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A Closer Look At Prophylactic Irradiation For Heterotopic Ossification Prevention After Foot Amputations
Partial ray resections and transmetatarsal amputations are common procedures in the field of podiatric surgery for those with diabetic foot infection or vascular disease. It is well known that biomechanical abnormalities and irregular foot structure lead to areas of increased pressure that are often the etiologies behind foot ulcerations.1 Another common cause of increased pressure in this patient population includes the formation of heterotopic ossification (HO) postoperatively from surgical intervention involving bone resection. This increase in bone formation can lead to overlying skin and tissue breakdown, wound infection and the need for subsequent surgeries.2 This article will investigate the pathophysiology of HO, diagnostic workup and treatment options, with a focus on radiation therapy.
Key Concepts In Heterotopic Ossification
The clinical definition of HO is an abnormal formation of mature lamellar bone in soft tissue.2 On plain film radiographs, HO will appear as a circumferential ossification with a radiolucent center, with a detectable radiologic density only present four to six weeks after bone injury or resection.2 One may also define this condition radiographically as more than three millimeters of bony regrowth on repeat radiographs.3,4
This process further divides into two groups; acquired and inherited HO. The acquired form is usually associated with either musculoskeletal or neurogenic trauma. In some rare instances, there are also hereditary forms of HO such as myositis ossificans progressiva, which produces bony growth in extraskeletal sites.2 One may also see HO formation following lower extremity trauma, including both acute injury and surgical procedures that include bony resection. The incidence of HO development following partial foot amputations is as high as 75 percent3, and can develop as early as three weeks following a traumatic event or surgical procedure.2 Risk factors for HO development can include performing bony resection with hand tools versus power tools, failure to irrigate after bone resection and a previous patient history of HO formation.3–5
Chalmers and colleagues proposed that osteogenic precursor cells, inducing agents and a permissive environment are all requirements for the formation of HO.6 The process takes place due to an inflammatory response resulting from amplification of biochemical mediators and growth factors, in which the biochemical signaling recruits mesenchymal stem cells that differentiate into cartilage and/or bone.7 These inflammatory cytokines are thought to play a key role in directing progenitor cells to transform into an osteogenic class of cells.8
Currently, there is no universal consensus on classification of HO in the foot and ankle based on imaging results. Boffeli and team developed a classification scheme for radiographic staging.9
• Grade I describes observance of an HO island in the soft tissues adjacent to bone;
• Grade II exhibits bone formation less than one cm in length;
• Grade III demonstrates more expansive bony formation, measuring greater than one cm in length; and
• the distinction of “a” or “b” after each grade indicates HO with or without an associated ulcer, respectively.9
While radiographs are the most commonly used diagnostic tool, three-phase bone scan is the most sensitive imaging modality.2 The initial blood pooling phase will detect an increase in signal uptake to the affected area just two-and-a-half weeks after injury, whereas typical radiographs can take up to four weeks to show ossification. Increase in activity during the delayed phases of bone scan can be present until six to 12 months after the injury.2
The development of HO can lead to a myriad of complications in the comorbid population, including induction of pathologic fractures, development of pressure ulcerations in weightbearing areas, increased pain, reducing ambulatory status and neurovascular impingement leading to neuropathy or limb ischemia.10 Complications like these can be limb-threatening for patients who acquire HO after undergoing a partial foot amputation. This can cause increased plantar pressure to the foot, thus increasing the likelihood of re-ulceration.10
What You Should Know About Treatment Options
Current treatment modalities for HO include the conservative use of off-loading pads or orthoses at bony prominences. If unsuccessful, surgical resection of the abnormal bone formation is often required.11 In patients who are at high risk for developing HO, particularly those with previous history of HO formation, the recommendation is to execute prophylactic management in the immediate post-operative course to prevent recurrence. This aims to disrupt the inductive signaling pathway, altering the osteoprogenitor cells in the target tissue, and modifying the environment that is conducive to osteogenesis.12
Prophylactic treatment is divided into two groups: primary prophylaxis for patients with initial trauma or those post-amputation thought to have a high risk of developing HO; or secondary prophylaxis for those with current HO who are undergoing bony resection.13 Medications, including non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates, have shown success in preventing HO, however they are not without systemic complications and are only for use in select patients.14 Radiation therapy is another method of prophylactic management, used successfully in the prevention of HO throughout various areas of the body.15 Radiation works by preventing the differentiation of mesenchymal progenitor cells into HO-forming osteoblasts.16 When directly comparing NSAID use to irradiation, there was an overall HO incidence of 11.1 percent for the 7 Gray (Gy) radiation group and 16 percent for NSAID group, showing that a single 7Gy fraction is superior.17 Bisphosphonates have questionable efficacy as they may simply delay HO mineralization as opposed to preventing it.13
Management Of Heterotopic Ossification With Irradiation
Most commonly, HO prophylaxis via radiation therapy is sufficient to prevent bony growth in a single-dose of irradiation.9 Higher and repetitive doses of radiation therapy can disrupt wound healing, causing the tissue to be in an inflammatory state, which is not ideal after surgical resection and wound closure.18 Either a linear accelerator or a Cobalt-60 unit with anteroposterior and posteroanterior opposed fields delivers the radiation.19 It is given at a low dose, between 700 and 800cGy and 6MV photons with the beam directed at the area of concern.9 The treatment can be given either pre- or postoperatively in regard to timing surrounding bony resection, however within 48 hours for each is key for the best result.15 Although studies show similar results in HO prevention, it is more common to dose radiation postoperatively.20
In a study by Redda and colleagues, high-risk patients received a single fraction of 7Gy to prevent HO, with excellent results, as 76 percent of patients experienced a complete response.21 Another study by Blount and team compared a single dose of 7Gy to a conventional 2Gy fractionation scheme and found 7Gy to be as efficacious with no increase in side effects.22 There have been few side effects reported with the use of low-dose radiation for the prophylactic treatment of HO in the foot and ankle. Some examples of these complications include wound healing delays (although this is associated with larger doses of radiation), secondary malignancies, delayed bone healing, joint swelling and infertility.15,21
Concluding Thoughts
HO formation can be a common struggle in our patient population for patients with diabetes post-amputation. It is important to perform a full work-up with imaging preoperatively to understand if a patient has a prior history of HO, as this is the biggest risk factor for future formation.3 If possible, it is ideal to use radiation therapy as prophylactic treatment in these amputation cases to prevent HO. Based on several comparative studies, radiation therapy is the most successful at prevention when compared to other prophylactic options. As demonstrated, it is easy to administer and has very little side effects. It is a very useful tool to consider when faced with the challenge of treating or preventing HO after partial foot amputation.
Dr. Kavanagh is a second-year podiatry resident at MedStar Georgetown University Hospital in Washington, D.C.
Dr. McKeon is a first-year podiatry resident at MedStar Georgetown University Hospital in Washington, D.C.
Dr. Miller is a current Research Fellow in the Department of Plastic Surgery Limb Salvage Division at Georgetown University Hospital in Washington, D.C.
Dr. Atves is an Associate of the American College of Foot and Ankle Surgeons, an Assistant Professor of Plastic Surgery at Georgetown University Medical Center, and Director of the MedStar Georgetown Foot and Ankle Research Fellowship in Washington, D.C.
Dr. Steinberg is a Fellow and Past President of the American College of Foot and Ankle Surgeons. He is the Co-Director of the Center for Wound Healing at MedStar Georgetown University Hospital and the Director of the Podiatric Residency Program at MedStar Washington Hospital Center in Washington, D.C.
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