The Contribution of Experimental in vivo Models to Understanding the Mechanisms of Adaptation to Mechanical Loading in Bone

Abstract

Changing loading regimens by natural means such as exercise, with or without interference such as osteotomy, has provided useful information on the structure:function relationship in bone tissue. However, the greatest precision in defining those aspects of the overall strain environment that influence modeling and remodeling behavior has been achieved by relating quantified changes in bone architecture to quantified changes in bones' strain environment produced by direct, controlled artificial bone loading. Jiri Hert introduced the technique of artificial loading of bones in vivo with external devices in the 1960s using an electromechanical device to load rabbit tibiae through transfixing stainless steel pins. Quantifying natural bone strains during locomotion by attaching electrical resistance strain gages to bone surfaces was introduced by Lanyon, also in the 1960s. These studies in a variety of bones in a number of species demonstrated remarkable uniformity in the peak strains and maximum strain rates experienced. Experiments combining strain gage instrumentation with artificial loading in sheep, pigs, roosters, turkeys, rats, and mice has yielded significant insight into the control of strain-related adaptive (re)modeling. This diversity of approach has been largely superseded by non-invasive transcutaneous loading in rats and mice, which is now the model of choice for many studies. Together such studies have demonstrated that over the physiological strain range, bone's mechanically adaptive processes are responsive to dynamic but not static strains; the size and nature of the adaptive response controlling bone mass is linearly related to the peak loads encountered; the strain-related response is preferentially sensitive to high strain rates and unresponsive to static ones; is most responsive to unusual strain distributions; is maximized by remarkably few strain cycles, and that these are most effective when interrupted by short periods of rest between them.

Keywords: bone; experimental models; mechanical loading; mechanical strain; mechanostat.

Figure 1

Quantifying the mechanical strain stimulus. Rosette (A) or linear (C) electrical resistance strain gages are bonded to the surface of bones to measure the strain stimulus being engendered during a variety of activities and also to match experimental groups with different bone stiffness. (B) A strain gage bonded to a human tibia and (D) to a mouse tibia.

Figure 2

The invasive rabbit loading model. Jiri Hert was the first to describe an artificial mechanical loading model in 1969. Loading was applied through surgically implanted pins in the lapine tibia. Using this approach and assessing the adaptive response of the bone Hert and his co-workers were able to establish, amongst other findings, that adaptive bone (re)modeling occurred without the need for any central nervous connection (–44).

Figure 3

The invasive sheep loading model. Lance Lanyon adapted Hert’s original loading model to the sheep radius and combined the loading with strain measurements using implanted strain gages (45).

Figure 4

The functionally isolated invasive turkey loading model. Lanyon and Rubin further applied the invasive loading model to the functionally isolated avian ulna, which had the advantage that the loaded bone is isolated from the confounding influence of background strain stimuli (–48).

Figure 5

The non-invasive axial murine tibial loading model. (A) De Souza et al. adapted the non-invasive rat (56) and ulna (33) axial loading models to the tibia enabling study of trabecular and cortical compartments in a single loaded bone (34). (B) Representative μCT scans demonstrating trabecular and cortical bone formation within a single loaded bone (58).

Figure 6

The “lazy zone” is an artifact associated with background mechanical strain stimuli. Increasing mechanical strain is associated with a linear increase in bone mass in studies when background strains are eliminated in the isolated avian ulna [(A), (91)] and combined sciatic neurectomy and tibial loading models [(B), (86)]. This indicates there is no “lazy zone” in bone’s adaptation to loading [(C), (86)]. MES, minimum effective strain stimulus.