The Effect of Aging on Skeletal Mechanoresponsiveness: Animal Studies - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 190

is expedited in menopausal women as a result of estrogen deficiency. This
often results in osteoporosis, a condition characterized by low bone mineral
density (BMD T-score below -2.5), deteriorated skeletal microstructure and
increased risk of fracture [ 12 ]. The condition affects approximately 44 million
people in United States, with an estimated 1.5 million osteoporotic fractures
per year and associated costs of $18 billion [ 13 , 14 ]. Because the social and
economic cost associated with osteoporosis is high, there have been numerous
efforts to develop pharmacological therapies (see '' Bisphosphonates and PTH
for Preventing Fractures '' by Burr and Allen for a review of this topic). Briefly,
anti-catabolic therapies target osteoclastic resorption, while anabolic therapies
target osteoblast formation. The most commonly used class of drugs are bis-
phosphonates, which primarily act to block resorption. Although bisphospho-
nates have undisputed efficacy in reducing fracture incidence, recent concerns
have emerged about long-term ([5 years) treatment [ 15 ]. Currently, synthetic
parathyroid hormone 1-34 is the only FDA approved drug that has been shown
to result in anabolic bone modeling. But the duration of treatment with PTH is
limited to 2 years, as continued treatment was shown to increase chances of
osteosarcoma in rats [ 16 ]. Thus, there remains a need to develop additional
options to treat osteoporosis. Non-pharmacologic approaches that modulate
bone accrual and adaptation can potentially be harnessed to develop non-
invasive anabolic treatments with minimal side effects. Physical loading/
exercise is one approach. A better understanding of how aging influences
skeletal responses to loading is critical towards development of such a treat-
ment option(s).
The aim of this chapter is to provide an overview of animal studies that have
addressed the question of age-related changes in bone mechano-responsiveness.
By mechano-responsiveness we mean the net ability of bone to sense and respond
to any changes in its mechanical environment. If we consider a study comparing
two groups subjected to an identical loading environment (i.e., mechanical input),
group A is more mechano-responsive than group B if the magnitude of adaptation
(i.e., the response) in group A is greater than in group B. We do not address
possible underlying mechanisms that might relate to sensing, transduction and cell
function, each of which might be affected by aging and could contribute to changes
in bone mechano-responsiveness.
When examining the effects of aging, the ages at which comparisons are made
are of critical importance. As noted below, some studies have examined ''aging''
by comparing young versus mature animals, and few studies have conducted
studies using truly old animals. Aging is a continuum, but for simplicity we can
separate the lifespan into four distinct phases: young, mature, middle aged, old.
When describing the results from the literature, we have attempted to describe ages
in these terms, as summarized in Table 1 . Our rationale for this is based largely
on the work of Harrison et al. at Jackson Labs [ 17 ].