The effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer

Abstract

SummaryIn this study we report bone mineral density (BMD) changes during clodronate and antioestrogen treatment in women with breast cancer having discontinued hormone replacement therapy (HRT) at the time of operation compared to women who had not used HRT immediately before the operation. 61 postmenopausal women with operable breast cancer were treated with the adjuvant antioestrogen tamoxifen 20 mg or toremifene 60 mg daily for 3 years. All patients were randomized to clodronate (1.6 g daily orally) or control groups for 3 years. 23 patients had recently (recent users) and 38 never or not for at least 1 year before operation used HRT (non-users). BMD of lumbar spine and femoral neck were measured before antiresorptive therapy (antioestrogens and clodronate) and at 1, 2, 3 and 5 years thereafter. All patients were disease-free at the time of BMD measurements. Patients who had recently used HRT had more significant bone loss as compared to HRT non-users at 3 years in lumbar spine -3.0% vs. + 1.2% (P < 0.001), but not in femoral neck -0.4% vs. + 1.7% (P = 0.27). Adding 3-year clodronate treatment to antioestrogen therapy improved BMD marginally at 3 years: lumbar spine + 1.0% vs. -1.7% (P = 0.01) and femoral neck + 2.4% vs. -0.4% (P = 0.12). This was also seen at 5 years of follow-up, 2 years after termination of the antiresorptive therapy: HRT recent users vs. HRT non-users in lumbar spine -6.5% vs. +0.5% (P < 0.0001) and in femoral neck -4.8% vs. -1.5% (P = 0.38); and clodronate vs. controls in lumbar spine -1.0% vs. -3.2% (P = 0.06) and in femoral neck -0.1% vs. -5.2% (P = 0.001, respectively). The type of endocrine therapy (tamoxifen and toremifene) had no significant influence on BMD changes. We conclude from this study that postmenopausal women who have recently discontinued HRT experience more rapid bone loss than HRT non-users. Neither 3-year antioestrogen therapy alone nor antioestrogen together with clodronate could totally prevent the bone loss related to HRT withdrawal in lumbar spine, even though clodronate seemed to retard it.

Toremifene in the treatment of breast cancer

“…Comparative studies have shown that both toremifene and tamoxifen prevent reductions in BMD in the lumbar spine and proximal femur, and that these effects are reflected by changes in a wide range of bone biochemistry markers such as pyridinoline, deoxypyridinoline and urinary cross-linked aminoterminal telopeptide of type Ⅰ collagen [53][54][55] . Toremifene and tamoxifen have also been used successfully in combination with the bisphosphonate clodronate, with no significant differences between them [56,57] . Some beneficial effects on BMD have been observed in premenopausal women at high risk for developing breast cancer taking toremifene 60 mg as chemoprevention, therefore making an attractive alternative to tamoxifen.…”

Bone Mineral Density and Lipid Changes During 5 Years of Follow-up in a Study of Prevention of Breast Cancer with Toremifene in Healthy, High-risk Pre- and Post-menopausal Women

“…In our experience, by contrast, the inferiority of toremifene was the product of 0.54% mean reduction from baseline in the toremifene-treated patients compared with 3.32% increase in BMD in the placebo group. The mean BMD response with placebo during the first year of our investigation compares favourably with the response to various forms of osteoporosis therapy in postmenopausal women [11,12], including some experiences with combination HRT [13,14] and raloxifene [15]. A marked placebo response, rather than a substantive decline in BMD with toremifene, is thus the major factor contributing to the overall statistical difference.…”

“…Statistical testing of the revised primary endpoints used an analysis of variance model with the effects: treatment group (placebo vs. toremifene); country (UK vs. Finland); time (12,24,36 and 60 months), and menopausal status (pre-versus postmenopausal). Interactions for treatment group by time, treatment group by menopausal status, and treatment group by menopausal status and time were also examined.…”

Guidelines for Osteoprotection in Breast Cancer Patients on an Aromatase Inhibitor

“…Mounting evidence now suggests that treatment with bisphosphonates prevents AIBL [2,22,46,[60][61][62][63][64][65]. Because of the increased bone loss associated with the use of AIs, three international randomized studies, the Zometa-Femara Adjuvant Synergy Trials [Z-FAST, ZO-FAST, and E-ZO-FAST] were performed to evaluate the bone protective effects of bisphosphonates during endocrine treatment with letrozole.…”