As the world population ages, there will be an increasing burden of osteoporotic fractures that require strategies to facilitate optimal healing. This review will summarize symposium presentations from the OTA's Basic Science Focus Forum that critically review issues central to translational research and clinical care that affect patients with osteoporotic fractures.
FRACTURE MODELS: DIFFERENCES IN DIAPHYSEAL AND METAPHYSEAL HEALING
Osteoporotic fractures of long bones are most frequently located in the metaphyseal regions, such as the distal radius, proximal humerus and proximal femur, as trabecular bone is highly affected by the microarchitectural deterioration characteristic of osteoporosis. There is evidence that differences exist in bone healing between the metaphyseal and diaphyseal regions of long bones, with less periosteal callus formation in the metaphysis than in the diaphysis.1 Most experimental fracture healing studies are based on the model of Bonnarens and Einhorn,2 with a midshaft fracture of the femur or tibia and internal fixation by intramedullary nailing. This is also true for experimental studies on osteoporotic fracture healing and there is an obvious gap between the diaphyseal experimental surgical models and the most common clinical fractures.3 This fact may limit the conclusions that can be drawn from these studies.
There are 3 general prerequisites for developing a clinically relevant metaphyseal fracture model for osteoporosis: (1) A complete fracture in the metaphyseal region should be created; (2) stable fixation of the fragments should be similar to that performed clinically, which is usually plate fixation; and (3) the bone condition should be consistent with osteoporotic bone.4 The first metaphyseal fracture healing model with plate fixation in small animals was published by Stuermer et al.5 Through an anterior-medial approach from the medial femoral condyle to the middle of the tibia, they performed a transverse osteotomy of the proximal tibial metaphysis followed by plate fixation of the proximal tibia with a T-shaped titanium miniplate. However, the animals underwent ovariectomy at the time of the osteotomy and did not have osteopenic or osteoporotic bone at the time of the bone repair. Alt et al6 recently published a rat model with varying osteotomy defects at the distal femoral metaphysis in ovariectomized (OVX) rats (performed 12 weeks before the osteotomy procedure) and the additional use of a calcium-, phosphorus-, vitamin D3-, soy-, and phytoestrogen-free diet. The defect was a wedge-shaped osteotomy in the femur with a lateral height of 3 or 5 mm in relation to the horizontal osteotomy and was stabilized with a T-shaped miniplate. Defects with a lateral height of 3 mm exhibited stable bone healing after 6 weeks and the authors concluded that these could be used for metaphyseal bone repair studies, including those using biomaterials. Defects with a 5-mm height did not consolidate and were considered a critical size fracture defect model.
Using the above model with a 3-mm wedge-shaped defect at the distal metaphysis, biomechanical testing showed that flexural rigidity in OVX animals with the aforementioned multideficiencies diet was significantly reduced in a nondestructive 3-point bending test at a 3-mm lever span compared with sham operated animals.7 Microcomputed tomography assessment revealed bridging cortices and consolidation of the defect in both groups without detectable differences in total ossified tissue or vascular volume fraction. However, histology showed differences between the groups with a higher amount of cartilaginous remnant and more nonmineralized tissue in the OVX rats compared with a more mature appearance of bone consolidation in the sham group.
In conclusion, investigators have shown differences in metaphyseal fracture healing in OVX and non-OVX rats. These studies include those that used models with osteotomies of the metaphyseal region of the distal femur or proximal tibia with miniplate fixation. Therefore, experimental fracture healing models for osteoporosis should include the targeting of metaphyseal bone repair to best understand the most common osteoporotic fractures.
MECHANICAL TESTING: SELECTION OF A MODEL
The most important parameters to evaluate when developing a biomechanical model for the fixation of osteoporotic bone are the material and structural properties of the bone. The loading conditions, boundary conditions, and construct parameters are also important; however, they would be set in a manner similar to that in the fixation of normal quality bones.
If one compares osteoporotic cortical bone with a similar-sized normal quality bone, there is very little difference in the modulus of elasticity (stiffness) or yield stress (where plastic deformation begins). There is, however, a difference in the ultimate stress (the point of fracture) between osteoporotic and normal bone, as osteoporotic bone is more brittle and thus fractures more easily than normal cortical bone. The most significant effect that osteoporosis has on the biomechanical properties of bone can be seen on gross samples of cancellous bone, where there is a dramatic effect on trabecular density that is directly proportional to bone stiffness and strength. The effective modulus of elasticity is related to the density of the sample, and because an osteoporotic sample has fewer trabeculae than a normal metaphyseal sample, it therefore has less bone and a decreased stiffness and strength.
The main changes affecting fracture fixation of long bones are the structural diaphyseal changes, as the cortical thickness of the diaphysis is reduced and the diaphyseal diameter is increased. The moment of inertia, or the resistance to bending and twisting (structural stiffness in bending and torsion), increases with cortical thickness and cortical diameter, so these change very little with osteoporosis. However, the thinner cortex and more brittle bone make the diaphysis much more sensitive to stress concentrations from screws and screw holes, and screws are more vulnerable to loosening because fewer threads are engaged in the thinned cortex.
Osteoporotic deceased donor bones have all of these material and structural property changes, so they provide realistic models to evaluate cortical fixation constructs. Some animal models of osteoporosis are available, but they are generally in small animals that do not have the same haversian systems as humans and so validation may be difficult. Synthetic models are also available with a choice of wall thickness and composite density, but these models are not uniformly validated for simulating any specific clinical application. Finally, computer models are promising, as control over geometry and bone properties is limitless.
The most common clinical problem surrounding fixation in osteoporotic bones is the location of the cancellous bone changes. Not only is bone density reduced, but the patterns of density change limit the locations where fixation can be achieved. The best models for testing are real human osteoporotic bones, as the local mechanical properties and distribution of bone are real. Synthetic models use a foam material to simulate cancellous bone in the metaphyseal regions, which is much more similar to cancellous properties than the synthetic cortical bone materials, however the distribution of these materials is unlike real osteoporotic bone. Therefore, each application of fixation in one of these models would need to be validated. Computer models can take all of these factors into account and tailor the model to specific bones or patients. But these models must also be validated to ensure that assumptions about bone-implant interfaces, material thresholds for slippage, crack propagation, etc. are realistic.
To summarize, one should always define the clinical problem to be addressed as thoroughly as possible. The optimal model can then be selected and validated for behavior matched to known clinical behavior with known fixation configurations.
MEDICAL MANAGEMENT OF OSTEOPOROSIS
The medical management of osteoporosis is directed at enhancing bone mass, improving bone quality, and lowering fracture risk. The presentation of a patient with osteoporosis often occurs in the setting of a new fracture. A medical strategy to prevent subsequent fractures should be developed. However, treatment modalities should not interfere with the fracture healing process. There are 3 major components that should be addressed by orthopaedic surgeons: (1) providing an adequate calcium and vitamin D environment to facilitate well-mineralized bone and improve bone quality; (2) preventing excessive bone resorption; and (3) providing an anabolic stimulus to enhance bone formation.
Vitamin D and Calcium
Multiple studies have demonstrated that in the elderly population, vitamin D deficiency is quite common, with rates approximating 60%. The newly raised level of normality for 25-hydroxy vitamin D is 32 ng/mL. Calcium values less than 9.5 mg/dL with a normal albumin of 4.0 g/dL will elicit secondary hyperparathyroidism, which over time can lead to gradual loss of bone mass and quality. The preferred calcium is calcium citrate and the total calcium ingested at any given time should not be greater than 500 mg, for values higher than that are poorly absorbed.
The most commonly used antiresorptive agents for osteoporosis are the bisphosphonates, which inhibit and destroy osteoclasts. All bisphosphonates have prolonged bone residence time (30–60 years), will increase bone density, and decrease vertebral (70%) and nonvertebral fractures (40%). The bisphosphonates can cause indigestion and are now given as either a weekly or monthly dose. There have been 3 clinical trials using alendronate and zoledronic acid. They have shown no inhibition for forearm, lower extremity metaphyseal fractures, and hip fractures, however at the same time preventing regional and general osteoporosis. Denosumab is an antibody directed against receptor activator of nuclear factor kappa B ligand—the signal to produce osteoclasts.8 Six monthly injections prevent vertebral and hip fractures to a degree comparable with that obtained with bisphosphosphonates. Denosumab has a 2 month bone residence and does not inhibit fracture healing.
The only anabolic agent available in the United States is teriparatide (Forteo), a recombinant form of parathyroid hormone (PTH). Teriparatide increases bone formation markers and, after several months, the bone resorption markers begin to rise. It produces expansion of the bone and, unlike the bisphosphonates, increases the number of trabeculae. The bisphosphonates will increase bone at approximately 2–3% per year, whereas teriparatide can yield an increase of up to 11% per year. Randomized clinical trials of teriparatide have led to enhanced healing for distal radius and pelvic fractures and decreased failure rates for spine fusion and pedicle screw pull out.9
Both antiresorptive agents and PTH will increase the size of the callus. There is a delay in callus maturation with bisphosphonates and there is enhanced callus progression with PTH, particularly in the cartilage phase. The strength of the bone is unaltered with bisphosphonates because of the increased callus size but is improved with PTH. Therefore, if the fracture is expected to heal without delay, such as with a metaphyseal or epiphyseal fracture, then bisphosphonates are the most cost-effective way to treat osteoporosis. Ideally, treatment would be initiated after 6 weeks to allow early fracture biology to progress without influence from the drug. Conversely, if there are problem fractures, which might be expected to experience difficult healing, then PTH should be chosen as the antiosteoporotic agent, with the understanding that PTH enhances bone repair in animal and human studies.
In light of the association of bisphosphonates and denosumab with osteonecrosis of the jaw and atypical femoral fractures, the use of all antiosteoporosis medication after hip fractures has steadily declined between 2002 and 2011,10 despite the clear benefits in preventing additional fractures. Renewed efforts should be directed at improving the use of antiresorptive medications in patients at risk for further low-energy fractures.
ATYPICAL FEMUR FRACTURES—NEW INFORMATION
The first report by the American Society of Bone and Mineral research defined atypical femur fractures (AFF) as atraumatic or low-trauma subtrochanteric femur fractures. There are 5 major criteria necessary for a fracture to be classified as an AFF: (1) location between the lesser trochanter and the supracondylar flare; (2) no or minimal trauma; (3) transverse or short oblique pattern; (4) lack of comminution; and (5) complete fracture extension through both cortices, often associated with a medial spike (incomplete fractures only involve the lateral cortex). There are 7 minor criteria that are not absolutely necessary for, but may be associated with, AFF: (1) periosteal reaction of the lateral cortex; (2) generalized increase in cortical thickness of the femoral diaphysis; (3) prodromal symptoms, including aching pain of the groin or thigh; (4) bilateral fractures and symptoms; (5) delayed healing; (6) comorbidities, including vitamin D deficiency, rheumatoid arthritis, or hypophosphatasia; and (7) use of pharmaceutical agents, such as bisphosphonates, glucocorticoids, or proton pump inhibitors.11
Many risk factors for AFF have been identified, including adherence to bisphosphonate therapy,12 female sex, Asian ethnicity,13 and early menopausal age.14 Hip geometry also plays a role in patient risk for AFF. Patients with varus prefracture neck-shaft angles, shorter hip axis lengths, and narrower center-edge angles are at a higher risk of sustaining an AFF.15 The absolute risk of an AFF varies depending on patient risk factors, with patients on bisphosphonate therapy having an absolute risk ranging from 3.2 to 50 cases per 100,000 person-years.16
AFFs can be reliably treated surgically with intramedullary nailing. Egol et al reported, in a series of 33 patients with 41 complete bisphosphonate-associated AFFs treated with intramedullary nailing, that 98% of patients healed by 12 months but exhibited delays in healing. Patients had good recovery, with 66% of patients noting resolution of pain and 64% of patients reporting return to baseline function within 1 year.17 Prophylactic intramedullary nailing prevents progression of incomplete to complete AFF. Oh et al18 demonstrated that incomplete AFFs prophylactically treated with intramedullary nailing healed at a mean time of 14.3 weeks.
AFFs continue to be a serious issue for the orthopaedic community. Many of the risk factors associated with AFFs cannot be modified, but AFFs can be reliably treated and, if detected early, prevented from progressing fully with intramedullary nailing.
AUGMENTATION OF FIXATION: SELECTION OF AN OPTIMAL MATERIAL
A comprehensive strategy for the improved treatment of osteoporotic fractures must address both biological and mechanical issues and includes 4 specific approaches: (1) removal of inhibitors to bone healing; (2) introduction of bone healing stimulants; (3) application of bone augmentation or substitutes; and (4) modification of fracture fixation constructs. Known inhibitors of bone healing (such as smoking, alcohol, antiinflammatory medications, and steroids) should be removed, together with optimal control of medical issues (including malnutrition, diabetes, infection, and thyroid disease). Stimulation of bone healing can be achieved through surgical (bone marrow aspirates, platelet gels, and bone morphogenetic proteins),19–2119–2119–21 medical (vitamin D, calcium, bisphosphonates, and PTH), or physical means (ultrasound, direct electrical stimulation, pulsed electromagnetic fields, and extracorporeal shock). Improved fracture fixation in osteoporotic bone can be achieved by increasing cortical purchase (use of longer plates, intramedullary struts, or extending fixation into adjacent bones), improving implant–bone interfaces (hydroxyapatite surface coatings), increasing the rigidity of the construct (locked plates or additional plates in a 90/90 orientation), or by improving screw purchase through cement injection during or after screw placement.
Fracture fixation in osteoporotic bone can be augmented with either biologic or synthetic bone substitutes. Common biologic bone substitutes include structural or nonstructural autograft or allograft and demineralized bone matrix. Common synthetic bone substitutes include calcium phosphates,22 calcium sulfates,23 and polymethyl methacrylate bone cement.24 Properties for an ideal bone substitute include: (1) void filling capacity; (2) structural support; (3) osteoconductivity; (4) osteoinductivity; (5) osteogenicity; (6) low morbidity; (7) low cost; and (8) high availability. There is currently no bone substitute that fulfills all of these requirements and substitutes should be chosen based on the most critical need when treating a particular fracture. At times, particular clinical problems may warrant a void filler or structural support that will readily allow for bone growth or osteoconduction. Other clinical situations may not require structural support but rather the stimulation of a biologic healing response.
With an aging population, there will be an increased incidence of fractures associated with osteoporotic bone. Biological and mechanical translational research should use clinically relevant models to better understand the conditions relating to fracture care in the elderly population. Furthermore, there is a need for clinicians to better understand when and how to prescribe medical management to prevent bone fractures in patients with osteoporosis, and what adjuncts, such as biomaterials for surgical augmentation, are available.
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