Cancer treatment-induced bone loss (CTIBL) is a consequence of various breast cancer therapies. However, skeletal effects of human epidermal growth factor receptor 2 (HER2) targeted therapies, including neratinib, remain unknown. Links between gut health, microbiome and bone, support investigations into probiotic supplementation mitigating CTIBL. We demonstrated (ANZBMS 2023 conference) compromised trabecular bone microarchitecture with neratinib in albino Wistar (AW) rats that was mitigated by Blautia luti (B.luti). This study aimed to explore the effect of neratinib B.luti on the bone-fat switch in vivo and investigate human bone marrow stromal cell (hBMSC)-derived osteoblasts in vitro.
Female AW rats (n=40) were randomly allocated to; vehicle control [VC; 0.5% hydroxypropyl methylcellulose; n=4], neratinib (N; 50mg/kg/day; n=4), B.luti (BL; 107 CFU; n=8), B.luti prior to neratinib [N+BL (P); n= 8], B.luti prior to and concurrent with neratinib [N+BL (P&C); n=8], and B.luti concurrent with neratinib [N+BL (C); n=8]. After a 28-day treatment period, tibia were decalcified, sectioned, and stained with H&E to assess number of osteoblasts and bone marrow adipocytes (BMAds). Non-fasting serum was analysed for systemic osteocalcin (OCN) levels by ELISA. Expression of HER receptors in hBMSCs was determined by RT-PCR, and in vitro assays performed to evaluate osteogenic differentiation and function in the presence of neratinib.
Osteoblast numbers significantly decreased (p= 0.014; linear regression) in N compared to VC rats, accompanied by increased, although not significant, BMAds. B.luti did not significantly affect cell numbers. Serum OCN levels did not significantly differ between treatment groups. HER1 and HER2 were expressed by hBMSCs, albeit at low levels relative to control gene (GAPDH), with the effect of neratinib on osteoprogenitor differentiation and function currently under examination.
Neratinib’s influence on the osteoblast population is evident by the significant decrease in numbers in vivo. Expression of HER1 and HER2 by hBMSCs suggest neratinib may directly affect osteoprogenitors.