Skeletal Mechanoresponsiveness: Effects of Sex Hormones - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 215

adult, increased mechanical loading is anabolic and enhances bone mass, whereas
reduced mechanical loading results in bone loss. The effects of loading are
modulated by a number of other factors that individually influence bone mass.
Sex hormones are also critical regulators of skeletal growth in males and
females during periods of increasing and decreasing skeletal mass. At least 50% of
adult bone peak mass is accrued during puberty, a stage of rapid bone growth [ 1 ].
In the healthy adult skeleton, both estrogens (the primary female sex hormones)
and androgens (the primary male sex hormones) positively impact bone remod-
eling and the maintenance of bone mass, primarily by suppressing resorption and
bone remodeling [ 2 - 5 ]. In women, estrogen deficiency following menopause
contributes to the rapid decline in bone mass and decreased skeletal structural
capacity that can lead to osteoporosis and fracture [ 5 , 6 ]. Declines in sex hormones
with age in males are more gradual but produce similar effects [ 7 , 8 ].
The tissue-level effects of estrogen and estrogen withdrawal on bone mass in
the presence of mechanical stimuli are well documented [ 5 , 9 , 10 ]. In preclinical
models using skeletally mature animals, hormone deficiency produces cancellous
bone loss initially with subsequent cortical bone loss. While estrogen deficiency
uniformly increases bone turnover, the loss of cancellous bone mass is not uniform
and may in fact be related to the complex distribution of mechanical stimuli in the
skeleton [ 10 , 11 ].
Identifying the role of sex hormones on the mechanoresponsiveness of the
skeleton is critical to understanding aging and developing therapies for age- and
hormone-related bone loss. Reduced responsiveness to exercise has been reported
in female rodents compared to males and could reflect not only hormonal but also
growth factor differences [ 12 , 13 ]. From a practical perspective, mechanical
loading is a candidate anabolic stimulus to overcome and treat hormone-defi-
ciency-induced bone loss. A variety of loading approaches have been examined in
animal models to counteract hormone deficiency with variable success [ 14 - 17 ].
Mechanistically, several cellular pathways for bone mechanotransduction are
regulated by interactions between estrogen and cellular estrogen receptors (ERs)
present in bone cells [ 18 - 20 ] (Fig. 1 ). The responses of estrogen and androgen
receptor deficient mouse models to controlled skeletal loading have been examined
to elucidate the signaling pathways and adaptive mechanisms. A great deal
remains to be learned about the bone anabolic and anti-resorptive actions induced
by ERs; progress has been limited by available mouse genetic models to isolate
specific contributions and skeletal mechanotransduction approaches to study the
effects of mechanical stimuli in vivo.
The skeletal response to surgically induced hormone deficiency is well
established in a variety of animal models [ 21 ]. In preclinical models, hormone
deficiency can be induced by surgical removal of the gonads in both males
(orchidectomy, ORX) and females (ovariectomy, OVX). In adult rodents ORX and
OVX both produce cancellous bone loss initially. Until recently the adult OVX rat
was the most commonly used model; however, the focus has shifted to mouse
models due to the ability to characterize and manipulate the mouse genome.
Transgenic technology has led to the creation of knockout (KO) mouse models