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Review Article

Emerging Options for Biologic Enhancement of Stress Fracture Healing in Athletes

Miller, Timothy L. MD; Kaeding, Christopher C. MD; Rodeo, Scott A. MD

Author Information
Journal of the American Academy of Orthopaedic Surgeons: January 1, 2020 - Volume 28 - Issue 1 - p 1-9
doi: 10.5435/JAAOS-D-19-00112

Abstract

Single-sport specialization is increasingly common among competitive athletes. Athletes as young as their pre-teen years choose to train and compete nearly year-round in one sport and often at a single position within that sport. As such, overuse injuries including stress fractures are increasingly common not only among distance runners but also among other field and arena sports such as soccer, lacrosse, basketball, ballet, and gymnastics.1 In addition, the intense training that often accompanies single-sport specialization likely contributes to an increased severity of the stress fractures encountered among these athletes.1,2 A robust understanding of emerging strategies for approaching and treating these injuries is paramount to maximize the athlete's participation, minimize time lost, and to optimize performance while mitigating the risk of worsening injury.

Using a Holistic Approach

Because the shortest time to union and return to full activity are the goals of treating stress fractures in elite athletes, the traditional treatment strategy of immobilization and extended rest from sports participation is often impractical or unacceptable. Multiple biologic and mechanical factors influence a bone's ability to remodel as well as heal a bony stress injury. Optimal treatment requires taking a holistic approach to athletes presenting with this injury. Maximizing an athlete's biologic capacity to repair damaged bone requires assessment of the athlete's nutritional, hormonal, and emotional status as well as their biomechanics, bone mineral density, and medication usage.2 Athletes at greatest risk for recurrent or severe stress fractures are those presenting with the female athlete triad (low-energy availability, menstrual dysfunction, and decreased bone mineral density) and relative energy deficiency in sport. A team approach to treatment that includes nutrition counseling, sports psychology evaluation, endocrinology assessment, and biomechanical analysis is necessary in these high-risk athletes.

Risk Stratification

Stress fractures result from an imbalance between the creation and repair of microtrabecular injury within bone that is caused by repetitive microtrauma. Commonly the term “stress reaction” is used to describe an overuse injury of bone that has not progressed to a radiographically identifiable fracture line. Because stress fractures occur along a continuum of severity and the clinical picture varies by location, a classification system is necessary to assess and effectively communicate regarding these injuries. In the early 2000s Boden and colleagues3,4 stratified stress fractures as low-risk or high-risk. Injuries at high-risk sites require the most aggressive treatment to prevent complete fracture, delayed union, re-fracture, and osteonecrosis. These sites are listed in Table 1. High-risk sites require extended time to heal after diagnosis and typically occur where tensile forces are concentrated and/or vascularity is decreased.3 More recently, Kaeding and Miller5 have combined clinical and radiologic factors to create a grading system for severity of bony stress injuries (Table 2) that has shown high interobserver and intraobserver reliability among sports medicine and orthopaedic clinicians. In addition, this system has been shown to reliably predict time to healing and return to sports participation after the diagnosis of a stress fracture.6,7

Table 1 - Stress Fracture Sites Considered to be High Risk for Propagation and Poor Healing Due to Tensile Forces or Relative Hypovascularity4
High-risk Stress Fracture Sites
Femoral neck superior cortex
Patella
Tibial diaphysis anterior cortex
Medial malleolus
Talus
Tarsal navicular
Fifth metatarsal proximal metadiaphysis
Great toe sesamoids

Table 2 - The Kaeding-Miller Classification System for Stress Fractures of Bone5
Grade Pain Radiographic Findings (X-ray, MRI, CT, or Bone Scan)
I Imaging evidence of stress injury
No fracture line
II + Imaging evidence of stress injury
No fracture line
III + Nondisplaced fracture line
IV + Displaced fracture (≥2 mm)
V + Nonunion

Biologic Healing Enhancement

Once the risk and severity levels have been determined for a bony stress injury in an athlete, healing optimization must be initiated and biologic healing enhancement options may be considered. Osteobiologics is a term used to describe materials that have been identified and developed to promote bone healing. The following is a general overview of biologic options that are approved by the FDA and readily available for healing enhancement of bone. These options can be divided into two groups: direct injectable modalities and indirect systemic stimulating treatments. Tables A1 and A2 (Appendix, Supplemental Digital Content 1, http://links.lww.com/JAAOS/A371) summarize the evidence to support each option's use. It should be borne in mind that not every option is ideal for every bone or even each area of the affected bone. Some options may be used in combination or as an adjunct to internal fixation with implant. Each option carries its own risks and benefits, and the appropriate indications and long-term outcomes of these treatment options are yet to be determined. A general approach to guide the treatment of these fractures and when to consider emerging osteobiologic options to enhance healing is shown in Figure 1.

Figure 1
Figure 1:
Chart showing the recommended treatment algorithm for application of osteobiologic treatments to stress fractures in athletes. ESWT = extracorporeal shock wave therapy, PTH = parathyroid hormone

Concentrated Bone Marrow Aspirate

Concentrated bone marrow aspirate is a biologic treatment that uses an individual's own mesenchymal stromal cells to stimulate bone healing. The local application of bone marrow aspirate concentrate (BMAC) for the treatment of delayed healing is a promising alternative to autogenous bone grafting and may help to reduce donor site morbidity, although rigorous data on its efficacy are currently lacking.8 Osteoblastic progenitor cells are available in the bone marrow aspirate of the iliac crest, proximal tibial metaphysis, and calcaneus (Figure 2), with the iliac crest providing the highest yield of osteoblastic progenitor cells.9 A review of in vivo studies on the use of BMAC for the treatment of segmental bone defects in animal long bones indicated markedly increased torsional stiffness in BMAC-treated defects and earlier bone healing on histologic evaluation when BMAC was applied.10

Figure 2
Figure 2:
Image showing bone marrow (A) aspirated from the calcaneus with the use of a 30-mL syringe. Intraoperative AP fluoroscopy image (B) of the left fifth metatarsal as bone marrow aspirate concentrate is injected percutaneously into the intramedullary canal at the site of a proximal metaphyseal delayed union. C, Intraoperative photograph of concentrated bone marrow aspirate mixed with calcium chloride being injected into a proximal fifth metatarsal delayed union site.

Autologous BMAC injection has been shown to improve bone healing in distraction osteogenesis of the tibia.11 Multiple authors have advocated its use in the management of fractures at high-risk sites because it can be applied in multiple ways. These include percutaneous injection to the surface of the bone, intramedullary injection with or without demineralized bone matrix, and after core decompression at metaphyseal sites. A systematic review by Imam et al12 concluded that the most common BMAC applications for bone include enhancement of healing of fractures, nonunions, and bone defects. The same study, however, concluded that standardization of commercial processing of the material has yet to be optimized to assure consistency of the final product.12 Murawski and Kennedy13 demonstrated that percutaneous screw fixation of acute proximal fifth metatarsal fractures augmented with BMAC provided predictable healing results while permitting athletes a return to sport at their previous levels of competition at a mean of 5 weeks postsurgery with few complications. In addition, augmentation of femur fracture fixation with autologous BMAC has shown a trend toward decreased time to union.14 It should be noted that although multiple studies using BMAC for sports-related fractures including stress fractures among elite athletes have shown shorter healing times than those previously reported without its use, no controlled comparative study has been published on this topic. Although there are some early data to support a role for BMAC in bone healing, it must be understood that the number of true stem cells by formal criteria is very low in currently available minimally manipulated formulations available in the United States.1517 It is critically important to distinguish minimally manipulated cell preparations from sorted, culture-expanded, laboratory-prepared cells. The current FDA regulations do not permit ex vivo cell sorting and subsequent culture to isolate and expand the quantity of stem cells. In fact, some have suggested that the term stem cell be abandoned in favor of connective tissue progenitors to make clear that current techniques used by clinicians in the United States contain very few stem cells. Connective tissue progenitors are defined as a heterogeneous population of tissue resident cells that can proliferate and generate progeny with the capacity to differentiate into one or more connective tissues. These cells are present in many tissues including adipose tissue and possess a limited capacity for tissue repair and osteogenic differentiation.18 However, connective tissue progenitors do not possess the characteristics of self-renewal and the ability to reconstitute all of the parenchymal cells of a specific tissue, and thus should be distinguished from a pluripotent stem cell.

Autologous Platelet-Rich Technologies

Autologous platelet-rich technologies including platelet-rich plasma (PRP) and autologous conditioned plasma are referred to as osteopromotive materials when used in bone healing applications. The efficacy of these options for enhancing bone healing has been demonstrated in both animal and human models.1923 Guzel et al19 compared 30 female rats that received PRP after undergoing mid-diaphyseal transverse femur fractures with 30 rats that did not receive PRP at the fracture site. Earlier weight bearing and accelerated fracture healing were observed in the PRP-treated animals. In addition, the PRP-treated femurs were able to withstand a greater maximal load compared with rats that did not receive PRP. A systematic review of 29 articles comparing PRP-treated fractures with non-PRP control groups demonstrated multiple beneficial effects on animal long-bone fractures. Eighty percent of studies reported increased bone area with 89% reporting earlier bone healing on histologic/histomorphometric assessment. All authors reported greater torsional stiffness and increased bone formation on radiographs in the PRP-treated groups.20

Despite the positive results of platelet-rich technologies seen in preclinical (animal) studies, less conclusive results have been reported in human clinical studies. There are few well-designed human studies.2224 Studies by Gandhi et al23 have suggested a role for PRP in enhancing fracture healing among diabetic patients and other high-risk fractures. Their results among diabetic rat femur fractures indicated that percutaneous administration of PRP improved cellular proliferation in the early stages of fracture healing and mechanical strength in the late stages.23 Studies with standardized protocols for preparation and administration of platelet-rich materials employing randomization and control groups are required to confirm efficacy in human stress fractures.

Injectable Bone Graft Substitutes

The utility of injectable bone graft substitutes for stimulating healing of stress fractures, insufficiency fractures, and nonunions in humans is currently under investigation. This option includes a combination of concentrated bone marrow aspirate and demineralized bone matrix injected into a fracture site. The technique uses the osteogenic properties of BMAC combined with the osteoconductive potential of bone matrix to stimulate healing and fracture callus formation.25 An example of this option, Intraosseous BioPlasty(Arthrex), involves percutaneously performing a core decompression of the affected metaphyseal bone site and injecting a mixture of bone marrow concentrate, calcium chloride clot, and demineralized bone matrix (Figure 3). It has been used in combination with arthroscopy to stimulate healing of subchondral bony defects of the tibia and is currently used in the distal femur and proximal tibia for subchondral insufficiency fractures.26 This option is not recommended in the diaphyseal region of long bones, and the appropriate indications and long-term outcomes of these treatment options are yet to be determined.

Figure 3
Figure 3:
Intraoperative photograph showing (A) injection of a mixture of concentrated bone marrow aspirate and demineralized bone matrix at the proximal tibial metaphysis. Intraoperative anterior-posterior fluoroscopy image showing (B) injection of a mixture of concentrated bone marrow aspirate and demineralized bone matrix at the proximal tibial metaphysis through a fluted cannula. A core decompression of the proximal tibial metaphysis has been performed before injection.

Subchondral Calcium Phosphate Bone Substitute

Subchondral injection of calcium phosphate bone substitute is a recently developed surgical technique whose application includes the treatment of subchondral insufficiency fractures most commonly of the distal femur and proximal tibia by providing structural support to areas of decreased bone mineral density.27 Authors have additionally described its use in the foot and ankle including the treatment of bone marrow lesions of the talus and calcaneus.2830 This procedure is performed by drilling into metaphyseal subchondral bone with a cannulated fluted guide pin (Figure 4). Under fluoroscopy, engineered calcium phosphate paste is injected into subchondral bony defects forming a macroporous scaffold for bone to increase the density and possibly improve the structural integrity of subchondral bone. Initial results of the procedure have shown that over the first 24 weeks following the procedure, recipients reported notable relief from pain and improvement in functional capacity.31 A recent review of eight studies by Astur et al32 indicated that subchondral calcium phosphate injection for the treatment of 164 patients with bone marrow lesions of the femoral condyle and tibial plateau allowed markedly improved pain and knee function with an average time of 3 months to return to full activity. It should be noted that these surgical techniques have been developed and used for treatment of subchondral insufficiency fractures, which are much more common in the setting of early degenerative joint disease rather than athletic stress fractures. Data on its use in stress fractures in athletes is minimal, although its use in this population is increasing.

Figure 4
Figure 4:
Intraoperative anterior-posterior fluoroscopy image of the proximal tibia after injection of calcium phosphate paste through a fluted cannulated drill. A blush of increased density is noted in the surrounding medial metaphyseal bone.

Pulsed Parathyroid Hormone

Pulsed recombinant human parathyroid hormone (PTH, −34) is an endocrine-based injectable treatment strategy that has been shown to increase fracture callus formation in multiple animal models.3336 It is a regulator of calcium and phosphate homeostasis and induces an anabolic response in bone when applied at intermittent low doses.34 PTH acts within the pathway of bone morphogenic proteins (BMP's). It is FDA-approved for the treatment of osteoporosis, although its off-label use has included poorly healing fractures and nonunions. Topical gel alternatives that can be applied locally are currently in development to increase ease of use and patient compliance.

The effect of PTH on fracture healing in humans has been evaluated with mixed results. However, it has been shown to achieve the primary end point of accelerated healing with improved early fracture callus formation compared with placebo in distal radius fractures.37Although evaluation of its administration in animal models has shown that supraphysiologic doses of PTH increase fracture site strength, callus size, and bone remodeling along with increased bone mineralization, its effect on fracture healing in humans remains indeterminate.38

Electrical Osseous Stimulation

Pulsed electromagnetic fields (PEMF) and low-intensity pulsed ultrasound (LIPUS) are FDA-approved, noninvasive modalities that increase the production of regulatory mediators required for physiological bone healing.39 PEMF (Figure 5) creates a magnetic field and a secondary electronic impulse, activating a series of enzyme reactions that upregulate growth factors such as BMPs, transforming growth factor-β and calmodulin, leading to bone cell proliferation and fracture healing.40 Benazzo et al were able to achieve union in 22 of 25 lower extremity stress fractures (navicular, second and fifth metatarsal, tibia, fibula, and talus) in athletes at an average of 52 days using an alternating electrical field.41

Figure 5
Figure 5:
Photograph showing a 21-year-old female college soccer player on whom a pulsed electromagnetic field bone stimulator is applied to treat a proximal tibial stress fracture.

PEMF bone stimulators have been shown to be the most effective for delayed unions of the tibial shaft and fifth metatarsal shaft. Streit et al41 performed a randomized controlled trial of eight delayed unions or nonunions of the fifth metatarsal that were treated with active or inactive PEMF after biopsy of the fractures site. The average time to complete radiographic union for the active PEMF groups was 8.9 weeks compared with 14.7 weeks for the inactive PEMF group. The same study also noted that the group treated with active PEMF demonstrated increased production of placental growth factor as well as BMP-5 and BMP-7.41

The effect of low-intensity pulsed ultrasound occurs through its ability to stimulate osteocyte mechanoreceptors, thereby activating ion channels40. Definitive results of LIPUS are lacking; however, Tomohiko et al42 described how they used it to treat five high school and collegiate soccer players with fifth metatarsal Jones fractures. All athletes healed or had no progression of the fracture despite being allowed to continue soccer activity. The authors suggested that treatment with LIPUS may allow in-season athletes to continue activity without time off despite a fifth metatarsal fracture.

Extracorporeal Shock Wave Therapy

Extracorporeal shock wave therapy (ESWT) is a noninvasive topically applied modality that has been used by sports medicine orthopaedic surgeons and podiatrists for the treatment of overuse injuries of soft tissues and bone since the late 1980s.4345 The therapeutic basis of ESWT lies in its ability to use mechanotransduction to stimulate osteoblast formation, bone turnover, and increased local angiogenesis.43 Furia et al46 have reported its success rates for treatment of stress fracture delayed unions and nonunions in military personnel to be equal to those of surgical repair with minimal risk for complications. Other authors have indicated extended time to healing and a high likelihood of requiring internal fixation in addition to the use of high-intensity ESWT.44 The results in the literature are mixed but it can be considered as an adjunctive treatment for refractory stress fractures showing radiographic indication of delayed healing.

Vitamin D Supplementation

Much recent research has focused on identifying the role of vitamin D in preventing and healing stress fractures. Vitamin D insufficiency is likely more common among athletes than previously recognized with serum 25-hydroxycholecalciferol [25(OH)D3] level being the study of choice for identifying vitamin D deficiency and insufficiency. The ideal level for the athlete is not fully established but has been suggested to be 40 to 50 ng/mL. Shimasaki et al47 reported that soccer players with 25(OH)D3 of <30 ng/mL had a markedly increased risk of developing fifth metatarsal stress fractures. Players with serum levels of <20 ng/mL were nearly three times as likely to develop a fifth metatarsal stress fracture. Similar results have also been reported by Davey et al.48

Farrokhyar et al49 reported that 56% of 2,313 athletes surveyed had low serum 25(OH)D3 levels, with the risk of low serum vitamin D being markedly higher during winter and spring and in geographic regions higher than 40° north latitude.

Much of the research regarding vitamin D's effect on stress fractures has been conducted among military personnel. A recent systematic review and meta-analysis of 761 military personnel with stress fractures and 1,873 controls concluded that low serum 25(OH)D3 likely predisposes military personnel to lower extremity stress fractures.50 A prospective study by Lappe et al51 found that the average serum 25(OH)D3 concentration was markedly lower in female military recruits who had sustained a stress fracture than those without stress fractures. The same authors have suggested that calcium and vitamin D3 supplementation may have prevented a notable percentage of military recruits from sustaining a stress fracture and led to a notable decrease in the financial burden of time away from military duty.

It is currently recommended that most athletes receive at least 800 to 1,000 international units (or perhaps as much as 5,000 IU) of vitamin D3 daily. For athletes with measured low vitamin D or low bone mineral density, the therapeutic goal for supplementation should be approximately 50 ng/mL.52 As much as 50,000 IU per week may be prescribed for individuals with severe vitamin D deficiency with minimal risk of side effects. Although recent research indicates associations between serum 25(OH)D3 and risk of stress fracture, there is currently little level-1 evidence confirming the efficacy of vitamin D supplementation for preventing and expediting the healing of stress fractures.

Summary

Stress fractures and other stress injuries of bone are increasingly common among competitive athletes, particularly those who choose to specialize in a single sport. Historically, few treatment options other than cessation of the causative activity combined with immobilization of the affected area were available. Rest from the causative activity remains a component of the treatment protocol for stress fractures; however, for elite and professional athletes, biologic treatments offer a minimally invasive option that may expedite healing and allow earlier return to sports participation. Additional research is required to determine the ideal combination of osteopromotive treatment options that will maximize the rate of healing and minimize the risk of fracture propagation on return to athletic participation.

References

Levels of evidence are described in the table of contents. In this article, references 11, 22, 23, 33, 37, 41, and 51 are level I studies. Reference 19 is a level II study. References 7, 14, 21, 25, and 47 are level III studies. References 6, 8, 12, 13, 18, 27, 29, 31, 32, 40, 42, 48, 50, and 52 are level IV studies. References 10, 26, 28, 30, and 38 are level V studies.

References printed in bold type are those published within the past 5 years.

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Supplemental Digital Content

Copyright 2019 by the American Academy of Orthopaedic Surgeons.