BIOCERAMICS IN THE TREATMENT OF BENIGN BONE TUMORS

Introduction: Benign bone tumors are relatively common. The majority occur in children. Ward published, The Relative Incidence of Benign Bone Tumors in the Burden of Musculoskeletal Diseases in the United States in 2008. Ward determined that the national prevalence of benign bone tumors in rank order was 1,511 osteochondromas, 1,246 unicameral bone cysts, 769 giant cell tumors, 733 enchondromas, 632 aneurysmal bone cysts, and 577 metaphyseal fibrous defects. Benign bone tumors frequently create “contained” osseous defects that can lead to pathological fracture. Treatment is dependent on the aggressiveness of the lesion, location, containment, and bone strength. The Enneking staging system for benign bone tumors characterizes them as “latent”, “active”, or “aggressive”. Latent benign bone tumors remain quiescent or heal spontaneously. Active benign bone tumors progress but are limited by natural barriers such as the bone cortex or periosteum. Aggressive tumors do not respect these natural barriers and will extend into the soft tissues. Latent and even some active benign bone tumors can at times be observed. Most active and almost all aggressive benign bone tumors need to be treated. Tumors of all type that lead to pathological fracture need to be treated. Intralesional excision and grafting is commonly performed. Intralesional excision requires exposure of the entire tumor cavity, excision of all the lesional tissue, extending the margins with adjuvants if necessary, and filling the defect. There are many choices of graft material including autogenous bone graft, allograft, and bone graft substitutes. The defects created by benign bone tumors are contained and are thus good candidates for grafting with a bioceramic. Bone graft substitutes are attractive options because they are reported to be effective, avoid donor site morbidity, and are readily available. These biomaterials can be placed open or injected. Bioceramics are a class of osteoconductive bone graft substitutes that act as a scaffolding material for bone repair. They contain hydroxyapatite, calcium phosphate, calcium sulfate, or composite materials. Some of these are naturally occurring such as coral while others are manufactured. The history of bioceramics dates back to 1892 with the use of calcium sulfate for space occupying lesions by Dr. Dressman and subsequently Dr. Leonard Peltier. The original material was Plaster of Paris which is non-inflammatory and nonreactive and encouraged bone healing in a contained lesion. Subsequently, coralline hydroxyapatite was reported for similar lesions followed by other ceramics. All of these bone graft substitutes have the advantage of being non-immunogenic, non-inflammatory, in an unlimited supply, and packaged sterile. Mechanically, they have variable structural properties. They can be combined with osteoinductive cytokines. The purpose of this exhibit is to review the published pre-clinical and clinical outcomes with various bioceramics for the treatment of benign bone tumors. We will review their chemistry, strength, and biodegradation.

BIOCERAMICS IN THE TREATMENT OF BENIGN BONE TUMORS

Steven Gitelis, MD | Ross Wilkins, MD | Yale Fillingham, MD | Cara Cipriano, MD AAOS Biological Implants Committee

Leonard Peltier, MD Early developer of Plaster of Paris bone

graft substitute

The published literature of the last ten years was reviewed for studies related to the use of

bioceramics as graft material for benign bone lesions. The studies were characterized based

on levels of evidence and evaluated in terms of their methodology and clinical relevance.

Levels of Evidence for Primary Research Question

Therapeutic Studies—Investigating the Results of Treatment

Level I

• High-quality randomized controlled trial with statistically significant difference or no statistically significant difference but narrow confidence intervals

• Systematic review2 of Level-I randomized controlled trials (and study results were homogeneous3)

Level II

• Lesser-quality randomized controlled trial (e.g., <80% follow-up, no blinding, or improper randomization)

• Prospective4 comparative study5

• Systematic review2 of Level-II studies or Level-I studies with inconsistent results

Level III

• Case-control study7

• Retrospective6 comparative study5

• Systematic review2 of Level-III studies

Level IV • Case series8

Level V • Expert opinion

• JBJS Author Instructions

SEM composite graft material (calcium sulfate/calcium phosphate)

SEM Bone-apatite appearing grafted with composite material (calcium sulfate/calcium phosphate)

METHODS

SYNTHETIC CERAMIC GRAFTS IN ORTHOPAEDICS

1 month 1 year multiple years

Relative in vivo absorption time **

References: Lee RW, et al. The role of fixation and bone quality on the mechanical stability of tibial knee components. CORR. (273): 177-83, 1991. LeGeros RZ. Properties of osteoconductive biomaterials: calcium phosphates. CORR. (395): 81-98, 2002. J. McCanless, et al, “In Vitro and In Vivo Evaluation of a Slower Resorbing Calcium Sulfate Cement”, Trans. 19th Eur. Conf. on Biomaterials, EP43, 2005. Urban RM, et al. Increased bone formation using calcium sulfate-calcium phosphate composite graft. CORR. 459: 110-7, 2007.

Calcium Sulfate Dihydrate (CSD)

CaSO4 · 2H2O

Typically provided as pre-formed shapes or as a paste

Two different types of CSH crystals

Giant gypsum crystal

β-TCP (Calcium Phosphate)

Ca3O8P2

Porous β-TCP granule designed to mimic

cancellous bone structure

Typically provided as porous granules or pre-formed porous shapes

Ceramic Composites CSD/ CP composite

Coralline-derived HA/CC composite

Self forming CP scaffold (after 15 days of accelerated dissolution, in vitro)

Provided as pre-formed porous granules or shapes or as a paste

A CS/ CP composite material at 13 wks in canine humerus model

Substituted Hydroxyapatite

A substituted HA material at 13 wks in canine humerus model

Ca10(PO4)N·(X2-)M· (OH)2

Typically provided as pre-formed shapes or as a

paste

Hydroxyapatite (HA)

Ca10(PO4)6·(OH)2

Typically provided as a paste

HA crystals

0

20

40

60

80

100

0 10 20 30 40 50

CSD

CSD/CP Composite

β-TCP

HA

Relative Absorption Rates of Ceramic Materials

% M

ass R

emai

ning

0

5

10

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30

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40

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50

CSD 1* CSD 2A* CSD 2B* CSD/ CP Composite

Substituted HA

Stre

ngth

(MPa

)

Compressive Strength in Wet Conditions for Selected Absorbable Ceramics

WET (1-2 hrs)

WET (24 hrs)

* Tested at 1 hr Cancellous bone (Lee, et al., CORR, 273: 177-183, 1991)

** In addition to graft composition, numerous factors affect the ultimate absorption rate of grafts in vivo including, but not limited to: Anatomic location Individual patient physiology Graft volume Graft configuration (e.g., granules vs. bolus) and porosity

Pre-op ABC

07/12/06

10/03/06

BIOCERAMIC REPLACEMENT

Calcium Sulfate/Calcium Phosphate Composite

GCT Talus Talo-navicular fusion

Calcium Sulfate

Results

PRE-CLINICAL TESTING Canine Critical-Size Axial Defect Model A critical-size axial defect model (Figure 1) developed at Rush University has been used successfully for nearly thirty years to perform pre-clinical testing of various bioceramic bone graft substitutes. In this bilateral model, a 13 X 50 mm defect is created in the canine proximal humerus and filled with the test or a control material (Figure 2) such as autologous cancellous bone graft, normal unoperated bone or predicate bioceramics. Untreated, the defects will not heal (Figure 3). The data presented here are from a study comparing a CaSO4/CaPO4 ceramic composite to CaSO4 dihydrate pellets, autologous bone graft and normal canine bone.

Figure 1. Diagram of the critical-size defect (yellow dotted line) created in the canine proximal humerus. The blue lines indicate where transverse sections are taken for histomorphometric analysis. The red box indicates the location of an 8 X 20 mm core for biomechanical compression testing.

Figure 3. Contact x-ray of a transverse section of an untreated defect after 6 weeks. Note that there is only minimal bone formation at the periphery of the defect. Histologically, the center of the untreated defects contained fibrous tissue.[1]

Figure 2. Immediate post-op radiographs of the right and left canine proximal humerus, demonstrating the placement of the composite ceramic (test) and CaSO4 pellets (control) in the 13 X 50 mm defects.

Conclusions

Histomorphometric

Biomechanical

0

5

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30

35

40

45

50

13 Weeks 26 Weeks Normal Bone

Are

a Fr

actio

n of

New

Bon

e (%

)

Amount of New Bone (%)Composite CeramicCaSO4 PelletsAutograft

Composite Ceramic CaSO4 Pellets Autograft

Figure 8. The area fraction of mineralized new bone was greater in defects treated with the composite ceramic at 13 wks compared to defects treated with CaSO4 pellets, autograft or normal bone (p≤0.025).

Figure 10. The typical nature of new bone in the defects after 13 weeks. (A) Defects treated with the composite ceramic showed new bone with incorporation of the CaSO4/CaPO4 matrix (dark stained) and TCP granules (gray). (B) Defects with CaSO4 pellets and (C) autograft contained new bone without residual material. (D) Normal bone of the canine proximal humerus. (Undecalcified ground sections; stain, basic fuchsine and toluidine blue; original magnification, ×100). [2]

A B C D

13 week Composite Ceramic

13 week CaSO4 Pellets 13 week Autograft Normal Bone

Figure 11. The typical nature of bone in a defect treated with composite ceramic (A) at 26 weeks with few TCP granules (gray) and a trabecular architecture resembling normal bone (Figure 10-D). (B) Defects treated with conventional CaSO4 pellets with no pellets remaining and (C )defect treated with autograft. (Undecalcified ground sections; stain, basic fuchsine and toluidine blue; original magnification, ×100). [2]

A B C

26 week Composite Ceramic

26 week CaSO4 Pellets 26 week Autograft

Composite Ceramic • Superior to conventional CaSO4 pellets and autograft bone

More bone and increased strength at 13 weeks Normal architecture and strength at 26 weeks

• Exploits the different resorption rates of CaSO4 and CaPO4

CaSO4/CaPO4 matrix: early resorption and vascular infiltration TCP granules: scaffold for bone formation and early strength

Canine Critical-Size Axial Defect Model • Successful model to study various bone graft substitutes

• Can follow healing of defects of over time radiographically and histologically

• Allows for histomorphometric and mechanical data from same animals

0

1

2

3

4

5

6

7

8

9


Ulti

mat

e C

ompr

essi

ve S

tres

s (M

pa)

Strength of New Bone (MPa)Composite CeramicCaSO4 PelletsAutograft


Figure 12. The ultimate compressive stress of the cored bone samples was greater in defects treated with the composite ceramic than in defects treated with CaSO4 pellets, autograft or normal bone at both 13 and 26 weeks (p ≤ 0.047).

0

100

200

300

400

500

600


Elas

tic M

odul

uls

(Mpa

)

Stiffness of New Bone (MPa)Composite CeramicCaSO4 PelletsAutograft


Figure 13. The elastic modulus of defects treated with the composite ceramic was several fold greater (p ≤0.025) than defects treated with CaSO4 pellets after 13 and 26 wks. There was no difference in modulus between the composite ceramic-treated defects compared to normal bone at either time period.

Figure 14. Typical stress-strain curves for composite ceramic (red), CaSO4 pellets (blue) and normal bone (black) at 26 weeks.

Strain (%)

Stre

ss (M

Pa)

Ceramic composite

Normal Bone

CaSO4 Pellets

Yield

0

5

10

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20

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30

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40

45

A B C D Pellets Composite Ceramic

Autograft Normal Bone

Perc

ent

Area Fraction of New Bone at 13 Weeks

CaSO4 Pellets

Figure 15. Bar graph comparing data on the area fraction of restored bone from the present study with data from previous studies of other bone graft materials using this critical-sized defect model at the 13-week evaluation time point. A-D represent data for other CaSO4-based bone graft substitutes.[2]

Area Fraction of New Bone

0

10

20

30

40

0 5 10 15 20 25 30

Weeks

Per

cent

PRO-DENSEAutograft

Area Fraction of Normal Bone

Ceramic composite

Autograft

Figure 16. Line graph of amount of new bone filling defects treated with the ceramic composite (blue line) and autograft (green line) over time (2, 3, 4, 6, 8, 13 and 26 weeks). The data are compared to the amount of bone found in a normal canine humerus (red dashed line).

Methods of Analysis 1. Serial clinical radiographs Rate of implant material resorption

and replacement with new bone

2. Stained histological sections Area fraction of new bone and

residual implant material

3. Biomechanical compression

testing Strength and stiffness of new bone

Figure 5. (A) Mechanical test specimens (yellow dashed lines) are cored from the center of each defect (black dashed lines). (B) The resultant mechanical test cylinders are 8 mm X 20 mm. (C) Unconfined, uniaxial compression tests are performed on each core (arrow) using a modified compression subpress (ASTM D695) and a servo hydraulic mechanical testing system with a 1000N Dynacell Dynamic Load Cell (Instron Corp).

A B

C

Figure 4. New bone and residual implanted materials are quantified by superimposing a point-counting grid on digital images of the central 12-mm diameter of the defect area. The data are expressed as the percent area fraction.

Test Control

Radiographic

Figure 7. Transverse section radiographs of restored defects that had been treated with the composite ceramic after 13 (A) and 26 (B) weeks and autologous bone graft after 13 weeks (C). Black circles define the area of the bone defect. D: Transverse section of an unoperated canine humerus demonstrating normal trabecular architecture.[2]

A B

C D

Post-op 2 Weeks 6 Weeks 13 Weeks 26 Weeks

Composite Ceramic

CaSO4 Pellets

Autograft

Figure 6. Serial radiographs of bone defects treated with equal volumes of composite ceramic, CaSO4 pellets or autologous bone graft. Replacement of the composite ceramic with new mineralized bone was apparent, beginning at 2 weeks and continued until 26 weeks when replacement with new bone was nearly complete. Resorption of CaSO4 pellets was essentially complete by 6 weeks.

13 wk Composite 26 wk Composite

13 wk Autograft Normal canine bone

Figure 9. Defect treated with composite ceramic at 6 weeks. The majority of the CaSO4/CaPO4 matrix had been resorbed, allowing deep infiltration of capillaries (black arrows) and venules (V). Newly formed bone lined with osteoblasts covered the surfaces of the remaining CaSO4/CaPO4 matrix (white arrows) and the TCP granules (TCP) (Undecalcified ground sections; stain, basic fuchsine and toluidine blue; original magnification, ×154).[2]

References [1] Turner TM, J Bone Joint Surg Am. 2001; [2] Urban RM, CORR 2007

CLINICAL OUTCOMES HYDROXYAPATITE

Progressive graft incorporation. Eur J Pediatr Surg 2012;22:143–147 .

Hydroxyapatite Clinical Outcomes by the Numbers

Studies with Level 1 Evidence 0





Total Number of Articles 12

Average Number Patients 40

Average Months of Follow-up 69

Method of Evaluation, Function only

1

Method of Evaluation, Radiographic only

7

Method of Evaluation, Both 0

Method of Evaluation, None 4

Diagram showing the three stage radiographic classification. Stage 1, clear margin; stage 2, hazy margin; stage 3, absorbed margin. Stage 3 was subdivided into stage 3A, absorption less than 50% of the margin of CHA and stage 3B, absorption more than 50% of the margin of CHA.

Progressive graft incorporation J Bone Joint Surg [Br] 2004;86-B:719-25.

CLINICAL OUTCOMES CALCIUM PHOSPHATE Calcium Phosphate Clinical

Outcomes By the Numbers










2


7



CLINICAL OUTCOMES CALCIUM SULFATE

Calcium Sulfate Clinical Outcomes by the Numbers









Method of Evaluation, Function only 2


6


Method of Evaluation, None 3 Graft dissolution and bone healing. Clin Orthop Relat Res (2009) 467:2949–2954

CLINICAL OUTCOMES COMPOSITE GRAFT

ABC bone repair and remodeling. Clin Orthop Relat Res (2012) 470:2014–2020

Progressive graft dissolution and bone repair in Unicameral Bone Cyst Computed tomogram of composite graft revealing cyst repair

Composite Graft Clinical Outcomes by the Numbers










3


1



SUMMARY AND CONCLUSIONS

After reviewing the literature regarding bioceramics for benign bone tumors, most of the articles suggest that these bone graft substitutes are an acceptable alternative to autogenous bone graft. Pre-clinical animal modeling is helpful but does not eliminate the need for sound clinical studies. Animal testing, however, offers quantitative mechanical and histological data. Clinical articles, however, suffer from the same major weaknesses. The studies are generally Level III or Level IV evidence and relatively small. The measured outcomes are inconsistent. Some of the studies look at function, while others look at x-rays. Some of the studies report on the oncological outcome, most notably local recurrence. When treating benign bone tumors it is hard to conclude that a local recurrence has anything to do with the bone graft substitute. It has more to do with the biology of the bone tumor and the adequacy of excision. Radiological assessment is also inconsistent in most of these studies. Plain radiographs are used which do not accurately determine the amount of bone repair. Computed tomography would be a more accurate method. It can be difficult to determine new bone formation from residual radio-opaque bioceramic. One important question is whether it makes any difference at all. In a contained osseous defect, is it critical to form bone in the medullary space, or is it more important to thicken the cortical margin previously thinned by the tumor? The radiographs can show dissolution of the bioceramic. What we really don’t know is whether dissolution is critical for a successful outcome. Some of these materials completely dissolve while others dissolve very little over many years.

The true test of a successful outcome for grafting a benign bone tumor comes down to two clinical factors. First, has the patient recovered to full function without limitations?; and second, has the bone repair process been adequate enough to avoid fracture? These two factors are far more important than the x-ray appearance but, unfortunately, are not reported in most of the published literature. The ideal study would be a prospective randomized trial comparing bioceramic to autogenous bone graft. The patients would be assessed radiographically using computed tomography and a functional evaluation done to determine if the patients have returned to normal activity level. This study should include complications such as infection, drainage, and, most notably, fracture as adverse outcomes. Ideally, the study would be performed on a single diagnosis such as unicameral bone cyst. The tumors have to be consistently treated either open or percutaneously. The above-described study, however, would be extremely difficult to complete by a single institution. Ward noted the relative infrequency of these tumors, and it would take a great deal of time to accrue a population with ample power to answer the question regarding outcomes with bioceramics versus autogenous bone graft. Almost by necessity a multi-institutional study would have to be conducted and only one type of bioceramic utilized. Despite these shortcomings, bioceramics for contained osseous defects is a promising technique. They avoid the morbidity of autogenous bone graft and may even be applied percutaneously by injection. One added potential value is their ability to carry pharmaceuticals. In the future, combination products including a bioceramic combined with inductive proteins, mesenchymal stem cells, or pharmaceuticals may help diminish the risk of local tumor recurrence. Currently these combined products are under investigation by numerous manufacturers and laboratories, and more will become available in the future.

Author disclosures are in the Final Program

and in the AAOS Orthopaedic Disclosure program

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BIOCERAMICS IN THE TREATMENT OF BENIGN BONE TUMORS