1. Heterotopic Ossification: Incidence and Prevention May 17, 2012 Dr. Kristi Wood

2. Introduction Definition: ectopic bone formation within muscles and connective tissues

3. Background First described in 1883 by Reidel Acquired many names –Paraosteoarthropathy –Myositis ossificans –Periarticular new bone formation –Periarticular ectopic ossification –Neurogenic osteoma –Neurogenic ossifying fibromyopathy –Heterotopic calcification

4. Etiology Trauma –Frequent complication following THA and acetabular surgery Abductor compartment most commonly involved Neurologic injury Genetic abnormality

5. Incidence 3-90% following THR –42-57% average 1 3-7% clinically significant, up to 25% Increased risk following hip resurfacing (RR 1.6) 2 Following TKA: low (0.9%) 3 1-Spinarelli et al (2011) Musculoskelet Surg. 95:1-5. 2-Smith et al (2010) Acta Orthopaedica. 81(6):684-695. 3-Atamaz et al (2006) Acta Orthop Traumatol Turc. 40(3):202-6

6. Risk Factors Male Old age Hx HO in ipsi > contra hip Hip fusion Hypertrophic arthritis Ankylosing spondylitis Diffuse idiopathic skeletal hyperostosis Paget’s disease Post-traumatic arthritis Osteonecrosis Rheumatoid arthritis 1-Board et al (2007) J Bone Joint Surg [Br]. 89-B:434-40.

7. Risks related to surgical technique Extent of soft tissue dissection Bone trauma Persistence of bone debris –Reamings, marrow or dust Hematoma Lateral approach 1 –Lower risk with posterior 2 (vs anterolateral/transtrochanteric) ? Increased risk with Cemented 1 vs uncemented 3 Psoas tendon release 1-Pavlou et al (2012) Hip Int. 22(1):50-5. 2-Ashton et al (2000) J Orthop Surg. 8:53-7. 3-Spinarelli et al (2011) Musculoskelet Surg. 95:1-5.

8. Theories of Pathophysiology Inappropriate differentiation of pluripotent mesenchymal stem cells –Interplay b/w local and systemic factors Over-expression of BMP-4 PG-E 2 COX-2 pathway (vs Warfarin)

9. Brooker Classification Grades: 1 – islands of bone 2 – bony spurs, > 1 cm gap between bony ends 3 – gap < 1 cm 4 – apparent ankylosis

10. Brooker Classification Grades 1-2 –Does not influence the outcome of THR Grades 3-4 –Less favourable outcome Puhl et al (2005) Strahlenther Onkol 181:529-33.

11. Presentation Typically asymptomatic Presents with: –Impingement –Instability –Decrease ROM/ankylosis –Nerve irritation –Trochanteric bursitis Pain uncommon

12. Investigations Xray – no abnormality for 4-6 weeks –Increased uptake on bone scan as early as 3 weeks post-op Rises in osteoclastic and osteoblastic markers as early as 1 week Extensive bone formation within 3 months but full maturation takes up to 1 year

13. Prevention MAINSTAYS NSAIDs Radiotherapy NEW THERAPEUTIC MODALITIES – under investigations

14. NSAIDs Reduce incidence of HO by 1/2 - 2/3 S/E –GI bleeding –Renal impairment –Exacerbation of asthma –?Risk of bleeding from anti-platelet effect

15. NSAIDs – Which one? Indomethacin remains gold standard 1 –Only drug proven effective after acetabular surgery Naproxen, diclofenac equally as effective 1 Ibuprofen –Decreased HO but no change in clinical outcome –Increased major bleeding complications Rofecoxib 2,3 /celecoxib 1 –equally effective with significantly less GI s/e –? Safety of COX-2 inhibitors re: cardiovascular 1-Macfarlane et al (2008) Expert Opin Parmacother. 9(5):767-86. 2-van der Heide et al (2007) Acta Orthop 78(1):90-4. 3-Grohs et al (2007) Acta Orthop. 78(1):95-8.

16. NSAIDs – Which one? Indomethacin –Effective in reducing HO after hip arthroscopy Especially in male patients undergoing osteoplasty for correction of FAI 1-Bedi et al (2012) Am J Sports Med. 40(4):854-63.

17. NSAIDs – Dose/Duration Indomethacin – typically 25 mg PO TID x 5-6 weeks 1 –Increased rate of non-union of long bones Concern with trochanteric osteotomy or uncemented components At least 7 days 2,3 1-Board et al (2007) J Bone Joint Surg [Br]. 89-B:434-40. 2-Fijn et al (2003) Pharm World Sci. 25(4):138-45. 3-van der Heide et al (2007) Acta Orthop 78(1)90-4.

18. Radiotherapy Marginally more effective than NSAIDs at preventing Brooker grades 3-4 Dose: variable, many doses studied –7-8 Gy given in a single dose seems both efficacious and convenient 1 Timing/duration: –Pre-op (< 4 hours before) or post-op (within 72 hrs) 1 1-Board et al (2007) J Bone Joint Surg [Br]. 89-B:434-40.

19. Radiotherapy Side effects –Testis very radiosesitive Decreased sperm count with > 0.2 Gy –dose 0.11 Gy with testicular shield (safe) –Slowed # healing trochanteric nonunion Uncemented implants (shielding?) No documentation of radiation-induced tumours in HO prophylaxis -no radiation induced tumour with receiving < 30 Gy (50 yr review)

20. Radiotherapy – Non-hip surgery For patients at high risk for developing further HO, prophylactic RT appears to be a safe and effective adjunct to surgery in prevention of HO recurrence (30 patients) 1 –Elbow –MCP –Knee 1-Mishra et al (2011) J Med Imaging Radiat Oncol. 55(3):333-6

21. Combination NSAIDs + radiation Lowest risk of HO Especially useful in prophylaxis against recurrent HO after excision

22. NSAIDs vs Radiotherapy No significant difference between NSAIDS or radiation in prevention of HO (statistically or clinically) (Systematic review and meta-analysis) 1 Risks: no significant difference, but wide 95% CI so ? differences possible in future studies 1 Costs (Medicare data) 2 : –NSAIDS - 19.71 –Radiation therapy - 898.55 1-Vavken et al (2009) Clin Orthop Relat Res. 467:3283-3289 2-Strauss et al (2008) Int J Radiat Oncol Biol Phys. 71:1460-64

23. New therapeutic modalities Under investigation Noggin BMP type 1 receptor inhibition Nuclear retinoic acid receptor  (RAR-) 1 –Retinoic acid signalling is a strong inhibitor of chondrogenesis –RAR- agonists are potent inhibitors of HO (in mice) Free radical scavengers 1-Shimono et al. (2011) Nat Med. 17:454

24. Current recommendations 2007 JBJS [Br] – no indication for prophylactic treatment following routine replacement 1 –Primary prevention for ‘high risk’ Defiinition varies –Prophylaxis for those undergoing excision of HO 2012 J Ortho Trauma - Italian multicentre trial – findings favour routine administration of prophylaxis after THA 2 –Used celecoxib 200 mg BID for 14-20 days –23% vs 55% HO (treated vs untreated, p<0.0001) –Treated-no Brooker 3-4 vs untreated-Brooker 3-4 8.9% 1-Board et al (2007) J Bone Joint Surg [Br]. 89-B:434-40. 2-Barbato et al (2012) J Orthopaed Traumatol. Published online.

25. Conclusions HO is common after THA, moreso with resurfacing NSAIDs are effective, safe, cost-wise option to prevent HO Gold standard is indomethacin but celecoxib/naproxen/diclofenac are alternatives –Indomethacin – 25 mg PO TID x 5-6 weeks Consider radiotherapy in pt’s undergoing HO excision –7-8 Gy single dose 4 hrs before-72 hrs after OR