Breast Neoplasms: McCloskey EV

Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey EV, Powles T, Selby P, Coleman RE. · Department of Rheumatology, University of Aberdeen, United Kingdom. · Cancer Treat Rev. · Pubmed #18515009 No free full text.

Abstract: In postmenopausal women, the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1-3% per year leading to an increase in fracture incidence compared to that seen during tamoxifen use. The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy (average 7-8% per annum). Pre-treatment with tamoxifen for 2-5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors, particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor. However, skeletal status should still be assessed at the commencement of aromatase inhibitor therapy. The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors. These patients are considered to be at high risk of clinically important bone loss and should have a baseline dual energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD). Randomised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting. Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels. Bisphosphonates, along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss. Due to the rate of bone loss associated with breast cancer treatments, and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk, the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis. Management recommendations have been summarised in two algorithms, one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy.

McCloskey EV, Guest JF, Kanis JA. · WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, England. · Drugs. · Pubmed #11511021 No free full text.

Abstract: The bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are now the treatment of choice for the management of hypercalcaemia of malignancy. The incidences of hypercalcaemia and other skeletal complications (bone pain, pathological fracture) remain high despite apparent responses to systemic therapy, with particularly high event rates in women with advanced skeletal metastases of breast cancer. This review focuses on studies addressing the long-term efficacy of bisphosphonates to reduce skeletal complications in breast cancer (5 studies) and multiple myeloma (4 studies), with particular reference to controlled studies of sufficient magnitude and duration to allow confidence in the estimation of efficacy. Bearing in mind the limitations of differences in trial design and the lack of direct studies comparing drugs, adequate exposure to a bisphosphonate reduces the incidence of skeletal complication by 30 to 40% in both breast cancer and multiple myeloma. Oral clondronate and intravenous pamidronate have similar efficacy in both diseases, but the duration of efficacy may differ between drugs. Both agents have shown intriguing survival benefits in subgroups of patients. The numbers needed to treat (NNT) to prevent a skeletal complication during one year are lowest in metastatic skeletal disease in breast cancer (NNT < 8) but also compare very favourably with other disease for patients with recurrent nonskeletal breast cancer or multiple myeloma (NNTs 7 to 31 depending on the complication to be prevented). Treatment costs of both breast cancer and multiple myloma are driven by inpatient and outpatient hospital visits so that bisphosphonate regimens should be developed that reduce both. Further research is required to determine if subgroups of patients can be better identified that will derive particular benefit, or perhaps no benefit at all, from bisphosphonate therapy. It is not known whether more potent bisphosphonates will deliver greater clinical efficacy in the future.

Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T. · WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, UK. · Br J Cancer. · Pubmed #10098755 No free full text.

Abstract: Because treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3-9.9], and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1-57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer.

Powles TJ, Howell A, Evans DG, McCloskey EV, Ashley S, Greenhalgh R, Affen J, Flook LA, Tidy A. · Breast Unit, Parkside Oncology Clinic, Wimbledon, London, UK. · Menopause Int. · Pubmed #18380954 No free full text.

Abstract: OBJECTIVE: To assess the safety and tolerability of a standardized 40 mg red clover isoflavone dietary supplement (Promensil, Novogen) in women with a family history of breast cancer to evaluate the feasibility of using the supplement for prevention of breast cancer in healthy women. STUDY DESIGN: Healthy women aged 35-70 years (n = 401) with at least one first-degree relative with breast cancer received red clover isoflavones or placebo for three years in a randomized, double-blind, placebo-controlled pilot trial. Participants were assessed clinically and blood samples taken for biochemical analysis every six months. In addition, study participants underwent mammography, bone density and transvaginal ultrasound (postmenopausal women only) once per year. RESULTS: No significant differences in breast density, endometrial thickness, serum cholesterol, follicle stimulating hormone levels and bone mineral density were detected between those taking red clover isoflavones and placebo. In postmenopausal women, some significant differences in bone marker levels were seen between active and placebo groups, at six months and at 12 months. The adverse event profile was similar across all red clover isoflavone and placebo groups. CONCLUSION: This three-year study supports the growing body of evidence that treatment with red clover isoflavones is safe and well tolerated in healthy women. Supplements containing red clover isoflavones did not adversely affect breast density, skeletal strength or cardiovascular status. In postmenopausal women, endometrial status was not adversely affected. The adverse event profile was similar between red clover isoflavones, and placebo and endocrine status did not differ.

Brown JE, McCloskey EV, Dewar JA, Body JJ, Cameron DA, Harnett AN, Ruutu M, Purohit OP, Tähtelä R, Coleman RE. · Academic Unit of Clinical Oncology, Weston Park Hospital University of Sheffield, Sheffield S10 2SJ, UK. · Calcif Tissue Int. · Pubmed #17874331 No free full text.

Abstract: Biochemical markers of bone metabolism are strongly associated with skeletal complications in metastatic bone disease. The bisphosphonate clodronate reduces skeletal morbidity by inhibiting bone resorption. This study investigated the use of bone markers to assess the efficacy of oral clodronate across a range of clinically relevant doses. There were 125 patients with metastatic bone disease randomized to daily oral clodronate (800, 1,600, 2,400 and 3,200 mg) or placebo in a double-blind, multicenter study. Urinary N-terminal telopeptide of type I collagen (U-NTX), serum C-terminal telopeptide of type I collagen (S-CTX), urinary calcium (U-Ca), and bone alkaline phosphatase were measured weekly for a 6-week treatment period. Doses of >or=1,600 mg clodronate produced mean reductions of >40% in U-NTX, S-CTX and U-Ca, all significantly different from placebo (P=0.0015, 0.001, 0.0036, respectively), after 6 weeks. Evaluation of least significant changes in markers suggested that the commonly used 1,600 mg dose was most appropriate for breast cancer patients. However, this dose was suboptimal for other (mainly prostate cancer) patients, who showed better response to 2,400 mg. The number of adverse events in the treatment arms was not significantly different from that in placebo, but a higher number of patients had diarrhea in the 3,200 mg arm and withdrew from the study. This trial is the first to explore the dose-response relationship of clodronate in oncology using specific markers of bone turnover. It has confirmed that the 1,600 mg dose is safe and effective for breast cancer patients but may be suboptimal for the other tumors studied.