Elsevier

Seminars in Oncology

Volume 37, Supplement 2, October 2010, Pages S15-S29
Seminars in Oncology

Implications of Bone Metastases and the Benefits of Bone-Targeted Therapy

https://doi.org/10.1053/j.seminoncol.2010.10.002Get rights and content

Several cancers, including those originating in the breast, prostate, and lung, exhibit a propensity to metastasize to bone, resulting in debilitating skeletal complications. These sequelae, such as intractable pain, pathologic fractures, spinal compression, and hypercalcemia, greatly erode the patients' quality of life. Bisphosphonates, a class of antiresorptive drugs, are now the mainstay of the treatment of skeletal-related events in myeloma bone disease and many solid cancers with bone metastases. Current evidence indicates that newer-generation nitrogen-containing bisphosphonates, particularly zoledronic acid, are potent inhibitors of bone resorption. In addition, increased understanding of the pathogenesis of bone metastasis has resulted in the development of several bone-targeted therapies including a monoclonal antibody targeting the receptor activator of nuclear factor (NF)-κB ligand (RANKL). In this review, clinical evidence regarding the efficacy and safety of currently available bone-targeted therapies including bisphosphonates and anti-RANKL monoclonal antibody in the treatment of bone metastasis due to breast cancer, prostate cancer, lung cancer, and multiple myeloma bone disease will be summarized.

Section snippets

Bisphosphonates in the Treatment of Bone Metastasis

Randomized clinical trials have demonstrated that prolonged administration of oral or intravenous (IV) bisphosphonates significantly reduces the frequency of skeletal-related events (SREs) in patients with bone metastases from breast cancer. Although clodronate has demonstrated considerable activity in terms of reduction of SREs and palliation in the treatment of bone lesions of breast cancer, questions remain regarding the durability and survival effects. In a randomized placebo-controlled

Bisphosphonates in the Treatment of Prostate Cancer

Although prostate cancers are predominantly sclerotic or osteoblastic, they also have an osteolytic component that might be responsive to bisphosphonates. Consequently, several trials have investigated clodronate, pamidronate, and zoledronic acid in patients with prostate cancer. While several early clinical trials indicated that intravenous clodronate might have analgesic effects in patients with bone pain associated with metastatic bone disease from prostate cancer, subsequent trials failed

Bisphosphonates in the Treatment of Myeloma Bone Disease

Clodronate therapy has demonstrated particular clinical efficacy in myeloma bone disease. In the Finnish Leukemia Study Group placebo-controlled randomized trial in patients with multiple myeloma, 350 patients were treated with either placebo or clodronate 2,400 mg/d in addition to melphalan/prednisolone for 2 years; only 68 of these patients did not present with overt skeletal disease41 (Table 3).19, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 A significantly lower proportion of patients showed

Lung Cancer

Current clinical evidence with clodronate therapy in the treatment of bone metastasis from lung cancer is sparse and shows ambivalence in terms of analgesic effects. In an early small retrospective study in patients with non-small cell lung cancer (NSCLC), Caristi et al showed that clodronate in addition to radiation therapy decreased occurrence of pain worsening and increased complete pain relief compared with radiation therapy alone56 (Table 4).56, 57, 58, 59, 60, 61 In contrast, Piga et al,

Safety of Bone-Targeted Therapy

Oral bisphosphonates are commonly associated with gastrointestinal adverse events such as epigastric pain and esophagitis.63 IV bisphosphonates are often associated with typical infusion-related side effects such as injection site reactions, flu-like syndromes, and sometimes renal issues. The most commonly reported adverse events reported in the pivotal trial comparing zoledronic acid and pamidronate reported by Rosen et al were bone pain, nausea, fatigue, emesis, and fever.18 Renal

Current Treatment Guidelines

According to the American Society of Clinical Oncology (ASCO), infusional bisphosphonates pamidronate 90 mg (delivered over 2 hours) or zoledronic acid (4 mg over 15 minutes every 3 to 4 weeks) are recommended for management of bone-related metastases in women with breast cancer who show evidence of bone destruction by plain radiography.65 However, the presence or absence of bone pain is not considered a determinant of initiation of bisphosphonate therapy. In patients with bone metastasis from

Conclusions

The natural history of bone metastases due to solid tumors or myeloma bone disease shows dismal prognosis. Skeletal complications due to bone metastasis are strong determinants of quality of life and survival in these patients. Based on solid evidence, treatment with bisphosphonates, particularly pamidronate and zoledronic acid, is deeply entrenched in the treatment paradigm of management of bone disease. In contrast to analgesics or radiation therapy, bone-targeted therapy is not only used

Statement of Conflict of Interest

A. Lipton discloses the following potential conflicts of interest: Consulting fees: Amgen Inc; Cephalon, Inc; Novartis Pharmaceuticals Corporation; and Thar Pharmaceuticals. Speaker's bureau: Amgen Inc, Genentech, and Novartis Pharmaceuticals Corporation. Contracted research: Monogram Biosciences, Oncogene Science/Siemens HealthCare Diagnostics, Novartis Pharmaceuticals Corporation. Expert testimony: Novartis Pharmaceutical Corporation.

Acknowledgment

The author wishes to thank Nathan Kelly, PhD, and Trudy Grenon Stoddert, ELS, for their assistance in preparing the manuscript for publication.

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    Publication of this article was supported by an educational grant from Novartis Pharmaceuticals Corporation.

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