administration. However, Lipton cited a benefit of both modes of administration over oral bisphosphonate therapy.

“Neither is oral; Zometa is IV and Xgeva is subcutaneous, so compliance is less of a problem than with the oral bisphosphonates. When [patients] come for their chemotherapy, or to see their doctor, once a month, they come in and get a shot,” Lipton said.

Lipton also stressed the importance of proper calcium and vitamin D supplementation, and that while severe events such as ONJ do occur in patients receiving monthly therapy with bone-targeted agents they are comparatively rare.

Clinical Pearls

• Patients with advanced cancer and bone metastases are at risk for skeletal-related events (SREs) such as pathologic fracture and spinal cord compression.
• Intravenous or subcutaneous administration of bone-targeted therapies may facilitate compliance and adherence with therapy for bone metastases.
• Current treatments to prevent SREs in patients with bone metastases include zoledronic acid, a bisphosphonate, and denosumab, an inhibitor of RANKL.
• Unlike zoledronic acid, denosumab does not require IV administration or monitoring of renal function and is not associated with acute-phase reactions.

“ONJ has been reported in patients receiving monthly bone-targeted agents, but the true incidence of ONJ is about 0.5% to 1.0% per year—not nearly as high as that reported in retrospective studies. [ONJ] is numerically higher, but not statistically higher, with Xgeva, and it’s important that people have their bone and their teeth checked beforehand and avoid dental surgery because the incidence of ONJ goes up with invasive dental surgery [when] they are on the bone-targeted agent,” Lipton explained.

Given the proven benefit of denosumab and other bone-targeted agents in preventing SREs, further study will be needed to define the optimal doses, duration of therapy, combination(s), and/or sequence of therapies to further enhance and facilitate treatment of bone metastases in patients with prostate, breast, and other advanced cancers.¹

References

1. McKay RR, Taplin ME, Choueiri TK. Optimizing bone health and minimizing skeletal morbidity in men with prostate cancer.Hematol Oncol Clin North Am. 2013;27(6):1261-1283
2. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel.Ann Oncol. 2008;19(3):420-432.
3. Aapro M, Saad F, Costa L. Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases.Oncologist. 2010;15(11):1147-1158.
4. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force Report: Bone Health in Cancer Care.J Natl Compr Canc Netw. 2009;7(suppl 3):S1-S32; quiz S33-S35.
5. Coleman RE. Risks and benefits of bisphosphonates.Br J Cancer. 2008;98(11):1736-1740.
6. Zometa [package insert]. East Hanover, NJ:. Novartis Pharmaceuticals Corporation; Revised April 2014.