Skeletal Mechanoresponsiveness: Effects of Sex Hormones - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 217

biophysical stimuli such as mechanical loading could be used to treat and possibly
also inhibit bone loss resulting from age related sex hormone deficiency.
Exercise has been used extensively in preclinical studies as a treatment for
hormone-induced bone loss. Treadmill running is the most commonly used
exercise approach in rodent studies [ 10 , 12 , 16 , 17 , 26 - 28 ]. Other exercise routines
studied include tower/ladder climbing [ 29 - 31 ] and jumping [ 15 , 32 ]. Whole body
vibration also perturbs the mechanical environment of the skeleton and has been
used in several studies [ 33 - 38 ].
The mechanical environment of the skeleton during exercise is complex
and difficult to quantify; therefore, mechanical parameters such as peak load
magnitude cannot be directly related to adaptation. The mechanical environment
during whole body vibration is similarly difficult to determine. Methods that
directly load the skeleton in vivo, such as tibial four-point bending [ 39 ] or axial
tibial compression [ 40 ], allow the applied loading to be controlled and quantified.
These extrinsic loading protocols reduce the confounding effect of body mass and
load level differences present in exercise studies. Controlled loading methods have
been used to examine the skeletal response to loading in the absence of hormones
[ 14 , 41 ]. Here we focus on mechanical loading from exercise and direct loading
approaches applied to hormone-deficient rodent models.
The majority of studies examining osteoporosis induced by surgical sex
hormone deficiency have been performed in the ovariectomized (OVX) rat.
Appropriate controls involve sham surgery, subjecting the animals to similar
treatment and handling. OVX rats gain considerable fat mass following surgery
[ 42 ], and outweigh sham surgical controls even when pair-feeding is performed.
OVX of the skeletally mature rat (8-9 months of age) is a well-characterized
model that captures key features of cancellous and cortical bone changes seen in
humans [ 43 ]. Growing rats can be used to study skeletal changes with hormone
deficiency and have greater bone loss with OVX than adults, but changes in bone
mass occur through different mechanisms than are present in postmenopausal
women [ 42 ]. The other primary rodent model, the mouse, is less well-established
as a surgical model of osteoporosis. Bone changes with hormone deficiency vary
by mouse strain [ 44 ]. However, the mouse is a powerful tool for studying signaling
and genetic regulation of bone mass [ 45 , 46 ], as will be described later.
2.1 Hormone-Deficiency and Exercise
Hormone deficiency due to surgical removal of the gonads decreases cancellous
and cortical bone volumes. Treadmill exercise increases bone mass following OVX,
but consistent recovery of cancellous bone measures to the levels of sham-operated
controls occurs only in growing animals [ 12 , 16 , 17 ]. Rats that underwent OVX at
weaning (3 weeks) and subsequently exercised by treadmill for 16 weeks were more
responsive to mechanical loading at the femoral neck than sham-operated animals
[ 12 ]. The OVX-induced reduction in femoral neck strength was compensated