The Effect of Aging on Skeletal Mechanoresponsiveness: Animal Studies - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 191

Table 1 Ages that represent different phases in life for mice, rats and humans

Young Mature Middle Aged Old

Mouse a 1-3 months 4-6 months 10-14 months 18-24 months

Rat b 1-3 months 5-7 months 12-16 months 21-28 months

Human 10-15 years 20-30 years 38-47 years 56-69 years
a The mouse versus human comparison is based on Flurkey et al. [ 17 ] for C57Bl/6J mice, which
have a median lifespan of *26 months [ 61 ]. They state that ''mice older than 24 months are
useful for pathology and life span studies; they are not as useful for normal aging studies''. They
classify mature adult mice as 3-6 months, but we believe that 3 months is too young to be
considered ''skeletally mature'' and consider 5-6 months best for mature adult status [ 69 ].
Longevity data for other mouse strains is similar to C57Bl/6 but not necessarily identical [ 70 ]
b The rat ages are based on simple linear interpolation from the mouse ages, assuming an average
longevity of *30 months in rats [ 71 ]. Others have recommended 9 months as an age at which
rats reach peak bone mass and is appropriate for interventions such as ovariectomy [ 72 ]

2 Overview of Approaches to Study Bone Responses
to Mechanical Loading Using In Vivo, Animal Models

A number of animal models have been developed to study the influence of mechanical
loading on bone. These models have been used to examine the effects of external
loading parameters such as strain magnitude, strain rate, frequency and number of
loading cycles. Generally these models involve alteration of the mechanical environ-
ment of the bone (usually, but not limited to, forelimbs and hindlimbs) and studying the
resulting changes in bone cell function/activity (e.g., bone formation rate), bone
structure and mechanical properties. Use of many of these models was reviewed by
Robling et al. [ 18 ], who emphasized that the objective of any loading model is to
generate or apply force that produces bone deformation, i.e., strain. Depending on the
mode of loading, these can be classified as intrinsic or extrinsic loading models (Fig. 1 ).
Intrinsic loading models utilize physiological activity that engenders contractile
muscle forces and joint reaction forces that result in bone loading. Typically, the
animal is trained to mimic certain forms of exercise (e.g., running, jumping,
swimming, climbing) that result in more strenuous loading (i.e., more loading
cycles or higher force) compared to the habitual loading environment of a cage-
dwelling lab animal. Being physiologic in nature the loading involves active
contributions of muscle and the associated effects (e.g., increased blood flow) on
bone and other tissues. However, there are limitations with intrinsic approaches:
the local loading (strain) parameters at the skeletal site of interest are difficult to
control in this type of model; the training regimens are not strictly ''voluntary'' as
the investigator places the animal in a setting that gives them strong incentive to
complete the activity and thus may produce physiological stress. On the other hand
extrinsic loading models allow one to exert better control over loading (strain)
parameters. Such extrinsic loading models make use of external devices to directly
load the skeletal segment of interest and thus alter the mechanical environment of
the bone. Most of our knowledge of the quantitative relationships between loading
and bone response is derived from studies using such extrinsic models [ 18 ].