Biomedical Engineering Reference
In-Depth Information
when considered against the effectiveness of mechanical stress to activate bone
formation in preclinical research models. One reason for this may be that the strains
engendered by exercise in clinical studies are of lower magnitude than in preclinical
studies. Another possibility is that the difference between exercise-induced strains
and strains engendered during other daily activity is smaller in free-living humans
than in caged animals. Alternatively, there are a myriad of factors that could mediate
or moderate the adaptive skeletal response to loading, including, but not limited to,
hormones [e.g., parathyroid hormone (PTH)], minerals (e.g., calcium), growth fac-
tors (e.g., insulin-like growth factor), cytokines [e.g., interleukin 6 (IL-6)], and
signaling factors (e.g., prostaglandins). A few examples of factors that have potential
to influence the skeletal response to exercise are discussed below.
3.3.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Prostaglandin E
2
(PGE
2
) increases in bone in response to mechanical loading
and is an essential signaling factor for bone formation [
15
,
96
]. The key enzyme
for prostaglandin production is cyclooxygenase (COX), which is inhibited by
NSAIDs. There is consistent and compelling evidence that NSAIDs attenuate the
bone formation response to mechanical stress in laboratory animals [
16
,
23
,
54
].
A limitation of the preclinical studies is that they have used acute loading only.
However, if NSAIDs consistently block bone formation in response to repeated
bouts of loading, this would suggest that the benefits of exercise training on BMD
may not be fully realized in people who use NSAIDs. Observational studies of the
association of NSAID use with BMD or fracture risk have been mixed, demon-
strating adverse, neutral, or even beneficial effects of NSAID use [
5
,
13
,
68
,
76
,
92
].
However, because PGE
2
can stimulate both bone formation and resorption, NSAIDs
may have both anti-formation and anti-resorptive effects on bone metabolism [
75
].
Importantly, the timing of NSAID administration is a key determinant of the bone
formation response, which is attenuated when NSAIDs are given before mechanical
loading, but not when they are given after [
16
,
25
,
54
]. Thus, the mixed associations
of NSAID use with BMD in observational studies may reflect the fact that none of the
studies considered the reason for or timing of NSAID use (e.g., before exercise to
reduce musculoskeletal discomforts).
There has been one proof-of-concept clinical study to determine whether using
NSAIDs before exercise inhibits the adaptation of BMD to exercise training [
47
].
Premenopausal women underwent a 9-month exercise training intervention and took
either ibuprofen 400 mg or placebo before and after every exercise session. The
randomized treatment assignments were: (1) ibuprofen before exercise, placebo
after, (2) placebo before and after exercise, and (3) placebo before exercise and
ibuprofen after. Consistent with preclinical research, the least favorable adaptations
in BMD tended to occur in the group that took ibuprofen before exercise sessions.
However, an unexpected finding was that use of ibuprofen after exercise sessions
augmented the increases in BMD when compared with placebo. It is possible that
NSAID use after exercise permits the activation of the bone formation, but
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