Effects of TKIs on bone metabolism:untargeted consequences with targeted therapies

[D.ap]

http://erc.endocrinology-journals.org/c ... 7.full.pdf


Summary


The literature reviewed shows the promise of TKIs as a targeted therapy for multiple malignancies, while high- lighting the importance of understanding the respective signaling pathways to anticipate potential side effects as summarized in Table 1. Even TKIs that do not have target receptors in common appear to have similar effects on bone metabolism, suggesting to an extent a class effect. In the case of imatinib, off-target kinase effects account for cellular effects leading to decreased osteoclastogenesis, possibly decreased overall bone turnover, as well as alterations in calcium and phosphate metabolism. It is difficult to discern the effect of chronic imatinib (or other TKI) therapy on risk for fragility fractures; no clear safety signal has emerged. Patients who are concomitantly receiving potent antiresorptive medications (bisphosh- phonates and denosumab) and TKIs that have potent inhibitory effects on osteoclast activity should be mon- itored for potential complications known to occur with the latter: acutely, hypocalcemia, and over the long term, osteonecrosis of the jaw and atypical subtrochanteric fractures. Most newer TKIs are being studied in the setting of advanced cancers, many of which can metastasize to bone. Thus, bone issues pertinent to a long-term therapy with imatinib for chronic-phase CML, such as long-term osteoporotic fracture risk, are ostensibly less relevant to such patients with a limited life expectancy – bone morbidity due to skeletal-related events has greater importance. We make note that the common TKI side effect of secondary hyperparathyroidism, classically thought to be a metabolic issue related to osteoporotic fracture risk, has recently been shown to have possible importance in the setting of zoledronic acid therapy for metastatic prostate carcinoma to bone – higher baseline PTH level was associated with decreased overall survival (Berruti et al. 2012). Newer classes of TKIs with potent antitumor effects will be likely associated with similar off-target effects on bone metabolism. In the setting of metastatic cancer to bone, the TKI class effect of osteoclast inhibition, combined with anti-tumor effects, theoreti- cally should create synergy to lessen skeletal-related morbidity and mortality.

[Bonni Hess]

Dear Debbie, Thank you for sharing this VERY interesting and equally concerning information. Given Brittany's long term 8 years of Cediranib treatment, we are especially concerned about this issue and will address it at her late September Clinical Trial appointment with Dr. Sawyer as well as now scheduling her overdue annual full body bone scan as soon as possible. With deepest gratitude for your ongoing dedicated research and faithful sharing, and with my special caring thoughts and continued Hope, Bonni