ABSTRACT: Considerable advances in oncology over recent decades have led to improved survival, while raising concerns about long-term consequences of anticancer treatments. In patients with breast or prostate malignancies, bone health is a major issue due to the high risk of bone metastases and the frequent prolonged use of hormone therapies that alter physiological bone turnover, leading to increased fracture risk. Thus, the onset of cancer treatment-induced bone loss (CTIBL) should be considered by clinicians and recent guidelines should be routinely applied to these patients. In particular, baseline and periodic follow-up evaluations of bone health parameters enable the identification of patients at high risk of osteoporosis and fractures, which can be prevented by the use of bone-targeting agents (BTAs), calcium and vitamin D supplementation and modifications of lifestyle. This review will focus upon the pathophysiology of breast and prostate cancer treatment-induced bone loss and the most recent evidence about effective preventive and therapeutic strategies.
Project description:Cancer therapy-induced bone loss (CTIBL) is a form of secondary osteoporosis associated with systemic chemotherapy and hormonal ablation therapy. The monitoring and treatment of CTIBL is an important component of comprehensive cancer care, especially for patients with curable disease and long life expectancies. Whereas oral bisphosphonates remain the most commonly used therapeutic option for CTIBL, additional treatment options may be required for patients who do not respond adequately or are intolerant to bisphosphonates, have renal insufficiency, or are receiving treatment with nephrotoxic medications. For these patients, denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-?B ligand (RANKL), offers an effective and well-tolerated alternative. Several recent randomized trials have examined the use of denosumab as treatment for CTIBL associated with hormone ablation therapy for breast and prostate cancer. Recent data suggest a possible role for RANKL inhibitors in both chemoprevention and the prevention of cancer recurrence through direct effects on breast tissue and breast cancer stem cells. The outcomes of several international Phase III clinical trials currently underway will help clarify the role of denosumab in patients undergoing cancer therapy.
Project description:Osteoporosis is one of the most frequent diseases in postmenopausal women, leading to an increased fracture risk due to the physiologic loss of the bone protective effects of estrogen. Hereby, several risk factors for fracture such as prevalent fracture, low bone mineral density (BMD), age, low body mass index, family history, tendency to falls, smoking, use of SSRIs, glucocorticoid use etc. have been identified. In addition, the further reduction in endogenous estrogens with chemotherapy (CHT), GnRH analoga or aromatase inhibitors (AIs) continuously increases fracture risk. Breast cancer (BC) on the other hand is the most frequent cancer type in women. Recent reports indicate a continuous increased incidence, whereas mortality, due to early diagnosis and treatment improvements, is decreasing. Dependent on specific tumor characteristics, radiation, CHT, antibody treatment as well as endocrine treatment have been included into the adjuvant clinical treatment setting. Some but not all of these cancer-specific treatments interfere with bone turnover, leading to an accelerated bone loss referred to as cancer treatment-induced bone loss (CTIBL). Whereas CHT leads to an unspecific increase in bone resorption, AI reduces residual serum endogenous estrogen level and is associated with a decrease in BMD and increased fracture risk. Independent of the type of AI administered, bone loss is 2-3-fold increased compared with healthy, age-matched postmenopausal controls. Therefore, several guidelines have emerged to help managing CTIBL in women with BC including strategies to identify and treat those at highest risk for fractures. This review summarizes the current knowledge on CTIBL and fracturing risk and indicates preventative strategies.
Project description:The bone-targeted agents (BTAs), bisphosphonates and denosumab, have an established role in the treatment of metastatic breast cancer bone disease and the prevention of cancer-treatment-induced bone loss. Evidence in support of their ability to improve survival in early breast cancer now indicates that the bisphosphonates are effective in postmenopausal women (naturally or chemically induced), but denosumab does not have similar benefits when added to standard adjuvant therapy. In postmenopausal women with early breast cancer, the choice of BTA may differ depending on the indication for treatment; for fracture prevention in low disease recurrence risk patients, denosumab may be favoured (in comparison with placebo) to maintain bone health, and when disease recurrence prevention is a priority in higher risk patients, bisphosphonates may be favoured. The reason for the lack of efficacy of BTAs in premenopausal/perimenopausal patients still remains unanswered and will need preclinical research to evaluate novel treatment combinations with BTAs in this patient group. This review covers the past, present, and future indications for BTAs in both metastatic and early breast cancer.
Project description:New therapeutic options in breast cancer have improved survival but consequently increase the relevance of late complications. Ovarian suppression/ablation and aromatase inhibitors (AI) in the adjuvant setting have improved outcome, but have clinically important adverse effects on bone health. However, investigation and management of cancer treatment-induced bone loss (CTIBL) is poorly defined with no national guidance. In 2004, a questionnaire was sent to over 500 breast surgeons and oncologists who treat breast cancer within the United Kingdom. The questionnaire evaluated access to bone densitometry and specialist expertise as well as attitudes to investigation of CTIBL and anticipated changes in the use of AI for postmenopausal early breast cancer. A total of 354 completed questionnaires were received, 47 from clinicians not currently treating breast cancer. Of the 307 evaluable questionnaires, 164 (53%) were from breast surgeons, 112 (36%) from clinical oncologists and 31 (10%) from medical oncologists. Although most respondents recognised that CTIBL was the responsibility of the treating breast team, investigations for CTIBL are limited even though most had adequate access to bone densitometry; 98 (32%) had not requested a DXA scan in the last 6 months and 224 (73%) had requested fewer than five scans. In all, 235 (76%) were not routinely investigating patients on AI for bone loss. A total of 277 (90%) felt that their practice would benefit from national guidelines to manage these patients, and the majority (59%) had little or no confidence in interpreting DXA results and advising on treatment. This questionnaire has highlighted clear deficiencies in management of CTIBL in early breast cancer. The development of national guidelines for the management of these patients and educational initiatives for breast teams are urgently required.
Project description:BACKGROUND:Patients with cancer can experience bone metastases and/or cancer treatment-induced bone loss (CTIBL), and the resulting bone complications place burdens on patients and healthcare provision. Management of bone complications is becoming increasingly important as cancer survival rates improve. Advances in specialist oncology nursing practice benefit patients through better management of their bone health, which may improve quality of life and survival. METHODS:An anonymised online quantitative survey asked specialist oncology nurses about factors affecting their provision of support in the management of bone metastases and CTIBL. RESULTS:Of 283 participants, most stated that they worked in Europe, and 69.3% had at least 8 years of experience in oncology. The most common areas of specialisation were medical oncology, breast cancer and/or palliative care (20.8-50.9%). Awareness of bone loss prevention measures varied (from 34.3% for alcohol intake to 77.4% for adequate calcium intake), and awareness of hip fracture risk factors varied (from 28.6% for rheumatoid arthritis to 74.6% for age >?65 years). Approximately one-third reported a high level of confidence in managing bone metastases (39.9%) and CTIBL (33.2%). International or institution guidelines were used by approximately 50% of participants. Common barriers to better specialist care and treatment were reported to be lack of training, funding, knowledge or professional development. CONCLUSION:This work is the first quantitative analysis of reports from specialist oncology nurses about the management of bone metastases and CTIBL. It indicates the need for new nursing education initiatives with a focus on bone health management.
Project description:INTRODUCTION:Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer. MATERIALS AND METHODS:Studies were identified through the Medline database. Key search terms included: AMG-162, bisphosphonates, denosumab, RANK-ligand and zoledronic acid. Information available in abstract form only was retrieved from major oncology meetings, such as the American Society of Clinical Oncology (ASCO) annual meeting, ASCO breast meeting, European Cancer Organization, European Society of Medical Oncology and the San Antonio Breast Cancer Symposium. RESULTS:Denosumab was consistently well tolerated throughout clinical trials, although the observed incidence of osteonecrosis of the jaw was comparable to that with bisphosphonates. Efficacy as determined by a reduction of skeletal-related events was at least equal to zoledronic acid, and superior in one phase III study conducted in patients with metastatic breast cancer. Clinical trials investigating the role of denosumab for the prevention of CTIBL and breast cancer recurrences are currently ongoing. CONCLUSION:In conclusion, denosumab appears to be an effective and safe treatment option in patients with bone metastases from breast cancer with the potential of also preventing CTIBL.
Project description:BACKGROUND:Optimal dosing of bone-targeted agents (BTAs), in patients with bone metastases remains an important clinical question. This trial compared 4-weekly versus 12-weekly therapy. PATIENTS AND METHODS:Patients with bone metastases from breast or castration-resistant prostate cancer (CRPC), who were going to start or already on BTAs, were randomised 1:1 to 4-weekly or 12-weekly BTA treatment for one year. Primary end point was change in health-related quality of life (HRQoL)-physical function European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30). Secondary end points included pain (EORTC-QLQ-BM22), global health status (EORTC-QLQ-C30), symptomatic skeletal events (SSEs) rates and time to SSEs. Primary analysis was per protocol and a non-inferiority margin of 5 points was used. RESULTS:Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). Using repeated-measures analysis, across all time points, patients in the 4-weekly arm had a mean HRQL-physical subdomain score which was 1.2 (95% confidence interval: -1.6 to 4.0) higher than the 12-weekly arm. The study met the definition of non-inferiority for our primary outcome. Secondary outcomes showed no significant difference in scores for pain, global health status, SSE rates and SSE-free survival between arms. Subgroup analyses for cancer type, prior BTA use or BTA type showed no significant difference between arms. CONCLUSION:These results in addition to those previously reported for de-escalating zoledronate and systematic reviews in both breast and prostate cancers, would support that de-escalation of commonly used BTAs is a reasonable treatment option.
Project description:In order to design studies assessing the optimal use of bone-targeted agents (BTAs) patient input is clearly desirable.Patients who were receiving a BTA for metastatic prostate or breast cancer were surveyed at two Canadian cancer centres. Statistical analysis of respondent data was performed to establish relevant proportions of patient responses.Responses were received from 141 patients, 76 (53.9%) with prostate cancer and 65 (46.1%) with breast cancer. Duration of BTA use was <3 months (15.9%) to >24 months (35.2%). Patients were uncertain how long they would remain on a BTA. While most felt their BTA was given to reduce the chance of bone fractures (77%), 52% thought it would slow tumour growth. Prostate patients were more likely to receive denosumab and breast cancer patients, pamidronate. There was more variability in the dosing interval for breast cancer patients. Given a choice, most patients (49-57%) would prefer injection therapy to oral therapy (21-23%). Most patients (58-64%) were interested in enrolling in clinical trials of de-escalated therapy.While there were clear differences in the types of BTAs patients received, our survey showed similarity for both prostate and breast cancer patients with respect to their perceptions of the goals of therapy. Patients were interested in participating in trials of de-escalated therapy. However, given that patients receive a range of agents for varying periods of time and in different locations (e.g. hospital vs. home), the design of future trials will need to be pragmatic to reflect this.
Project description:Bone metastases (BMs) are common in patients with breast cancer and can lead to skeletal-related events (SREs), which are associated with increased pain and reduced quality of life (QoL). Bone-targeted agents (BTAs), like zoledronic acid and denosumab, reduce the incidence of SREs and delay progression of bone pain.We evaluated the management of BMs and pain in six European countries (Belgium, France, Germany, Italy, Spain, and UK) using the Adelphi Breast Cancer Disease Specific Programme, which included a physician survey and patient-reported outcomes (PROs) to assess the impact of BMs on pain and QoL.301 physicians completed patient record forms for 2984 patients with advanced breast cancer; 1408 with BMs and 1136 with metastases at sites other than bone (non-BMs). Most patients with BMs (88%) received a BTA, with 81% receiving treatment during 3 months following BM diagnosis. For those who did not receive a BTA, the main reasons given were: very recent BM diagnosis, perceived low risk of bone complications, and short life expectancy. Most patients with BMs (68%) were experiencing bone pain and, of these, 97% were taking analgesics (including 28% receiving strong opioids). Despite this, moderate to severe pain was reported in 20% of patients who were experiencing pain. PROs were assessed in 766 patients with advanced breast cancer (392 with BMs, 374 with non-BMs). Overall, patients with BMs reported worse pain and QoL outcomes than those with non-BMs, those not receiving a BTA reported worse pain.Despite the large proportion of patients receiving BTAs in this study, some patients with BMs are still not receiving early treatment to prevent SREs or to manage pain. Improving physicians' understanding of the role of BTAs and the importance of early treatment following BM diagnosis has the potential to improve patient care.
Project description:The hormone dependent breast and prostate cancers have in general a very good survival, due to the anti-hormonal treatment. A disadvantage of this treatment is the increased risk of osteoporosis and fractures. It is surprisingly to note that denosumab has the same impact on fracture reduction incidence for both sexes, but with different reimbursement criteria. Furthermore there is only reimbursement in case of osteoporosis and not for cancer patients who are at an increased risk of developing osteoporosis. The clinician detects the accelerated bone loss during follow-up, but has to wait until there is osteoporosis. The impact of osteoporosis on the quality of life is severe and underestimated. Management of cancer should not only focus on survival, therefore it is time to reconsider the reimbursement criteria, discuss the willingness of society to pay for bone health and make choices regarding the advice we give to our patients.