Successful Long-Term Mandibular Reconstruction and Rehabilitation Using Non-Vascularised Autologous Bone Graft and Recombinant H

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British Journal of Oral and Maxillofacial Surgery 53 (2015) 870–874

Successful long-term mandibular reconstruction and

rehabilitation using non-vascularised autologous bone graft

and recombinant human BMP-7 with subsequent endosseous

implant in a patient with bisphosphonate-related

osteonecrosis of the jaw

∗

Ishrat Rahim, Stephen Salt, Manolis Heliotis

Regional North West London Maxillofacial Unit, Northwick Park Hospital, London, United Kingdom

Accepted 6 August 2015

Available online 29 September 2015

Abstract

We describe a case of extensive osteonecrosis of the mandible after a dental extraction in a 71-year-old woman who was taking alendronic

acid (Fosamax , Merck) for osteoporosis. Bone damaged by bisphosphonate-related osteonecrosis of the jaw (BRONJ), also now known

as medication-related osteonecrosis of the jaw (MRONJ), can be regenerated and ﬁlled with endosseous implants using non-vascularised

autologous grafts.

Keywords: Bisphosphonates; BRONJ; MRONJ; Mandibular reconstruction; Bone morphogenic proteins; BMPs; Endosseous implants

Introduction have an inﬂuence for more than 5 years after treatment has

ﬁnished.2

Bisphosphonates work because they inhibit osteoclasts. A recent paper from the American Association of

This reduces bony resorption but also disrupts normal Oral and Maxillofacial Surgeons (AAOMS) suggests that

remodelling. Resorption of old extracellular matrix induces bisphosphonate-related osteonecrosis of the jaw (BRONJ)

osteoblasts to form new bone, but after bisphosphonates have should now be named medication-related osteonecrosis of

been given intravenously or orally, they are liberated only the jaw (MRONJ). This is deﬁned as an area of exposed

when the bone into which they were deposited is resorbed. bone in the maxillofacial region, or bone that can be probed

The half-life of bisphosphonates in bone can be in excess of through a ﬁstula (either intraoral or extraoral and which has

10 years, and their effect extends far beyond the duration persisted for more than 8 weeks) in a patient who is currently

of treatment. Alendronic acid taken orally may continue to taking or has previously taken antiresorptive or antiangio-

genic medication, and has not had radiotherapy to the jaw.

The risk of osteonecrosis of the jaw after the extraction of

∗

Corresponding author at: Regional North West London Maxillofacial teeth among patients who have taken bisphosphonates orally

Unit, Northwick Park Hospital, Watford Road, Harrow, London HA1 3UJ, is estimated to be 0.5%, compared with between 1.6% and

United Kingdom. 3

14.8% when they had the medication intravenously. A recent

E-mail addresses: [email protected] (I. Rahim), [email protected]

national study concluded that the risk can be considered

(S. Salt), [email protected] (M. Heliotis).

http://dx.doi.org/10.1016/j.bjoms.2015.08.006

I. Rahim et al. / British Journal of Oral and Maxillofacial Surgery 53 (2015) 870–874 871

“rare”, as it occurs between only 1/10 000 and 1/1000 post- abscess was incised and drained under local anaesthetic and

menopausal women who are taking bisphosphonates orally she was given a course of doxycycline.

for osteoporosis. Two months later, radiological examination showed a

Any dentoalveolar procedure must be considered care- pathological fracture of the right body of the mandible

fully in these patients: most obviously the extraction of teeth, (Fig. 1), and she had a partial mandibulectomy to remove

but also periodontal and endodontic operations. What is the necrotic tissue adjacent to the fracture. The remaining

relatively unknown, is how the jaw of a patient taking bis- bony defect after resection was about 36 mm long. A tita-

phosphonates, particularly those with BRONJ, will respond nium reconstruction plate (Synthes Compact 2.0 LOCK

to bone grafts from a distant autologous site, and how this Mandible, Oberdorf, Switzerland) was inserted and the dis-

newly-grafted bone will react to implantation. We describe a charging cutaneous sinus was formally excised and closed

case in which both were possible. (Fig. 2). Three weeks after the operation the intraoral wounds

The AAOMS classiﬁcation of MRONJ is largely the same had healed well, and there was no evidence of discharge from

as that of BRONJ. It is divided into 3 stages of severity, and the sinus.

appropriate management has been advised for each. Opera- We considered inserting a graft to aid bony regeneration

tion is still reserved for stage 3 MRONJ alone, for example, because reconstruction plates used on their own will eventu-

for exposed and necrotic bone or ﬁstulas that probe into ally fail. After full assessment and discussion of all possible

bone with evidence of infection, and one or more of the fol- treatments, the patient consented to have a bone graft from

lowing: pathological fractures, extraoral ﬁstulas, oroantral the iliac crest with the additional use of recombinant human

or nasal communications, extension of the exposed necrotic (rh) protein BMP-7 (known in the United States as osteogenic

bone beyond the region of alveolar bone, or osteolysis that protein (OP)-1).

extends to the inferior border of the mandible or ﬂoor of Seven months after the initial procedure, the reconstruc-

the sinus. However, operation can trigger progression. One tion plate and defect were opened up. Two cubic centimetres

prospective study into the effectiveness of resection of the jaw of mostly cancellous bone was harvested from the left iliac

in patients with cancer and MRONJ showed a recurrence rate crest. The harvested cortical bone was ﬁrst ﬁxed to the

5 ®

of 9.4% 6 months after the operation. Resection of the jaw mandible with 1.3 mm (Synthes , USA) screws. The cancel-

also poses the challenge of reconstruction and rehabilitation. lous bone was then mixed with rhBMP-7 3.5 mg (Osigraft®

Several patients have had mandibular defects caused by Howmedica International) and Type I collagen, and applied to

MRONJ reconstructed successfully with ﬁbular free ﬂaps the defects in and around the reconstruction plate. Haemosta-

and osseointegrated implants. Autologous non-vascularised sis was achieved and the wounds were closed. Radiological

bone grafts, on the other hand, are more likely to fail and examination 4 months later showed considerable growth of

because of this, reconstruction with a ﬂap is more usual. new bone (Fig. 3). We then made a removable denture,

When we operated in April 2009, we knew of no other reports but the patient could not tolerate it. After a detailed dis-

of reconstruction with autologous non-vascularised bone and cussion of the risks of implantation into the bone, a single

bone morphogenetic protein (BMP) complex with subse- titanium implant 9.5 mm long and 3.5 mm wide (Ankylos ,

quent insertion of an endosseous implant into the regenerated DENTSPLY Implants, Mölndal, Sweden,) was placed into

bone. the regenerated bone about a year after the graft. To keep

the partial lower cobalt chrome denture in place, a precision

abutment was attached to the osseointegrated implant about

8 months later (Figs. 4 and 5).

Case report Enough bone was regenerated and there was full osseoin-

tegration of the implant. Five years after the bone graft and 4

A 71-year-old woman of Indian origin was referred for inves- years after the implant, both were still securely in place and

tigation of an extraction socket that had not healed almost functioning well (Fig. 6).

a year after removal of a second molar on the lower right

side. Her medical history included rheumatoid arthritis and

osteoporosis for which she had been taking alendronic acid Discussion

(Fosamax , Merck) orally every week for several years.

Examination, an orthopantogram, and a bone biopsy con- Although there has been much discussion about the recon-

ﬁrmed the diagnosis of MRONJ. She was given analgesics struction of mandibular defects after disease and trauma, little

and asked to follow a strict regimen of oral hygiene. The is known about mandibular reconstruction in patients with

bisphosphonate was replaced with strontium ranelate. MRONJ, possibly because incidences are relatively low and

Four months later, she complained of a swollen face and resection is reserved for stage-3 disease.

severe pain in the right body of the mandible. There was a There have been several reports on the use of vascularised

localised collection of pus adjacent to the right lower border free ﬁbular ﬂaps in which there was either minimal or no

7–9 6

of the mandible, which could be expressed from the extraction recurrence of MRONJ. Ferrari et al, described one patient

socket intraorally as well as from an extraoral sinus. The who had restoration of a mandibular defect with a ﬁbular

872 I. Rahim et al. / British Journal of Oral and Maxillofacial Surgery 53 (2015) 870–874

Fig. 1. Orthopantogram showing patchy radiolucency and pathological fracture of the right mandible.

Fig. 2. Orthopantogram after resection and ﬁxation with the rigid plate.

Fig. 3. Orthopantogram showing the regenerated bone and endosseous implant; inset: periapical view.

I. Rahim et al. / British Journal of Oral and Maxillofacial Surgery 53 (2015) 870–874 873

Fig. 4. Implant in place (left) and ﬁtting surface of partial cobalt chrome denture showing precision attachment (right).

cancellous bone, is relatively vascular, and therefore has a

higher turnover of bisphosphonate-affected bone and is rich

in osteoblasts. We thought that the iliac crest would be largely

free of bisphosphonate by the time of grafting, which was

around 13 months after the bisphosphonate had been stopped,

and 7 months after the mandible had been resected.

Two rhBMPs have been available commercially to date:

® ®

rhBMP-2 (InductOs , Medtronic) and rhBMP-7 (Osigraft ,

Howmedica International). The decision to use BMP-7 as an

adjunct to the autologous bone graft was made on the basis

that it would minimise the incisions, dissection of muscle, and

the amount of bone harvested, and allow quick postoperative

mobilisation. This was key given the patient’s multiple medi-

cal problems and already compromised mobility. We wished

to minimise morbidity at the donor site, so only 2 cm was

harvested from the iliac bone.

Fig. 5. Partial denture in place. The bone may have regenerated without the use of BMP.

However, in our experience, such a small volume grafted

on its own has never successfully reconstructed a defect of

this size. It is therefore a feasible assumption that the use of

BMP-7 made an important contribution. Another suggested

beneﬁt of BMP is the improvement in the way that soft tissues

heal, so they are useful in the treatment of necrotic or poorly- 11

vascularised bone.

There is much information about the risk of complica-

tions when endosseous implants are used in patients treated

with bisphosphonates. However, while some suggest that the

12 13,14

implants are at a higher risk of failure, others disagree.

In our patient, the endosseous implant integrated successfully

into the regenerated bone and enabled function to be restored

by retaining a partial denture.

The limitations of rhBMPs include the fact that they may

Fig. 6. Postoperative appearance of access incision. not produce enough bone for the procedure, and the recom-

15,16

binant factors are expensive. Other side effects include

free ﬂap and immediate placement of 6 endosseous implants. ectopic bone formation and osteolysis. BMPs may also be

They had optimal function and were aesthetically pleasing, carcinogenic, given that some patients who develop MRONJ

and there was no recurrence or complications. In 2009, Marx also have bone cancer. They have potent growth factors that

described the use of cancellous marrow grafts supplemented encourage cell proliferation; however, as yet there is incom-

by platelet-rich plasma growth factor in selected mandibular plete evidence to support this hypothesis.

continuity defects. Restoration of function is the main goal of mandibular

We used autologous bone that had been exposed to reconstruction, so success is judged by the presence of newly-

alendronic acid because the iliac crest, particularly the formed bone that is capable of supporting dental implants.

874 I. Rahim et al. / British Journal of Oral and Maxillofacial Surgery 53 (2015) 870–874

We have shown that even in patients who have taken bis- 5. Bedogni A, Saia G, Bettini G, et al. Long-term outcomes of surgical

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We have no conﬂicts of interest.

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Ethics statement/conﬁrmation of patient permission

11. Boyne PJ. The restoration of resected mandibles in children without the

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Ethical approval was not required. All information, including

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radiological images and photographs have been published nate use and dental implant failure among middle-aged women. J Clin

with the patient’s permission. Periodontol 2012;39:408–14.

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