Tissue selective effects of bazedoxifene on the musculoskeletal system in female mice

Abstract

The actions of selective estrogen receptor modulators are tissue dependent. The primary objective of the current study was to determine the tissue selective effects of bazedoxifene (BZA) on the musculoskeletal system of ovariectomized (OVX) female mice, focusing on strengths of muscle-bone pairs in the lower hindlimb. Treatment with BZA after ovariectomy (OVX+BZA) did not prevent body or fat mass gains (p<0.05). In vivo plantarflexor muscle isometric torque was not affected by treatment with BZA (p=0.522). Soleus muscle peak isometric, concentric and eccentric tetanic force production were greater in OVX+BZA mice compared to OVX+E2 mice (p≤0.048) with no effect on maximal isometric specific force (p=0.228). Tibia from OVX+BZA mice had greater cortical cross-sectional area and moment of inertia than OVX mice treated with placebo (p<0.001), but there was no impact of BZA treatment on cortical bone mineral density, cortical thickness, tibial bone ultimate load or stiffness (p≥0.086). Overall, these results indicate that BZA may be an estrogen receptor agonist in skeletal muscle, as it has previously been shown in bone, providing minor benefits to the musculoskeletal system.

Effects of VCD-induced ovarian failure on single muscle fiber contractility in a mouse model of menopause

“…Using a VCD mouse model of ovarian failure to characterize the effects of the perimenopausal transition on single muscle fiber contractility, we found either an increase in contractile performance, or no change as compared with controls. In terms of muscle contractile function, this model of ovarian failure appears to yield divergent findings as compared with classic OVX post-menopausal (4-8 weeks post surgery) models [7,8,10,11,14,18,19], and is more in line with results from studies on human (49-57yrs) single muscle fibres [45,46]. However, timecourse changes are yet to be identified.…”

“…Reducing circulating ovarian hormones through the OVX model results in a reduction in absolute force production as compared with controls [7,8,10,11,14,18,19] on average 4-8 weeks following surgery. However, using a VCD-induced model of ovarian failure, we found the opposite during the menopausal transition, an ~33% increase in SOL single muscle fiber force as compared with controls, and no change in force generation for fibers from the EDL.…”

“…Additionally, when force is normalized to muscle mass, 'specific force' for both SOL and EDL muscles can be 9-30% lower [7,8,10] than controls for both whole muscle [10] and single muscle fibers [7,8], indicating impairments in intrinsic contractile processes. As well, there have been reports of no difference in specific force with reductions in circulating ovarian hormones [11,13,14]. In studies in which reduced circulating 17β-estradiol levels caused reductions in absolute and specific force, 17β-estradiol replacement protected against these impairments in force generation [2,8,10,[15][16][17][18].…”