Cancer Therapy-induced Bone Loss Research Articles

Bones, breasts, and bisphosphonates: rationale for the use of zoledronic acid in advanced and early breast cancer

Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby inhibiting the release of growth factors necessary to promote cancer cell growth, differentiation, and tumor formation in bone. These agents have demonstrated efficacy for delaying the onset and reducing the incidence of skeletal-related events in the advanced breast cancer setting, and have been shown to prevent cancer therapy-induced bone loss in the early breast cancer setting. Emerging clinical data indicate that the role of bisphosphonates in advanced and early breast cancer is evolving. Retrospective analyses and recent clinical trial data show that zoledronic acid may improve outcomes in some patients with breast cancer. Data from ABCSG-12 and ZO-FAST suggest that zoledronic acid may improve disease-free survival in the adjuvant breast cancer setting in postmenopausal women or women with endocrine therapy-induced menopause, and recent data from a predefined subset of the AZURE trial added to the anticancer story. However, the overall negative AZURE trial also raises questions about the role of bisphosphonates as an anticancer agent in patients with breast cancer. Overall, these data suggest that the addition of zoledronic acid to established anticancer regimens may have potential anticancer benefits in specific patient populations, although more studies are required to define its role.

Understanding and Optimizing Bone Health in Breast Cancer

Bone is the preferred site of metastasis for breast cancer, and presence of skeletal lesions is associated with significant morbidity and poor prognosis. Skeletal-related effects such as pain, pathologic fractures, spinal compression, and hypercalcemia are frequent consequences of skeletal lesions of breast cancer that have debilitating effects on the patients’ quality of life. In addition to direct cancer effects on the skeleton, therapies commonly used to treat patients with breast cancer such as chemotherapy and aromatase inhibitors (AI) result in cancer therapy-induced bone loss (CTIBL) which is associated with increased risk of skeletal complications such as fractures. Bisphosphonates are a class of antiresorptive drugs that are now firmly established as the cornerstone of the management of skeletal-related events due to breast cancer. Other novel bone-targeting agents such as the anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody denosumab are also showing promising activity in the treatment of bone metastasis secondary to breast cancer. Moreover, recent provocative evidence suggests that bisphosphonates might also exhibit antitumor activity via direct and indirect mechanisms. The goal of this review is to summarize the pathophysiology of osteolytic bone lesions secondary to breast cancer, provide clinical evidence of currently available bone-targeted drugs in the treatment of bone metastasis and CTIBL, and explore the antitumor activity of current bone-targeted agents in patients with breast cancer.

Zoledronic acid for breast cancer therapy-induced bone loss

The addition of zoledronic acid to aromatase inhibitors is associated with improved bone mineral density, but not with an effect on clinically-meaningful end points such as fractures. The oncology community should prioritize the design of trials evaluating more relevant end points, such as fragility fracture risk, for treatment-induced bone loss and critically assess the effects of such treatment on breast cancer survival.

Bone Disease in Breast Cancer: The Era of New Targeted Therapies

Breast cancer is the most common malignancy among women in the United States. Treatments for breast cancer can have significant effects on bone. Chemotherapy use in premenopausal women often leads to premature menopause, resulting in accelerated loss of bone mineral density. Hormonal therapy, particularly aromatase inhibitors in postmenopausal women, can also decrease bone density. In addition, a majority of patients with metastatic breast cancer have bony involvement, leading to bone pain, increased risk of fracture, and other morbidities. Thus, a thorough understanding of factors associated with cancer therapy-induced bone loss and treatment options are essential to providing quality care to cancer survivors. This article summarizes risk factors, evaluation, and treatment options for cancer therapy-induced bone loss and metastatic bone disease in breast cancer. In addition, emerging data regarding new targeted therapies and the effect of bone-targeted agents on breast cancer recurrence are discussed.

Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures. Many small studies have demonstrated that cancer therapy—induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting. Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of earlystage breast cancer. Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.

Zoledronic acid for cancer therapy-induced and postmenopausal bone loss

Background: Cancer therapy-induced bone loss (CTIBL) and bone loss in postmenopausal (PMW) increase fracture risk. Objective: To review the efficacy and safety of zoledronic acid (ZA) for prevention and treatment of CTIBL and postmenopausal bone loss. Methods: Using PubMed, a search of the English language literature (January 1950 to November 2007) was performed to identify articles evaluating ZA in CTIBL patients without bone metastases and for postmenopausal bone loss; articles were reviewed and evaluated. Results/conclusion: Intermittent administration of ZA increases BMD, decreases bone turnover markers, and is well tolerated in both cancer patients without bone metastases and osteopenic/osteoporotic PMW. In osteopenic/osteoporotic PMW, ZA also decreases fracture rates and prevents second fractures. The optimal regimens in these populations are unknown.

E06-03: Management of bone metastasis - role of bisphosphonates

Bisphosphonates are used in patients with metastatic bone disease to prevent skeletal-related events (SREs) such as bone pain, fractures and spinal cord or nerve compression and hypercalcemia of malignancy. (1Body JJ Bisphosphonates for malignancy-related bone disease: current status, future developments.Support Care Cancer. 2006; 14: 408-418Crossref PubMed Scopus (77) Google Scholar) Bisphosphonates are synthetic analogs of pyrophosphate. The four bisphosphonates used are Clodronate, Pamidronate, Zoledronic acid and Ibandronate. (2Selvaggi G Scagliotti GY Management of bone metastases in cancer: A review.Crit Rev Oncol/Hem. 2005; 56: 365-378Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) The latter drug is the newest and it is used outside of the U.S. since it has not been approved yet by the U.S. Food and Drug Administration. Bisphosphonates work mainly by inhibiting normal and pathologic osteoclast-mediated bone resorption thereby preventing bone loss. They do this by accumulating in sites of active bone formation making the sites more resistant to dissolution by osteoclasts. In lung cancer patients who die from their disease, 30%-40% will be diagnosed with bone metastases. The majority of these patients will have symptomatic bone involvement. In the U.S., Zoledronic acid, 4 mg infused for 15 minutes every 3-4 weeks is used to treat lung cancer patients with metastatic bone disease. In a randomized phase III double-blind, placebo controlled trial, in patients with non-small cell lung cancer (NSCLC) and other solid tumors, in a 21-month follow-up of the patients, the patients receiving Zoledronic acid, 4 mg experienced less SRE's (38%) compared to the patients receiving the placebo (47%).(3Rosen LS Gordon D Tchekmedyian NS et al.Long-term efficacy and safety of Zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors.Cancer. 2004; 100: 2613-2621Crossref PubMed Scopus (559) Google Scholar) Median times to first SRE were 230 days and 163 days respectively. Bisphosphonates are generally well tolerated. The most common side effects include flu-like symptoms (e.g. fever, myalgia, arthralgia) occurring in 10%-20% of patients which usually occurs 12 to 48 hours after the infusion and lasting 6 to 24 hours. Other side effects include bone pain, weakness, anemia, nausea, dyspnea and peripheral edema. These are usually mild to moderate. Ocular effects include uveitis which is rare. Oral bisphosphonates are generally associated with gastrointestinal intolerance, esophagitis and diarrhea. Two more serious complications include renal dysfunction and osteonecrosis of the jaw (ONJ). Since all bisphosphonates undergo renal clearance, their administration may result in elevated serum creatinine levels. Therapy should be withheld with increase in serum creatinine levels > 0.5 mg/dL above upper limits of normal. ONJ is a rare disorder characterized by temporary or permanent lose of blood supply to the jaw resulting in the development of necrotic bone in the mandible or maxilla. Symptoms include pain, swelling or infection of gums, loosening of teeth and poor healing of the gums. To minimize the risk of ONJ, patients must maintain excellent oral hygiene, limit alcohol and tobacco use, obtain dental assessments prior to starting bisphosphonates and avoid dental procedures while being treated with bisphosphonates. Bisphosphonates should be discontinued for 3 months prior to undergoing a dental procedure. Future development of the use of bisphosphonates include (1Body JJ Bisphosphonates for malignancy-related bone disease: current status, future developments.Support Care Cancer. 2006; 14: 408-418Crossref PubMed Scopus (77) Google Scholar) trials investigating whether high-dose bisphosphonates can reduce metastatic bone pain, (2Selvaggi G Scagliotti GY Management of bone metastases in cancer: A review.Crit Rev Oncol/Hem. 2005; 56: 365-378Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) studies of adjuvant therapy with bisphosphonates in order to prevent bone metastases and (3Rosen LS Gordon D Tchekmedyian NS et al.Long-term efficacy and safety of Zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors.Cancer. 2004; 100: 2613-2621Crossref PubMed Scopus (559) Google Scholar) Use of bisphosphonates to prevent cancer-therapy induced bone loss.

Screening, Prevention, Detection, and Treatment of Cancer Therapy-Induced Bone Loss in Patients With Breast Cancer

PURPOSE/OBJECTIVES To identify protocols to screen, detect, prevent, and treat cancer therapy-induced bone loss resulting in osteoporosis in patients with breast cancer. DATA SOURCES Published books and articles. DATA SYNTHESIS Normal bone remodeling is affected by hormonal stimulation. Breast cancer therapies target hormones that promote cancer cell growth. Chemotherapy regimens and hormone ablation may cause ovarian failure, resulting in decreased hormone levels. A decrease in hormones, in estrogen- and progesterone-positive and -negative patients, introduces an environment for decreased bone remodeling, which may result in thinning bone and osteoporosis. The acceleration of bone loss leading to osteoporosis can result in higher fracture rates among breast cancer survivors. CONCLUSIONS With proper use of screening tools, patient education, and advice about lifestyle changes, all prior to cancer treatment, healthcare professionals may decrease or prevent bone loss in patients with breast cancer. Doing so minimizes healthcare costs and decreases morbidity and mortality rates in breast cancer survivors. IMPLICATIONS FOR NURSING As more individuals diagnosed with breast cancer are surviving for extended periods of time, oncology nurses are providing long-term follow-up care. Part of the care should include proper screening and patient education for healthier recovery and prevention of further healthcare complications as a result of cancer treatment.

Screening, Prevention, Detection, and Treatment of Cancer Therapy-Induced Bone Loss in Patients With Breast Cancer

To identify protocols to screen, detect, prevent, and treat cancer therapy-induced bone loss resulting in osteoporosis in patients with breast cancer. Published books and articles. Normal bone remodeling is affected by hormonal stimulation. Breast cancer therapies target hormones that promote cancer cell growth. Chemotherapy regimens and hormone ablation may cause ovarian failure, resulting in decreased hormone levels. A decrease in hormones, in estrogen- and progesterone-positive and -negative patients, introduces an environment for decreased bone remodeling, which may result in thinning bone and osteoporosis. The acceleration of bone loss leading to osteoporosis can result in higher fracture rates among breast cancer survivors. With proper use of screening tools, patient education, and advice about lifestyle changes, all prior to cancer treatment, healthcare professionals may decrease or prevent bone loss in patients with breast cancer. Doing so minimizes healthcare costs and decreases morbidity and mortality rates in breast cancer survivors. As more individuals diagnosed with breast cancer are surviving for extended periods of time, oncology nurses are providing long-term follow-up care. Part of the care should include proper screening and patient education for healthier recovery and prevention of further healthcare complications as a result of cancer treatment.

Natural history, treatment patterns, and economic burden of cancer therapy induced bone loss (CTIBL) among breast and prostate cancer patients (pts): A study overview

8243 Background: Accelerated bone loss has been observed in men and women undergoing cancer treatment. In recent years, the use of aromatase inhibitors and gonadotropin-releasing hormone agonists h...

Natural history, treatment patterns, and economic burden of cancer therapy induced bone loss (CTIBL) among breast and prostate cancer patients (pts): A study overview

8243 Background: Accelerated bone loss has been observed in men and women undergoing cancer treatment. In recent years, the use of aromatase inhibitors and gonadotropin-releasing hormone agonists h...