In this cohort study of postmenopausal breast cancer patients receiving AIs as adjuvant therapy, the bone quality marker pentosidine was increased by AI and reduced with BMAs. Bone turnover markers and BMD also showed significant improvement with BMAs. These results indicate that administration of BMA exerts not only an inhibition of bone loss, but also an improvement of bone quality in patients receiving AIs.
Fracture and osteoporosis are important adverse events in postmenopausal breast cancer patients receiving adjuvant AIs, and the prophylactic administration of BMA is recommended for patients with a high risk of bone-related adverse events[12,13]. Because long-term prescription of BMA can cause serious adverse events, such as osteonecrosis of the jaw and atypical femoral fracture in breast cancer, an appropriate evaluation of the risk of AI related fracture is desirable[14,15]. Although low BMD in femoral neck or lumbar spine is regarded as an independent risk factor for fracture, a certain proportion of patients with a non-osteoporotic range of BMD experience nontraumatic fractures[16,17]. In a cohort study of postmenopausal women, more than half of osteoporotic fractures occur in cases with a non-osteoporotic range of BMD. The Fracture Risk Assessment Tool (FRAX) is used to estimate the risk of osteoporotic fracture using femoral neck BMD and clinical risk factors, which include age, prior non-traumatic fracture, glucocorticoid use, low body mass index, family history of osteoporosis, smoking, and excess alcohol intake, which are also associated with incidence of fracture. However, FRAX is not designed to estimate the risk of AI-related fracture, and the estimated fracture risk by FRAX tends to be lower than that of the actual fracture incidence in breast cancer patients receiving AI. Thus, the evaluation of other risk factors is warranted to determine appropriate administration of BMA to prevent AI-related fracture in postmenopausal breast cancer patients.
Independent of BMD, bone quality is regarded as an important factor of bone strength when considering the risk of osteoporotic fracture. The trabecular structure, including trabecular number, separation and homogeneity of the trabecular network, is also deteriorated with exemestane. A follow-up study of 29,407 postmenopausal women aged 50 years and older showed that patients with bone loss by BMD and a low Trabecular Bone Score (TBS) were at the same risk of fracture as those with osteoporosis by BMD and high TBS. In an accompanying study of a randomized control trial evaluating exemestane, an AI, for prevention of breast cancer in healthy postmenopausal women, high-resolution peripheral quantitative CT showed a significant decrease in volumetric BMD and cortical thickness at the distal radius and distal tibia with exemestane. These findings suggest that deterioration of bone quality is also an important AI-related bone adverse effect.
Serum and urine pentosidine have been investigated as bone quality markers. Pentosidine is positively correlated with deteriorated collagen crosslinks AGEs, and elevated pentosidine is shown as an independent risk factor of fracture in postmenopausal women. In this study, we evaluated the serum change of pentosidine in postmenopausal breast cancer patients receiving adjuvant AIs with or without BMAs. First, approximately half of subjects administered adjuvant AIs without BMA had an elevation of pentosidine. AI treatment can be associated with not only a decrease of BMD, but also a deterioration of bone quality. Second, the administration of BMA significantly suppressed an AI-induced pentosidine increase and BMD decrease. Our findings are consistent with a previous study evaluating the effects of denosumab on prostate cancer patients treated with hormonal therapy. BMA therapy can maintain BMD and prevent a deterioration of bone quality in patients treated with hormonal therapy. Finally, measurement of baseline and change of pentosidine may provide additional risk assessment of osteoporotic fracture in breast cancer patients receiving AIs. In univariate linear regression analysis, there was no significant difference between the pentosidine low and high groups in regard to age, height, weight, BMD and bone turnover markers.
This study has several limitations. First, this is a cohort study with a relatively small number of cases and a short duration of follow up. A prospective study with a larger number of cases with a long-term period is warranted to confirm our findings. Second, BMAs were essentially prescribed for patients with a high risk of osteoporotic fracture determined by low BMD and/or clinical factors in this study. The effect of BMA on preventing AI-induced bone quality deterioration is uncertain in patients with a normal range of BMD. Finally, no bone quality assessment other than pentosidine was done in this study. Imaging studies evaluating bone structure should be done in future study to confirm our findings.
In summary, this study demonstrated that serum pentosidine significantly increased with AI therapy in postmenopausal women with hormone receptor positive breast cancer, and administration of BMAs inhibit an AI-induced increase of pentosidine. A prospective long-term study is warranted to confirm the relationship between pentosidine and non-traumatic fracture during adjuvant AI therapy.