Understanding The Potential Impact Of Diabetes On Bone Biology And Biomechanics
It is well established that poorly controlled diabetes mellitus leads to vasculopathy, immunopathy and neuropathy, all of which may contribute to osteopathy. However, in order to understand the nuances of bone healing in the diabetic population, one must first have a strong grasp of the fundamentals of bone biology and biomechanics (see “A Helpful Primer On Bone Structure” below). Bone is a dynamic medium with a multifactorial purpose including support of soft tissues, protection of soft tissues, locomotion and being a mineral reservoir. The growth, maintenance and healing of bone requires its formation throughout one’s life. In fact, the rate of bone turnover approaches 100 percent in the first year of life but declines to an approximate 10 percent turnover rate during adolescence. Bone has a tensile strength that is almost equal to that of cast iron yet is 10 times more flexible. Bone constantly changes in response to hormonal and mechanical signals. Seemingly dissimilar conditions such as embryonic development, bone growth, bone remodeling, fracture healing and arthrodesis all rely on the same basic premise that mesenchymal stem cells functioning in a vascular environment will become normal osteoblasts that secrete a specialized extracellular matrix. This matrix will mineralize and the osteoblasts trapped within the mineralized matrix will become osteocytes. This will be followed by osteoclasts, which herald the remodeling process to convert immature woven bone into mature lamellar bone, and to resorb and replace mature lamellar bone. Although there is only one real mechanism for bone formation, it may occur within a cartilage precursor (enchondral bone formation), an organic matrix membrane (intramembranous bone formation) or via the deposition of new bone on pre-existing bone (appositional bone formation). A Pertinent Overview Of Bone Healing There are over 6.2 million fractures per year in the United States. These fractures will generally heal either via secondary (enchondral) or primary (direct or intramembranous) bone healing. The route of bone formation is contingent upon the degree of interfragmentary stability. Perren’s theory of strain states there is a relationship between decreasing strain and increasing the potential for osteogenesis across a fracture or fusion site.1 According to Perren’s theory of strain, when there are two given fracture segments, the healing interface will have force generated motion potential that is contingent upon the stability of the original fixation construct. Mathematically, strain is equal to the change in the interface length divided by the original interface length for any given force. Therefore, with an unstable construct, the healing gap may undergo excessive motion with resultant increasing strain. Researchers have shown that strain of less than 2 percent will yield absolute stability and subsequent primary bone healing. One sees primary bone healing with compression screw fixation because of the great friction generated between the healing segments. Unfortunately, if the compression fails, there may be significant increased motion and subsequent strain. If strain exceeds 10 percent, there is a high likelihood of fibrous non-union. If strain resides between 2 to 10 percent, there will be micromotion with subsequent callus formation and secondary bone healing. Does Diabetes Delay Bone Healing? Now, how does diabetes affect bone healing scenarios? A study by Macey, et. al., tested the hypothesis that untreated diabetes mellitus would result in impaired fracture healing.2 This animal study used femora of normal rats and from untreated and insulin treated diabetic rats. Researchers created a closed femoral fracture in each rat population. When evaluating bone healing in the untreated diabetic rat population, they noted a 29 percent decrease in tensile strength and a 50 percent decrease in stiffness compared to the controls. Even more interesting was the fact that subsequent treatment with insulin of the previously untreated rats resulted in restoration of both tensile strength and stiffness of the bone callus that was not statistically different from the controls. A similar study by Funk, et. al., measured changes in structural and material properties of intact bone and bone with healed fractures in diabetic rats at three and four weeks.3 They concluded that the structural and material strength of femurs with healed fractures in diabetic rats are delayed by at least one week compared to the non-diabetic controls. However, a meta-analysis of closed foot and ankle fractures from the literature by Boddenberg led this author to the conclusion that diabetes itself does not pose a significant risk of delayed bone healing.4 In general, however, it is well accepted that type 1 diabetes is associated with a decrease in bone mass and delayed healing of fractures in human and animal models. In fact, a very recent paper by Kloting, et. al., showed an actual decrease of up to 80 percent in the expression of genes coding for a multitude of bone specific proteins in newly diagnosed and in well compensated diabetic rats.5 Case Study: When There Is Complete Midfoot Charcot Breakdown A 52-year-old type 1 diabetic male presented with complete midfoot Charcot breakdown and a full thickness ulceration to the plantar midfoot. Fortunately, nuclear and magnetic resonance imaging was negative for osteomyelitis. At the time of the initial debridement, the patient’s HbgA1C was 7.8. Due to the patient’s intrinsic bone healing compromise, we decided to proceed with reconstruction utilizing adjunctive external fixation and orthobiologics in the form of platelet gel concentrate (PGC), demineralized bone matrix (DBM) and internal direct current bone stimulation. Even with all the adjunctive measures, complete radiographic bone healing did not occur until 14 weeks postoperatively. Case Study: When A Patient Presents With Posttraumatic OA Of The Ankle In the second case, a 36-year-old type 1 diabetic female presented with long-term posttraumatic osteoarthritis of the ankle. The patient underwent an ankle joint arthrodesis. At that time, her HbgA1C was 7.2 and she had been a one-pack per day tobacco user for greater than 10 years. Due to both intrinsic and extrinsic bone healing compromise with this patient, we employed adjunctive measures including PGC, DBM and direct current bone stimulation. The patient achieved final consolidation at 10 weeks postoperatively. A Helpful Primer On Bone Structure Bone is classified as short (tarsals, carpals), flat (scapular, ilium) or long (tibia, fibula). The component tissues of bone include hematopoietic marrow, periosteum, cortical bone and cancellous bone. Cortical (compact) bone forms 80 percent of the mature skeleton. It is very dense with only 10 percent porosity. The compressive strength of bone is proportional to its density squared. Therefore, cortical bone may have a compressive strength 10 times greater than an equal volume of cancellous bone. Cancellous (trabecular) bone has approximately 20 times more surface area per unit volume than cortical bone. It also has about 50 to 90 percent porosity, which gives it a much higher rate of metabolic activity because of greater accessibility to adjacent cellular constituents. In long bones, there is a biomechanical interplay that takes place between the cortical and cancellous bone. This interplay may have greater consequences for the insensate diabetic patient. In long bones, the diaphyseal cortical regions will resist torsion and bending forces. Where the cortical bone thins out at the neck of the bone (the “cutback region”), it has the support of the underlying epiphyseal-metaphyseal cancellous bone. This allows for greater deformation under equal loads. This unique complex formed by articular cartilage, cancellous bone and cortical bone acts to absorb impact loads. Replacement of this complex by a joint prosthesis may eliminate shock absorption with resultant increased peak loads to the diaphyseal cortical bone. Cortical or cancellous bone may consist of woven (primary) or lamellar (secondary) bone. Woven bone consists of irregular and random oriented collagen fibrils. It is isotropic, meaning that it responds the same no matter the direction of applied forces. It is rarely present after the age of 4 with the exception of pathologic processes. Lamellar bone consists of densely packed, well-organized collagen fibrils. It is anisotropic as its mechanical properties will differ based on the direction of applied forces. Osteons form the bulk of the diaphyseal cortex. They are composed of irregular, anastomosing and longitudinal cylinders formed from concentric lamellae. This longitudinal orientation explains why long bones resist coaxial forces much better than perpendicular forces. Haversian canals form the central conduit of the osteon. These canals are connected to one another via canaliculi. Cement lines define and separate each individual osteonal complex. Canaliculi and collagen fibrils will not cross cement lines. For this reason, cracks will follow cement lines rather than cross osteons. In Conclusion When treating the diabetic patient for either trauma or for elective reconstruction, one must take into account the various factors that may impede normal bone healing. These factors may include poor long-term blood glucose control, poor nutritional status, poor vascularity and long-term osteodystrophy. In order to balance these deleterious factors, one should consider utilizing more aggressive fixation constructs, surgical strategies that yield little soft tissue compromise, tuning up nutritional factors and incorporating modern orthobiologic materials and techniques. Dr. Weinraub is a Fellow of the American College of Foot and Ankle Surgeons. He is a Clinical Assistant Professor of Medicine at the University of Virginia and a Clinical Assistant Professor of Orthopaedic and Podiatric Surgery at the Virginia College of Osteopathic Medicine. Dr. Weinraub can be contacted at firstname.lastname@example.org. Dr. Steinberg (pictured) is an Assistant Professor in the Department of Surgery at the Georgetown University School of Medicine in Washington, D.C. He is a Fellow of the American College of Foot and Ankle Surgeons.
References 1. Perren SM. Physical and biological aspects of fracture healing with special reference to internal fixation. Clin Orthopaedics and Related Research. 138: 175-195, 1979. 2. Macey LR, Kana SM, Jingushi S, Terek RM, Borretos J, Bolander ME. Defects of early fracture healing in experimental diabetes. J Bone Joint Surg Am, 71 (5), 722-733, 1989. 3. Funk JR, Hale JE, Carmines D, Gooch HL, Hurwitz SR. Biomechanical evaluation of early fracture healing in normal and diabetic rats. J Orthop Res. 18 (1), 126-132, 2000. 4. Boddenberg U. Healing time of foot and ankle fractures in patients with diabetes mellitus: literature review and report of own cases. Zentralbl Chir. 129 (6), 453-459, 2004. 5. Kloting N, Follak N, Kloting I. Is there an autoimmune process in bone? Gene expression studies in diabetic and nondiabetic BB rats as well as BB rat related and unrelated rat strains. Physiol Genomics, 24 (1), 59-64, 2005. Additional References 6. Boskey AL. Mineral matrix interactions in bone and cartilage. Clin Orthop, 281: 244-274, 1992. 7. Buckwalter JA, Glimcher MJ, Cooper RR, Recker R. Bone Biology. J Bone Joint Surg, 77A (8), 1276-1289, 1995.