Use of bisphosphonates to preserve bone health in postmenopausal women initiating adjuvant AIs in breast cancer

The use of bisphosphonates to reduce therapy-induced bone loss has been investigated in several clinical studies. Earlier studies have evaluated oral bisphosphonates such as clodronate1and risedronate2,3with 2-year mean differences in lumbar spine (LS) bone mineral density (BMD) ranging from +2.2% to 2.9%, and hip BMD of up to +3.7% in favour of bisphosphonate-containing over no bisphosphonate or placebo arms. The ARIBON trial of oral ibandronate (150mg/month) versus placebo for 2 years in post-menopausal women with hormone receptor-positive early breast cancer having osteopenia while on anastrozole showed a significant increase in LS and hip BMD of 2.98% and 0.6% respectively in the ibandronate group compared to placebo (p<0.01), with no fragility fractures in either group.4

A useful algorithm based on the National Osteoporosis Foundation guidelines was developed by Chien and Goss.5Under this algorithm, all patients on adjuvant AIs are required to have a thorough history and physical examination focusing on prior fractures, family history of fractures and height decrease and undergo a baseline BMD and annual height measurements, in addition to lifestyle modifications. Lifestyle modifications recommended include the following: total calcium intake of 1200-1500mg/day, vitamin D3supplementation of 800 U/day, weight-bearing exercises, moderate alcohol consumption (1-2 drinks/day) and smoking cessation.

Subsequent management is based upon the T-score as follows:

  • T-score >-1 rescreen in 1 year. If 1-year T-score >-1.0, screen every 1-2 years
  • T-score between -1.0 and -1.5 annual screening
  • T-score between -1.5 and -2.0 check vitamin D level [25(OH)D]. Consider bisphosphonate therapy depending on risk factors (advanced age, female sex, personal history of fracture as an adult, history of fracture in a first-degree relative, chronic corticosteroid use, immobility and inadequate physical activity, cigarette smoking, excessive alcohol consumption [>2 drinks/day], low body weight, estrogen deficiency [early menopause, menopause, bilateral ovariectomy, prolonged amenorrhea of >1 year], lifelong low calcium intake, vitamin D deficiency, chronic illness [i.e. hyperthyroidism, hyperparathyroidism, inflammatory bowel disease])
  • T-score <-2.0 check vitamin D level [25(OH)D]. Treat with bisphosphonate therapy

However, it remains unclear whether a particular bisphosphonate is superior.

More recent trials have focused on the efficacy of intravenous zoledronate. In particular, the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 bone sub-study which randomized premenopausal women with hormone receptor (HR)-positive early breast cancer to receive endocrine therapy (goserelin/anastrozole or goserelin/tamoxifen) alone or with adjuvant zoledronate (4mg, 6-monthly) for 3 years reported increased LS (+4%, p=0.02) and trochanter (+3.9%, p=0.07) BMD from baseline at 5 years.9For those not receiving zoledronate, the LS and trochanter BMD remained below baseline even at 5 years. The study was not powered to assess proportion of fractures between groups.

The Z-FAST and ZO-FAST trials studied the efficacy of zoledronate (4mg, 6-monthly) given up to a maximum of 5 years, either upfront or in a delayed fashion based on BMD T-scores <-2.0 or non-traumatic fractures, in postmenopausal women receiving adjuvant letrozole. In the Z-FAST study, the mean differences in LS and total hip BMD between upfront versus delayed therapy at 5 years were +8.9% and +6.7% respectively (p<0.0001 for both) in favour of upfront zoledronate, with no significant difference in fracture rates.10Mean differences at 5 years in LS and total hip BMD between the upfront and delayed groups were +4.3% (p<0.0001) and -5.4% (p<0.0001) in the ZO-FAST trial, with statistically similar fracture rates in both groups. 11

Using a Markov state transition model in a hypothetical cohort of women aged 60 years with hormone receptor-positive early breast cancer starting a 5-year course of adjuvant AI, a policy of baseline and annual BMD screening followed by selective treatment with oral bisphosphonates for those diagnosed with osteoporosis was found to be the most cost-effective use of societal resources. Incremental cost-effectiveness ratio (ICER) for annual BMD screening followed by oral bisphosphonates for those with osteoporosis, annual BMD screening followed by oral bisphosphonates for those with osteopenia, and universal treatment with oral bisphosphonates were US$87,300, US$129,300, and US$283,600 per quality-adjusted life year (QALY) gained, respectively. 12Results were sensitive to age at AI initiation, post-treatment residual effects of oral bisphosphonates, types of bisphosphonates, and a potential adjuvant benefit of intravenous bisphosphonates. Analysis of intravenous bisphosphonates use increased the ICERs for all strategies to more than USD $100,000 per QALY gained, but if potential of breast cancer recurrence reduction was considered, its use became more cost-effective, regardless of its impact on bone health.

Local data for cost-effectiveness analysis is not available at present.

The SCAN workgroup voted 10 to 2 in favour of the adoption of the treatment algorithm based on the National Osteoporosis Foundation guidelines as this approach gives a comprehensive recommendation based upon lifestyle modifications, inclusion of osteoporosis risk factors in decision making, and stratification of management based on T-score.

Two members supported the NCCN recommendations which state that the use of a bisphosphonate is generally a preferred intervention to improve BMD. One agreed that the use of bisphosphonates is generally a preferred intervention to improve BMD in women with early stage breast cancer. However, limited data on their effect on fracture rates in these patients exists, hence the choice of NCCN guidelines to reflect some uncertainties regarding optimal use of bisphosphonates. The other member preferred the flexibility the NCCN guidelines offered, in particular with regard to vitamin D testing, BMD evaluations and treatment. The optimal duration of bisphosphonate has not been established. Factors to consider include BMD, response to therapy, and risk factors for continued bone loss or fracture.

The workgroup acknowledges that there are no guidelines on the specific choice of bisphosphonate agent. Of note, the role of denosumab has only been addressed in the selected ESMO 2014 guidelines as it is a relatively newer agent on the market and hence is not covered in this edition of recommendations.

The workgroup acknowledges that local data regarding the use of bisphosphonates to preserve bone health in postmenopausal women initiating adjuvant AIs in breast cancer is lacking.