1. Chapter 23 Chapter 23 Prevention of Osteoporosis by Physical Signals: Defining a Potential Role for Nondrug Strategies in the Treatment of Musculoskeletal Injury and Disease Copyright © 2013 Elsevier Inc. All rights reserved.

2. FIGURE 23.1 The distribution of strain energy about the midshaft of the horse cannon bone (MCIII) during a gallop. Shown is strain energy density (SED) during that point in the stride in which peak strain is achieved (left panel), as well as the SED averaged over the entire stance phase of the stride (right panel). In the first case, SED ranges from a minimum of 600Pa to a maximum of 56,000Pa, and when averaged over the stride, from 461Pa to 51,375Pa. Importantly, while the distribution of the peak and time averaged SED is very nonuniform, the manner in which the bone is loaded remains constant (i.e. the site of peak and minimal SED varies very little). Source: adapted from Rubin et al. (2013) [42]. 2

3. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.2 Self-similarity in bone strain signals. (a) A 2-min strain recording from the caudal longitudinal gage of the sheep tibia while the animal took a few steps with peak strains on the order of 200 με. (b) A 20-s portion of that strain record shows peak strain events as large as 40 με. (c) Further scaling down to a 3-s stretch of the strain recording illustrates events on the order of 5 με. Source: adapted from Fritton etal. (2000). 3

4. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.3 A fluorescent photomicrograph of the periosteal surface of a turkey ulna diaphysis following 8 (top panel) and 16 weeks (bottom panel) of a mechanical regimen sufficient to cause a peak of 2000 με. The 8- week response shows consolidating primary bone. By 16 weeks, remnants of the original woven response can be seen serving as interstitial elements of primary and secondarily remodeled bone. In essence, the woven bone response has served as a strategic stage in the achievement of a structurally appropriate increase in bone mass. Source: reproduced with permission from Rubin etal. (1995). 4

5. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.4 Microradiographs of transverse sections of the ulna midshaft following 8 weeks of 1h/day of various electric field regimens. On the top left panel is an ulna subject only to a “dummy” coil, resulting in a 12% bone loss via intracortical and endosteal resorption. An ulna isolated from function but subject to a 75-hz sinusoidal electric field inducing 10μV/cm (bottom left panel) showed little modeling or remodeling activity, with a net increase in bone mass of 3%. A signal of the same magnitude but induced at 15hz resulted in substantial new bone formation on both the endosteal and periosteal surfaces, with little evidence of intracortical porosis, resulting in a 14% increase in bone area top right panel). Source: reproduced with permission from McLeod and Rubin (1992). 5

6. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.5 The sensitivity of cortical bone tissue to mechani­cal strain increases with loading frequency. The plot indicates the area increase (mm 2 ) in cortical bone measured for each additional one microstrain imposed on the turkey ulna, at each of five loading frequencies spanning the 1-Hz to 60-Hz range. Another way of inter­ preting these data is to consider that 1/10th of the strain is necessary to maintain cortical bone mass if the strain is induced at 60Hz, rather than 1Hz. Trabecular bone is even more responsive to frequency. Source: adapted from Qin etal. (1998). 6

7. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.6 Following 1 year of extremely low-level mechanical stimulation, parameters of both static and dynamic histomorphometry demonstrated a significant benefit to both the quantity and quality of bone from exposure to the mechanical signal. Shown here are fluorescent photomicrographs of a transverse section at the lesser trochanter of the femur of the mechanically stimulated sheep (bottom), showing more trabeculae, which are thicker, than control (top). Source: adapted from Rubin etal. (2002). 7

8. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.7 Strain is defined as a (load-induced) change in length relative to the structure's original length. 1000 microstrain, or 0.1% strain, reflects the amount of strain experienced by bone tissue during an activity such as walking. For a structure such as the 170-m Washington monument, 1000 με would represent a 17-cm change in length over the entire structure. In a giraffe tibia, 1000 με would reflect a 1-mm change over the bone's original 1000mm length. At the level of a 10-μm bone-lining cell sitting on the periosteum of that giraffe tibia, its dimensional change when subject to 1000 με would be 100Å. The mechanisms responsible for perceiving and responding to such small biophysical signals, whatever they may be, must be extremely sensitive. 8

9. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.8 Age-related changes in soleus muscle dynamics during postural activity. While the low- frequency (1–25hz) spectra are only slightly affected by age, high-frequency muscle dynamics (25–50hz) are markedly reduced in elderly people. If these higher-frequency vibrations are the dominant source of the high- frequency, low-magnitude strains in bone, it could be argued that the pathogenesis of osteopenia is rooted in degenerative changes in the neuromuscular system, rather than bone tissue per se. Source: adapted from Huang et al. (1999). 9

10. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 23.9 Stratification based on subjects’ body mass index (BMI) shows that the lighter women (BMI 24 lost no bone over the course of the year, and thus it was not possible to demonstrate the efficacy of treatment to inhibit a loss that was not occurring (p = 0.36). Source: adapted from Rubin etal. (2004). 10