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
Greece, 2004PMID 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.)
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
1998PMID 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, 2003PMID 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.
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, 2003PMID 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, 2001PMID 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, 1995PMID 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, 1994PMID 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, 1992PMID 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
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; 2003PMID 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; 1998PMID 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
Lahey Clinic, 2001PMID 11459729 -- "Re-irradiation for prophylaxis of heterotopic ossification after hip surgery." (Lo TC, Br J Radiol. 2001 Jun;74(882):503-6.)
U. Mississippi; 2012PMID 24674090 - [1]-- "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; 2014PMID 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
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.