Osteoporosis is a major public health problem especially for elderly women and is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures of the hip, spine, and wrist. Changes in bone mineral density (BMD) have long been considered the most important factor in the diagnosis of osteoporosis and in predicting the risk of osteoporotic-related fractures. However, some studies have indicated that there is an overlap on BMD between the groups with and without osteoporotic fractures and that bone density measurement alone is insufficient to evaluate the strength characteristics of the osteoporotic bone.39,49 To better predict the risk of osteoporotic fractures in elderly patients, it is essential to understand different approaches to biomechanical characterization of the osteoporotic bone and their limitations.
It generally is thought that the fracture repair mechanism in patients with osteoporosis is not different from that of healthy subjects. A bone fracture will repair and remodel depending on the ensuing microvascular and biomechanical conditions.1,24,52,54,73 The biomechanical conditions imposed to the fracture site are associated with the bone immobilization technique selected. It is very likely that during bone repair and regeneration, the type of stress applied and the amount of interfragmentary movement imposed to the fracture site may dictate the eventual outcome of the tissue and its formation mechanism. Therefore, in the musculoskeletal system, the mechanical environment plays a key role in repairing, maintaining, and remodeling bone in its material property and structural strength. However, no matter what kind of fixation device is applied to the fracture site, an accurate reduction is a requisite for bone healing in patients with bone insufficiency fracture such as those with osteoporosis. Failure to realign the fracture site would result in delayed union, malunion, or nonunion.19,23,56
We describe the biomechanical considerations of osteoporosis and fracture treatment by summarizing several previous studies with closely related characteristics. Bone structure and strength characterization are discussed using a hierarchical approach to form a basis and a background for our study. An innovative knowledge-based approach for fracture reduction planning and execution under external fixation is used to illustrate the benefits of treating osteoporotic fractures. Finally, a brief review of the results of several experimental animal models with different fracture types, gap morphologic features, rigidity of fixation devices, subsequent loading conditions, and biophysical stimulation is given to elucidate adverse mechanical conditions associated with different bone immobilization techniques that can compromise normal bone fracture healing significantly. This summary paper shows the key biomechanical knowledge and technology required by the surgeons to provide optimal treatment to trauma patients with concomitant osteoporosis and to enhance their clinical outcome with special emphasis on quality of life.
Osteoporotic Bone Structure and Strength Characterization
Mechanical properties of the bone can be described at different levels of the bone structures, from the macroscopic to ultramicroscopic levels, and under different mechanical basic assumptions, such as heterogeneous or homogeneous and isotropic or anisotropic assumptions.26,40–42 To better interpret the measures from various noninvasive techniques and correlate these measures with the risk of osteoporotic fracture correctly, it is essential to understand the hierarchical structure of the bone and different approaches to biomechanical characterization of the osteoporotic bone.
Because osteoporotic changes generally are initiated at cancellous bone and fractures associated with osteoporosis occur more frequently in the cancellous bone-rich regions, such as vertebral bodies of the spine, distal radius, and proximal femur, the upcoming sections will focus on discussing the osteoporotic changes of the cancellous bone only.
Macroscopic Approach to Mechanical Properties of Cancellous Bone
Macroscopic distribution of bone density and trabecular orientation have been studied in the various anatomic sites by dividing the epiphyseal region into small regions of interest (ROIs). Although a microscopic approach is applied to analyze the bone density and trabecular orientation in each ROI (as will be described), distribution of these parameters in each ROI represents a heterogeneous feature of the trabecular structure at the macroscopic level. These parameters often are used in estimating the mechanical properties of the cancellous bone.
Hagiwara et al34 analyzed the distribution of bone density and trabecular orientation in the osteoporotic human vertebral body. The BMD (bone mineral density) and trabecular orientation were measured for nine different regions (3 × 3 matrices) for individual vertebral bodies on 39 vertebral bodies from 11 human cadavers. The anisotropy was defined as the intensity of vertical trabecular orientation to the intensity of horizontal trabecular orientation measured with the two-dimensional Fourier transform of the soft radiograph image of the vertebral body (to be described). The results showed a significantly lower BMD and higher vertical trabecular orientation in anterior ⅓ regions of the osteoporotic vertebral body. This finding corresponds to the higher incidence of the vertebral fracture associated with osteoporosis in the anterior part of the vertebral body (a wedge-shaped fracture).
Microscopic Approach to Mechanical Properties of Cancellous Bone
Three different approaches have been used to investigate the mechanical properties of the cancellous bone at the microscopic level (Fig 1).
Homogeneous and Isotropic Approach
Within a small region, cancellous bone can be assumed to be a homogeneous material not related to the structure of individual trabeculae. With this approach, only bone density is evaluated and the isotropy of the cancellous bone is ignored. The bone density can be defined in several ways. An apparent density has been used for many investigations, which is defined as the mass of bone tissue divided by the bulk volume of the test specimen, including mineralized bone and bone marrow spaces.32,39 In the histologic study, the bone density can be defined as a ratio of the bone area to the entire field area. It sometimes is called as an area fraction. Radiographic density also is used often to define the bone density with calibrating by known hydroxyapatite (HA) density or normalizing by density of the control area. Although micro-CT uses the radiologic technique, the bone density can be defined as the volume of the bony tissue to the bulk volume of the test specimen including the bone marrow space.
Although the distinction between low-density cortical bone and high-density cancellous bone is arbitrary, the stress-strain properties of the cancellous bone are markedly different from those of cortical bone. A linear relationship between bone density versus the strength and elastic modulus has been reported for the cortical bone, but a nonlinear dependence of strength and elastic modulus of the cancellous bone on the bone density was shown.32 This nonlinearity has been well described as a power-law by Carter and Hayes.15 Their study indicated that the compressive strength of cancellous bone is related to the square of the apparent density, and the elastic modulus also is related to apparent density by a power-law function with an exponent range between 2 and 3.
Homogeneous and Anisotropic Approach
It generally has been accepted as a Wolff’s law that the directionality and density of the cancellous bone are related to direction and magnitude of the load applied to the bone.73 Anisotropy of the microstructure and mechanical properties of the cancellous bone have been recognized.32 Such anisotropic features on the trabecular pattern can be observed even on the plain radiograph.66,67 A study indicated the importance of changes in anisotropy of the trabecular structure for the diagnosis of the osteoporosis and prediction of the fracture risk associated with the osteoporosis in addition to the bone density measurement.39 Anisotropy of the trabecular structure can be described from a statistical point of view without expressing the orientation of individual trabeculae. This homogeneous-anisotropic approach is used frequently in analyzing the anisotropy of elastic modulus and strength of the fiber-reinforced composite material.
A two-dimensional Fourier analysis of the image has been used55 to estimate the principal directions of the trabecular orientation and intensities of the orientation along the principal directions, which can be used to describe the anisotropy of the trabecular structure. This technique was extended from an optical Fourier analysis to a digital Fourier transform using a fast-Fourier transform (FFT) algorithm, and it also has been applied to study soft tissue anisotropy.48,57 In the two-dimensional FFT analysis, location information of an individual element is extinguished and, as a result, all image information is gathered around an origin of the spectrum field (center of the spectrum field) (Fig 2). This feature of the two-dimensional FFT allows an easy and fast analysis of the trabecular orientation included in the image data by combining a polar analysis of the power spectrum.17,36,38,48 This technique also allows analysis of image data with a gray-level gradient without binalization of the gray-level. This feature is important to analyze radiographic data with a wide range of density gradient (gray-levels). However, the Fourier analysis does not allow analysis of geometric characteristics of individual trabeculae such as connectivity and thickness of the trabeculae, even though some of the characteristics can be analyzed by spatial frequency analyses in the spectrum field.
Anisotropy of the cancellous bone based on the three-dimensional trabecular orientation is more complex than that of the cortical bone based on the osteonal orientation. It has been recognized that the trabecular anisotropy varies with anatomic site and progress of the osteoporosis.69,71 The anisotropic features of the trabecular structure have been relatively well-studied on the vertebral body. The longitudinal trabecular orientation and transverse trabecular orientations are well known in the vertebral body and changes in a ratio between two trabecular orientation has been considered an important indicator in determining the initiation and progress of the osteoporosis in the vertebral body. Generally, the transverse trabeculi disappear as the osteoporosis progresses and, as a result, the longitudinal trabecular orientation becomes more dominant. These changes in the longitudinal and transverse orientations with osteoporosis are shown clearly by the Fourier analysis of the radiographic image (Fig 3). This increase in intensity of the longitudinal trabecular orientation seems to be beneficial in sustaining the compressive force applied to the direction of the longitudinal trabecular orientation with a limited bone mass. However, the change in intensity of the trabecular orientation associated with osteoporosis has a critical disadvantage.
In the majority of the mechanical tests of cancellous bone, including those in the studies cited previously, the test specimens were taken along the direction of the major trabecular orientation and the loading axis was parallel to this direction. This type of testing is called as an on-axis testing. Under the homogeneous-anisotropic approach, the mechanical properties in the orthogonal direction, such as transverse direction, are as important as those in the longitudinal direction.39 Several investigators have studied the mechanical properties of the osteoporotic bones in the orthogonal directions and reported a decrease in elastic modulus and strength in the transverse direction compared with those of the longitudinal direction. Those findings correspond to an increase in intensity of the trabecular orientation in the loading direction in the osteoporotic bone. The ratio of the elastic modulus in a major principal axis (longitudinal direction) to that in the minor axis (transverse direction) was reported as 1.00–1.51 in osteoporotic vertebral body34 and 1.05–7.04 in the bovine proximal tibia.36
Elastic modulus in arbitrary directions between the maximum principal axis and minimum principal axis can be determined by following the homogeneous-anisotropic-elastic theory:
where, E(θ) is Young’s modulus in arbitrary direction θ, E0 is Young’s modulus in the longitudinal direction, E90 is Young’s modulus in transverse direction, G is shear modulus, and ν is Poisson’s ratio.36,39Figure 3 shows the directional variation of the tensile Young’s modulus of the cancellous bone taken from the proximal bovine tibia.36 The intensity of the trabecular orientation was defined as the ratio of the intensity of trabecular orientation in the maximum principal axis to that in the minimum principal axis (anisotropic factor).25 The Young’s moduli do not vary with direction in the specimens with low intensity of the trabecular orientation (low anisotropic factor, Fig 3A). These types of specimens can resist the load from any direction and have features of the homogeneous-isotropic material, which is observed in the normal vertebral body. As the anisotropic factor increases, the directionality dependency increases. Young’s modulus decreases dramatically when the loading axis declines 15°–30° from the principal axis of the trabecular orientation. For example, when the intensity of the longitudinal trabecular orientation is four times higher than that in the transverse direction (anisotropic factor is four, Fig 3C), Young’s modulus decreases to approximately ¼ when the loading axis declines 30° from the longitudinal axis (Fig 3B). Because the Young’s modulus in 45° reflects on-axis shear modulus, the increase in the intensity of the trabecular orientation also causes a dramatic reduction of the shear modulus. These findings indicate that the osteoporotic change in increasing intensity of trabecular orientation in the loading direction may be beneficial to sustain the load in the direction, but osteoporotic bone with high intensity trabecular orientation is markedly weak for the loading with slightly different directions from the direction of the principal trabecular orientation or the shear load.
Heterogeneous and Anisotropic Approach
In the heterogeneous and anisotropic approach, the microscopic structure of the trabeculae is analyzed directly from the morphologic features of the individual trabeculae. A histologic study has elucidated the morphologic changes in osteoporosis.39 In addition to the two-dimensional histologic analysis, a continuous sectioning technique allowed the creation of a detailed three-dimensional reconstruction of the trabecular structure.7 Micro-CT scanning also has been used to create the three-dimensional trabecular structure. These three-dimensional reconstructions of the trabecular structure have enabled measurement of morphologic parameters, such as trabecular connectivity, individual trabecular volume and surface area, and three-dimensional anisotropy. However, this technique currently is not applicable for in vivo study in humans.
The relationship between the trabecular volume fraction and the connectivity of the trabeculae was investigated using micro-CT scanning but the results were controversial.39 Ding et al27 applied the micro-CT scanning technique to study osteoporotic changes in anisotropy and connectivity of the proximal tibia from humans. They showed the significant increase in the intensity of the trabecular orientation in the primary trabecular direction and strong trends in the decrease of trabecular connectivity with aging. They indicated that the remaining trabeculae in the elderly support the mechanical load mainly in the primary direction to compensate bone loss caused by age and the remodeling process.27
Kabel et al39 studied the relationship between the connectivity and the elastic properties of cancellous bone using the microstructural finite element model and reported that the connectivity density parameter had no or very limited value for assessment of the elastic properties by morphometric variables in normal bone but it might be a useful indicator of mechanical properties of the pathologic bones.
Ultrasound Properties of the Osteoporotic Bone
An ultrasound technique is gaining popularity as a method of preference for noninvasive, radiation-free assessment of osteoporosis. There is an increasing need for correlating the ultrasound results with the associated mechanical properties and trabecular structure because this method has a potential to estimate elastic modulus in the bone, which in turn predicts the fracture risk of the osteoporotic bones.
Previous studies on ultrasound measurement of the cancellous bone showed the importance of trabecular orientation along the ultrasound measurement axis as a significant contributor to the ultrasound measurement results.31,68 Turner and Eich68 concluded that only 36% of the variance in compressive strength of cancellous bone can be explained by apparent density without considering trabecular anisotropy. Minakuchi et al53 investigated the correlation between the compressive stiffness or ultrasound velocity and the BMD and the intensity of the trabecular orientation using calcaneal cancellous bone from humans. Equivalent bone density oriented along the loading and ultrasound axis was calculated as the product of bone density and trabecular orientation intensity along the same axis. The component of bone density oriented along the axis correlated significantly better than BMD with compressive modulus and ultrasound velocity. This investigation suggests the importance of the trabecular orientation in estimating the mechanical properties of the cancellous bone, in addition to the BMD and ultrasound results, in that the trabecular orientation reflects the mechanical properties of cancellous bone with anisotropic behavior.
However, ultrasound measures the density and anisotropy simultaneously, and these parameters cannot be separated in the ultrasound measurement. The information of anisotropy could be obtained from the ultrasound measurement, but the BMD should be measured separately in the identical location of the ultrasound measurement.
Minimally Invasive Surgery in Fracture Reduction
Osteoporosis is responsible for 1.5 million fractures each year.49 Poor bone quality in patients with osteoporosis presents the surgeon with difficult treatment decisions among cast or brace immobilization, internal or external fixation, intramedullary nailing, and Less Invasive Single-cortex Stabilization plate (LISS plate, AO Foundation, Davos, Switzerland), sometimes referred to as the internal external fixator. To promote fracture healing and remodeling, optimal biomechanical and microvascular environments should be introduced to the fracture site at every stage of the healing process. Among many factors, accurate reduction,19,23,56 precise axial dynamization,2,22,29,46 adequate stability,43,63 and self-regulated weightbearing30 have been documented to have beneficial effects on bone healing and remodeling. These requirements can be achieved by external fixation via thorough preoperative planning. In addition, the use of an external fixator could minimize soft tissue and periosteal disruption, allow additional readjustment, avoid implant removal, and allow pin insertion site selection to where bone quality and geometry would seem to be more suitable under osteoporotic conditions. Therefore, external fixation can be described as a minimum invasive surgical procedure for fracture reduction.
In current clinical practice, fracture reduction using an external fixator can be regarded as a trial and error process. Based on the image intensifier images, the surgeon has to manipulate the fracture so that the fracture’s proximal and distal fragments are aligned. After that, an external fixator is applied to stabilize the fracture endings by locking the fixator joints. Final adjustment often is necessary to reduce the fracture and correct any residual deformities. This approach would expose the surgeon and the patient to an excessive amount of radiation. In our laboratory, we are investigating an innovative knowledge-based approach to plan and execute fracture reduction and axial dynamization using a unilateral external fixator. This approach would allow the surgeon to perfectly reduce the fracture malalignment and minimize the use of an image intensifier.
Virtual Interactive Musculoskeletal System
Our knowledge-based approach was implemented using a powerful and versatile simulation software, Virtual Interactive Musculoskeletal System (VIMS), developed by our group.16 The VIMS consists of three modules: (1) VIMS-Model provides the mechanical models of the long bones, fixators frames, pins, and wires, (2) VIMS-Tool contains the computational algorithms for fixator-bone complex stiffness analysis and bone end displacement analysis through fixator joint adjustment, and (3) VIMS-Lab provides the virtual environments to simulate various operation scenarios for fracture reduction, dynamization, and stiffness testing simulations (Fig 4).
Knowledge-based Fracture Reduction and Dynamization Planning
To show the methodology, a unilateral external fixator (Dynafix, EBI, Parsippany, NJ) applied to a tibia midshaft fracture is used as an example. This fixator is composed of two telescoping pin clamps connecting to the proximal and distal tibia segments, a central rotary joint, and four sets of hinge joints. The tibia model was generated from the Visible Human Male dataset (NLM, Bethesda, MD), and the external fixator models were reconstructed using computer-aided design software. The bone-fixator system was modeled as a kinematic linkage chain system allowing rotation and translation at the fracture site through fixator joint adjustments. Before determining the malalignment of the fracture endings, a pair of bone pins were inserted to the distal tibia segment. The three-dimensional bone deformity (the relative position and orientation of the proximal tibia segment [P] with respect to the distal tibia segment [D]) and the relative position and orientation between the distal pin clamp  and the distal bone segment [D] can be expressed as 4 × 4 homogeneous transformation matrices,20DTP and DT1, respectively, which can be determined radiographically using established landmarks17 or by digitizing the two-dimensional projected contours of the tibia segments using roentgen stereophotogrammetry14,18,64 and registering the two-dimensional xray projection contours of the bone segments with a genetic three-dimensional surface model of the tibia using a three-dimensional to two-dimensional registration method.47 Before fracture reduction, the deformity matrix, DTP, can be expressed as a sequential transformation of each link of the fixator from the proximal end to the distal end by the following matrix equation 2:
where 8TP represents rigid body transformation of the proximal tibia segment with respect to the proximal pin clamp, 1T2 and 7T8 represent initial rigid body translations along the length of the telescoping slider mechanism within the body of the clamps, and 2T3, 3T4, 4T5, 5T6, and 6T7 are the initial rotations at the hinge joints. A pure axial dynamization can be achieved by paralleling the proximal pin clamp with the proximal tibia segment and loosening the proximal telescoping joint after final reduction. This can be accomplished by calculating the initial configuration of the external fixator by solving Equation 2 and setting 8RP = [I] (where 8RP is the rotation matrix of the proximal tibia with respect to the proximal pin clamp and [I] is a 3 × 3 identity matrix).
To correct the bone malalignment, a matrix equation that represents a sequential transformation from proximal to distal ends after fracture reduction has to be solved (Equation 3):
where DTP* is an identity matrix, DT1* = DT1 and 8TP* = 8TP, and 1T2*, 2T3*, 3T4*, 4T5*, 5T6*, 6T7*, 7T8* are the final rotation and translation matrix of the fixator joints. Equation 3 can be solved for the amount of rotation and translation at each joint of the external fixator with or without additional constraint conditions imposed using the nonlinear least square optimization method (Matlab, Mathworks, Natick, MA).
The optimal correction pathway was chosen according to clinical, anatomic, and biomechanical factors to minimize soft tissue disruption and to maximize bone consolidation. Using computer graphic simulation and animation, the validity of the analysis and the clinical relevance of this technology were tested in a virtual environment. In addition to making it easier for surgeons to use external fixates of varying designs for bone fracture reductions and bone deformity correction, the VIMS also can facilitate device design, medical personnel training, and education through model and analysis visualization using high resolution animations.
A complex deformity is shown in Figure 5A, which features a 5° X-angulation, 10° Y-angulation, 30° Z-angulation, 5 mm X-translation, 5 mm Y-translation, and 5 mm Z-translation. An initial and final configurations of the fixator joints were set according to preoperative planning. One of the correction options is shown graphically before and after successful fracture reduction (Fig 5B). For this final configuration, pure axial dynamization can be facilitated by loosening the proximal translation joint only (Fig 5C).
The fixator joint solutions for fracture reduction are infinite depending on initial guess, adjustment sequence of the fixator joints, and design configurations. Among all reduction options, it seems that simultaneous or small incremental adjustments provide a smooth reduction path. Using the VIMS Laboratory, clinicians can validate the results of the adjustment analysis and observe the steps necessary for different fracture reduction paths. It has been proven that the technique is applicable to any arbitrary form of initial malalignment.16,44 More important, this technique also would allow the initial configuration to be set to facilitate fixation through stronger bone and pure axial dynamization. We are developing the next-generation external fixator and the corresponding powered actuator to facilitate adjustment of fixator joints according to the preoperative plan. We think that the knowledge-based application of the external fixator for fracture reduction is a promising approach in future clinical practice.
Biophysical Stimulation to Enhance Fracture Repair
Mechanical stimulation can induce fracture healing or alter its biologic pathway.1,10,21,58,74 Repetitive loading under small strain and high frequency or overloading through an elevated exercise regime has been shown to cause bone hypertrophy.33,59 The added bone formation also is related to the direction and magnitude of overloading which will affect the internal state of stress of the repairing tissue. However, the regulating cellular mediators responsible for such a phenomenon remain unknown (Fig 6). If the underlying mechanism at the cell membrane or cytoplasmic level can be linked directly to the mechanical stimulant, the most effective modality to maintain or enhance bone regeneration may be established for the treatment of difficult fractures especially in patients with deficient osteogenic potential attributable to either local or systemic factors.
When the mechanisms for tissue formation at the cellular level are understood and well defined, physiologic conditions or pharmacologic agents may be developed to accomplish the same callus formation and bone regeneration effects without the mechanical interventions that often are difficult to administer under adverse conditions. However, the cellular mechanisms and the potential mechanoreceptors on the cell membrane sensitive to stress induced electromechanical or stream potential signals have yet to be identified. Such a discovery, if successfully accomplished, can significantly help to unravel the mystery of the mechanism regulating connective tissue remodeling and disuse atrophy, which only has been theorized without validation. Before then, it is important for the clinicians treating bone fractures to understand that there are different biologic, physiologic, and mechanical factors that can have positive or negative effects on fracture repair at the tissue level without the full knowledge of their intricate cellular mechanisms. It is equally important to recognize the possibility that mechanical loading may be the only irreplaceable element governing bone remodeling after successful initiation of the fracture repair process.
Experimental Studies Relating to Mechanical Loading and Fracture Repair
Rats and canines have been used as the experimental animal models for manually creating long-bone fractures or surgically producing transverse and oblique osteotomies.3,4,5 Gap and contact with and without static compression were used as the fracture end conditions, whereas rods, compression plates, and external fixators of different stiffness properties were used as the means of studying the effects of several fracture immobilization methods on bone healing patterns. In addition, passive axial dynamization through relaxing the telescoping mechanism on the side bar of an external fixator also was used to study its possible effects on fracture callus and bone histomorphometric features of bone.2 Radiographic, nuclear scintigraphic, static and dynamic weightbearing, histologic, biomechanical, cellular, and biochemical methods were used to quantitate the histomorphometry, mineral density, and mechanical properties of callus and newly formed bone to identify the unique features associated with each fracture type and fixation condition. The data associated with different experimental conditions were used to characterize different fracture healing types previously identified and possibly unrecognized as healing mechanisms.
Under rigid internal or external fixation, the morphologic features of the fracture union matched those of the contact or primary healing mechanism, with direct osteonal migration across the fracture gap. However, periosteal and endosteal callus and new bone formation were common, depending on the loading condition and micromovement at the fracture site inherent to the specific immobilization method used. Interfragmentary compression did not alter the basic morphologic features of fracture repair, except for the proportional reduction of periosteal callus. Osteonal migration also occurred despite the presence of fracture gap, although the woven bone within the gap had transversely oriented collagen fibers laced with longitudinal migrating osteons. When less rigid internal fixation (intramedullary nail without interlock) and external fixation (smaller and fewer pins in unilateral frame) methods were used, fracture repair followed the secondary healing mechanism with an abundant amount of periosteal and endosteal callus but without osteonal migration.58 Bone formation occurred secondary to endochondral and intramembranous ossification. The distribution of endochondral ossification and intramembranous ossification depended on the biologic environment and loading conditions. The transformation from callus to mineralized woven bone occurred early in the healing period and increased its volume quickly to replace cartilage and undifferentiated tissue.51 This transformation is responsible for the mechanical strength or the cortical bone at the tissue level as shown by the mechanical indentation results in different regions of the maturing callus in a fracture-healing model.
Axial dynamization, passively and actively, under external fixation in stable and unstable fracture types seemed to provide an increased amount and more uniform distribution of periosteal callus. As the load was transmitted through the fracture site after dynamization, there were fewer pin tract problems because of reduced pin-bone interface stress. However, changing fixator stiffness by removal of excessive pins or connecting sidebars did not show any positive effect on augmenting bone fracture healing. Without exception, weightbearing was proven to be important, especially in restoring the fractured bone to its original mechanical strength. Finally, axial dynamization was able to enhance more advanced bone remodeling which is related closely to the loading response according to Wolff’s hypothesis.73
Other Forms of Biophysical Stimulation on Bone Fracture Healing
As early as 1955, Yasuda77 discovered the electric callus phenomena and postulated that “dynamic energy exerted upon bones is transformed into callus formation.” Now, after approximately a half century, the ability to manipulate bone and other connective tissue using external energy still is doubted by some60 despite years of basic research and clinical investigations. Instruments delivering low-intensity pulsed ultrasound (LIPU), pulsed electromagnetic fields (PEMF), low power direct current (DC), or extracorporeal shock wave stimulation are being promoted by the industry with mixed responses in the orthopaedic community.45,61,62
Cultured cell and tissue subjected to different physical and electrical signals of varying intensities have been studied using molecular biology and histomorphologic analyses. Single cell studies under a carefully controlled stimulation environment using specially designed equipment, have been conducted to investigate the basic mechanism of cellular response under stimulation. Biochemical pathways activated in signal transduction under various types of electrical stimulation have been studied on bone cells.13 Various animal models from rats, rabbits, canines, sheep, and horses simulating fresh fracture, delayed union, and limb lengthening were studied to evaluate the energy sources and their dose effects on tissue response judging from the radiographic, histomorphologic, and biomechanical results.37
The low-intensity pulsed ultrasound was reported to enhance fracture healing by stimulating earlier synthesis of extracellular matrix (ECM) protein, the aggregan in cartilage, possibly altering chondrocyte maturation through the endochondral bone formation pathway.76 Pulsed electromagnetic fields stimulation was reported to induce osteogenesis through upregulating BMP-2 and BMP-4 in osteoblasts.8 The application of direct current would reduce local tissue oxygen concentration, which could transform polymorphic cells to bone.12 Such mechanism also applied to mesenchymal cells associated with bone fracture hematoma. It has been postulated that the extracorporeal shock waves produce microtrauma or microfracture and induce neovasculization through hematoma formation, which increases osteoblast or fibroblast activity.70
In animal experiments, positive effects of stimulation were found consistently in different models and under various simulated clinical conditions. The type of tissue formation in the bone healing process was found to follow closely the cellular mechanism associated with the specific form of energy. In a well-controlled canine unilateral delayed union model (Fig 7), pulsed electromagnetic fields stimulation for 1 hour or 4 hours per day for 8 weeks significantly increased weightbearing on the affected limb (Fig 8) with higher mechanical strength of the healing osteotomy attributable to periosteal new bone formation (Fig 9). Another striking finding in this study was the effect of pulsed electromagnetic fields on reducing cortical porosity in the bone adjacent to the osteotomy when compared with the nontreated group (Fig 9).37
There are numerous clinical reports to support effectiveness of such biophysical stimulation on fresh fracture, delayed union, and bone lengthening. Several prospective, randomized clinical studies have shown the efficacy of low-intensity pulsed ultrasound in stimulating bone formation after fracture,35,45 nonunion,75 and bone lengthening.61 Pulsed electromagnetic fields stimulation has been in clinical use for approximately 30 years on patients with delayed fracture healing and nonunion and has been shown to be effective in some clinical case reports.6,28,60 Double-blinded studies confirmed the clinical effectiveness of pulsed electromagnetic fields stimulation on osteotomy healing9,50 and delayed union fractures.65 Brighton et al11 did a multicenter study of nonunions and reported an 84% clinical healing rate of nonunions with direct current treatment. Schaden et al62 reported 76% of nonunions or delayed unions treated with one time extracorporeal shock wave therapy resulted in bony consolidation with a simultaneous decrease in symptoms.
All these results would strongly support the validity of applying stimulation as a reliable therapeutic modality in bone fracture repair augmentation. Unfortunately, almost all commercially available devices on the market today have not fully used the potential of such technology. None has attempted to optimize the dose effect by considering a time-related tissue change as the basis to adjust the stimulation signal intensity and treatment protocol. It is even more disappointing that the engineers of the manufacturers responsible for design and production of these devices never attempted to produce a uniform field intensity at the site of stimulation with minimal scattering of energy to the adjacent normal tissues. The sciences related to connective tissue modulation through external energy stimulation should be transferred to the technology, which can be brought to the clinical arena as a system to provide reliable enhancement on tissue repair, regeneration, remodeling, and maintenance, and make noninvasive tissue engineering a calculated reality.
Mass reduction of the bone in the osteoporotic change causes structural changes of the bone especially at the microstructural level. Subtle reduction in the bone mass in the transverse direction increases the intensity of the trabecular orientation in the loading axis. This structural change may be effective to resist loading when the direction of the loading coincides with that of the trabecular orientation. However, such structural change narrows the tolerable loading directions, which in turn may increase the fracture risk. Different types of noninvasive techniques provide different information on the structural changes in osteoporosis. To interpret the information correctly and effectively, it is important to understand the structural level of the bone and underlying assumptions on which the individual measurement is based.
After long bone fractures in patients with osteoporosis, although their healing mechanisms are not drastically different from those of normal individuals, fixation strength of different methods will be affected significantly because of alteration of cortical and trabecular bone structural and material properties. Even under reduced loading, fracture site gap movement can vary, which could induce adverse effects on bone union pathways. Therefore, appropriate bone fracture reduction is more important in the elderly patients with osteoporosis. The use of VIMS simulation software and bone fixation device model will be critical to plan and achieve ideal reduction regardless of what method of immobilization is used.
The use of an external fixator particularly is attractive in the elderly population because it is the least invasive method to provide adequate immobilization regardless of the type of fracture and anatomic site involved. In addition, it will maintain the vascular status at the fracture gap whereas pin placement can be remote from the fracture where bone dimension and structural strength are superior. Adjustment of the fracture alignment and gap reduction plus dynamic stimulation can be implemented accurately after the treatment and reduction protocol developed using the VIMS technology.
Finally, when elderly patients with long bone fractures cannot do the necessary rehabilitation program including partial weightbearing exercises after fracture fixation, adjuvant physical or biophysical stimulation may be applied to enhance bone union and improve the quality of life among these patients who are bedridden or wheelchair bound. Although different types of stimulation have been shown to be effective on either fresh fractures or in delayed unions, more basic science research and clinical trials are needed to make these potentially powerful alternative medicine modalities more reliable through signal delivery transducer design, tissue response monitoring, dose and signal optimization, and customized and knowledge-based treatment protocol development for each patient and the fracture involved. With all these special considerations, bone fracture treatment outcome in elderly patients and patients with osteoporosis should not be different from those involving other fractures. The need of coordinated research and development in the related biomechanics field is timely and urgent to prepare us for the exponential increase of aging population worldwide in the coming decades.
We thank all individuals who worked in our laboratory and who contributed significantly to the studies summarized in this report.
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