To date, three human trials evaluating the potential of high-frequency vibrations at very low-levels (<0.5g) to positively influence bone mass and morphology have been completed. In the first, sixty-two post-menopausal women were randomized into in a double-blind, placebo controlled pilot study23
. Thirty-two women stood on vertically vibrating devices at an acceleration magnitude of 0.2g and signal frequency of 30Hz for two ten-minute periods per day. Evaluating those in the highest quartile of compliance (86% compliant), placebo controls lost 2.1% in the femoral neck over the year, while vibration treatment was osteoprotective. In this quartile, the spine of lighter women (<65kg) exhibited a relative treatment benefit of 3.4% greater BMD. In the second study, twenty children with cerebral palsy were randomized into low-level vibration treatment (0.3g, 90Hz, 10min/d) or placebo controls24
. Over the 6mo trial, tibial volumetric bone mineral density (BMD) of children who stood on placebo devices decreased by 11.9%, while children who stood on active devices increased by 6.3%. This benefit was achieved with an overall compliance of 44% of the 10 min/d period, implying that the anabolic response was triggered, rather than accumulated, by even brief exposures.
In the third study, a 12mo trial was performed in 48 young women, with half of the subjects subject to 10min/d low-level whole body vibrations (30Hz, 0.3g)25
. A per protocol (PP) analysis demonstrated that women had to stand on the vibrating plate for at least 2 min/d to achieve a gain in bone mass, including a 3.9% net benefit in cancellous bone of the spine or a 3.0% net benefit in cortical bone of the femur (). In this study and in contrast to the previous two, muscle was included as an outcome measure. The low-level mechanical signal elevated muscle mass, with a 7.2% net benefit in the total paraspinous musculature, a 5.2% net benefit in the psoas muscle and a 7.9% net benefit in the erector spinae (). Together, these investigations demonstrated the ability of the human musculoskeletal system to derive structural benefits from the application of very low-level mechanical signals. As the target populations in these three studies were unlikely to be very active, exposure of their skeletons to a very large number of very small mechanical events could be considered a surrogate for specific aspects of the habitual loading environment. Unfortunately, the limited number of assays employed in these small clinical studies makes it difficult to extract information regarding relations between muscular- and skeletal adaptation and animal models may be more suitable to address these questions.
Changes of musculoskeletal variables in control and treated women over the length of the 12mo trial. Variables with significant differences between the two groups are bolded.
Similar to clinical data, animal studies have consistently demonstrated that vibrations, applied at very low levels for short daily durations can increase bone formation26–28
, decrease bone resorption16
, and result in a skeleton with higher mass and strength6,29,30
. As expected from a stimulus that alters cellular metabolism, skeletal changes are accompanied by the differential expression of key molecules in vivo
including iNOS, RANKL, or MMP-228
. In vitro
experiments directly highlight the sensitivity of bone cells to vibratory signals of different magnitudes as shown by the altered transcriptional levels of c-fos and c-myc31
. Whether signaling pathways are dependent on the magnitude of the vibration, and whether vibrations of any magnitude are regulated differently from exercise induced mechanical signals, is currently unknown.
Similar to clinical studies, data from animal models indicate that in addition to low-magnitude accelerations, higher-magnitude accelerations can also raise bone formation and mass35–38
. Only few investigations were designed to directly contrast the effects of low-magnitude versus high-magnitude accelerations. Considering the non-linearity by which vibrations are transmitted into the musculo-skeleton, it may not be surprising that the attempt to associate bone formation with acceleration magnitude has produced equivocal results. For instance, a whole body vibration intervention in mice was equally effective in increasing trabecular bone volume in the tibial metaphysis when the signal was applied at 0.1g and 1.0g29
. In the ovariectomized rat, a 3g vibration regime was more efficacious than a 0.5g or 1.5g signal in preventing the detrimental changes induced by the loss of estrogen. However, the loading frequency and number of loading cycles also differed substantially between the three interventions, making it difficult to isolate the effect of acceleration magnitude. Taken together, there is currently no experimental data suggesting that efficacy of vibratory regimens increases with acceleration magnitude.
Substantiated with evidence that bone's anabolic and catabolic activity can be altered by low-level vibratory mechanical signal, its impact on the musculoskeletal system was investigated recently in the mouse39
. Eight-week old BALB/cByJ mice subjected to a 45Hz, 0.3g signal had a 14% greater trabecular bone volume in the tibial metaphysis while periosteal bone area, bone marrow area, cortical bone area, and the moments of inertia of this region were all significantly greater (up to 29%). The soleus muscle also realized gains, with an up to 29% greater total cross-sectional area as well as type I and type II fiber area (). Thus, similarly to clinical data, both muscle and bone can readily respond to the low-level mechanical signal in a murine model.
Figure 2 Upon application of low-level (0.3g) whole-body vibrations for 15min/d, differences in cross-sectional muscle area of the soleus were readily available after 6wk. The ratio between type I (slow, stained black) and type II (fast, stained white) muscle (more ...)
The specific type of cell that is sensing and responding to high-frequency, low-level mechanical signals has not been elucidated. Studies using larger force magnitudes at much lower frequencies have suggested that the cellular sensors for mechanical signals are embedded within the bone (i.e., osteocytes), rather than on bone surfaces40
, given that osteocyte signaling regulates both mechanically induced bone formation41
. Nevertheless, both osteoblasts and osteoclasts are also sensitive to mechanical information. Recent evidence suggests that the mechanism by which low-level, high-frequency mechanical stimuli are converted into a biologic response within a bone involves the selective proliferation and differentiation of specific progenitor cells in the bone marrow43,44
. Conceivable, any cell located either on a bone surface, residing within the extracellular matrix, or located within the marrow can directly receive a signal from a foot-based vibration device that is transmitted through the appendicular skeleton.
Future studies that will relate the mechanical environment induced by vibrations to changes in cellular activity may provide clues toward identifying the origin of the biochemical signal leading to bone formation. For instance, if vibrations generate non-uniform distributions of strain and its by-products across a bone and spatially correlate with biologically relevant signals, it could be argued that cells within the matrix act as sensors. Lack of correlations, in particular if the cellular response was relatively uniform in distribution, could be interpreted as the signal originating from the marrow or the involvement of a biologic mechanism that integrates and processes the mechanical information from osteocytic sensors. Considering that the distribution of mechanical parameters engendered by high-magnitude vibrations is likely to be distinct from those induced by low-magnitude vibrations, such studies may also be used to test whether the identity of the sensory system is dependent upon the amplitude of the vibration.