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474
J.A. Weiner and W.K . Hsu
In spine surgery, osteogenic potential is classi­cally provided by decortication of the fusion bed and supplementation with autogenous graft mate­rial – the most widely used being iliac crest and local bone. The process of decortication exposes underlying cancellous bone and releases growth factors critical to the recruitment and differentia­tion of osteogenic progenitor cells. These grafts offer a source of viable osteoblasts and stem cells that begin the process of bone healing.

Bone Healing Process

While the mechanism of bone injury in fractures is remarkably different than spine fusion, it has been established that the process of bone healing is extraordinarily similar [33]. Bone healing has been classified into three distinct yet overlapping phases: early inflammatory, repair or prolifera­tive, and late remodeling [34]. The inflammatory phase begins immediately following a fracture with hematoma formation in the injured bone and generally lasts 1–3 days [35]. This hematoma results from bleeding vessels within the damaged periosteum and cancellous bone. The inflamma-
tory phase is mediated via a growth factor cas­cade, which includes TGF-β, BMPs, FGF, PDGF, IGF-1, osteoprotegerin, and VEGF. These factors are released from platelets, macrophages, and fibroblasts within the local hematoma during the first week and serve to begin the process of osteo­induction and osteogenesis (Table 35.1) [36]. During this critical period, cells involved in the healing process receive their nutrient and oxygen supply from the exposed cancellous bone and muscle. Toward the end of the inflammatory phase, deposition of matrix results in the forma­tion of an immature callus.
During the repair or proliferative phase, fibro­plasia occurs, leading to the replacement of the crude callus by immature woven bone over the course of several weeks. More specifically, the necrotic bone at the margins of the fracture site or decorticated bone is resorbed by recruited osteo­clasts [36]. A periosteal response also occurs with angiogenesis and formation of soft callus [37]. Within the fracture site or fusion bed, recruited mesenchymal stem cells differentiate into chon­drocytes within the hypoxic fracture regions. Within these areas, soft callus will steadily take on the appearance of cartilage and help to stabilize
Table 35.1 Local factors involved in bone healing
Type Source Role
Bone morphogenetic protein Mesenchymal stem cells
Fibroblast growth factor Vascular endothelium
Insulin-like growth factor Liver
Platelet-derived growth factor Platelets
Vascular endothelium growth factor Vascular endothelium
Osteoprotegerin (TNF-α[alpha] superfamily)
RANK ligand Vascular endothelium
Extracellular matrix Vascular endothelium
Basement membrane
Paracrine signaling
Smooth muscle cells Activated macrophages Vascular endothelium
Smooth muscle
Vascular endothelium Smooth muscle cells Osteocytes
Smooth muscle Osteocytes
Recruitment and differentiation of mesenchymal cells Mineralization of extracellular matrix
Mitogen Supports vascularization and bone development
Activation of osteocytes Anabolic for bone tissue
Mitogen for mesenchymal cells Supports angiogenesis
Angiogenesis
Blocks RANK ligand interaction with RANK receptor → promotes bone formation
Osteoclastic differentiation and activation
35 Basic Science of Bone Fusion
475
the fracture site [36]. Chondrocyte growth and dif­ferentiation are stimulated by growth factors released during the inflammatory phase, including TGF-β, BMPs, FGF, PDGF, and IGF-1. Irregular woven bone gradually replaces this cartilage via the process of endochondral ossification [34].
During the last phase of bone repair, irregular woven bone within the callus is transformed into lamellar bone. This process occurs when osteo­clasts resorb the newly woven bone and osteo­blasts replace this matrix with the lamellar bone. Importantly, this remodeling phase leads to resto­ration of mechanical strength and stability. A criti­cal aspect of appropriate remodeling is the biomechanical force applied to the healing site. Lamellae are aligned parallel to the axis of the greatest force, and adequate mechanical loading is required to augment osteogenesis and generate bone with the proper anatomic configuration [38].
Through the concepts of fracture fixation, it has been well established that proper biomechani­cal forces are necessary for bone healing [39]. When sufficient osteogenic cells and biologic fac­tors are present, the course of bone healing is influenced mainly by the amount of strain and mechanical load across a bone defect. The forces across a fracture or bone defect, along with the fixation, determine the interfragmentary move­ment. A stiff fixation minimizes interfragmentary movements and results in limited stimulation of callus formation, while a flexible fixation can enhance the callus formation. However, an unsta­ble fixation can cause the interfragmentary strain to exceed the rupture strain of bone leading to nonunion [
40]. Ideally, the proliferating osteo-
blasts respond to the mechanical strain, and the final product of bone healing has the same biome­chanical properties of the original bone it replaced.

Clinical Application of the Basic Science of Bone Healing

While the basic science of bone healing can be quite complex, it is critical that spine surgeons have a thorough understanding of how bone heal­ing principles apply to their fusion patients. As demonstrated above, bone repair in the context of
spine fusion is a multifaceted process that requires five major components: a sufficient pop­ulation of osteogenic cells, an osteoconductive matrix within the region where new bone tissue is needed, osteoinductive signals within the fusion bed, a local blood supply, and desirable biome­chanical forces.
Critical components of bone healing
1 Sufficient population of osteogenic cells
2 Osteoconductive matrix
3 Osteoinductive signals
4 Local blood supply
5 Desirable biomechanical forces
A deficiency in any one of those elements can have a profoundly detrimental effect on spine fusion. To date, numerous systemic factors have been identified both in the laboratory and clini­cally that directly or indirectly impact bone regeneration [41–45] (Table 35.2). A working knowledge of the bony repair mechanisms can allow the surgeon to maximize chances for suc­cessful fusion.
Table 35.2 Systemic factors/conditions affecting bone healing
Positive factors Negative factors
Adequate nutrition
Vitamin D Vitamin D deficiency
Parathyroid hormone
Calcitonin Sepsis
Insulin Corticosteroids
Insulin-like growth factor
Testosterone Nonsteroidal anti-inflammatory
Estrogen Adriamycin
Thyroxine Methotrexate
Vitamin A Rheumatoid arthritis
Growth hormone Syndrome of inappropriate
Anabolic steroids Castration
Vitamin C
Malnourishment (iron deficiency anemia, negative nitrogen balance)
Tobacco
Calcium deficiency/osteoporosis
drugs
antidiuretic hormone
476
J.A. Weiner and W.K . Hsu
Nutritional Deficiency
Nutritional status has been well established as a predictor of surgical outcomes in the general sur­gical literature for decades [ deficiencies lead to increased complication rates, length of hospitalization, and mortality. The impact of poor nutrition on orthopedic proce­dures and bone healing has more recently become a focus of research [49]. Jensen et al. established that nearly 35% of patients undergo­ing elective orthopedic procedures are clinically malnourished, defined by serum albumin <3.5 g/ dL [50]. This rate of malnutrition should be highly concerning for the spine surgeon because of associations with delayed wound healing, diminished immunocompetence, surgical site infection, prolonged hospitalizations, and poor bone healing [51, 52].
Identification of a nutritional deficit in preop­erative spine fusion patients, especially those undergoing an elective procedure, is critical for maximizing the chances of a successful outcome. While numerous methods such as anthropomor­phic measurements, skin antigen testing, and nitrogen balance studies exist for nutritional eval­uation, the clinical tests most commonly used to assess the nutritional status of surgical patients are the serum albumin level and the total lympho­cyte count. These tests are practical, cost­effective, widely available, and highly reproducible in the surgical patient population [53]. Serum albumin is a representative marker of visceral protein mass; decreased levels are due to both decreased synthesis and increased catabo­lism. The conditions leading to decreased albu­min levels are often found in patients with poor functional and nutritional statuses. Furthermore, decreased albumin levels are associated with poor wound healing, postoperative infectious, complications, mortality, and immune suppres-
54]. Serum albumin levels less than 3.5 g/
sion [ dL are widely accepted to represent a state of malnutrition [
55]. Furthermore, the severity of
the deficiency is correlated with the incidence of complications. In 2016, Kamath et al. reported that joint arthroplasty patients with preoperative albumin <3.0 g/dL had a 15.4% rate of unplanned
46–48]. Nutritional
ICU admission compared to 3.8% for patients with an albumin 3.0–3.5 g/dL [56].
Similarly, poor nutritional status causes a decrease in total lymphocyte count – a marker of immune competence [57]. This decrease in immune competence is believed to underlie the increased risk for surgical site infection in this patient population. Current research indicates that protein-calorie malnutrition causes a cata­bolic state which limits the body’s ability to undertake anabolic processes, including forming new lymphocytes. A total lymphocyte count less than 1500–2000 cells/mm3 is considered by most authors to represent a clinical state of malnutri­tion [57].
When this diagnosis is made, correction of all nutritional deficiencies should be part of the pre­operative optimization process. Correction for malnutrition is primarily accomplished conserva­tively through dietary counseling, as well as meal fortification with protein and energy-rich foods [58]. However, when patients fail conservative management, oral nutritional supplements, such as Ensure, can be effective in improving nutri­tional status [55, 59]. Risk factors for correction failure include complex medical comorbidities, such as gastrointestinal disease, psychiatric con­ditions, or cancer. These patients should be medi­cally optimized with the aid of a comprehensive care team before undergoing surgery.
Vitamin D Deficiency
Vitamin D plays a critical role in maintaining metabolic bone homeostasis. Vitamin D defi­ciency, a condition present in 33% of healthy young adults and more than 50% of general med­icine inpatients [ effects on bone health. As vitamin D is depleted, absorption of calcium decreases and parathyroid hormone is upregulated. This hormonal dysregu­lation can cause an increase in osteoclast bone resorption and predisposes patients to osteoporo­sis, osteomalacia, and fractures [
The previously unknown prevalence of vita­min D deficiency has led to a recent awareness of this problem. In 2010, Bogunovic et al. reported
60], can have serious deleterious
61].
35 Basic Science of Bone Fusion
477
that 43% of a 723-patient cohort scheduled to undergo an orthopedic procedure were deficient in vitamin D [
62]. In addition to predisposing to
fractures, an overabundance of osteoclastic resorption may impede bone formation needed for spinal arthrodesis [
63]. Considering the finan-
cial and clinical burden of pseudarthrosis, knowl­edge of the prevalence, evaluation, and treatment for hypovitaminosis D is critical for all spine surgeons.
Despite the established importance of vitamin D in musculoskeletal health, most spine surgeons fail to recognize the value in testing preoperative levels. A 2009 study by Dipaola et al. revealed that only 12% of spine surgeons order metabolic tests, including serum levels of vitamin D, before fusion surgery and only 20% as part of a pseudar­throsis workup [64]. This is despite the fact that nearly 70% of patients with spine pathology are insufficient or deficient in vitamin D, those with severe pain being the most deficient [65, 66]. Numerous studies, both in animal models and humans, have established vitamin D as a critical mediator of fracture healing [67–70]. More recently, Metzger et al. demonstrated that vita­min D modulates the consolidation of bone after grafting for posterolateral spinal fusion in a rat model. Specifically, their results indicate that increased levels of dietary vitamin D correlate directly with the density of the fusion mass [71].
Given the impact of vitamin D on spine fusion and the prevalence of deficiency, it is the authors’ recommendation that preoperative testing of serum vitamin D levels should be routine. Thresholds for vitamin D levels which are well established in the literature (Table 35.3) [61, 72] should be used to institute treatment. Patients deficient in vitamin D are typically prescribed 50,000 IU of oral vitamin D2 (ergo­calciferol) per week for 8 weeks followed by maintenance therapy of 1500–2000 IU/day
61]. Furthermore, the relatively brief treatment
[ duration often allows completion before sur­gery and provides for high patient compliance [73]. Given the high prevalence of vitamin D deficiency and low risk of treatment, it is also acceptable to consider supplementation with 2000 IU/day of oral vitamin D3.
Table 35.3 Serum 25-hydroxyvitamin D [25(OH)D] concentrations and health
nmol/L ng/mL Health status
<30 <12 Vitamin D deficiency, leading to
30 to <50
≥50 ≥20 Generally considered adequate
>125 >50 Emerging evidence links
12 to <20
rickets in infants and children and osteomalacia in adults
Vitamin D insufficiency
for bone and overall health in healthy individuals
potential adverse effects to such high levels, particularly >150 nmol/L (>60 ng/mL)

Cigarette Smoking

The impact of tobacco smoke on human health remains a critical problem facing the orthopedic surgeon worldwide. Cigarette smoke has a well­established role in the pathogenesis of numerous smoking-related disorders including chronic obstructive pulmonary disease (COPD), cancer, and atherosclerosis [74, 75]. More recently rec­ognized, smoking also exacerbates musculoskel­etal disease and presents serious challenges in the treatment of orthopedic conditions [76]. In addi­tion to promoting osteoporosis, degenerative disk disease, and surgical site infections, smoking impedes osseointegration and bony union – del­eterious effects associated with higher rates of revision procedures [ smoking has been shown to have a negative impact on outcomes with a lumbar pseudarthro­sis rate nearly double that of nonsmokers (26.5% vs. 14.2%) [
80].
Defining a single mechanism by which ciga­rette smoke impedes bone healing is challenging, as cigarette smoke contains upward of 4000 dis­tinct chemical components. However, several mechanisms are postulated to be involved. Carbon monoxide present in the smoke displaces oxygen from hemoglobin, significantly diminish­ing the capacity for blood to carry vital oxygen to proliferating osteoblasts at the site of bone heal­ing or growth [81]. Nicotine, a potent anti­inflammatory and immunosuppressive substance, has been shown to have deleterious effects on
77–79]. In spine surgery,
478
J.A. Weiner and W.K . Hsu
fibroblasts, red blood cells, and macrophages [82–84], in addition to diminishing blood flow to tissues by promoting vasoconstriction [
84, 85].
Numerous other studies have proposed that reac­tive oxygen species and other pro-inflammatory constituents are responsible for the dysregulation of bone homeostasis, reduction in bone mineral density, and inhibition of fracture healing [
86–88].
More recent research has identified dioxin, a potent carcinogenic by-product of combustion, as playing a major role in the inhibition of osteo­genesis [43]. In vitro and in vivo work has shown that dioxin has toxic effects on bone, adversely affecting bone growth and remodeling, matrix composition, mechanical strength, and osteoblast differentiation [89]. These effects occur indepen­dent of nicotine and have a dramatically larger impact. Although the exact mechanism of osteo­blastic inhibition from smoking remains some­what unclear, many surgeons currently associate nicotine with the negative impact of smoking on bone healing. The association of dioxin and the AhR pathway with bone healing inhibition from cigarettes offers a promising new approach to the mitigation of these effects.
With the negative effects of smoking so well established, spine surgeons must consider their options when treating patients who smoke. All patients have both modifiable and non-modifi­able risk factors that can impact patient out­comes after spine procedures. Therefore, it is critical that modifiable risk factors, like smok­ing, are minimized before taking a patient to surgery. Many have advocated for smoking ces­sation programs before elective procedures [80,
90]. These programs have demonstrated that an
active smoking intervention program started 6–8 weeks before surgery can halve the fre­quency of postoperative complications, with the greatest effect on wound-related and cardiovas­cular complications [
90]. Furthermore, given
the emerging evidence that nicotine may not be the primary culprit behind inhibition of bone healing [43], surgeons should consider nicotine replacement therapy as method for increasing patient compliance with cessation programs. Given the deleterious consequences of smoking
and the large impact of cessation, preoperative counseling and enrollment in cessation pro­grams are an essential aspect of preoperative patient care.

Bisphosphonates and Teriparatide

With an overall low bone mass prevalence of
43.9%, there are an estimated 43.4 million adults in the United States at increased risk for fracture. In 2008, 15.8% of women over the age of 55 were prescribed bisphosphonates to increase their bone mineral density and reduce their risk for fracture [91]. More recently, many patients have been prescribed anabolic agents such as teriparatide. However, due to the cost of anabolic agents, most physicians still recom­mend anti- catabolic drugs as the first-line treat­ment for osteoporosis. Bisphosphonates inhibit osteoclastic bone resorption, preventing bone loss and improving bone strength [92, 93]. However, the effect of bisphosphonates on bone healing remains controversial. As previously discussed, osteoclasts are essential for remodel­ing during the transformation from immature callus into mature bone. The impact on remod­eling causes adverse effects such as atypical femur fractures and osteonecrosis [94]. While the association with abnormal remodeling is well defined, the overall effect of bisphospho­nates on bone healing is less clear. A recent meta-analysis of eight randomized control trials revealed that bisphosphonates do not cause a clinically detectable delay to bone healing regardless of the timing of bisphosphonate delivery [95].
Teriparatide, a recombinant PTH analog, has been utilized since 2002 to increase bone mineral density in postmenopausal women suffering from osteoporosis. Unlike bisphosphonates, teripara­tide is an anabolic agent that has the ability to stimulate new bone formation. There has been abundant evidence from animal studies that indi­cate teriparatide can improve fracture healing [96, 97]. Significant improvements in callus vol­ume, callus mineralization, bone mineral content, strength, and rate of successful union at the frac-
35 Basic Science of Bone Fusion
479
ture site have been demonstrated [98]. However, studies in humans have been relatively limited, and further research is needed to delineate the impact of anabolic agents on bone healing in humans. Currently, teriparatide is being used “off label” for the management of fractures and non­unions, as well as perioperative optimization of surgical patients.

Electrical Stimulation

The role for electrical stimulation in bone healing has been somewhat controversial. Basic science research suggests that pulsed electromagnetic field (PEMF) therapy likely enhances bone heal­ing through stimulation of the calcium­calmodulin pathway secondary to the upregulation of bone morphogenetic proteins, transforming growth factor-β, and other cyto­kines [99, 100]. A recent meta-analysis of 15 tri­als, performed in 2016, indicated that that electrical stimulation reduced the relative risk for radiographic nonunion or persistent nonunion by 35% and the absolute risk by 15% [101]. Four trials found that stimulation produced a signifi­cant improvement in patient-reported pain scores [101]. However, functional outcome data are lim­ited and further randomized controlled trials are needed.

Clinical Case

History

A 59-year-old male with grade I degenerative spondylolisthesis and severe spinal stenosis at L4–L5 causing neurogenic claudication, low back pain, and buttock pain. The patient previ­ously failed conservative management for 2 years at which point he underwent open decompression and posterolateral spinal fusion at L4–L5. He was subsequently pain-free for 1 year and then developed recurrent back pain without neuro­logic symptoms. Standing exacerbates his symp­toms; sitting or leaning forward temporarily relieves pain. The patient has a past medical his-
tory significant for hypertension. Of note, he is a current smoker with a 40 pack-year history. A complete workup was performed, including post­operative lumbar CT.

Examination

Physical examination demonstrated a positive straight-leg raising on the right at 30 degrees. The remainder of the examination was normal.

Pretreatment Images

MRI of the lumbar spine demonstrated recurrent degenerative spondylolisthesis (Fig. 35.2). CT scan of the lumbar spine demonstrated screw loosening at L4–L5 and lumbar pseudarthrosis (Fig. 35.3).

Diagnosis

L4–L5 pseudarthrosis.

Treatment

The patient was informed of the risk factors for pseudarthrosis, including smoking, malnutrition, and vitamin D deficiency. The patient elected to participate in a 6-week smoking cessation pro­gram and utilized nicotine patches during the perioperative period. The patient was subse­quently revised with a lateral interbody fusion with Polyether ether ketone (PEEK) cage at the L4–L5 level (Fig. and 5 cc of Mastergraft were utilized to promote successful arthrodesis.
35.4). A small kit of INFUSE

Outcome

The patient had radiographic evidence of fusion on CT at 6 months. No clinical signs or symp­toms of pseudarthrosis. Patient denied continued low back pain.
480
Fig. 35.2 Pre-revision (a) sagittal and (b) axial MRI of the lumbar spine demonstrating recurrence of the L4–L5 degenerative spondylolisthesis
J.A. Weiner and W.K . Hsu
Fig. 35.3 Pre-revision (a, b) sagittal and (c) coronal CT scan demonstrating radiolucency surrounding the L4 and L5 pedicle screws and an L4–L5 pseudarthrosis
35 Basic Science of Bone Fusion
Fig. 35.4 Intraoperative (a) AP and (b) lateral fluoroscopy after placement of Polyether ether ketone (PEEK) lateral interbody cage
481

Conclusion

While the basic science of bone healing is com­plex, it is important that spine surgeons have a thorough understanding of how bone healing principles apply to their fusion patients. Bone healing requires five major components: a suffi­cient population of osteogenic cells, an osteo­conductive matrix, osteoinductive signals, a local blood supply, and desirable biomechanical forces. Deficiency of any one component can lead to pseudarthrosis. With that knowledge, it is imperative that spine surgeons optimize their patients preoperatively by evaluating for and correcting nutritional and vitamin D deficiency, osteoporosis, and tobacco use. Surgeons must understand the importance of stress, strain, and osteogenesis to optimize their biomechanical constructs and graft choice intraoperatively. Finally, surgeons should understand the biologic mechanism, clinical role, and efficacy of adjunct therapies, such as pulsed electromagnetic field therapy and bisphosphonates, on bone healing.

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