HISTORY AND PHYSICAL EXAM
A 37-yr-old female marathon runner presented to an outpatient sports medicine clinic for evaluation of right lateral foot pain. Eighteen months prior, she was diagnosed with right plantar fasciitis and partial tear at the calcaneal attachment, confirmed on magnetic resonance imaging (MRI). Initial symptoms resolved with physical therapy and a Baxter’s nerve block, and she had returned to her previous training regimen of running approximately 40 miles per week. Four months before this current presentation, she developed a new pain in the dorsolateral aspect of her right midfoot. She described the pain as constant aching, deep, and worse in the evening. The pain had progressively worsened, and she had difficulty bearing weight on her right foot. Her medical history was notable for iron-deficiency anemia, stress fracture in her left foot as a child, and anorexia nervosa treated during her teenage years and early 20s as an outpatient. She reported no current efforts to restrict food intake, but typically eats only one full meal per day, and has lost 10 to 15 lb for the last 6 mos. She maintains an ovo-lacto-vegetarian diet and takes vitamin B12, C, and D supplements. She underwent a hysterectomy for excessive menstrual bleeding 3 yrs prior but until that point had regular 28-day cycles since menarche at age of 13 yrs.
On examination, body mass index was 18.9 kg/m2. Arches were neutral, and no swelling, deformity, discoloration was noted in her right foot, nor any asymmetry compared with her left. There was tenderness to palpation over the dorsolateral aspect of the right midfoot approximately at the area of the base of the fourth metatarsal. Range of motion, strength, and sensation of the lower limbs were normal.
Question: What is the differential diagnosis for this patient’s lateral foot pain?
The differential diagnosis of lateral foot pain in this patient includes injury to the soft tissues, bones, joints, and/or nerves. More common soft tissue injuries to the tendons and ligaments in the lateral foot and ankle include lateral ankle sprain (most commonly the anterior talofibular ligament), chronic ankle instability, peroneal tendinopathy, or persistent plantar fasciitis. Common etiologies of bone pain include bone stress injury (stress reaction/stress fracture) of the cuboid, calcaneus, lateral metatarsals, or os peroneum. Joint abnormalities, such as osteochondral injury, osteoarthritis, ankle impingement, gout, sinus tarsi syndrome, or tarsal coalition should also be considered. Finally, compression of the sural or lateral plantar nerve may also cause pain in this area.
Question: What type of diagnostic imaging should be performed to aid in diagnosis?
Standing three-view x-rays of the right foot were read as normal. Because of clinical concern for fracture, a computed tomography scan of the right foot was obtained, which demonstrated a chronic cuboid fracture near the fourth metatarsal articulation not seen on imaging 18 mos prior. Magnetic resonance imaging demonstrated patchy bone marrow edema adjacent to the fracture site of the cuboid (Fig. 1).
Question: How would you manage this patient? What other tests are indicated in patients who develop stress fractures?
DIAGNOSIS, MANAGEMENT, AND DISCUSSION
The patient was diagnosed with a cuboid stress fracture, which was initially managed conservatively, maintaining the injured foot in a walking boot for 2 mos. Unfortunately, there was delayed healing of the fracture, and the patient continued to have persistent pain with inability to run 6 mos after diagnosis. Surgical fusion was recommended; however, she elected to consider alternative options because of concern that fusion would limit her ability to run in the future.
As an alternative to surgery, we treated this patient’s injury with a series of two off-label orthobiologic injections performed under ultrasound guidance. First, 3 ml of bone marrow aspirate concentrate (BMAC) isolated from the patient’s posterior superior iliac spine was injected into the dorsal cuneocuboid joint (Fig. 2A). Ten days later, 3 ml of leukocyte-poor platelet-rich plasma (2% hematocrit) was injected into the cuneocuboid joint and the dorsal intermetatarsal ligaments between the third and fourth metatarsals. Interval between injections was as per treating clinician’s preferred protocol. The ligaments were treated in addition to the joint because she had pain to palpation in this soft tissue region separate to the pain in the region of the bony injury. Bone marrow aspirate concentrate and platelet-rich plasma were obtained using a commercially available system (Arthrex Angel; Arthex Inc, Naples, FL). Two months after injection, the patient’s pain had completely resolved. Repeat MRI 10 weeks after BMAC injection showed near complete resolution of cuboid bone edema, consistent with nearly completely healed cuboid fracture (Fig. 2B). The patient remained pain free at 6- and 12-mo follow-up and was able to return to her previous weekly running regimen. To assess for additional biological risk factors for bone stress injury (BSI), the patient underwent further assessment including blood work and a dual-energy x-ray absorptiometry scan. Vitamin D, thyroid stimulating hormone, gonadotropins, and gonadal steroids were all within normal limits. Dual-energy x-ray absorptiometry Z-scores were +1.3 and +2.8 for the total hip and lumbar spine, respectively.
Bone stress injuries occur because of failure of bone to withstand repetitive submaximal loading, resulting in structural fatigue and potentially fracture. Bone stress injuries in runners are most commonly found in the tibia and metatarsals, although they may also occur in other bones of the lower limb, pelvis, and spine.1 Clinicians should be suspicious of BSI in patients with focal pain with activity, particularly if the athlete has recently increased their training load. Physical examination findings including focal tenderness to percussion or vibration, pain with single leg hop, and edema are suggestive of BSI but have not been validated in the literature.1 Early detection of BSI is important as it may reduce the time required for return to sport.2
Isolated cuboid stress fractures are rare as the cuboid is not directly involved in weight bearing. However, it does serve as the main midfoot support of the lateral column and is subjected to several forces during ambulation. Fractures of the cuboid may lead to long-term disability if there is permanent deformity or dysfunction.3 Disruption of the plantar fascia may result in decreased arch stability and increase strain in the midfoot including the plantar ligaments,4 and may have contributed to BSI in this patient.
Standard radiographs (x-rays) are typically the initial imaging modality used to evaluate for potential BSI. However, the false-negative rate may be as high as 90%,2 and cuboid fractures are particularly difficult to assess on x-ray because of overlapping of the bones in the two-dimensional image. Magnetic resonance imaging is considered the imaging modality of choice for diagnosis of BSI and is also useful for evaluating soft tissue injuries. The severity of BSIs is typically graded based on MRI findings using a four-point scale.2 Computed tomography scan may also be useful for determining the definitive fracture pattern and stability. Nonoperative management is typically indicated for cuboid fractures, unless there is articular displacement of greater than 1 mm or shortening of the lateral column by greater than 3 mm.3
In addition to anatomy and biomechanics, other biological risk factors also contribute to development of BSI. The Female Athlete Triad (Triad) is a syndrome described as the following three interrelated conditions: (a) low energy availability with or without disordered eating, (b) menstrual dysfunction, and (c) low bone mineral density.5 Presence of one or more Triad risk factors increases the risk for developing a BSI.5 This patient is at increased risk for BSI because of her history of eating disorder and previous BSI as a child. Bone mineral density as measured by dual-energy x-ray absorptiometry was above average in this patient (Z-scores less than −1.0 are suggestive of low bone mineral density in female athletes in weight-bearing sports). A detailed discussion on diagnosis of Triad conditions and risk stratification can be found in a 2014 consensus statement by the Female Athlete Triad Coalition.5 A new syndrome, relative energy deficiency in sport, has also been proposed by the International Olympic Committee, expanding the concept of Triad to describe how a low energy availability state may negatively impact health and performance in both female and male athletes.6
The use of BMAC has shown promise in treatment of stress fractures in a case report of injection through a cannulated screw to treat a stress fracture nonunion of the medial cuneiform.7 A retrospective case-control study of diabetic patients with nonunion ankle fractures showed improved healing with BMAC in comparison with bone grafts from the iliac crest.8 Preclinical studies suggest that platelet-rich plasma may also promote healing of bone injuries; however, high-quality clinical studies are lacking.9 Specifically, heterogeneity in study quality and lack of standardization in preparation methods, injection number, and postrehabilitation protocols have limited the ability to translate findings into clinical practice.10
Bone stress injuries of the cuboid are rare but should be included in a differential for lateral midfoot pain, particularly in athletes with risk factors for BSIs. Although these fractures can typically be effectively managed conservatively, targeted regenerative medicine therapies may enhance bone formation in cases of delayed or nonunion. Although it is possible that this patient’s stress fracture may have healed without additional intervention, the relatively rapid resolution of her previously recalcitrant symptoms suggest that healing was likely enhanced with orthobiologic treatments. However, further studies including randomized controlled clinical trials are essential to further validate our findings and to standardize treatment approaches.
This clinical vignette conforms to all American Journal of Physical Medicine & Rehabilitation Resident Fellow Section CARE checklist guidelines and reports the required information accordingly (see Supplemental Checklist, Supplemental Digital Content 1, http://links.lww.com/PHM/A933).
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