Evidence Statement
Aromatase inhibitor therapy
Adjuvant endocrine therapy, either with SERMS, such as tamoxifen or aromatase inhibitors, is generally given for 5–10 years. Tamoxifen has partial ER agonist activity in bone and is protective in postmenopausal women, but leads to accelerated bone loss in premenopausal women. Aromatase inhibitors block oestradiol production, reducing circulating oestradiol by >98%. Aromatase inhibitors inhibit oestradiol-mediated negative feedback on gonadotropin production. They cannot be used in premenopausal women unless ovarian function is suppressed, typically by pharmacological or surgical means.16–18
In postmenopausal women, aromatase inhibitors are preferred because of modest improvements in breast cancer outcomes compared with tamoxifen.19 Although endocrine treatment in premenopausal women is evolving, the use of ovarian suppression plus an aromatase inhibitor is becoming more frequent, especially in younger women (<35–40 years) with high-risk breast cancer.20
In postmenopausal women, aromatase inhibitors are associated with a two- to threefold accelerated decline in BMD and bone loss is greatest within the first two years. Approximately 10% of untreated postmenopausal women will have a new clinical fracture within three years of aromatase inhibitor treatment.21 In premenopausal women, bone loss is even higher, with rates of 7–9% in the first 12 months; after five years of treatment, 13% of women have osteoporosis by DXA criteria.20 In RCTs, bisphosphonates prevented aromatase inhibitor-induced bone loss, but the studies were not powered for fracture end points.22–25 In contrast, a large trial reported a 50% reduction in clinical fracture rates with denosumab (60 mg given six-monthly for three years) compared with placebo in postmenopausal women.21
Of note, given the rapid offset of denosumab action and risk of rebound vertebral fractures, delays in the six-monthly administration should be avoided and, according to current evidence, a course of denosumab treatment needs to be followed by a bisphosphonate (refer to Section 3.2). Women should be informed about this prior to starting treatment.
Androgen deprivation therapy
Although testosterone is important for bone health due to direct effects on the male skeleton, a large proportion of its bone-protective actions are indirect, via aromatisation to oestradiol. In addition, testosterone improves bone strength through anabolic effects on muscle mass. Loss of muscle increases fracture risk due to a higher propensity for falls.7 ADT usually involves depot preparations of gonadotropin-releasing hormone (GnRH) analogues and reduces sex steroids to castrate levels. Newer treatment modalities, such as abiraterone, also inhibit extratesticular sex steroid synthesis and lead to even more profound sex steroid deprivation.26,27
Low BMD is highly prevalent among men even prior to commencement of ADT, and under-recognised. A study among 236 Australian men (mean age 70 years) with prostate cancer newly commencing ADT showed that, at baseline, 11% had osteoporosis and 40% had osteopenia.28 Sixty-one percent of the men with osteoporosis were unaware of the diagnosis. Even in the absence of ADT, bone health is a concern in older men with prostate cancer.
During the first year of ADT, BMD loss is accelerated by two- to sevenfold relative to the 0.5–1% bone loss occurring in ageing men.12 DXA may underestimate ADT-associated bone loss, especially the loss of cortical bone, which can exceed 10%.29 BMD continues to decline with long-term ADT, albeit at a lower rate. Large registry studies have shown that ADT increases relative fracture risk by 30–60%.15 In a cohort study of more than 50,000 men who survived for at least five years after prostate cancer diagnosis, fracture incidence approached 20%, and the number needed to harm for the occurrence of any fracture was 28 for GnRH agonist use and 16 for orchidectomy.30
Multiple RCTs have shown bisphosphonate therapy prevents ADT-associated BMD loss, but they were too small to provide fracture outcomes.15 In contrast, a large RCT in men receiving ADT showed that denosumab reduced the incidence of vertebral fractures (RR at three years 0.38 versus placebo; P=0.006) in men receiving ADT with a median T-score of –1.5 at randomisation, with a number needed to treat to prevent one incident vertebral fracture of 42.31