Several in vivo experiments of external loading in rats have shown that intermittent treatment with parathyroid hormone (iPTH) and high-magnitude loading synergistically increase bone formation [62–65]. Although high-impact exercise to increase bone strength would be difficult for older patients with skeletal fragility, iPTH could reduce the loading level necessary to stimulate a loading-related anabolic effect.

An experiment was performed to investigate this concept [37]. In brief, female C57BL/6 mice from 13 to 19 weeks of age were given daily injections of vehicle or iPTH (1–34) at low (20 μg/kg/day), medium (40 μg/kg/day), or high (80 μg/kg/day) dose. For three alternate days per week during the last 2 weeks of this treatment, the tibiae and ulnae on one side were subjected to dynamic axial loading. Two levels of peak load magnitude, one sufficient to engender an osteogenic response and the other insufficient to do so, were applied. The whole tibiae and ulnae were analyzed by high-resolution μCT and histomorphometry. As a result, in the tibia, loading at a level sufficient by itself to stimulate osteogenesis produced an osteogenic response in the low-dose iPTH (1–34)-treated trabecular bone and in the proximal and middle cortical bone treated with all doses of iPTH (1–34). In the ulna, loading at a level that did not by itself stimulate osteogenesis was osteogenic at the distal site when combined with high-dose iPTH (1–34). At both levels of loading, there were synergistic effects in cortical bone volume of the proximal tibia and distal ulna between loading and high-dose iPTH (1–34) (Fig. 1.5). Images of fluorescently labeled bones confirmed that such synergism resulted from increases in both endosteal and periosteal bone formation. No woven bone was induced by iPTH (1–34) or either level of loading alone, whereas the combination of iPTH (1–34) and the sufficient level of loading stimulated woven bone formation on endosteal and periosteal surfaces of the proximal cortex in the tibiae. Consistent with these experimental data, daily treatment with teriparatide could synergistically produce bone gain with physiological levels of mechanical loading in humans [66].

The combination effects of bisphosphonates and mechanical loading were studied in a variety of external loading models in rodents. As mentioned earlier, mechanical loading can stimulate bone formation independently of bone resorption [14], and pamidronate did not change osteogenesis caused by loading in the rat tail [15]. Similarly, alendronate, risedronate , and zoledronic acid at clinical doses did not influence periosteal expansion induced by loading in the rat ulna [67]. In contrast, the response of the cortical bone to loading was impaired by zoledronic acid in the mouse tibia [68] and minodronate at higher doses but not the optimal dose for osteoporosis treatment in the rat tibia [69].

An experiment was performed to assess the separate and combined effects of risedronate and mechanical loading on the trabecular and cortical bone [39]. In brief, 17-week-old female C57BL/6 mice were given daily subcutaneous injections of vehicle or risedronate at a dose of 0.15, 1.5, 15, or 150 μg/kg/day for 17 days. From the fourth day of treatment, the right tibiae were subjected to mechanical loading for three alternate days per week for 2 weeks. Trabecular and cortical sites in the tibiae were analyzed by high-resolution μCT and histomorphometry. As a result, in the non-loaded tibiae, treatment with the higher doses of risedronate at 15 or 150 μg/kg/day resulted in higher trabecular bone volume and trabecular number than in vehicle-treated controls, whereas such treatment was associated with no differences in cortical bone volume at any dose. In the loaded tibiae, loading induced increases in trabecular and cortical bone volume compared with contralateral controls primarily through increased trabecular thickness and periosteal expansion, respectively, independently of risedronate treatment. In conclusion, the response to mechanical loading in both trabecular and cortical bone in mice was not impaired by risedronate , even over a 1000-fold dose range (Fig. 1.6). This is consistent with mechanical loading -related bone modeling [14]; formation and resorption occur on different surfaces during bone modeling, and thus, modeling-based bone formation and resorption are not coupled. In considering the optimization of clinical treatments for osteoporosis, it is reassuring that antiresorptive therapy and mechanical loading can exert independent beneficial effects.

The adult skeleton in humans would continuously respond to change in mechanical environment to maintain resultant strain of the bone [52, 76], while increased bone strength by an osteoporosis drug results in decreased bone strain regardless of suppressing bone resorption or promoting bone formation. This suggests that the effect of osteoporosis therapy is limited by skeletal adaptation to mechanical strain , i.e., the natural homeostatic system in the skeleton (Fig. 1.7) [77, 78], which is consistent with the fact that there exists a powerful effect that returns bone mass to its pretreatment level after the withdrawal of treatment with osteoporosis agents. In addition, this theory can provide a new significant insight into the mechanisms by which vitamin D or warfarin affects the skeleton [79–81].

A strategy to reduce the limitation of osteoporosis therapy is pharmacologically enhancing skeletal response to mechanical stimulation. Advantages of this strategy include increasing bone strength safely in a structural appropriate manner, depending on local mechanical environment at each skeletal site. Among drugs currently approved for the treatment of osteoporosis, only intermittent treatment with parathyroid hormone would have such a possibility; although high-impact exercise to increase bone strength is not easy for older patients with skeletal fragility, teriparatide has been suggested to have a synergistic effect with even low, physiological levels of mechanical loading in animals [37] and humans [66].

There is, however, a disadvantage of the strategy to enhance skeletal response to mechanical stimulation. The skeleton is adapted to the mechanical environment resulting from habitual physical activity, but not to the unusual direction of mechanical force by falls. As a result, the enhancement of bone response to daily physical activity might not efficiently reduce the risk of fall-related hip or non-vertebral fractures. One approach to overcome this disadvantage is to find an agent that has the effect of mechanical strain . For example, it has been shown in animals that the production of sclerostin secreted by osteocytes is increased by skeletal disuse and decreased by skeletal loading [36, 42, 82–84].

Consequently, anti-sclerostin antibodies such as romosozumab and blosozumab can be considered as the alternative drugs of mechanical strain -related stimulus [85]. The latest findings include marked modeling-based bone formation by romosozumab in monkeys [86] and rapidly increased bone formation as well as decreased bone resorption by romosozumab [87, 88] and blosozumab [89, 90] in postmenopausal women. In contrast to bone remodeling, modeling-based bone formation and resorption are not coupled, and mechanical stimulation is a natural uncoupling factor that stimulates bone formation and inhibits bone resorption.

In phase 2 studies of postmenopausal women with low areal bone mineral density (BMD), romosozumab and blosozumab markedly increased areal BMD at the lumbar spine and hip dose-dependently, but areal BMD at the one-third radius was not changed even by the highest dose of romosozumab [88] or blosozumab [90]. Experimental evidence that the production of sclerostin secreted by osteocytes is increased by skeletal disuse and decreased by skeletal loading [36, 42, 82–84] implies that even the highest doses of romosozumab and blosozumab were not enough for the radius because the levels of sclerostin expression in non-weight-bearing bones such as the radius could be higher than those in weight-bearing bones such as the lumbar spine and hip. Several lines of evidence to support this hypothesis include (1) patients with sclerosteosis due to deficiency of sclerostin have higher areal BMD at the radius as well as the lumbar spine and hip [91] and (2) appropriate doses of anti-sclerostin antibodies effectively increase bone mass in animals with skeletal disuse or unloading [92, 93]. If correct, the highest doses of romosozumab and blosozumab are unlikely to cause unwanted bony overgrowth at non-weight-bearing sites such as the face and skull in postmenopausal women with osteoporosis, while further higher doses of these drugs would be required to improve skeletal fragility in patients with reduced physical activity.

The existence of other mechanotransduction pathways independent of sclerostin [94], however, indicates that treatment with an anti-sclerostin antibody cannot escape from the mechanostat -related limitation of osteoporosis therapy (Fig. 1.7) [77]. In fact, both romosozumab and blosozumab treatments in postmenopausal women with low areal BMD showed that marked changes in circulating bone formation and resorption markers returned to the pretreatment levels within a year despite the continued treatments [88, 90]. This theory is also compatible with the relation between circulating sclerostin and bone mass; sclerostin -related high bone mass in patients with sclerosteosis or van Buchem disease and heterozygous carriers of these diseases is linked to lower levels of circulating sclerostin [95, 96], while circulating sclerostin and bone mass in normal women and men have a positive correlation [97, 98]. The discrepancy suggests that higher bone mass associated with other mechanotransduction pathways independent of sclerostin would cause lower mechanical strain in the skeleton and thus could result in compensatory higher sclerostin production according to the mechanostat .

Fall-related fracture occurs if the energy from the fall is higher than that the bone can absorb. Force-displacement curve obtained from a biomechanical test shows that energy absorption, the area under the curve, represents bone fragility and an ideal strategy for the improvement of bone fragility is to increase both of the force and displacement at failure [99] (Fig. 1.8a).

From a material point of view, stiffness and toughness of bone tissue generally depend on mineral and collagen, respectively [100]. There is a yield force at which a bone begins to deform plastically, and mechanical strain from normal physical activity would be linked to the pre-yield “elastic” deformation associated with mineral, but not to the post-yield “plastic” deformation associated with collagen (Fig. 1.8b). Consequently, mechanical strain -related feedback control could compensate mineral-related, but not collagen-related, impairment of bone quality to maintain “elastic” deformation [78]. Indeed, this theory is compatible with clinical data relating to bone quality. Examples of the mechanostat -based compensation for mineral-related impairment of bone quality would include rickets/osteomalacia and use of warfarin [77, 79–81], while the impairment of bone quality associated with collagen cross-links significantly contributes to skeletal fragility in diabetes [101–103].

Finally, it is possible to speculate that daily treatment with teriparatide improves bone fragility at the hip through the mechanostat -based “modeling-related direct” and “remodeling-related compensatory” mechanisms (Fig. 1.8c). The enhancement of skeletal response to mechanical loading [37, 62–66] would result in the former effect. In contrast, a decrease in the degree of mineralization after the treatment [104] might act to improve bone fragility if compensated efficiently, because compensatory bone gain by the mechanostat to maintain the pre-yield “elastic” deformation could increase the yield force at which a bone begins to deform plastically and thus the energy that the bone can absorb. This possibility is supported by histomorphometric data showing that 1 or 2 years of the treatment results in increases in modeling- and remodeling-based bone formation [105], because the mechanostat suggests that the former “modeling-related direct” effect does not continue for a long time [77].