Estrogen signal cascade activation by estrogens binding to the estrogen receptor is crucial for bone integrity namely bone mineral density and structural and mechanical bone quality in women. Downregulation of this pathway by aromatase inhibitors in postmenopausal women or GNHRH agonists in combination with aromatase inhibitors which suppress estradiol serum levels to a minimum, therefore harm the bone.
Cancer is known as a disease with a (high) potential of leading to death thereby resulting in a clear disposition of the patient to undergo the most effective treatment option suggested by the treating physician. In early hormone receptor (HR) positive, postmenopausal breast cancer patients this is the adjuvant use of aromatase inhibitors which have been shown to improve disease free survival compared to tamoxifen (1). Additionally, a longer duration of the estrogen serum level suppression (7-10years versus 5 years) has lead to a better outcome (2). In premenopausal patients, the use of GNRH agonists in combination with aromatase inhibitors are the most effective treatment leading to the best outcome in those often high risk patients. Therefore, the standard adjuvant endocrine treatment for HR positive postmenopausal and high risk premenopausal patients is the use of an aromatase inhibitor (in combination with GNRH agonists) for 5-10 years.
As elegantly described by Hadji et al. in the updated joint position statement on management of aromatase-inhibitor associated bone loss, breast cancer patients with nearly complete suppression of estrogen serum levels suffer from loss in bone mineral density as well as bone quality resulting in increased fracture risk (3). This has been shown in premenopausal patients as well by our group, as the combination of GNRH agonists with aromatase inhibitors leads to a substantial loss in bone mineral density within 3 years, however valid fracture data are missing in this group of patients (4). Fractures of postmenopausal patients treated with aromatase inhibitors are underreported in clinical trials resulting in an underestimated fracture risk in this patient population. The primary endpoint of the phase III, randomized, double-blind ABCSG-18 trial was fracture risk in 3,425 postmenopausal breast cancer patients treated with an aromatase inhibitor thereby focusing on fracture detection with repetitive imaging and clinical investigations (5). The trial showed that about 15% of those patients experience at least one clinical fracture within 5 years of AI treatment.
The position paper by Hadji et al. underlines the necessity that oncologists have to focus on bone health which is impaired as a side effect of the anti-cancer endocrine treatment. Not only there is an indication for supportive bone health therapy/prevention including physical exercise, supplementation of Vitamin D and increased calcium intake, but also intensified diagnostic steps including bone mineral density measures. The threshold to initiate a bone specific anti-resorptive therapy should be low, which is well considered in the position paper by suggesting the use of bisphosphonates or denosumab in patients with bone compromising endocrine treatment and a t score below -2 or at least two risk factors for lower bone health. This is a pragmatic and straightforward way for oncologists to take care of the bone of patients during an oncologic treatment.
But there is another indication to use bone specific anti-resorptive treatment in oncologic patients. As Hadji et al. point out there is a wide body of evidence that especially bisphosphonates but also denosumab impact disease outcome in breast cancer patients. According to a meta-analysis bisphosphonates significantly reduce bone recurrence, distant recurrence and breast cancer mortality beside their impact on bone health. The absolute benefit of bisphosphonates on disease outcome is between 1.5%-3.3% which is about the benefit of aromatase inhibitors over tamoxifen. In line, with that the position paper recommends the use of bisphosphonates in premenopausal patients with ovarian suppression as well as in higher risk postmenopausal breast cancer patients.
The position paper gives clear advice for oncologists why, when and how to use anti-resorptive bone specific agents in breast cancer patients and recommends the use with a low therapeutical threshold: because bone specific anti-resorptive agents not only improve bone health and reduce fractures but also improve cancer disease outcome.
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