Heterotopic Ossification and the Case for Developing a Risk Scoring System

Jeffrey C. Schneider, MDMedical Director, Trauma, Burn & Orthopedic Program, Spaulding Rehabilitation HospitalProgram Director, Boston-Harvard Burn Injury Model System Associate Chair, Dept. of Physical Medicine and Rehabilitation, Harvard Medical School

American Academy of Physical Medicine and Rehabilitation October 1, 2015

The contents of this lecture were developed in part under a grant from the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR #90DP0035).

Disclosures

• Definition: Ectopic formation of lamellar bone in soft tissue.• Clinical significance– Impair range of motion and function– Pain– Nerve compression with neuropathic symptoms

What is HO?

HO Occurs in a Variety of Conditions with Varying Frequency

• Spinal cord injury 10-20% symptomatic

• Brain injury 8-28%• Stroke 1%• Burn injury 2%• Orthopedic trauma 14-35%• Blast injury up to 60%• Hip arthroplasty 2-90%

Why Do Patients Develop HO?

• Pathogenesis is not well understood

• Areas of investigation– Immobility– Excessive force– Neurologic cascade

Role of Mobility

• Retrospective data review of 91 consecutive SCI patients to examine if immobility effects HO development– HO developed in 10/56 SCI patients that received delayed

passive ROM (>7 days after injury)– HO developed in 0/35 SCI patients that received early passive

ROM (< 7 days after injury)– HO development was not related to age, gender, neurologic LOI,

complete SCI, anticoagulation therapy, pressure sores, associated injury, etiology.

– Period of immobility followed by PROM resulted in HO development

Daud, Disabil Rehabil

Role of Excessive Force

• 216 Rabbits immobilized hind limb for 5 weeks• Intervention: Daily 5 minutes passive

movements, maximum range and forcibly exercised vs. no intervention.

• Results: – HO developed in the intervention group and not in

the immobilization only group

Michelsson, Clinical Ortho Rel Research

Role of Excessive Force

• Joints immobilized in extension developed extensor muscle HO and joints immobilized in flexion developed flexor muscle HO.

• Longer duration immobilization and more frequent exercising were associated with higher grade HO

• Diazepam during immobilization, anesthesia during manipulations and excision of femoral nerve did NOT prevent HO formation

• Forcible exercising without immobilization did not result in HO

Michelsson, Clinical Ortho Rel Research

Role of Neurologic Mechanism

• Impact of neural damage on osteogenesis• Four Groups of 50 Rats:– Brain, SCI and peripheral nerve injuries; control

• Intervention: bone graft implant• Results: – Brain and peripheral nerve injuries demonstrate

evidence of increased osteogenesis– SCI demonstrate decreased osteogenesis

Ottinowksi, Pat Pol

Active Investigation: Role of a Neurologic Mechanism.

Sullivan, Bone Joint Res; Reichel, J Hand Surg Am

Prevention and Treatment

• Prevention: NSAIDs and radiation used with modest results in some populations (SCI; THA), but lack of evidence in other populations and significant side effects limit their use.

• Treatment: Medications have limited evidence. Surgical excision last resort.

Challenges of studying uncommon problems

• For intervention studies, a relatively large number of research subjects are required to treat a low frequency problem

• Broad-based prophylaxis interventions unnecessarily treat many that will never develop the problem and subject them to adverse effects of the intervention

• To date there is a lack of research investigating interventions for HO in multiple patient populations.

Benefits of Identifying High Risk Patients

• Ability to identify those at high risk for HO development will:– Mitigate unnecessary and untoward effects of prophylaxis treatment for those

that will never develop HO– Facilitate design of intervention studies for prophylaxis– Facilitate human studies that examine the underlying mechanism

Burn Injury Population

Aim: Determine risk factors for development of HO at time of presentation to the hospital and develop a risk scoring system in the burn population.

Burn Injury Population

• There is sparse data on prevention of HO in burns

• Shafer, et al. 2008 retrospective review (n=57)– Bisphosphonates (etidronate) administered within 1 week

of admission (300mg mg bid) group demonstrated increased incidence of HO compared to control group

HO Risk Scoring System: Burn Model System Database as a Model

•Burn Model System National Database•Longitudinal data• Detailed demographic and medical data• 20+ years• 5000+ patients• 6 BMS centers• Data at hospital discharge, and 6 , 12 and 24 months

•Data is publicly accessible

•SCI and TBI Model System Databases

HO Risk Scoring System: Methodology

•Burn Model System National Database 1994-2013

•Inclusion Criteria:• Age 18-65, > 20% TBSA that requires allograft• Age >65, >10% TBSA that requires allograft• Electrical injury that requires allograft• Burn to critical area (head, hand, feet) that requires allograft

•Covariates known at admission:• Demographic: Age, gender, race• Medical: etiology, place of burn (indoor/outdoor), inhalation injury,

bone exposure, burn size, burn location, burn location that required grafting* (location of deep burns)

HO Risk Scoring System: Methodology

•Analysis Plan• Descriptive statistics calculated for those with and without HO

• Missing data was handled with multiple imputation

• Logistic regression analyses performed to determine significant early predictors of HO development

• Overall model performance assessed by c-statistic

• HO risk scoring system developed using Framingham Heart Study methodology

Results: Characteristics of Population

Characteristics With HO Without HONumber of subjects 98 2699Age, mean year± SDs 42.4 ± 13.3 41.5 ± 15.8Male, number (%) 81 (83) 2039 (76)Ethnicity, n (%)

White 72 (73.5) 1874 (70)Black, non-Hispanic 7 (7.1) 349 (13)Hispanic 11 (11.2) 312 (11.6)Other 8 (8.2 ) 158 (4.9)

Concomitant Medical Problems, n (%)

30 (31%) 919 (34%)

TBSA Burn, mean percent ± SD 48.5 ± 18.1 17.7 ± 15.2Etiology, n (%) Fire/Flame 85 (87) 1621 (60) Scald 2 (2) 238 (8.8) Contact with hot object 1 (1) 129 (4.8) Grease 1 (1) 244 (9) Chemical 3 (3) 54 (2) Electricity 3 (3) 178 (6.6) Flash 3 (3) 120 (4.5) Other 0 (0) 88 (4.3)

Incidence = 3%

Results: Logistic Regression Analysis

Variable Odds Ratio 95% CI p-value

TBSA burn < 30% 1.13 1.04-1.24 0.004

TBSA burn > 30% 1.04 1.02-1.06 <0.001

Head and neck graft 2.72 1.70-4.32 <0.001

Arm graft 5.06 1.63-15.76 0.005

Trunk graft 2.40 1.30-4.42 0.005

C-statistic = 0.92

Results: Logistic Regression Analysis

• C-statistic – Common statistical measure to compare goodness

of fit for logistic regression models– Area under the Receiver Operating Characteristic

(ROC) curve• 0.5 = no better than chance• 1.0 = perfect prediction

• C-statistic = 0.92 Excellent Model Discrimination

HO Scoring System

Predictor PointsTBSA: 11-20 2 21-30 4 31-40 6

41-60 7 61-80 8 81-90 9 91-100 10Arm graft 2Head/neck graft 1Trunk graft 1

HO Scoring System

Study limitations

• Retrospective database study– HO may be underdiagnosed

• Generalizability– 6 Large centers– Database inclusion criteria selects more severe burns

• Limited overall number of patients with HO (98) – Power?

Discussion

•Development of a scoring system is able to stratify HO risk and aids design of future diagnostic and intervention studies.

•Focusing on factors present at hospital presentation enables risk stratification on admission.

•Large multicenter datasets, such as the Model System Databases, are useful tools to develop risk stratification of uncommon problems, such as HO.

Acknowledgments

• Colleen M. Ryan, MD• Benjamin Levi, MD• Prakash Jayakumar, MBBS• Katie Mathews, BA• Vivan Shie, BS• Lynne Friedlander, MEd• Betty Chernack, MD

• Karen Kowalske, MD• Dagmar Amtmann, PhD• Nicole Gibran, MD• Paul Cederna, MD• Aviram Giladi, MD• David Herndon, MD• Richard Goldstein, PhD• Ross Zafonte, DO

The contents of this lecture were developed under a grant from the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR #90DP0035,). NIDILRR is a Center within the Administration for Community Living (ACL), Department of Health and Human Services (HHS). The contents of this lecture do not necessarily represent the policy of NIDILRR, ACL, HHS, and you should not assume endorsement by the Federal Government.

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