# Radiation Oncology/Heterotopic ossification

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## Etiology

* HO is a dystrophic calcification, occurring in the setting of soft-tissue insult
** Traumatic - fractures, dislocations, contusions, operations, burns
** Neurogenic - spinal trauma, head injury
** Genetic - fibrodysplasia ossificans progressive (FOP), progressive osseous heteroplasia (POH), Albright's hereditary osteodystrophy (AHO)
* Locations
** Hip most common - typically after ORIF (52% any grade, 19% Grade III-IV) or THA (43% any grade, 9% Grade III-IV)
** Elbow common with burn injuries
** Other major joints sometimes affected
** Rarely soft tissue locations not associated with joints (quadriceps contusions, abdominal muscles after surgery)
* Clinical Presentation
** Most commonly incidental finding on radiograph
** If symptomatic, typically decreased range of motion; can sometimes present as complete ankylosis
* Risk factors (best studied for hip; limited info for other organs)
** History of HO most important (60-90% risk)
Hip surgery risk factors :
| Patient | Clinical | Surgical |
| History of HO | T-type fracture | Lateral/anterolateral approach |
| Male | Fracture with dislocation | Trochanteric or femoral osteotomy |
| Hypertrophic OA | Multiple injuries | Extended iliofemoral approach |
| Ankylosing spondylitis | | |
| Skeletal hyperostosis | | |
| Prior hip surgery | | |

## Pathophysiology

* Heterotopic Ossification of the Elbow
* Heterotopic Ossification of the Hip
* Inappropriate differentiation of pluripotent mesenchymal cells into osteoblasts
* Dysfunction of bone formation/remodelling process
* Components necessary
** Osteogenic precursor cells
** Inducing agents (BMPs likely involved)
** Permissive environment
* RT 30/1 given to rats within first week of healing prevents bone repair, but same dose during second week has no effect. It is speculated that osteogenic progenitors are present early, and are radiosensitive due to high mitotic rate as they are proliferating and differentiating into osteoblasts and chondrocytes
* From clinical trials, it appears this window is during first 3-4 days

## Classification

Brooker Classification: (radiographic)
* I - islands of bone within the soft tissue (clinically silent)
* II - bone spurs from the pelvis or proximal femur; >= 1 cm gap between opposing surfaces (clinically insignificant)
* III - bone spurs from the pelvis or proximal femur; < 1 cm gap between opposing surfaces (clinically significant)
* IV - ankylosis (clinically significant)

## Treatment Overview

* Clinically significant HO - surgery
* Prophylaxis modalities
** NSAIDs (Indomethacin)
** RT - better by meta-analysis, but absolute gain <2%. Dose dependent, with 6/1 comparable to NSAIDs, and higher doses better
* RT schedule
** Typically 7 Gy - 8 Gy single fraction; 5.5/1 appears insufficient
** Timing <4 hours pre-operatively OR <72 hours post-operatively
* RT side effects
** Carcinogenesis concern (see #Second malignancy risk)
** Trochanteric non-union (but data from older surgical techniques that had high nonunion rates in nonirradiated patients as well)
** Testicular tolerance (for hip prophylaxis)
*** One abstract suggests that 8 Gy hip dose results in mean testicular dose of 25 cGy -> reversible azoospermia
*** Testicular shielding reduced dose by ~50%
* Data mostly available for hip, although other sites are treated as well

## RT vs. NSAIDs

Meta-analysis
* Greece, 2004 PMID 15465207 -- "Radiotherapy vs. nonsteroidal anti-inflammatory drugs for the prevention of heterotopic ossification after major hip procedures: a meta-analysis of randomized trials." (Pakos EE, Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):888-95.)
** Meta-analysis. 7 randomized trials, 1143 patients.
** Prevention: Brooker Grade 3-4: RT more effective than NSAIDs, RR 0.42 (SS), absolute risk difference 1.8%; Any Grade: RR 0.75 (NS)
** Subgroups: early preop (16-20 hours) not effective; 6 Gy/fx comparable to NSAIDs; higher doses better (SS)
** Conclusion: RT almost twice more effective than NSAIDs, but absolute benefit gain small (<2%)
Randomized
* Wurzburg, Germany (1995-1996) -- RT 7/1 vs NSAID x 2 weeks
** Randomized. 100 patients, total hip replacement. Arm 1) prophylactic RT 7/1 given 16-20 hours before surgery vs. Arm 2) NSAID (Voltaren 2 x 75 mg/d x 2 weeks) starting first postop day. Historical control 100 patients with no prophylactic therapy
** 1998 PMID 9788422 -- "Preoperative irradiation versus the use of nonsteroidal anti-inflammatory drugs for prevention of heterotopic ossification following total hip replacement: the results of a randomized trial." (Kolbl O, Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):397-401.)
*** Outcome: HO preop RT 48% vs. NSAID 11% (SS). For clinically significant HO (Brooker III-IV), no difference between RT and NSAID. Historical control 68% (SS)
*** Conclusion: RT and use of NSAID can reduce incidence of clinically relevant HO after THR
Risk of Long Bone Non-Union with NSAIDs
* JBJS, 2003 PMID 12892193 -- "Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion." (Burd TA, J Bone Joint Surg Br. 2003 Jul;85(5):700-5.)
** 282 patients with open reduction and internal fixation of an acetabular fracture randomized to XRT or indomethacin.
** XRT was 800 cGy x 1 within 72 hrs of surgery. Indomethacin was 25 mg tid x 6 wks.
** When comparing patients who received indomethacin with those who did not, a significant difference was noted in the rate of nonunion (26% v 7%; p = 0.004)
** Conclusion: Patients with concurrent fractures of the acetabulum and long bones who receive indomethacin have a significantly greater risk of nonunion of the fractures of the long bones when compared with those who receive XRT or no prophylaxis.

## Fractionation (Hip)

* Initial dose chosen in the 1980s was 20/10, based on pediatric observations of bony growth inhibition
* In 1988, a retrospective comparison of 20/10 with 10/5 showed no difference. RT was effective if delivered <=96 hours after surgery
* Also in 1988, a retrospective review of 7/1 schedule found it effective. All but 1 patients were treated <=72 hours
* In 1992, randomized comparison of 10/5 vs. 8/1 in <=96 hours after surgery found no difference
* In 1994, randomized comparison of preop RT 7-8/1 in <4 hours prior to surgery vs. postop RT 7-8/1 in <48 hours after surgery found no difference
* In 1995, in order to bring the dose even lower, retrospective comparison of 7/1 with 5.5/1 in <=72 hours after surgery found higher failure rate with 5.5 Gy
* In 1997, randomized trial of preop RT 7/1 in <4 hours vs. postop RT 17.5/5 in <72 hours found benefit for postop RT. The poor outcomes were seen in patients with significant disease (Grade III-IV) treated with preop RT. There was no difference in no/low risk disease (Grade 0-II)
* In 2003, a randomized comparison of 10/5 vs. 5/2 in <=96 hours after surgery found no difference in clinical HO
* Therefore, post-op RT 7/1 within 72 hours (and possibly up to 96 hours) is effective. RT 5/2 post-op may be effective clinically, but RT 5/1 post-op was not effective. Preop RT 7/1 is effective for low disease burden (preventive, or Grade I-II) if given <4 hours prior to surgery, and may be easier logistically
* Cornell, 2003 PMID 14513439 -- "The efficacy of 500 CentiGray radiation in the prevention of heterotopic ossification after total hip arthroplasty: a prospective, randomized, pilot study." (Padgett DE, J Arthroplasty. 2003 Sep;18(6):677-86.)
** Randomized. 59 patients. Treated with 10/5 vs. 5/2 in <=96 hours
** Treatment failure: 10/5 3% vs. 5/2 7% (p=0.09)
** Conclusion: 5/2 appears effective in preventing clinically significant HO
* German Cooperative Group, 2001 PMID 11697322 -- "Radiation prophylaxis for heterotopic ossification about the hip joint--a multicenter study." (Seegenschmiedt MH, Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):756-65.)
** Patterns of care study in 1999. 114 institutions, 5989 hips treated.
** RT dose: preop 7/1 most common (5-10 Gy); postop 7/1 most common (5-16). RT timing: preop 0.5-24 hours; postop 1-120 hours
** Failure rate: radiographic 11%, functional 5%. If treated >8 hours pre-op or >72 hours post-op higher failure rate
** Conclusion: Single dose 7 Gy has become standard in most institutions, either preop or postop
* Erlangen HOP2, 1997 (1992-1995) PMID 9300751 -- "Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy." (Seegenschmiedt MH, Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):161-71.)
** Randomized. 161 patients. Preop RT 7/1 (<4 hours) vs. Postop RT 17.5/5 (<=96 hours). Portals periacetabular and intertrochanteric soft tissues
** Failure rate: radiological overall 11%; preop 19% vs. postop 5% (SS). Functional 14% Highest failure in pre-op RT for Brooker Grade III-IV (39%), otherwise preo-op and post-op outcomes comparable
** Conclusion: preop RT inferior to postop RT, except in Grade I-II, where no difference
* Erlangen HOP1, 1997 (1987-1992) PMID 9300751 -- "Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy." (Seegenschmiedt MH, Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):161-71.)
** Randomized. 249 patients, high risk. Post-op RT 10/5 vs. 17.5/5. Portals periacetabular and intertrochanteric soft tissues
** Failure rate: radiological overall 9%; low dose 11% vs. high dose 6% (NS). Functional 7%
** Conclusion: no difference in post-op dose
* Lahey Clinic, 1995 PMID 7713977 -- "Single-dose irradiation for the prevention of heterotopic ossification after total hip arthroplasty. A comparison of doses of five hundred and fifty and seven hundred centigray." (Healy WL, J Bone Joint Surg Am. 1995 Apr;77(4):590-5.)
** Retrospective. 107 hips in 94 patients. Post-op RT, either 7/1 (88 hips) or 5.5/1 (19 hips)
** Failure rate: radiographic 7/1 10% vs. 5.5/1 63% (SS); symptomatic 0/88 vs. 2/19
** Conclusion: recommend 7/1
* Rochester, 1994 PMID 8083129 -- "Randomized trial comparing preoperative versus postoperative irradiation for prevention of heterotopic ossification following prosthetic total hip replacement: preliminary results." (Gregoritch SJ, Int J Radiat Oncol Biol Phys. 1994 Aug 30;30(1):55-62.)
** Randomized, multi-institutional. 98/122 patients with risk factors, following elective hip replacement. Treated with pre-op RT 7-8/1 <4 hours vs. post-op RT 7-8/1 <48 hours. Fields to soft tissues between periacetabular region of pelvis and intertrochanteric portion of femur. Median F/U 9.5 months
** Failure rate: radiographic preop 26% vs. postop 28% (NS); clinical 2% vs. 5% (NS)
** Conclusion: no difference between preop and postop
* Rochester, 1992 PMID 1541613 -- "Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field." (Pellegrini VD Jr, J Bone Joint Surg Am. 1992 Feb;74(2):186-200.)
** Randomized. 62 hips in 55 patients at high risk. Treated with postop RT 8/1 vs. 10/5 limited field (includes lateral aspect of greater trochanter). Minimum F/U 6 months
** Failure rate: Single fraction 21% vs. multifraction 21%
** Conclusion: Single fraction effective.
* Lahey Clinic, 1988 (1981-1986) PMID 3136510 -- "Heterotopic bone formation after hip surgery: prevention with single-dose postoperative hip irradiation." (Lo TC, Radiology. 1988 Sep;168(3):851-4.)
** Retrospective. 23 patients at high risk. RT post-op 7/1, given <=72 hours. Minimum F/U 6 months
** Failure rate: 4%
** Conclusion: 7/1 appears comparable to fractionated doses
* UCLA, 1988 (1980-1986) PMID 3343154 -- "The use of postoperative irradiation for the prevention of heterotopic bone formation after total hip replacement." (Sylvester JE, Int J Radiat Oncol Biol Phys. 1988 Mar;14(3):471-6.)
** Retrospective. 28 patients at high risk. 1980-1982 RT 20/10, then 1982-1986 10/5. Median F/U 1 year
** Conclusion: 10/5 as effective as 20/10, and should begin as early as possible, in <4 days

## Other sites

Elbow
* Incidence
** Isolated dislocation: 3-10%
** Dislocation + fracture: 15-20%
* Rush Univerisity; 2011 PMID 22016869 -- "Radiation therapy for heterotopic ossification prophylaxis afer high-risk elbow surgery." (Strauss JB, Am J Orthop (Belle Mead NJ). 2011 Aug;40(8):400-5.)
** Retrospective. 44 patients, status post surgery and single-fraction radiation, with NSAID use. Median follow up 4.5 months
** Outcome: radiographic evidence of HO in 48%, however in all cases small and not functionally significant. No complications
** Conclusion: RT in combination with NSAID is safe and efficacious
* Cleveland Clinic; 2010 (1993-2006) PMID 20637977 -- "Postoperative single-fraction radiation for prevention of heterotopic ossification of the elbow." (Robinson CG, Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1493-9.)
** Retrospective. 36 patients, 72% had evidence of HO prior to surgery, elbow surgery followed by single fraction 7 Gy RT (median 1 day postop). Median F/U 8.7 months
** Outcome: new HO 8%; all patients improvement in ROM from baseline
** Conclusion: RT after surgery associated with favorable functional and radiographic outcomes
** Comment (PMID 21195881): most of these were for secondary prophylaxis, after development of HO, rather than primary prophylaxis after the initial injury
* NYU; 2003 PMID 15156818 -- "Prevention of heterotopic ossification at the elbow following trauma using radiation therapy." (Stein DA, Bull Hosp Jt Dis. 2003;61(3-4):151-4.)
** Retrospective. 11 patients. Trauma followed by ORIF, and post-op RT 7/1 in <=72 hours. Minimum F/U 12 months
** Failure: radiographic 27%, clinical 9%. No healing complications
* Frankfurt; 2001 (Germany) PMID 11341414 -- "Radiation therapy for the prevention of heterotopic ossification at the elbow." (Heyd r, J Bone Joint Surg Br. 2001 Apr;83(3):332-4.)
** Case series. 9 patients with clinically significant HO at elbow. Post-op RT, 5 patients 5/2, 4 patients 6-7/1. Mean F/U 7.7 months
** Failure rate: 0; 8/9 patients had clinical improvement
* Miami; 1998 PMID 9160948 -- "Early excision of heterotopic ossification about the elbow followed by radiation therapy." (McAuliffe JA, J Bone Joint Surg Am. 1997 May;79(5):749-55.)
** Retrospective. 8 patients with HO at elbow. Post-op RT 10/5. Median F/U 4 years
** Failure: 0

## Re-treatment

* Lahey Clinic, 2001 PMID 11459729 -- "Re-irradiation for prophylaxis of heterotopic ossification after hip surgery." (Lo TC, Br J Radiol. 2001 Jun;74(882):503-6.)
** Case reports. Single dose-reirradiation
** Conclusion: possible and safe

## Dosimetry

* Louisville; 2008 PMID 18982191 -- "Evaluation of scrotal and testicular radiation doses for heterotopic ossification prophylaxis." (Patel H, Am J Orthop. 2008 Sep;37(9):E163-6.)
** Prospective. HO in hip/femur region. TLD placed inside and outside testicular shield
** Outcome: mean inside dose 10 cGy, mean outside dose 20 cGy
** Conclusion: Given that sperm abnormalities have been reported with 15 cGy, young males should be counseled and treated with a testicular shield

## Second malignancy risk

1 case report exists in the literature
* U. Mississippi; 2012 PMID 24674090 - -- "Radiation-induced sarcoma following radiation prophylaxis of heterotopic ossification." (Mourad WF, Pract Radiat Oncol. 2012 Apr;2(2):151-154.)
** 7 Gy x 1. High grade undifferentiated sarcoma of the proximal thigh diagnosed 16 months after prophylactic RT in a 51 yo.
* University of Cambridge; 2014 PMID 25089852 -- "Prophylactic radiotherapy against heterotopic ossification following internal fixation of acetabular fractures: a comparative estimate of risk." (Burnet NG, Br J Radiol. 2014 Oct;87(1042):20140398. doi: 10.1259/bjr.20140398. Epub 2014 Aug 4.)
** Estimation of competing risks:
*** Risk of fatal cancer by ICRP (International Commission on Radiologic Protection) risk: 1:1,000 to 1:10,000
*** Risk of fatal cancer by Trott and Kemprad method: 1:3,000; may rise to 1:2,000 for younger patients and fall to 1:6,000 for elderly patients
*** Risk of gastric bleeding or perforation from indomethacin: 1:180 to 1:900 in older patients
*** Risk of death from reoperation for HO: 1,4000 to 1:30,000
** Conclusion: Results endore multidisciplinary management

## Reviews

* Harvard, 2006 - PMID 16863921 — "Heterotopic ossification: Pathophysiology, clinical features, and the role of radiotherapy for prophylaxis." Balboni TA et al. Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1289-99.