Fracture healing Mr Lee Van Rensburg FRCS Basic

Fracture healing Mr Lee Van Rensburg FRCS Basic sciences course 2014 Thanks to: Matthew Porteous Henry Wynn Jones

FEBRUARY 2008 · VOLUME 90 -A · SUPPLEMENT 1

Subject · · · · Bone Structure - Done Indirect healing Direct healing Strain theory Blood supply Inhibition/ Augmentation What’s new? Approach to Non union

Fracture Healing · Indirect healing (Secondary, Callus) · Direct healing (Primary)

Fracture Healing · Indirect healing (Secondary, Callus) Formation of bone via tissues which undergo change in material structure until skeletal continuity is restored · Direct healing (Primary)

Indirect Fracture Healing · Impact

Indirect Fracture Healing · Impact · Haematoma ¨ ¨ Haemopoetic cells secrete growth factors Fibroblasts, osteoprogenitor cells, mesenchymal cells

Indirect Fracture Healing · Impact · Haematoma · Inflammation ¨ Granulation tissue * 100% strain at failure

Indirect Fracture Healing · · Impact Haematoma Inflammation Soft Callus ¨ 2 weeks ¨ 10% strain at failure

Indirect Fracture Healing · · · Impact Haematoma Inflammation Soft Callus Hard Callus ¨ 2% strain at failure

Indirect Fracture Healing · · · Impact Haematoma Inflammation Soft Callus Hard Callus Remodeling ¨ ¨ Years Wolff’s law

Indirect Healing Movement at fracture strength site time

VOL. 84 -B, No. 8, NOVEMBER 2002

Perren’s Strain theory (interfragmentary strain theory) · Interfragmentary strain determines the subsequent differentiation of fracture gap tissue · 10 to 100% fibrous tissue · 2 to 10% - cartilage and enchondral ossification · < 2% - bone

Indirect Healing Movement · Movement is desirable · Provided the movement does not disrupt the healing cells 10 mm 40 mm 5 mm 10 mm

Resorbtion Small gap with movement High strain stimulates resorbtion Resorbtion increases gap decreases strain

Comminuted fragment

Indirect Fracture Healing

Intramembranous Osification (Periosteal boney callus) Formation of bone on, or in, fibrous connective tissue (formed from condensed mesenchyme cells) Vs Enchondral ossification Hyaline cartilage first

Direct Fracture Healing · Fracture stable ¨ No movement under physiological load · Bone ends compressed ¨ Can occur in cortical and cancellous bone

Direct Fracture Healing · No callus · Cutting cones cross fracture site · Lay down new osteones directly

Direct Healing · Movement ¨ ¨ Undesirable Even small amounts likely to disrupt healing

Absolute stability

Wrong

Relative stability

Complete instability

Fractures MUST have a blood supply to heal

Bone blood supply · Endosteal ¨ Inner 2/3 rds · Periosteal ¨ Outer 1/3 rd · Disrupted by a fracture · Further damaged by surgery

Bone blood supply Reaming · Damages endosteal blood supply · Blood flow reverses BUT · Stimulates callus

Bone blood supply Plates · Damage periosteal blood supply · Causes underlying necrosis

Bone blood supply plates · Can be reduced by ¨ ¨ LCDCP Locking plate

Augmentation of fracture healing · Inhibition · Augmentation

VOL. 89 -B, No. 12, DECEMBER 2007

Inhibition · Patient ¨ Age - Some evidence (skeletally mature) * Clavicle, NOF ¨ ¨ ¨ Gender - No (male higher energy) Diabetes – Yes double time to union Anaemia – Some, Chronic iron defficiency Nutrition – If malnourished yes PVD – Not directly assesed but if injure vessel 40% longer to unite Hypothyroidism – Yes at risk Postmenopausal female VOL. 89 -B, No. 12, DECEMBER 2007

Inhibition · Medication ¨ NSAID

· NSAIDs reduce vascularity around fracture. · Additional reduction in healing independent of blood flow. · Best to avoid in fractures prone to non union or poor vascularity. VOLUME 88 -A · SUPPLEMENT 3 · 2006

· COX 2 NSAIDS inhibit fracture-healing more than non-specific NSAIDS. · Magnitude of effect is related to duration of treatment. · On discontinuation, prostaglandin E 2 levels are gradually restored. VOLUME 89 -A · NUMBER 1 · JANUARY 2007

Inhibition · Medication ¨ ¨ ¨ NSAID – Yes Corticosteroids – Appears to be longer Statins – Conflicting animal, no human? beneficial Smoking – Yes for tibia 40% more likely non union Nicotine replacement – conflicting high dose no, low dose may improve, better than smoking Alcohol – Yes dose dependent

Inhibition · Medication ¨ Antibiotics * Quinolones * Rifampicin * High dose local Gentamycin ¨ Anticoagulants (hep and warfarin) * Yes animal model * No human studies ¨ Bisphonates

· Bisphonates – inhibit Osteoclasts. · Standard doses (osteoporosis), do not inhibit healing. · Do delay remodeling of callus. · Higher doses eg. for Pagets or metastatic bone disease not clear. VOLUME 87 -A · NUMBER 7 · JULY 2005

Inhibition · Timing * Viz NSAIDS and steroids more effect in inflammatory phase

Augmentation of fracture healing · · · Bone Grafts Bone Graft Substitutes Osteo-inductive agents Mechanical methods Ultrasound Electromagnetic fields

Bone Graft Properties · Osteoconduction ¨ 3 D scaffold · Osteo-induction ¨ Biological stimulus * Mesenchymal cells Osteoprogenitor cells · Osteogenic ¨ Contains living cells that can differentiate to from bone · Structural

Autograft

Osteo-inductive agents · Transforming growth factor Superfamily ¨ ¨ ¨ BMPs GDFs (growth differentiation factors) Possibly TGF-β 1, 2, and 3.

Demineralized bone matrix · Acid extraction of allograft ¨ ¨ ¨ type-1 collagen non-collagenous proteins osteoinductive growth factors: BMP, GDFs, TGF 1, 2 + 3 Different companies , processing different ALLOGRAFT, no reported infection transmission

BMP 7 (OP-1) · Tibial non-unions ¨ RCT OP 1 v autogenous graft ¨ No difference in union rate ¨ Less infections ¨ Friedlaender et al J Bone Joint Surg Am. 2001; 83 Suppl 1(Pt 2): S 151 -8. · Open Tibia ¨ OP 1 v control ¨ Less secondary interventions ¨ Mc. Kee et al Proceedings of the 18 th Annual Meeting of the Orthopaedic Trauma Association; 2002 Oct 11 -13

· OP 1 · 653 cases, overall success rate 82% Injury, Int. J. Care Injured (2005) 36 S, S 47—S 50

· BMP £ 3000 per vial · Mean number of operations * Pre BMP 4. 16 * Post BMP 1. 2 · Hospital stay and cost * Pre BMP 26. 84 days and £ 13, 844. 68 * Post BMP 7. 8 days and £ 7338. 40 · Overall cost using BMP-7 - 47. 0% less. Injury, Int. J. Care Injured (2007) 38, 371— 377

BMP 2 · BESTT · Open tibial fractures ¨ ¨ Control v 6 mg v 12 mg Higher dose * * Fewer secondary procedures accelerated time to union improved wound-healing Reduced infection rate Govender et al Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002; 84: 2123 -34.

Osteoconductive Making the break. Karin Hing's fellowship has brought independence to pursue her work on bone graft substitutes.

Osteoconductive · RCT’s osteoconductive materials Vs autograft encouraging. ¨ Calcium sulfate * Predictable resorption * Resorbs a little too fast ¨ Calcium phosphates * Tricalcium phosphate TCP * Hydroxyapatite * TCP is more rapidly absorbed than hydroxyapatite, TCP inadequate when structural support is desired ¨ Injectable osteoconductive cements * Several variations

Concentrated bone marrow aspirate · Non union – 75 -95% success · Aseptic non-unions ¨ ¨ Only works if adequate cell concentration Hernigou Pet al Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am. 2005; 87: 1430 -7 · Concentrated BM aspirate ¨ ¨ Ongoing multicentre RCT in France Open tibial fractures

Composite synthetic graft · Prospective multicenter RCT · 249 long-bone #, min two years FU · Bone graft v biphasic calcium phosphate mixed with bovine collagen + autogenous bone marrow · No sig. diff. ¨ · More infections with bone graft (22 v 9 p=0. 008) Chapman MW et al. Treatment of acute fractures with a collagen-calcium phosphate graft material. A randomized clinical trial. J Bone Joint Surg Am. 1997; 79: 495 -502.

Mechanical · · · Controlled axial micromotion Compression Distraction LIPUS Electromagnetic

Controlled axial micromotion · Prospective RCT 102 tibial fractures ¨ 1. 0 mm at 0. 5 Hz /30 minutes per day · Sig. reduction ¨ ¨ · Time to union Secondary surgery Kenwright J, Goodship AE. Controlled mechanical stimulation in the treatment of tibial fractures. Clin Orthop 1988; 241: 36 -47.

Low Intensity Ultrasound · Several RCTs · Reduced time to union ¨ ¨ Non-op tibia (No benefit in nailed #) Scaphoids Impacted distal radius Jones · May reduce time to healing · JW Busse et al. The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. Canadian Medical Association Journal 2002 166: 437 -441 Sonic Accelerated Fracture Healing System (SAFHS®) Exogen 2000®

· Acute fractures with ultrasound · Inconsistency in evidence ? Type II failure · Available evidence supports the use of ultrasound in the treatment of acute fractures of tibia and radius treated with plaster immobilization. (non op) · No benefit of LIPUS in the treatment of fractures of the tibia managed with intramedullary fixation. J Trauma. 2008 Dec; 65(6): 1446 -52

· Clinical relevance of any demonstrated effect is more difficult to justify. · Study may demonstrate a statistically significant effect of LIPUS, which may not be clinically relevant. · Overall low rate of nonunion in the studies raises the question of the usefulness of LIPUS in patients who have a fracture that is likely to heal anyway. · LIPUS therapy may be useful in patients with a potential for delayed union ¨ complex fractures, significant comorbidities, smokers J Trauma. 2008 Dec; 65(6): 1446 -52

· Evidence for the effect of low intensity pulsed ultrasonography on healing of fractures is moderate to very low in quality and provides conflicting results. · Although overall results are promising, establishing the role of low intensity pulsed ultrasonography in the management of fractures requires large, blinded trials BMJ. 2009; 338 b 351

· Current evidence on the efficacy of low-intensity pulsed ultrasound to promote fracture healing is adequate to show that this procedure can reduce fracture healing time and gives clinical benefit, particularly in circumstances of delayed healing and fracture non-union. · There are no major safety concerns. · Therefore this procedure may be used with normal arrangements for clinical governance, consent and audit

Electromagnetic Fields · Exact Mechanism of action unknown · Research suggests pulsed EM fields affect: ¨ Encourages mineralisation ¨ Angiogenesis ¨ Increases DNA synthesis ¨ Alters the cellular calcium content in osteoblasts EM fields can be generated: · Direct-current stimulation using implanted electrodes · Inductive coupling produced by a time-varying magnetic field · Capacitative coupling

Electromagnetic Fields · Five methods for application of electromagnetic fields ¨ Direct current (dc) delivered via a percutaneous cathode and an anode in contact with the skin ¨ Direct current (dc) delivered by a completely implanted system ¨ Capacitive coupled electric field (CCEF) through conductive plates attached to the skin. ¨ Pulsed electromagnetic fields (PEMF) through externally applied coils which induce low level current ¨ Combined electromagnetic fields (CMFs) which use both dynamic and static magnetic fields

Electromagnetic devices · In vivo ¨ Osteoblasts BMP, TGFs, IGF · Small RCT ¨ 66% vs 0 healing of tibial non-union Scott G, King JB. A prospective double blind trial of electrical capacitive coupling in the treatment of nonunion of long bones. J Bone Joint Surg [Am] 1994; 76 -A: 820 -6. · Several series ¨ 64 -87% union of tibial non-union

· Small, methodologically limited trials with wide confidence intervals · Leaves impact of electromagnetic stimulation of fracture-healing uncertain. · Current evidence justifies neither enthusiastic dissemination nor confident rejection of this therapeutic modality. Mollon B. et. al. J Bone Joint Surg 2008: 90: 2322 -2330

· Clinically relevant treatment effect using electromagnetic stimulation. · Despite some methodological inconsistencies, the randomised trial evidence is consistent, and statistically significant. · Conclude - available evidence supports the use of electromagnetic stimulation in the treatment of non-union of the tibia. Injury, Int. J. Care Injured (2008) 39, 419— 429

Whats new G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis • BTM’s - Bone Turnover Markers • Metabolic bone disorders • Possible use in fracture prediction • Delayed union • Non union • Bone formation • Osteoblastic activity • Bone resorption • Osteoclastic activity VOL. 92 -B, No. 3, MARCH 2010

Whats new G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis 3 Groups 1. Bone-resorption markers 2. Osteoclast regulatory proteins 3. Bone-formation markers VOL. 92 -B, No. 3, MARCH 2010

Whats new G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis 1. Bone-resorption markers 2. Osteoclast regulatory proteins • Factors involved with fusion of mononuclear osteoclast precursors to form mature multinucleated osteoclasts • Factors include: • Receptor activator of nuclear factor NF-k. B ligand (RANKL) • c-fms protooncogene • Modulation of osteoclastic activity is controlled by: osteoprotegerin (OPG) VOL. 92 -B, No. 3, MARCH 2010

Whats new G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis 1. Bone-resorption markers 2. Osteoclast regulatory proteins 3. Bone-formation markers • Type-III collagen, is the initial collagen laid down during fracture healing and is replaced by type-I collagen to form bone. VOL. 92 -B, No. 3, MARCH 2010

Whats new G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis 1. Bone-resorption markers 2. Osteoclast regulatory proteins 3. Bone-formation markers • Hence markers of bone healing include fragments of type-I and type-III procollagen • • Type-III collagen N-terminal propeptide, (PIIINP) Type-I collagen C-terminal propeptide, (PICP) Type-I collagen N-terminal propeptide (PINP) Specific measures of osteoblastic activity include : • Osteocalcin the major non-collagenous protein of bone matrix • Bone-specific alkaline phosphatase (BSAP) VOLUME 92 -A d NUMBER 3 d MARCH 2010 VOL. 92 -B, No. 3, MARCH 2010

Whats new G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis VOL 92 -A , No 3, MARCH 2010 VOL. 92 -B, No. 3, MARCH 2010

Non union · · · · 24 year old PVA Head injury Closed humeral shaft Radial nerve intact Humeral brace 6 months

Non union approach · General * Inhibition (smoking, NSAIDS) · Biology · Mechanics (stability) · Particular Current Opinion in Orthopaedics 2006, 17: 325– 330

Non union approach · General · Biology * (atrophic vs hypertrophic) * Open * Infected * Blood supply · Mechanics (stability) · Particular Current Opinion in Orthopaedics 2006, 17: 325– 330

Non union approach · General · Biology · Mechanics (stability) * Brace (functional management) * Plate Fixation * Intramedullary Nail * External fixation · Particular Current Opinion in Orthopaedics 2006, 17: 325– 330

Non union approach · · General Biology Mechanics (stability) Particular Acta Orthopaedica 2006; 77 (2): 279– 284

6 weeks 4 months

Non union 2 · · 40 YO male High energy MVA Open grade 2 IM nail primary Rx 4 months post injury

Non union approach · General · Biology ¨ ¨ ¨ Atrophic (autograft) Avascular (nail – endosteal, cerclage periosteal) Open fracture ? Infection · Mechanics ¨ ¨ Instability No shelf viz compression (Biasetti II) · Particular ¨ No nail to nail

· 10 months post injury · Nail removed · Plate ¨ ¨ 9 hole, LC-DCP SMALL FRAGMENT Proximal – 2 ? 3 cortices Distal – 4? cortices · No growth

Questions www. easytrauma. co. uk

· Gap healing Questions * AO - Metaphyseal bone fairly rigidly fixed, no callous, no cones but strain right to convert fibrous tissue to bone (get lucky) * Implant to bone gap and filling * Defect (Gap) distraction osteogenesis · Electromagnetic stimulation Injury (2008) 39, 419— 429 · BMP in tissue