Impact of skeletal complications on patients’ quality of life, mobility, and functional independence

Costa, Luís; Badı́a, Xavier; Chow, Edward; Lipton, Allan; Wardley, Andrew M

doi:10.1007/s00520-008-0418-0

Cited by 172 publications

(119 citation statements)

References 71 publications

(116 reference statements)

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“…(1) Up to 80% of patients with advanced breast cancer develop bone metastases associated with bone loss and fracture, which contribute to incapacitating pain and limited or total loss of mobility. (23–25,37) Pain, the first symptom in many cancer patients, substantially decreases the quality of life (23–25,37) and is poorly addressed by the current first-line therapies. (5) Skeletal-related events (SREs) and pain due to breast cancer metastases are treated using radiation therapy, opiates, and bisphosphonates.…”

Section: Discussionmentioning

confidence: 99%

Disease modification of breast cancer–induced bone remodeling by cannabinoid 2 receptor agonists

Lozano-Ondoua

Hanlon

Symons-Liguori

et al. 2012

Journal of Bone and Mineral Research

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Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB2) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB2 agonists reduce breast cancer–induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB2 agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB2-mediated effects in vivo were reversed by concurrent treatment with a CB2 antagonist/inverse agonist but not with a CB1 antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB2 agonists as a novel treatment for breast cancer–induced bone pain, in which disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone pain, and increased survival without the major side effects of current therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Disease modification of breast cancer–induced bone remodeling by cannabinoid 2 receptor agonists

Lozano-Ondoua

Hanlon

Symons-Liguori

et al. 2012

Journal of Bone and Mineral Research

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“…Hypercalcemia in malignancy is a reversible but potentially life-threatening consequence of advanced disease (2). SREs, such as fracture and spinal cord compression, are associated with poorer physical, functional and emotional status, lower overall quality of life (13,15) and reduced survival in cancer patients (16,17). …”

Section: Introductionmentioning

confidence: 99%

Comparison of the efficacy and safety of denosumab versus bisphosphonates in breast cancer and bone metastases treatment: A meta-analysis of randomized controlled trials

et al. 2014

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Breast cancer is the most common type of cancer in females worldwide. Patients with breast cancer and bone metastases may experience increased osteoclast activity, resulting in local bone destruction and skeletal complications, including pain, hypercalcemia and skeletal-related events. Intravenous bisphosphonates (BPs) are the standard treatment administered to patients with breast cancer and bone metastases to prevent skeletal-related events. However, in certain patients, BPs may cause renal toxicity, acute-phase reactions and osteonecrosis of the jaw. More effective, safer and more tolerable therapies, which prevent bone destruction and skeletal complications, are required in order to improve patient quality of life. Denosumab is a fully human monoclonal antibody that binds to and neutralizes receptor activator of nuclear factor-κB ligand, which is a key mediator in the pathogenesis of a broad range of skeletal diseases, thereby inhibiting osteoclast function and bone resorption. Therefore, we conducted a meta-analysis to compare both the safety and efficacy of denosumab and BPs in the treatment of breast cancer and bone metastases. Five databases, two clinical trial registry platforms and reference lists of relevant papers were analyzed. The meta-analysis concluded that denosumab was more effective at preventing pain and skeletal-related events than BPs, in patients with breast cancer and bone metastases. Patients receiving denosumab demonstrated a higher level of clinical improvement in terms of health-related quality of life than patients receiving BPs. Compared with BPs, denosumab reduced the incidence of certain indicators of adverse events, including pyrexia, bone pain, edema and renal failure.

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“…They are associated with debilitating skeletal complications, commonly referred to as skeletal-related events (SREs) and comprising pathologic fracture, radiation to bone, surgery to bone or spinal cord compression [2]. As well as being associated with increased mortality [3,4], SREs can be associated with severe pain, impaired mobility and reduced quality of life [1,5]. Improvements in the management of breast cancer have led to increased survival times for patients with metastatic bone disease, but this means that the life-time risk of developing SREs has also increased.…”

Section: Introductionmentioning

confidence: 99%

Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?

Moos

Haynes

2013

JCM

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Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL) pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer.

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Impact of skeletal complications on patients’ quality of life, mobility, and functional independence

Cited by 172 publications

References 71 publications

Disease modification of breast cancer–induced bone remodeling by cannabinoid 2 receptor agonists

Disease modification of breast cancer–induced bone remodeling by cannabinoid 2 receptor agonists

Comparison of the efficacy and safety of denosumab versus bisphosphonates in breast cancer and bone metastases treatment: A meta-analysis of randomized controlled trials

Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?

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