Bone formation and resorption in patients after implantation of β-tricalcium phosphate blocks with 60% and 75% porosity in opening-wedge high tibial osteotomy

Bone Formation and Resorption in Patients After Implantationof b-Tricalcium Phosphate Blocks With 60% and 75% Porosityin Opening-Wedge High Tibial Osteotomy

Takaaki Tanaka,1 Yoshio Kumagae,1 Mitsuru Saito,2 Masaaki Chazono,2 Hirokazu Komaki,2

Takahiro Kikuchi,1 Seiichiro Kitasato,2 Keishi Marumo2

1 Department of Orthopaedic Surgery, NHO Utsunomiya National Hospital, Utsunomiya City, Tochigi 329-1193, Japan

2 Department of Orthopaedic Surgery, Jikei University School of Medicine, Nishi-Shinbashi, Minato-Ku,Tokyo 105-0003, Japan

Received 7 August 2007; revised 7 November 2007; accepted 19 November 2007Published online 19 February 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.b.31041

Abstract: Most of the implanted porous b-tricalcium phosphate (b-TCP) can be resorbed.

However, b-TCP block with 75% porosity is inadequate for weight-bearing sites until bone

incorporation occurs. Thus, the authors have recently developed b-TCP block with 60%

porosity, which is approximately sevenfold greater in terms of compressive strength than that

of b-TCP with 75% porosity. The authors investigated bone formation and resorption of b-

TCP after implantation in patients of b-TCP blocks with two different porosities. From May

2003 to November 2004, medial opening high tibial osteotomy was performed in 25 patients

with a mean age of 66 years. The opened defect was fixed with a Puddu plate. Then 6–8 cm3of

b-TCP block with 75% porosity was used to fill the cancellous bone defect, except on the

medial side where 2.83–3.18 cm3 of wedge-shaped b-TCP block with 60% porosity was

implanted. At least 2 years after surgery, the 25 patients had no correction loss, and bone

formation was noted in all cases. Complete or nearly complete resorption of b-TCP with 60

and 75% porosity was obtained within 3.5 years. Thirteen biopsy samples obtained from the

60% porosity implantation sites showed good lamellar bone formation, and the percentage of

b-TCP remaining relative to the newly formed bone plus b-TCP ranged from 0.3 to 14.5%,

with a mean of 6.7%. The authors suspect that mechanical stress loading to the medial side of

the tibia facilitated bone formation and resorption of b-TCP with 60% porosity. ' 2008 Wiley

Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 86B: 453–459, 2008

Keywords: biodegradation; bone graft; bone remodeling; calcium phosphate(s); clinical

INTRODUCTION

The lateral closed-wedge high tibial osteotomy (HTO)

described by Jackson and Waugh1 and Coventry2 is an

established technique to treat osteoarthritis of the medial

compartment and varus deformity, but it has some prob-

lems such as peroneal nerve palsy, nonunion of fibula, and

loss of bone. To counter these problems, medial opening

HTO has become popular because it has some advantages

over the closed-wedge technique. However, a suitable

method to fill the opened defect in the medial opening pro-

cedure has not been identified. Autologous bone is the pre-

ferred graft material for filling opened defects. However,

autogenous bone grafting has procurement morbidities. Al-

lografts have commonly been used as substitutes for auto-

genous bone grafts in Europe and the United States but not

in Japan. Significant problems associated with allografts

include a low bone-fusion rate and disease transmission.3,4

Recently, bone substitute materials have been advocated as

alternatives to autografts and allografts. Hydroxyapatite is

widely used as a bone substitute because of its excellent

biocompatibility and osteoconductive properties.5,6 How-

ever, hydroxyapaptite biodegrades slowly and there is no

progressive bone formation during the repair of bone with

it.7 Good long-term results after opening HTO using hy-

droxyapatite as a bone filler were reported.8 However, if

severe varus or valgus knee deformity were to occur, fixing

a component in the tibia during total knee arthroplasty

might be difficult. In contrast, most of the implanted porous

b-tricalcium phosphate (b-TCP) can be resorbed within a

few years.9,10 However, the b-TCP with 75% porosity that

we have used has a compressive strength of only 3 MPa,

which is inadequate for weight-bearing sites until bone

incorporation occurs. Thus, we have recently developed

Correspondence to: T. Tanaka (e-mail: [email protected])

' 2008 Wiley Periodicals, Inc.

453

wedge-shaped b-TCP block with 60% porosity for opening

HTO. This b-TCP has a compressive strength of 20 MPa,

which is approximately sevenfold greater than that of

b-TCP with 75% porosity. In this study, we report bone

formation and resorption of b-TCP in the TCP-implanted

sites.

MATERIALS AND METHODS

Preparation of TCP

The b-TCP block used in this study was highly pure and

provided by Olympus Biomaterials (Tokyo, Japan). b-TCPwas synthesized using a mechanochemical method (wet

milling). Briefly, CaHPO4/H2O and CaCO3 at a molar ratio

of 2:1 were mixed into a slurry with pure water and par-

ticles of zirconium in a pot mill for 24 h and dried at

808C. The calcium-deficient hydroxyapatite was converted

to b-TCP by calcinations at 7508C for 1 h. After sintering

of the b-TCP powder at 10508C for 1 h, a porous b-TCPblock with a mean pore size of 200 lm and a porosity of

75% was obtained. Pore size distribution in the b-TCPblock with 75% porosity showed two peaks: [100 lm and

\5 lm (Figure 1). The b-TCP block with 60% porosity

was synthesized by the same method as the 75% material,

except that the amount of forming agent was changed. The

mean compressive strength of b-TCP blocks with 60 and

75% porosity was 20 and 3 MPa, respectively.

The volume of each piece of b-TCP block with 60%

porosity for a 10-mm opening was 1.06 cm3 and for a

12.5-mm opening was 1.39 cm.3 Three pieces of b-TCPwere implanted in all cases, but 1/3 of one piece was

removed in the case of small knees. Thus, 3.18 (1.06 3 3)

to 2.83 (3.18 2 1.06 3 1/3) cm3 of b-TCP blocks with

60% porosity was used for a 10-mm opening, and 4.17

(1.39 3 3) to 3.71 cm3 of b-TCP blocks with 60% was

used for a 12.5-mm opening. To fill the cancellous bone

defects, 6– and 7–8 cm3 of b-TCP blocks with 75% poros-

ity were used for 10- and 12.5-mm openings.

Operative Techniques and Biopsy Sampling

All patients provided informed consent to participate in this

study, which was approved by our institutional review board.

Since May 2003 to November 2004, opening-wedge

HTO was performed using b-TCP with 60 and 75% poros-

ity without autogenous bone graft. Twenty-five patients

(16 women and 9 men) with a mean age of 66 (range, 51–

80 years) were used for evaluation at a mean follow-up

point of 32.5 months (range, 25–42 months).

During opening HTO, the opened defect was fixed with

a Puddu plate [Figure 2(A,B)] after which the cancellous

bone defect was filled with b-TCP with 75% porosity

[Figure 2(A,C)], except on the medial side where three

wedge-shaped b-TCP blocks with 60% porosity were

implanted in front and back of the plate [Figure 2(A,D,E)].

Twelve patients received an opening of 10 mm and

13 patients an opening of 12.5 mm [Figure 2(E)]. Partial

weight-bearing was allowed 4–5 weeks after surgery, and

total-weight bearing was allowed at 7–8 weeks. The mean

preoperative standing femorotibial angle was 1818 (range,

177–1858), which was corrected to a mean angle of 1698.All patients were followed up at regular intervals in our

outpatient clinic and underwent radiographic examination.

Anteroposterior radiographs were used mostly for evaluation of

b-TCP with 75% porosity because the protruding part of the

Puddu plate, the so-called tooth part, overlapped the b-TCPblock with 60% porosity. Thus, resorption of the b-TCP block

with 60% porosity was estimated from lateral radiographs. Af-

ter b-TCP had been completely or nearly completely replaced

by bone (more than 90% of the TCP implanted area had been

replaced by bone) as determined radiologically, 13 patients

with a mean age of 68 years agreed to the removal of the

internal fixation devices and biopsies. During removal surgery,

the b-TCP implanted sites were observed macroscopically and

biopsy samples were obtained in front of the plate where b-TCP with 60% porosity was implanted [Figure 6(C)]. The bi-

opsy samples were fixed with 4% paraformaldehyde in phos-

phate-buffered saline for 24 h and then divided into a piece for

calcified sections and a piece for decalcified sections. Sections

decalcified with 0.25M EDTA were used for hematoxylin-eosin

(HE) and tartrate-resistant acid phosphatase (TRAP) staining.

Calcified sections were used for measurement of the amount

of new bone formation and remaining b-TCP. The surface

area of the remaining b-TCP was measured using an image

analyzer and was expressed as a percentage of the newly

formed bone plus b-TCP.All the patients were scored using the Japanese Orthopae-

dic Association (JOA) rating scale for osteoarthritis of the

knee.11 This scale contains four domains: pain on walking (30

points), pain on ascending or descending stairs (25 points),

range of movement (35 points), and joint effusion (10 points).

RESULTS

No adverse reactions to b-TCP or disturbances of wound

healing were observed in the postoperative period. The

Figure 1. Pore size distribution in b-TCP blocks with 60 and 75%

porosity shows two peaks:[50 lm and\5 lm.

454 TANAKA ET AL.

Journal of Biomedical Materials Research Part B: Applied Biomaterials

results obtained from 25 patients who had surgery at least

2 years before showed that no correction loss occurred and

bone formation was noted in all cases. At the latest follow-

up 25–42 months after surgery, the mean JOA knee score11

improved from 64 before operation to 90 points, and com-

plete or nearly complete replacement of both 60 and 75%

porosity TCP by bone was recognized in 18 patients (Fig-

ures 3–5). Thirteen of these patients agreed to the removal

of the fixation device and biopsies. During removal sur-

gery, macroscopic inspection revealed that the sites

Figure 2. Macroscopic appearance of the two types of b-TCP block and a Puddu plate for a 12.5-mm opening (A). Opening HTO is performed with 60 and 75% porosity b-TCP blocks. After plate

fixation (B), a b-TCP block with 75% porosity is implanted in the cancellous bone defect (C), and

then a wedge-shaped TCP block with 60% porosity, which is slightly larger than the protruding partof the Puddu plate, is implanted in the medial cortical defect in front and back of the plate (D). The

yellow arrow indicates a space for a TCP block with 60% porosity (C). Macroscopic appearance of

the left knee observed from the medial side. The yellow box indicates the operative field (E). [Color

figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

455HTO USING �-TCP


implanted with 60% porosity b-TCP in front and back of

the plate were completely replaced by bone (Figure 6) in

all cases. Histological examination of biopsies revealed

good lamellar bone formation in all cases [Figure 7(A)].

The residual b-TCP was noted in all cases (Figure 7). The

percentage of b-TCP remaining relative to the newly

formed bone plus b-TCP in those 13 patients ranged from

0.3 to 14.5%, with a mean of 6.7% [Figure 7(B)].

DISCUSSION

The purpose of this study was to assess bone formation and

b-TCP resorption after implantation of b-TCP blocks with

60 and 75% porosity in opening-wedge osteotomy. Most of

the porous b-TCP with 75% porosity, which we have used

since 1989, can be resorbed within a few years.9,10 How-

ever, it has a compressive strength of only 3 MPa, which is

inadequate for weight-bearing sites until bone incorporation

occurs. Correction loss and screw breakage after opening

HTO using b-TCP block with 75% porosity alone were

reported (an oral communication, September 2006). Origi-

nally, we implanted autogenous iliac bone on the medial

side of the tibia to support compression and filled the re-

mainder of the defect with b-TCP having 75% porosity.

Compressive strength can be increased by reducing poros-

ity. Thus, we have recently developed a wedge-shaped b-TCP block with 60% porosity for opening HTO. This b-TCP block has a compressive strength of 20 MPa, which is

approximately sevenfold greater than that of b-TCP with

75% porosity. During opening HTO, the opened defect was

fixed with a Puddu plate, after which b-TCP with 75% po-

rosity was used to fill the cancellous bone defect, except on

the medial cortical bone side where a wedge-shaped TCP

block with 60% porosity was implanted in front and back

of the plate. No correction loss has been found, and bone

formation was noted in all cases. The use of a b-TCP block

with 60% porosity avoided autogenous bone grafting and

shortened the surgical time. The change of porosity from

75 to 60% is only a 15% reduction, but the material

increased from 25 to 40%, a 1.6-fold increase. That is a

reason for the marked increase of compressive strength.

Figure 3. Anteroposterior radiographs of a 78-year-old man (case

1) with medial compartmental knee osteoarthritis (A). The mechani-

cal axis is corrected from varus (femorotibial angle 1788) to valgus

(1678) after a 10-mm opening HTO (B). The outer margin of theimplanted b-TCP with 75% porosity is unclear 4 weeks after implan-

tation (C). The solid and dashed arrows indicate area where 60 and

75% porosity TCP blocks were implanted, respectively. Radio-graphs of case 1. Six months (D), 1 year (E), and 2.5 years (F) after

surgery. Trace amount of remaining b-TCP indicated by the arrow is

that with 75% porosity.

Figure 4. Lateral radiographs of a 58-year-old woman (case 2) with medial compartmental knee

osteoarthritis. Resorption of b-TCP with 60 and 75% porosity can be seen over time. Radiographsof 12.5-mm opening HTO (A), and 4 months (B), 18 months (C), and 29 months (D) postoperatively.

The white arrows indicate b-TCP with 60% porosity.

456 TANAKA ET AL.


The reduction of porosity also reduced pore interconnec-

tion, suggesting a longer period for TCP resorption.

We have found that the type of bone affected b-TCPresorption. The rates of b-TCP resorption and bone forma-

tion were greater in cancellous bone defects than in cortical

bone defects in clinical cases.10 We also found that repair

of 5-mm cortical bone defects in rabbit tibiae was not

completed by implantation of b-TCP alone but required

addition of fibroblast growth factor-2 (FGF-2).12 These dif-

ferences in b-TCP resorption and bone formation may be

due to differences in blood flow in cancellous bone and

cortical bone. Based on these clinical and experimental

results, we estimated that b-TCP with 60% porosity

implanted in cortical bone defects would require quite a

long time for resorption. However, the results showed that

resorption of b-TCP with 60% porosity required less than

3.5 years. In contrast to these results, Altermatt et al.13

reported that most implanted b-TCP remains at least 7

years in loading-bone with calcaneal bone defects. They

used highly purified b-TCP with 60% porosity, but they

did not discuss pore structure in detail. We suspect that the

number and size of macropores and micropores and the

communications between pores were inadequate for b-TCPresorption and bone formation in their work.

Another reason for good resorption of b-TCP with 60%

porosity is thought to be the implant location. It is known

that bone cell differentiation and bone defect regeneration

depends on skeletal location and micromechanical loadings.

Handschel et al.14 have reported that b-TCP was poorly

resorbed after being implanted in a nonload-bearing envi-

ronment. However, the b-TCP granules (Cerasorb, Curasan,

Kleinostheim, Germany) used in their study differed in

pore structure from the b-TCP used in our study. In addi-

tion, we have experienced good TCP resorption in nonload-

ing sites of many clinical cases.9,10

It is of interest that most of the residual b-TCP is not

that with 60% porosity but that with 75% porosity, which

was implanted just inside of the protruding part of the plate

[Figure 3(F)]. This area has a poor blood supply, and the

mechanical stress was shielded due to the presence of a

plate. Considering these results, we conclude that mechani-

cal stress facilitates TCP resorption and bone formation.

There are some reports that question the usefulness of

b-TCP in opening HTO15,16 However, the amount of the

TCP implanted in the defects in these studies was not con-

sistent, and a 5-mm defect was too small to evaluate bone

formation. In this study, the amount used of each kind of

b-TCP and the location of the biopsy were consistent.

Thus, bone formation was easy to evaluate. The age group

of patients in this study was older than that in previous

reports.15,16 It is known that resorption of b-TCP depends

upon the amount implanted and the patient’s age. The

larger the implant and the older the patient, the slower is

the healing. However, this study showed that good b-TCPresorption occurred in the aged patients (Figure 3). There

was a correlation between TCP resorption and the amount

of TCP implanted, but no correlation between TCP resorp-

tion and the patient’s age in this study.

Histological findings obtained from 13 patients showed

that complete or nearly complete bone healing was

achieved in all cases. Bone formation and b-TCP resorption

were also observed in MR images taken after removal of

the plate and screws. In addition, remodeling in the b-TCPimplanted site was confirmed by macroscopic appearance.

During removal surgery of the internal fixation devices, it

was hard to distinguish the border between the TCP

implanted site and surrounding bone. Bleeding from the bi-

opsy site was also seen even in the presence of an air tour-

niquet [Figure 6(C)]. Histological findings obtained from

calcified sections showed that the percentage of residual

Figure 5. Anteroposterior radiographs of a 68-year-old woman (case 3) with medial compartmental

knee osteoarthritis. The defect with a 10-mm opening was filled with b-TCP blocks with 60 and75% porosity (A). Twenty-six months postoperatively, nearly complete resorption of b-TCP with

75% porosity can be seen but a small amount of b-TCP with 60% porosity remains (B), which is

also seen in the MR image (C). The white arrows indicate b-TCP with 60% porosity and the black

arrows indicate the area where b-TCP with 75% porosity was implanted.



b-TCP relative to the newly formed bone plus b-TCP is

6.7%. None of the cases had TRAP-positive cells even

though a small amount of b-TCP remained. This finding is

consistent with previous reports of human cases.17

The mechanism of bioceramic resorption involves two

processes: solution-mediated disintegration and cell-medi-

ated disintegration.18 An example of the first process is cal-

cium sulfate resorption. The b-TCP resorption is thought to

involve both solution- and cell-mediated disintegration.18–20

The b-TCP with 75% porosity used in our study had both

macropores and micropores, most of which were intercon-

nected. This structure facilitates the entry of proteins and

cells for bone formation and resorption. In previous animal

experiments, we have found numerous multinucleated giant

cells on the surface of b-TCP; most of these cells were

positively stained for TRAP in serial sections.21,22 This

result was obtained 2–4 weeks after implantation and is

consistent with the present clinical results in which the

outer margin of the implanted b-TCP with 75% porosity

was unclear 3–4 weeks after implantation [Figure 3(C)].

We also found clusters of multinucleated giant cells and

osteoblasts at the boundary between new bone and ceramic

2–4 weeks after surgery in a rabbit model. Ogose et al.17

observed a lining of osteoblastic cells on the surface of

b-TCP and new bone and a considerable number of osteo-

clast-like giant cells surrounding b-TCP in a human speci-

men 4 weeks after surgery. These findings suggest that

bone formation and resorption of b-TCP in humans occur

in a manner similar to that in experimental animals.

CONCLUSION

In conclusion, bone formation and resorption of b-TCP after

implantation of b-TCP blocks with 60 and 75% porosity in

opening-wedge HTO were completed within 3.5 years and

occurred in a manner similar to that in experimental ani-

mals. This phenomenon may be facilitated by mechanical

loading even in aged patients.

The authors gratefully thank Mr. H. Irie of Olympus Biomate-rials for supplying materials.

Figure 7. (A) Decalcified histological section stained with HE. The

biopsy specimen obtained from the site implanted with b-TCP with

60% porosity [Figure 6(C)] shows good lamellar bone formation witha vessel and remaining b-TCP (3200). (B) Calcified histological sec-

tion obtained from the b-TCP with 60% porosity implanted site in

case 2 [Figure 6(B)]. The area of the remaining b-TCP (brown) was

measured using an image analyzer and was expressed as percent-age to the newly formed bone plus b-TCP (toluidine blue, 320).

Figure 6. The surface of the defects of cases 1(A), 2(B), and 3(C) that were filled with a b-TCPblock with 60% porosity [Figure 2(E)], observed macroscopically, are replaced by bone 30, 29, and

26 months after surgery, respectively. The repaired area in each case is shown by broken lines. It is

hard to distinguish the border between the defect and the surrounding bone. Bleeding from the bi-opsy site is seen. The arrow indicates a biopsy site in case 3. The yellow boxes indicate area

where the Puddu plates were placed and the arrow heads indicate screw holes.

458 TANAKA ET AL.


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Documents

Bone formation and resorption in patients after implantation of β-tricalcium phosphate blocks with 60% and 75% porosity in opening-wedge high tibial osteotomy