Nonunion




Summary of Key Points





  • Pseudarthrosis of the spine is failure of bony fusion; symptoms may include pain, instability, or loss of correction/fixation.



  • The diagnosis of pseudarthrosis is challenging and requires a high index of suspicion.



  • Metabolic factors, patient factors, use and choice of instrumentation, fusion material, and surgical technique have all been shown to influence the rate of successful fusion.



  • Treatment involves a repeat attempt at fusion as well as the use of additional instrumentation, bone graft, osteobiologic bone substitutes, and osteoinductive recombinant bone morphogenetic proteins.



  • Cell therapies using stem cells and other progenitor cells have shown osteoinductive properties and offer promising potential for bone formation and regeneration.



Instrumented fusion remains the mainstay of treatment for spinal instability and deformity. Advances in instrumentation and techniques have allowed the reestablishment of normal or near-normal alignment through immobilization over multiple spinal segments. Solid bony union alone provides enduring spinal stability, and failure to achieve this goal can have consequences ranging from a benign radiographic finding to persistent pain or catastrophic construct failure. The nonunion rate varies with the type of operation performed, being higher when multiple-level fusions are attempted. A pseudarthrosis is defined as a documented failure of continuous bone formation over time that leads to a definitive absence of bone healing through a fracture or new bone formation at an intended arthrodesis site. From a practical standpoint, a nonunion in spine surgery has been defined as the absence of solid fusion 1 year after the operation with concomitant symptoms and signs. A large, population-based, prospective review of lumbar spine revisions showed that 23.6% of the indications were for pseudarthrosis. Overall, the true incidence of post–spine surgery nonunion is probably underestimated, because many cases are asymptomatic and require no treatment.


This chapter reviews the basic principles of bony fusion, clinically relevant factors influencing fusion, and specific principles designed to minimize the incidence of nonunion. As in every other surgical arena, an understanding of basic principles, coupled with common sense, best equips surgeons to deal with the variety of problems they encounter.




Biology of Bone Healing


Bone is a dynamic living tissue that undergoes constant remodeling. It is unique in its capacity to repair and regenerate after disruption. The unique qualities of bone are derived from its peculiar composite structure of organic and inorganic materials. The organic component, chiefly a strongly cross-linked (type I) collagen, gives bone plasticity that allows substantial deformation without fracture and tolerates stress in tension. The inorganic component, chiefly in the form of hydroxyapatite, precipitates around the collagen fibers in a process of nucleation and maturation of mineral crystals. The inorganic-mineral component of bone gives the tissue tremendous strength in compression and bending. The cellular components of bone include osteoblasts, osteocytes, and osteoclasts, connected through an intricate and well-organized system of canals.


Osteoblasts are derived from mesenchymal stem cells from the bone marrow and periosteum. Osteoblasts form bone in response to many stimuli and under different conditions such as growth, physiologic remodeling, fracture healing, and heterotopic ossification. Researchers have shown that new bone is formed in response to tumors and infections. An investigation has shown that osteoblasts have the ability to form bone during distraction osteogenesis, when substituting the void initially filled by autologous or allogeneic bone graft, demineralized bone matrix, or synthetic bone substitutes. The mature osteoblast produces proteins such as type I collagen, osteocalcin, and alkaline phosphatase, a key enzyme in bone mineralization. Osteoblasts become entrapped in their own osteoid matrix and develop long cytoplasmic processes to remain in contact with surrounding cells. They then begin expressing a whole new set of genes to continue bone turnover and mineral homeostasis. These cells are now considered osteocytes (mature bone cells). Osteoclasts are derived from hematopoietic stem cells. They exit the circulation close to the site to be remodeled and are responsible for bone resorption.


Achieving solid bony fusion is similar to fracture healing. It involves intramembranous and enchondral ossification. It progresses through an inflammatory, a reparative, and a remodeling phase. This sequence starts near the ends of the fusion mass, also called outer zone, followed by the same process in the center of the mass, or central zone. The surgery itself releases inflammatory factors and bone morphogenetic proteins that act as a catalyst for the inflammatory phase that spans the first 3 weeks. Bone formation starts with membranous ossification at the sites of decortication followed by enchondral bone formation on a cartilage scaffold. The fact that this process is delayed in the central zone explains why it is often the location for the nonunion. The fusion solidifies during the reparative phase through revascularization, resorption of necrotic tissue, and differentiation of osteoblastic and chondroplastic cells. Solid fusion is achieved during the remodeling phase that starts 6 weeks postoperatively. This entails remodeling of woven bone into mature lamellar bone as well as progressive resorption of graft material.


Clinically, bone healing in spine fusions has been demonstrated in multiple studies. Very high rates of fusion with new bone formation have been achieved in single (97.5%) and multilevel (86%) anterior cervical discectomy and fusion (ACDF) and plating with either autograft or allograft. Complete bone remodeling has been shown on computed tomography (CT) scan 6 to 12 months after the use of B-tricalcium phosphate to fill a partial ventral vertebrectomy defect done for cervical decompression surgery.


The process of bone healing after injury is an indistinct continuous sequence of inflammation, repair, and remodeling. The inflammatory response to injury includes vascular dilatation with exudate and edema, as well as inflammatory cell (polymorphonuclear lymphocytes, macrophages, and lymphocytes) infiltration. Various hormones, cytokines, growth factors, and matrix proteins (e.g., bone morphogenetic protein [BMP]) are involved throughout the healing process. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or chemotherapeutic agents given during the first week of healing may blunt the inflammatory response and impair bone healing. As the debris of the inflammatory phase are removed, fibroblasts begin laying down new matrix in the early phases of the repair. Initially, a fracture callus that is composed of fibrous tissue, cartilage, and woven bone may form to bridge the bony defect. This is then replaced by woven bone and, ultimately, by mature cortical or cancellous bone. This process may take 3 to 6 months or longer, depending on age and other factors. Although the general sequence of inflammation, repair, and remodeling that occurs in long bone fracture healing also occurs with bone graft repair, there are some distinct differences. Autograft bone used in spinal fusion is initially deprived of blood supply, although a robust nonspecific inflammatory response occurs as a result of preparation of the graft recipient bed. The collection of coagulated blood around the graft is somewhat analogous to the hematoma of an acute fracture, with the complex processes of inflammation ongoing within this milieu. Although some of the periosteum, endosteum, mesenchymal cells, and osteocytes within 0.2 to 0.3 mm of the borders survive transplant, most of the transplanted bone cells, separated from their blood supply, die. The cancellous portion of the bone graft may be revascularized within 2 weeks, and cortical bone is revascularized within 1 to 2 months. Cancellous bone is more rapidly remodeled and is initially strengthened during the remodeling phase, because osteoblasts are first laid down over the trabeculae.


Cortical bone is weakened during initial remodeling, and the process is slower than in cancellous bone. Bone graft is gradually replaced with new bone in a process called creeping substitution . Osteoclasts that act as cutting cones bore into the graft from the margins of host bone, followed by osteoblasts that lay down new bone. This process of healing and remodeling may leave as much as 50% to 90% of the original matrix, even after many years. The strength of cortical autograft is halved during the first 6 months after fusion but is gradually restored over 1 to 2 years. Autograft bone provides some living bone cells with the ability to make bone (i.e., osteogenic properties). It contains BMP and other substances capable of inducing cellular differentiation (i.e., it has osteoinductive properties), and it provides a scaffolding for bone growth (i.e., it has osteoconductive properties).




Harvesting and Handling of the Bone Graft


An effort to maximize the advantages of autograft bone as graft material begins with a plan to harvest sufficient quantity of bone for the planned application. Preoperative discussions with the patient about the potential need for multiple bone harvest sites helps avoid the problem of insufficient graft in most situations. Routinely preparing and draping both iliac crests allows ready access to alternative graft material when needed. On occasion, harvesting ventral iliac crest for a dorsal application may be performed before turning the patient into the prone position. In a situation with a high risk of nonunion or with failed prior fusion, a sufficient quantity of autogenous bone is desired. Occasionally, unconventional graft sources should be considered and planned for in advance. Reliance on a single source for graft material, with a less than anticipated volume yield of harvested bone, may increase morbidity at that harvest site, as a result of overzealous harvest and extension of the harvest beyond safe and reasonable boundaries.


Surgical exposure of the donor site should be performed to maximize the viability of the graft. Heating of bone with the electric cautery, although frequently unavoidable, has the potential of destroying those surface osteocytes most capable of surviving via diffusion of nutrients. A sharp periosteum elevator can be used to open the subperiosteal plane in a remarkably atraumatic fashion, with minimal blood loss. For tricortical bone grafts placed in compression, harvesting with an oscillating saw provides a graft that is better at resisting compressive loads than a graft harvested with an osteotome. The clinical significance of this is unknown. For bone used purely for onlay, one should bear in mind that 5 mm is the maximal thickness that can be nourished by diffusion of nutrients. If possible, the bone graft should be harvested within 30 minutes of planned use. The graft should be kept moist in a saline- or blood-soaked sponge before use. The graft should not be allowed to dry or come into contact with toxic chemicals (e.g., antibiotic solutions).




Preparation of Recipient Bed


Because few graft osteoblasts and osteocytes survive the transplant, it is imperative that preparation of the recipient bed be undertaken with utmost care and that the bed protects the viability of the tissues that will serve as the primary source of the cellular components required for bony fusion. This process begins with meticulous subperiosteal dissection of the donor site, with complete removal of all soft tissue capable of interposition between planned fusion sites. Soft tissue should be removed to minimize thermal injury, and the use of the bipolar cautery should be emphasized when possible. Areas of planned fusion should be decorticated, allowing contact of graft with cancellous bone, while avoiding weakening the structure of the recipient bed with overzealous destruction of the cortical bone. Drilling and burring should perhaps be performed with a self-irrigating drill or with aggressive irrigation from an assistant to avoid thermal injury to the recipient bed. Bone wax should not be used in the recipient bed.


Grafts should be well fitted into the recipient site. Meticulous crafting of the graft to the recipient site cannot be overemphasized, because direct bone-to-bone contact facilitates union. In some situations, cancellous bone can be packed into gaps when a perfect fit is simply not possible. The sequence of preparation of the recipient bed, decortication, and application of the bone graft must be considered relative to application of instrumentation, because access to the recipient bed may be compromised by the implant. This is particularly the case with pedicle screw fixation in which complete assembly of all of the components limits access to the transverse processes and lateral aspects of the articular surfaces. Thorough irrigation of the recipient site before placement of the graft avoids inadvertent loss of onlay graft material.




Selection of Graft Material and Instrumentation


The ideal graft material must have the capacity to form bone (i.e., osteogenic properties), induce undifferentiated mesenchymal cells to mature into osteoblasts (i.e., osteoinductive properties), serve as scaffolding for bone healing (i.e., osteoconductive properties), harbor no risk of infection, and be genetically identical to the patient. It should also be mechanically strong, durable, potentially viable, nonreactive to the host tissue, sterile, anatomic, and cost effective. Currently, the material that comes closest to these requirements is the patient’s own (autograft) bone. The most common choices for autograft in spine surgery include iliac crest, local bone, or rib. The disadvantages of an autograft include the potential for inadequate bone graft volume or quality, especially in pediatric patients and in the elderly. Additional risks include blood loss, infection, nerve injury, and, most commonly and bothersome at the iliac crest, chronic graft harvest site pain. The incidence of major complications with autograft harvesting can be as high as 10% or even 17.9% when using the same skin incision for iliac crest harvest and the primary spine procedure. Chronic persistent pain at the donor site ranges from 2.8% to 70% of patients, with most series reporting it to be about 20% to 30%.


Allograft bone has the advantage of being readily available in multiple structural forms and without donor site morbidity. Allograft has some osteoinductive and osteoconductive, but no osteogenic, properties. Vascular ingrowth and new bone formation are delayed with allografts. The mode of preparation of allograft may have an impact on its success as a graft material. Allograft bone may be treated with freezing, freeze drying, or ethylene oxide to reduce its immunogenicity; however, because it is genetically dissimilar to the patient, an inflammatory response similar to graft rejection noted in other tissue transplants may occur. Fresh-frozen allograft appears to have a superior fusion rate to freeze-dried graft, with ethylene oxide–sterilized grafts demonstrating uniformly poor results. Beyond the issue of efficacy, the potential risk of disease transmission is the main concern associated with the use of allograft bone.


Cervical Spine


The anterior approach is most commonly used for cervical spine surgery. Discectomy is followed by optional grafting with allograft or autograft strut, or to implant a cage with or without adjunctive plating. The reported outcomes of noninstrumented single-level ACDF procedures with the use of autologous ventral iliac crest bone graft (ICBG) include fusion rates between 83% and 100%. The use of allograft bone for single-level ACDF appears to yield results that are approximately equivalent to use of autograft bone. For multilevel ventral procedures, autograft classically appears to be superior. Equal fusion rates of 97.5% have been shown with the use of either autograft or allograft and ventral plating for multilevel ACDF. For bone struts used over multiple segments, pseudarthrosis rates with allograft are higher (41%) than with autograft (27%). When supplemented with dorsal fusion, the pseudarthrosis rate falls to 26%.


A separate study using notched fibular struts and a halo orthosis demonstrated delayed fusion, but seven of eight patients had good or excellent results. In fusions unsupplemented with dorsal instrumentation or a halo orthosis, autograft bone appears to be the favored graft material. For dorsal cervical fusions, autograft bone appears to be superior in some studies. Ventral plating to add stability to the ACDF construct, especially if multilevel, has clearly increased the union rate of the procedure. In one meta-analysis, the authors concluded that plating significantly increases the fusion rate of ACDF regardless of the number of levels. They also noted that corpectomies had higher fusion rates than multilevel ACDFs and that the use of plates improved the fusion rate of three-level but not two-level corpectomy surgery.


The use of a cylindrical titanium mesh cage packed with bone salvaged from the corpectomy may avoid the need for harvesting a separate graft. Fusion rates using this method of reconstruction have been reported to be greater than 90%. Use of rhBMP-2 in multilevel anterior cervical arthrodesis resulted in higher fusion rates without complications when the dose did not exceed 1.1 mg/level. Complications include increased seromas, dysphagia airway compromise, and were found to be dose-dependent. Due to the large number of serious complications when using BMP in the cervical spine (when considering all doses), the U.S. Food and Drug Administration (FDA) has recommended against its use in the cervical spine.


Lumbar Spine


It is well established that instrumentation in the lumbar spine increases fusion rates. In 1997, Fischgrund and coworkers published a prospective, randomized trial comparing decompression and dorsolateral fusion with and without instrumentation in patients with degenerative spondylolisthesis and spinal stenosis. The average follow-up was 2 years. The fusion rate was significantly better with instrumentation than without (82% versus 45%, respectively; P = .0015); however, no significant difference was found in clinical outcome. In 2004, Kornblum and associates analyzed the patients from the 1997 Fischgrund study (now with a follow-up of 5 to 14 years) and noted that the patients with a solid fusion did significantly better than patients with a nonunion. Other authors have also conducted prospective, randomized studies looking at the same issue. Whereas Zdeblick’s results also support rigid instrumentation, Thomsen and colleagues reported fusion in 68% of instrumented cases and in 85% of noninstrumented cases.


In the only randomized trial comparing circumferential fusion with dorsolateral fusion alone, a significantly higher fusion rate was found with circumferential fusion (92% versus 80%; P < .04). In a meta-analysis looking at different lumbar fusion procedures, Bono and coworkers concluded that the highest rate of fusion was obtained with a circumferential technique (91%; P = .06), followed by posterior interbody (89%; P = .05), anterior interbody (86%), and finally posterolateral (85%) techniques. The clinical relevance and cost of the circumferential procedure for fusion in the lumbar spine are still open to debate.


In a study of long-segment fusion to the sacrum (mean of 11.9 vertebrae) for adult spinal deformity, the pseudarthrosis rate was 24% (much higher than for short constructs). Half of these pseudarthroses occurred through the thoracolumbar junction and one fourth through the lumbosacral junction. Risk factors were kyphosis of 20 degrees or higher, positive sagittal balance of 5 cm, hip osteoarthritis, a thoracoabdominal approach, age older than 55 years, and incomplete lumbopelvic fixation (complete lumbopelvic fixation defined as L5-S1 interbody fusion and iliac screw fixation). Augmenting the number of fused levels into the upper thoracic spine did not improve the fusion rates.


In the lumbar spine, allograft bone plays a limited role with dorsolateral fusion. However, its use as a ventral interbody strut (particularly femoral shaft allograft packed with cancellous autograft) when used with dorsal segmental instrumentation has been substantiated. Posterior or transforaminal lumbar interbody fusion with rhBMP-2 has shown consistently high fusion rates (> 90%) with low complication rates (seroma or ectopic bone formation). In posterolateral fusion, the 4-year follow-up results showed higher fusion rates in the rhBMP-2 group (94%) than with the use of iliac crest autograft (69%). Combining rhBMP-2 with bone graft showed similarly high (> 95%) fusion rates. A meta-analysis concluded that BMP is a good alternative to autogenous bone graft, especially in cases when harvesting of autologous bone is contraindicated or undesirable, operation time is limited, and there are no contraindications for BMP use. The rate of nonunion at 24 months postoperative was almost half in the BMP groups. Whether this would prove to be more effective than iliac crest autograft is yet to be determined. The Yale Open Data Access (YODA) project provided an independent data review to evaluated the efficacy and safety of BMP. The study groups concluded that although fusion rates were similar, the use of BMP offered no significant clinical benefit to using autograft in spinal fusion. In fact, complications were incompletely reported in the original publications and were found to be greater when compared to autograft in posterolateral interbody fusions. Of note, the FDA does not approve the use of BMP in such cases.




Pediatric Spine Surgery


Operations for adolescent idiopathic scoliosis are currently being performed with fewer complications and with an all-posterior approach and pedicle screw instrumentation. The use of allograft versus autograft bone has been well studied for scoliosis. In uninstrumented cases, autograft performed superiorly. Instrumented dorsal fusions supplemented with allograft bone performed comparably in a pediatric population (although it took a long time to achieve fusion). Ventral allograft struts supplemented with autologous bone (packed into the hollowed marrow space of the allograft), in conjunction with dorsal fusion and segmental instrumentation, yielded better results than allograft fusion without ventral graft supplementation. When treating high-grade pediatric isthmic spondylolisthesis, uninstrumented in situ fusion showed 45% nonunion/0% neurologic compromise, posterior decompression and instrumented fusion showed 30% nonunion/0% neurologic compromise, and reduction with 360-degree fusion exhibited 0% nonunion/5% extensor hallucis longus partial weakness.




Bone Graft Substitutes


A bone substitute is a synthetic, inorganic or organic combination which can be inserted for the treatment of a bone defect instead of bone. Bone substitutes can be broadly categorized into bone grafts (autograft, allograft, xenograft), ceramics (hydroxyapatite, tricalcium phosphate, calcium sulphate), and growth factors (demineralized bone matrixes, platelet-rich plasma [PRP], bone morphogenetic protein [BMPs]).


Demineralized Bone Matrix


The aseptical processing of donor bone produces human demineralized bone matrix (DBM), essentially decalcified bone. What remains is a collagen matrix that attempts to replicate the tridimensional architecture of bone, facilitating and guiding host cell invasion, growth, and differentiation. It facilitates bone fusion through osteoinduction and, to a lesser degree, through osteoconductive properties. During the fabrication of DBM, the demineralization of allograft reduces its antigenicity and may uncover osteoinductive factors, including BMP. However, BMP-2 and BMP-7 exist in nanogram concentrations in DBM, which is 1 million times less than the concentration of BMP required to produce a lumbar fusion clinically. DBM may vary in its osteoinductive capabilities, based on the cadaveric bone from which it is derived, by vendor, and even among batches of the same brand. Several animal studies favor DBM when compared with autogenous bone in achieving spinal fusion. Clinically, the data are more limited. A prospective trial comparing allograft and DBM with autograft in ventral cervical fusion demonstrated only a higher rate of graft collapse and pseudarthrosis in the allograft group. In the lumbar spine, the use of DBM plus local bone achieved the same fusion rates as ICBG for a single-level posterolateral fusion.


Synthetic Bone Substitutes (Ceramics)


Numerous calcium-based synthetic products have emerged as bone graft substitutes or extenders in spine fusion. These products serve as scaffolds that support new bone ingrowth. During manufacturing, the porosity of these materials can be optimized for bony ingrowth. Calcium sulfate is not sufficient for use as an osteoconductive material, because it absorbs in only a few weeks, much before new bone has formed in a fusion. Hydroxyapatite takes several years to be reabsorbed, and its radiopacity makes the radiographic diagnosis of fusion difficult. Beta tricalcium phosphate absorbs in months, thus lasting an adequate period to conduct bone growth during fusion. For this reason, most ceramic products used in spine fusion these days are made of beta tricalcium phosphate or hydroxyapatite in combination with bovine collagen in varying ratios. Collagen affects the workability and reabsorption rate of the ceramic and may also serve as a carrier for osteoinductive agents, such as BMP.


Animal studies show excellent fusion rates (superior to the control group with autologous bone) when ceramics are used in combination with bone marrow aspirate (osteoinductive and osteogenic) and very poor results when ceramics are used alone. The authors concluded that the association of bone marrow aspirate is paramount to the success of the procedure.


In prospective case-controlled clinical series, the fusion rates for lumbar posterolateral fusion and transforaminal lumbar interbody fusion using ceramics in conjunction with bone marrow aspirate or local autograft yield similar good results as with ICBG (fusion rate from 92% to 100% for a single-level instrumented fusion). In the cervical spine, Momma has reported complete bone remodeling, after 6 to 12 months, on CT scan, after the use of beta tricalcium phosphate to fill a partial anterior vertebrectomy defect done for cervical decompression. The use of ceramics has shown lesser pain, operating time, blood loss, and complication in synthetic substitutes compared with iliac crest grafts. Ceramics are safe and available in a variety of forms but are limited by a much lower compression strength than cortical bone.


Bone Morphogenetic Protein


BMPs are a group of highly conserved secreted growth factors originally discovered because of their ability to induce the formation of bone and cartilage. Out of seven proteins originally discovered, six (BMP-2 through BMP-7) belong to the transforming growth factor-beta superfamily of proteins, whereas BMP-1 is a metalloprotease, involved in cartilage development. Since then more BMPs have been discovered and were found to be heavily involved in the skeletogenic process. BMP bone induction is a sequential cascade. The key steps in this process are chemotaxis, mitosis, and differentiation, as shown on early studies by Reddi. They are known to stimulate mesenchymal stem cells, osteoblasts and osteoclasts, leading to chemotaxis, proliferation, and differentiation. Low concentrations promote stem cells differentiation into chondrocytes and subsequent enchondral bone formation, whereas higher doses can induce intramembranous ossification Currently, only the use of recombinant human BMP2 and BMP7 has been approved both in Europe and the United States for selected clinical applications: BMP 2 with a collagen carrier (INFUSE, Medtronic Sofamor Danek, Minneapolis, MN) for anterior lumbar vertebral interbody fusion and BMP 7 (OP-1, Stryker, Kalamazoo, MI) for tibial nonunion. Multiple preclinical animal studies have shown that the use of BMP results in similar, if not superior, fusion rates with biomechanically stronger fusion masses when compared with autogenous bone graft.


Prospective, randomized clinical studies have shown that BMPs have at least comparable fusion rates and clinical outcomes when compared with ICBG in both interbody and posterolateral lumbar fusions.


One prospective nonrandomized study in the ventral cervical spine reports that fusion rates of allograft and recombinant human bone morphogenetic protein (rhBMP-2; 0.9 mg per level) were slightly better than those of ICBG. However, 50% of the patients receiving the BMP had significant neck swelling. Another study reported 27.5% clinically significant neck swelling after ACDF with BMP. The safe dose of BMP and the best method for delivery are yet to be determined in the cervical spine. In 2008, the FDA issued a warning concerning its use in cervical surgery.


Recently discovered bone morphogenetic protein-binding peptide (BBP) is a 19–amino acid peptide that has been shown to bind BMP and potentiate its effect of bone healing in animal studies. BBP may provide for improved fusion rates with a smaller dose of BMP required, potentially reducing cost, as well as potential side effects of BMP such as inflammation and ectopic bone formation.


Osteoinductive growth factors are available as extracted and purified, recombinant human BMP (rhBMP), and use of DNA in gene therapy rather than use of the protein itself. Cell-based and gene therapy represents an attractive alternative and a tentative approach to achieve bone substitution . Such an approach entails using cells as bioactive vehicles delivering osteoinductive genes locally to achieve bone regeneration. Mesenchymal, or stromal, multipotent stem cells (MSCs) have been employed with appropriate osteoinductive scaffolds. Such cells derived from bone marrow exhibit a high potential for osteogenic differentiation, both in vitro and in vivo upon inoculation into damaged bone.




Influence of Electromagnetic Stimulation on Bone Healing


Direct current stimulation was first proposed in 1972 as a modality for improving fusion. The application of pulsed electromagnetic fields for nonunion in long bone fractures appears to have no hazardous side effects. Areas of tension are associated with a net positive charge, and compressive stresses are associated with a net negative charge (10 to 100 mV) and osteogenesis. Electromagnetic stimulation is believed to promote osteogenesis as a result of more rapid angiogenesis and decreased osteoclastic activity. The effect of improved osteogenesis may be mediated by growth factors. More recent evidence also suggests the activation of a second messenger system involved in bone remodeling. Three broad types of electromagnetic fields are used: implantable direct current, pulsed electromagnetic fields, and capacitively coupled electrical energy. Pulsed electromagnetic fields and capacitive-coupled electrical energy are examples of external electromagnetic fields. These are delivered via external electrodes attached to a corset. Implantable direct current requires surgical placement of the electrodes and has been shown to be the most effective. Direct current may be more effective than external electrodes secondary to its increased precision in the distribution of current. The cost of these devices is not insignificant. Although some investigators have noted no significant benefit of electrical stimulation for canine spinal fusions, one randomized blinded study in 195 patients demonstrated a significant difference in fusion rates between stimulated (92%) and unstimulated (65%) groups. In a study of 59 patients who underwent reoperation for failed lumbar fusions, there was an 81% fusion rate in stimulated patients versus a 54% fusion rate in unstimulated patients. Another contemporary series found a 96% fusion rate with implanted stimulators versus 85% with no stimulation. Clinical trials have been faulted for having a high degree of variation in electrical stimulation protocols, surgical intervention, and disease-treated patient populations. With the current literature, the use of direct current stimulation is supported as option in patients younger than 60 years of age. Strong, consistent, and clear evidence supporting the effects of electrical stimulation on long-term fusion rates is yet to be published.




Factors Affecting Bone Healing


The timing of bone healing varies depending on the region of the spine under consideration and the type of graft used. If biosynthetic materials are used, the resorbing cells involved in creeping substitution are giant cells rather than osteoclasts. Maintaining stability of the construct under suitable conditions allows healing to proceed. This is affected by various biologic and local factors that determine the health of the host bone and the inflammatory response.


Smoking


Studies have shown a threefold to fourfold increase in the occurrence of nonunion of spinal fusions in smokers over that in nonsmokers. Smoking interferes with osteoblastic function, leads to increased bone resorption at fracture sites, and interferes with normal bone metabolism. Smoking has also been associated with bone mineral loss in several studies. Nicotine, the chemical most responsible for physical dependency, also has deleterious effects on spine fusion rates and revascularization of bone graft, as shown in animal studies. One particular article demonstrated decreased fusion rates in rabbits receiving systemic nicotine and also suggested that the bone formed during nicotine use has inferior biomechanical properties. These studies strongly indicate that the use of nicotine patches or gums, in an effort to curb patient smoking perioperatively and during bone healing, may be ill advised. It is likely, however, that other components of cigarette smoke also have a deleterious effect on fusion, although this is less documented. Even the pulmonary compromise associated with smoking, as reflected in a decreased arterial partial oxygen pressure, has been suggested as a potential explanation for increased nonunion rates in smokers.


A case-control study of two-level lumbar laminectomy and fusion demonstrated a nonunion rate of 40% in smokers and 8% in nonsmokers. Similarly, in a study of anterior cervical fusion with allograft, the authors found a higher rate of fusion in nonsmokers than in smokers (81% versus 62%).


Although there is consensus that smoking inhibits bony fusion, there is considerable disagreement over the management of the smoker facing spine fusion. An intermediate approach should be used in an attempt to avoid an excessively fatalistic or autocratic view. The decision should always be based on the urgency and severity of the disease.


Radiation Therapy


Radiation impairs bone healing, inhibiting cell proliferation and producing a vasculitic reaction that limits vessel ingrowth. Radiation delivered before long bone fracture in animals results in delayed fracture healing. In a canine model, bone healing was superior when radiation was given either preoperatively or only after 21 days postoperatively. The worst bone healing results were seen when radiation was administered on the third postoperative day. The total radiation dose, delivered preoperatively or postoperatively, has been shown to correlate well with reduction in strength of healing bone in an animal model. A total radiation dose exceeding 4000 cGy has been proposed to hinder fusion in patients undergoing perioperative radiation for neoplasm.


Delaying radiation at least until after the first or second postoperative week appears well founded, as the untoward effects of radiation seem maximal during that interval (both on bone and soft tissue healing). The total dose of radiation should be customized to the indication, with consideration given to delivering a minimal effective dose. With the advent of stereotactic radiosurgery, more targeted doses of radiation can be delivered to tumors, with fewer deleterious effects to the surrounding tissues.


Nutrition


Malnutrition has a negative impact on fracture healing, blunts the immune response, and impairs wound healing. A nutritional support team can provide vital preoperative evaluation and education to optimize nutritional status preoperatively and postoperatively.


Rheumatoid Arthritis and Ankylosing Spondylitis


Rheumatoid arthritis affects 1% of the world’s population, with 60% to 70% of patients with the disease eventually suffering cervical spine symptoms. In patients requiring fusion, bone healing is often compromised by osteoporosis, and the direct immunosuppressive effects of the disease itself (coupled with the effects of steroid medications) can lead to osteomyelitis. Despite these factors, the use of contemporary instrumentation and arthrodesis techniques in patients with rheumatoid arthritis has resulted in spine surgery fusion rates of 90% or higher in multiple centers.


Nonunion does not seem to be a problem when operating on patients with ankylosing spondylitis. Bony union is usually the rule in patients with ankylosing spondylitis after surgery, and fusion rates exceeding 95% have been reported after the correction of spinal deformity.


Age


Generally, skeletally immature patients have the greatest healing potential and heal more quickly. It is hypothesized that children may have a greater number of undifferentiated mesenchymal cells, and that these cells may be capable of more rapid differentiation when necessary. In one study looking at long thoracolumbar constructs, age greater than 55 years was a risk factor for nonunion.


Nonsteroidal Anti-Inflammatory Drugs


There is clearly a negative association between spine fusion and use of nonsteroidal anti-inflammatory drugs (NSAIDs) in animal models. In the clinical setting, a meta-analysis looking at the use of NSAIDs and spine fusion rates found that the odds ratio of a nonunion was higher (3.0) in the anti-inflammatory use group only in lower-quality studies. The better-quality articles failed to show an association of NSAID use and nonunion. The authors conclude that higher-quality, prospective, controlled, randomized studies are needed to further elucidate this issue.




Diagnosis of Nonunion


The diagnosis of pseudarthrosis remains a challenging endeavor that in most instances requires a high index of suspicion. It has classically been based on the triad of persistent pain, radiographic evidence of instability, and loss of correction/fixation. Diagnosis by imaging is often difficult and may require multiple modalities. Results may be misrepresented, not only by the limitations of technique but by the prejudgment of the surgeon. A study comparing radiographic analysis of ACDF fusion at 6 months between the surgeon and an independent panel had a correlation of k = 0.308. The correlation was even poorer when the surgeon noticed favorable clinical results.


Flexion-Extension Radiographic Studies


There is controversy concerning the angular amount of motion accepted in a segment to correlate with a solid fusion. Most studies range from 0 to 5 degrees. One study developed a finite element model to simulate different types of lumbar fusion and concluded that overall, a solid fusion should have less than 4.1 degrees of motion between the segments of interest. This study, however, did not account for instrumentation. Simmons considers a nonunion when more than 2 degrees of difference is seen between the flexion and extension films. One should keep in mind that with the advent of rigid instrumentation, pseudarthrosis may be present even without motion of the segment on dynamic radiographs.


Computed Tomography


CT has become widely used for the diagnosis of nonunion after spine surgery. A prospective study of intraoperative evaluation (the gold standard) versus imaging evaluation of pseudarthrosis after anterior cervical fusion found that CT most closely agrees with intraoperative findings ( P < .05) compared with plain radiography and MRI. Another study comparing thin-slice CT and dynamic radiography for the diagnosis of nonunion found poor correlation between the two methods.


Magnetic Resonance Imaging


Due to its cost and metal artifact on imaging after instrumentation, MRI is not a good choice for assessing bone union after fusion.


Nuclear Medicine and Ultrasound


Bone scans have a low sensitivity and positive predictive value for identifying pseudarthrosis and are considered to be ineffective for the reliable diagnosis of nonunion after spinal fusion. Single-photon emission CT scans have a sensitivity and a specificity of about 50% and therefore cannot be used reliably for the diagnosis of pseudarthrosis. The use of ultrasound in detecting pseudarthroses has been explored in the past to evaluate pseudarthrosis after posterolateral spinal fusion. It was found to be 100% sensitive but only 60% specific. In conclusion, ultrasound and nuclear medicine modalities do not seem to play a major role in modern intervertebral pseudarthrosis investigation.


No single modality has shown perfect accuracy. A high index of suspicion and possibly a combination of tests may be necessary to consolidate the indication for revision surgery. In the end, surgical exploration, aggressive curettage, and intraoperative stress testing remain the most accurate means of diagnosing a nonunion ( Fig. 209-1 ).


Feb 12, 2019 | Posted by in NEUROSURGERY | Comments Off on Nonunion

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