Fracture nonunion and segmental bone defects represent challenging clinical problems in orthopaedic trauma surgery. Fracture nonunion at the population level occurs in 9 to 19 fracture cases per 100,000 per year.¹,² The incidence of nonunion in long bone fractures varies with injury, treatment, and estimation methods: reported rates range from zero to 12% in femoral fractures, zero to 33% in humeral fractures, and 1% to 80% in tibial fractures.³,⁴ Nonunion is associated with high-energy polytrauma; open fracture; medications including NSAIDs, opioids, anticoagulants, anticonvulsants, benzodiazepines, and diuretics; osteoarthritis; diabetes and insulin use; osteoporosis; male sex; smoking; vitamin D deficiency; and renal insufficiency.⁴ Most nonunions occur in patients during their most productive years, between age 25 and 55 years.² Direct health care costs of nonunion treatment vary widely, with estimates ranging from $11,000 to $126,0000 USD per case.⁵,⁶,⁷,⁸,⁹

Segmental bone defects may be congenital, the primary result of severe trauma, or the sequelae of débridement or resection of bone for traumatic devitalization, osteomyelitis, or neoplasia.¹⁰ The incidence of segmental bone defects is more difficult to quantify because of the variety of etiologies resulting in segmental defects. Surgical management of segmental bone defects is morbid and expensive, with amputation rates of 8% to 15% at 2 years and direct costs of treatment of $52,155 to $305,938 per case.¹¹

It is important to provide context and evidence for the role of orthobiologic interventions in the treatment of fracture nonunion and segmental bone defects.

Understanding the etiology of a nonunion or segmental bone defect informs the planning of interventions to address the clinical problem. It is helpful to develop a problem list of factors that contributed to the nonunion or bone defect that may also influence the choice and success of treatment options.

Similar to an acute fracture, both nonunion and segmental bone defect are the result of a soft-tissue injury with a broken bone inside. The soft tissue enveloping the problematic bone (the periosteum, adjacent musculature, innervating nerves, vascular supply, fascial covering, and cutaneous tissues) may be compromised by the congenital issue, traumatic injury, prior surgery, infection, or chemotherapy and radiation. Open fracture and extensive soft-tissue injury increase the risk of delayed fracture healing by 13% to 16% in tibial fractures, whereas associated vascular injury increases the risk to almost 50%,²¹ even though the atrophic nonunion itself may not be dysvascular.²²,²³ Neurologic injury may degrade the stabilizing effect of adjacent muscles, contributing to nonunion, particularly about the humeral shaft.²⁴ Compartment syndrome independently predicts nonunion.²⁵

Modifiable patient risk factors for compromised bone healing include tobacco use, recreational drug use, and alcohol abuse.²⁶,²⁷,²⁸,²⁹ Medications taken by the patient including corticosteroids, opioids, diuretics, benzodiazepines, anticonvulsants, and anti-inflammatories³⁰ and medical conditions including anemia, vitamin D deficiency, and diabetes³¹,³² represent risk factors for nonunion as well as opportunities for medical optimization to improve the chance of treatment success. Previous treatment including the design of stabilization constructs,³³ prior stabilization of adjacent bones,³⁴,³⁵ the presence of a fracture gap at the initial fixation,³⁶,³⁷ previous radiation, chemotherapy, vascular procedures, or soft-tissue coverage procedures may also be contributing factors as well as considerations informing the management plan. Genetics may one day also play a role: single nucleotide polymorphisms in osteogenic genes have been associated with risk of delayed union following long bone fracture.³⁸

Eradication of infection is critical to the treatment of nonunions and segmental bone defects. Both entities are strongly associated with fracture-related infection (FRI) as sequelae of the initial injury as well postoperative surgical site infection and osteomyelitis.¹¹ Similar to consensus definitions developed across societies for periprosthetic joint injection, the AO Foundation, the European Bone and Joint Infection Society, and the Orthopaedic Trauma Association have developed a consensus definition for FRI based on diagnostic criteria developed from a stepwise algorithm of history, examination, laboratory values, and surgical findings.³⁹ However, FRI is not always a straightforward diagnosis. Infected nonunions and segmental bone defects may be quiescent or asymptomatic and serum biomarkers associated with infection may be within normal ranges.⁴⁰,⁴¹ Clinical consensus and evidence supports the use of serum leukocyte count (white blood cell), erythrocyte sedimentation rate, and C-reactive protein to evaluate for the possibility of infection.⁴²,⁴³,⁴⁴ Clinically relevant values may be center specific, with reported cutoffs of white blood cell count (10³ cells/µL) greater than 10.5 for men and greater than 11.0 for women; erythrocyte sedimentation rate (mm/hr) greater than 15 for men and greater than 20 for women; and C-reactive protein (mg/dL) greater than or equal to 0.9 for both men and women. However, recent data have called into question the utility of white blood cell, erythrocyte sedimentation rate, and C-reactive protein for diagnosis of FRI in nonunion and segmental bone defects as these studies demonstrated poor sensitivity and insufficient negative predictive value to rule out FRI.⁴¹ A high index of suspicion should be maintained when the initial injury was the result of an open fracture, previous surgery has been attempted, or there is a history of previous infection.¹⁶,⁴⁰,⁴⁵

The natural history of a segmental bone defect is variable, with rare reports of spontaneous healing of large long bone defects with uncompromised soft tissues.¹⁹,²⁰ By definition, a critical-size defect or nonunion will not heal spontaneously. Similarly, nonunion represents arrested fracture healing with no expected progress to union. Continued symptoms and failure of existing implants are to be expected.

Defining clinical success after surgery for nonunion or bone defects is a process of shared decision making and goal setting between the patient and treating team. Success may relate to objective measures of physical function including needs for assistance with activities of daily living, return to prior living situation, return to same or any occupation, and return to play. However, success can be very subjective to the patient. Cosmetic considerations as well as the psychological, social, and cultural consequences of interventions such as external fixation frames or outcomes such as amputation and prosthesis wear are important to discuss with the patient.⁴⁶,⁴⁷ It is important to discuss what might be the patient’s desired level of function versus what might be reasonably achievable and to consider that the specific outcome desired by the patient may change with time, age, and living situation and occupational need.

Successful treatment of a nonunion or segmental bone defect usually does not require flawless reconstruction of all tissues and structures. The function of the compromised limb segment can be improved with one-bone leg⁴⁸
or one-bone forearm⁴⁹ salvage procedures, iatrogenic synostosis to bridge segmental defects,⁵⁰ or arthrodesis to address periarticular segmental bone loss.⁵¹ In select patients with limited functional demands and/or limited life expectancy, benign neglect or deliberate nonsurgical care may lead to a useful, pain-free extremity with a functional, asymptomatic nonunion.⁵²

At the time of publication, no clinical practice guidelines have been published by the American Academy of Orthopaedic Surgeons, the Orthopaedic Trauma Association, or the Limb Lengthening and Reconstruction Society to guide treatment for segmental bone defects or nonunion.

In the absence of infection, nonsurgical management of nonunion or segmental bone defects may include medical optimization, immobilization, and external field bone stimulation. Medical optimization of metabolic and endocrine derangements potentially affecting bone healing is possible in 84% of patients with nonunion.⁵³ Functional bracing has been a historical approach to tibial union with reasonable success but may require secondary fibular osteotomy and months of orthotic use.⁵⁴ Low-intensity pulsed ultrasound (LIPUS) is an alternative to surgery for established nonunion, although the evidence is conflicting: a pooled success rate over 82% by systematic review of prospective and retrospective studies suggested LIPUS may reduce the time to radiographic fracture union,⁵⁵ but does not accelerate functional recovery.⁵⁶ Conversely, the multicenter randomized TRUST trial of LIPUS in closed and open tibial fractures found no effect on time to radiographic healing or functional recovery.⁵⁷

Hypertrophic nonunion, characterized by little to no biologic impairment of fracture healing, may be managed by débridement, biopsy for culture, and revision internal fixation. Débridement and culture of the undesired fibrous or cartilaginous tissues interposed between the fracture fragments is performed with stabilization of the nonunion site with a stiffer construct, often with compression across the fracture or distraction osteogenesis with deformity correction.

Atrophic nonunions require additional biologic intervention to stimulate bone formation at the defect site. Overall, surgical interventions for repair of atrophic nonunion are successful in 80% of cases even after infection, although multiple interventions may be necessary.⁵⁸ Interventions can be organized along an escalating ladder of complexity and risk, beginning with dynamization of intramedullary constructs, reamed intramedullary exchange nailing, compressing plating with or without grafting, staged antibiotic spacer methods, and distraction osteogenesis techniques. Dynamization of previously statically locked intramedullary implants is 54% successful when treating femoral and tibial nonunion.⁵⁹ Exchange nailing of the tibia can achieve union in 88% to 93% of cases but may require up to five nailing attempts, and at greater cost per attempt than dynamization.⁶⁰,⁶¹ Open compression plating with or without bone grafting around existing intramedullary implants has been reported.⁶² Distraction osteogenesis constructs such as external fixators or motorized intramedullary motorized devices can be used to compress a nonunion, with or without subsequent distraction to restore length.⁶³,⁶⁴

Aseptic segmental bone defects can be managed with bone grafting, distraction osteogenesis, acute shortening, and amputation.¹⁰ Although indications vary, primary autologous bone grafting has been recommended for defects up to 5 cm.¹⁰ Acute limb shortening with or without subsequent limb lengthening at the same site or via osteotomy at another level is an alternative for smaller defects. For defects greater than 5 cm, traditional alternatives include distraction osteogenesis, induced membrane staged management, and vascularized bone transfer (Table 2).

The induced membrane or Masquelet technique is a staged bone grafting procedure to address a segmental bone defect by first creating an environment conducive to bone formation then filling the void with graft.⁶⁵,⁶⁶ A polymethyl methacrylate spacer is placed in the defect. The spacer induces the formation of a vascularized, pseudosynovial membrane, which demonstrates neovascularization, secretion of bone morphogenetic protein (BMP)-2, type I collagen, interleukin 6 and vascular endothelial growth factor, and osteoblastic precursors.⁶⁷,⁶⁸ A second procedure is performed to incise the membrane, remove the spacer, and place bone graft during peak production of osteoinductive factors by the membrane around 4 to 8 weeks⁶⁸,⁶⁹ (Figure 2).

In contrast with bone grafting, vascularized bone autografts immediately provide complete, living histologic bone architecture and mechanical integrity with a single-stage operation. Vascularized bone grafts such as the fibula, medial femoral condyle, and distal radius preserve the nutrient, metaphyseal, or other perforating vessels responsible for the primary blood supply to the osseous segment of the graft. These procedures are technically demanding and require microsurgical expertise. Complications of vascularized bone grafts include persistent defects, mechanical failure, loss of vascular supply, infection, and donor site morbidity.⁷⁰,⁷¹ Rates of union after vascularized bone grafting of segmental defects vary from 70% to 100% with a mean time to union of 6 months in case series encompassing a range of defect sizes as well as indications after trauma, infection, tumor, and prior radiation.⁷²,⁷³,⁷⁴,⁷⁵

Distraction osteogenesis or bone transport is the creation of new bone at a surgical osteotomy by controlled mechanical strain over time. A mechanical assembly is surgically applied such that one or more segments of
bone may be translated along the axis of the limb segment over time. Distraction osteogenesis recapitulates phases and features of both intramembranous and endochondral bone formation, including a latent phase after corticotomy, a distraction phase during bone is grown by a process demonstrating aspects of intramembranous and endochondral bone formation as well as interleukin 6, insulinlike growth factor 1, group 1 BMPs, and vascular endothelial growth factor expression,⁷⁶,⁷⁷,⁷⁸ and a consolidation phase on docking of the transported segmented into the terminal bony aspect of the limb segment. Distraction osteogenesis may be achieved with circular external fixation frames pioneered by Ilizarov⁷⁹ (Figure 3), monolateral external fixators,⁸⁰ cable transport frames, and motorized intramedullary transport or limb lengthening.⁸¹ Multifocal distraction across corticotomy at multiple levels can decrease total transport time. An advantage of distraction osteogenesis is the potential for early weight bearing with a frame in place during distraction. However, distraction rates of typically 1 mm per day and the need to maintain a frame during consolidation may require fixator use for 6 to 12 months.⁸² Circular frame distraction osteogenesis is associated with a refracture rate of 5% and an amputation rate of 3%, with greater risk with longer transport segments.⁸²