ReviewBisphosphonates in oncology
Research Highlights
► Bisphosphonates are an integral part of treatment for patients with bone metastases from solid tumours and in multiple myeloma.► Prevention of skeletal morbidity with bisphosphonates has transformed the quality of life of patients with bone metastases. ► Bisphosphonates prevent bone loss associated with cancer treatments. However, selection criteria for intervention require further definition. ► Adjuvant use of bisphosphonates in early breast cancer may modify the disease course.
Introduction
Bone is a common site for metastasis in patients with solid tumours arising from the breast, prostate, lung, thyroid, and kidney. Approximately 70% of patients with advanced prostate cancer or breast cancer, and up to 40% of patients with other advanced solid tumours will develop bone metastases. Additionally in more than 50% of men with advanced prostate cancer and around 20% of women with advanced breast cancer, metastatic disease appears clinically confined to the skeleton [1].
Metastatic bone disease disrupts the normal homeostasis of bone, and the resulting increased and imbalanced bone metabolism leads to a disturbance of bone integrity, which may result in skeletal morbidity. This includes bone pain, pathological fractures, a need for orthopaedic surgery to prevent or repair major structural damage, spinal cord and/or nerve root compression, and hypercalcaemia of malignancy. As indicated elsewhere in this special issue, it is now generally accepted that osteoclast activation is the key step in the establishment and growth of bone metastases. Biochemical data indicate that bone resorption is of importance not only in classic “lytic” diseases such as myeloma and breast cancer but also in prostate cancer [2]. As a result, the osteoclast is a key therapeutic target for skeletal metastases irrespective of the tissue of origin.
In addition to the effects of spread of cancer to bone, there may also be important effects of cancer treatments on bone health. This is largely mediated through the endocrine effects of treatments including ovarian suppression, chemotherapy induced menopause, androgen deprivation therapy and the use of aromatase inhibitors in postmenopausal women. The improvements in cancer survival that have been achieved over the past 30 years mean that the long-term effects of treatment on the skeleton are now an important clinical problem and may require therapeutic intervention with bone-targeted treatments [3].
Section snippets
Bisphosphonates to prevent skeletal morbidity and relief of bone pain
Bone pain may be severe in metastatic bone disease, necessitating opiate analgesics and palliative radiation therapy, and is often accompanied by a substantial decline in patient-reported quality of life. Despite the many advances in the treatment of advanced cancer over recent decades, skeletal morbidity remains a major clinical problem with annual fracture rates of 20–40% and the occurrence of a significant skeletal complication every 3–6 months in the absence of bone-targeted therapies such
Optimum use of bisphosphonates in metastatic bone disease
Despite the obvious clinical benefits of bisphosphonates, it is clear that only a proportion of events is prevented, and some patients do not experience a skeletal event despite the presence of metastatic bone disease. It is currently impossible to predict whether an individual patient needs or will benefit from a bisphosphonate. Criteria are needed as to when in the course of metastatic bone disease bisphosphonates should be started and stopped. Because of the logistics and cost of delivering
Bisphosphonates and cancer treatment-induced bone loss
Advances in treatments for breast and prostate cancer have improved long-term survival leading to an increasing awareness of potential detrimental effects of such therapies on bone health. Many of the therapeutic approaches used in breast or prostate cancer are associated with bone loss, which in turns leads to an increased risk of fracture [35], [36], [37]. The majority of patients being treated for breast or prostate cancer are not under the care of a bone specialist, and several guidance
References (45)
- et al.
Practical guidance for the management of aromatase inhibitor-associated bone loss
Ann. Oncol.
(2008) - et al.
Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel
Ann. Oncol.
(2008) - et al.
Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases
Ann. Oncol.
(2003) - et al.
Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer
Pain
(2004) - et al.
Potential anticancer properties of bisphosphonates
Semin. Oncol.
(2010) - et al.
Exploring the anti-tumour activity of bisphosphonates in early breast cancer
Cancer Treat. Rev.
(2008) - et al.
Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients?
Eur. J. Cancer
(1996) - et al.
Clodronate decreases the frequency of skeletal metastases in women with breast cancer
Bone
(1996) - et al.
Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up
Ann. Oncol.
(2008) - et al.
Effect of oral clodronate on bone mass, bone turnover and subsequent metastases in women with primary breast cancer
Eur. J. Cancer
(2010)
The causes and treatment of bone loss associated with carcinoma of the breast
Cancer Treat. Rev.
Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group
Cancer Treat. Rev.
Clinical features of metastatic bone disease and risk of skeletal morbidity
Clin. Cancer Res.
Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors
J. Natl Cancer Inst.
Bisphosphonates for the relief of pain secondary to bone metastases
Cochrane Database Syst Rev.
Risks and benefits of bisphosphonates
Br. J. Cancer
Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer
J. Natl Cancer Inst.
Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial
Cancer
Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial
Cancer
Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): results of the Medical Research Council (MRC) Myeloma IX study
J. Clin. Oncol.
Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid
J. Clin. Oncol.
Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid
Cancer
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