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Medication-RelatedOsteonecrosisoftheJaws
FromOncePerYearIntravenousZoledronic
Acid(Reclast):Reportof4Cases
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IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015
227
Medication-Related Osteonecrosis of the
Jaws From Once Per Year Intravenous
Zoledronic Acid (Reclast): Report of
4 Cases
Cameron Y. S. Lee, DMD, MD, PhD,* and Jon B. Suzuki, DDS, PhD, MBA†
steonecrosis of the jaws is
a commonly reported side
effect with patients prescribed
oral antiresorptive medications (formerly known as bisphosphonates) to
treat osteoporosis and osteopenia.1,2
Oral antiresorptive agents are considered as the standard of care for the
prevention and treatment of women
with postmenopausal osteoporosis
and are the most widely prescribed
medications for this skeletal disorder.
Unfortunately, the entire dental profession is confronted with this adverse
side effect because of established
medical therapy in the management
of osteoporosis and the complications
of skeletal-related events.3,4
Oral medications approved by the
United States Food and Drug Administration (FDA) include the following antiresorptive agents: Alendronate sodium
(Fosamax; Merck & Co., Inc., Whitehouse Station, NJ)5; Risedronate sodium
(Actonel, Warner Chilcot, Dublin, OH)6;
and Ibandronate sodium (Boniva, Roche
O
*Private Practice in Oral, Maxillofacial and Reconstructive
Surgery; Professor of Surgery, Department of Periodontology
and Oral Implantology, Temple University Kornberg School of
Dentistry, Philadelphia, PA.
†Professor and Associate Dean, Temple University, Kornberg
School of Dentistry, Department of Periodontology and Oral
Implantology, School of Medicine; Department of Microbiology
and Immunology, Philadelphia, PA.
Reprint requests and correspondence to: Cameron Y. S. Lee,
DMD, MD, PhD, 98-1247 Kaahumanu Street, Suite 314,
Aiea, HI 96701, Phone: 808-484-2288, Fax: 808-484-1181,
E-mail: [email protected]
ISSN 1056-6163/15/02402-227
Implant Dentistry
Volume 24 Number 2
Copyright © 2015 Wolters Kluwer Health, Inc. All rights
reserved.
DOI: 10.1097/ID.0000000000000227
Osteonecrosis of the jaws is
a commonly reported side effect
with patients prescribed oral antiresorptive medications to treat osteoporosis and osteopenia. Oral
antiresorptive agents are considered as the standard of care for
the prevention and treatment of
women with postmenopausal osteoporosis. Because of patient’s noncompliance of the antiresorptive
medications, which may require
once-weekly or once-monthly oral
ingestion, a new once a year intravenous (IV) infusion of zoledronic
acid was recently introduced in the
management of osteoporosis. Reports of medication-related osteonecrosis of the jaw (MRONJ) have
been reported in patients with cancer treated with multiple doses of IV
zoledronic acid. However, there is
a paucity of reports occurring with
the once-yearly infusion of zoledronic acid (Reclast) for the management of osteoporosis. In this
article, we report 4 cases of patients who had a history of longterm oral antiresorptive therapy
and now were taking the onceyearly IV zoledronic acid (Reclast)
and soon developed MRONJ after
completing surgery of the maxilla
and mandible. (Implant Dent
2015;24:227–231)
Key Words: zoledronic acid (Reclast), osteoporosis, medicationrelated osteonecrosis of the jaws
Group, South San Francisco, CA).7 Each
of the medications differs in their binding
affinity to bone, potency, and duration.8,9
For patient’s convenience and individuals unable to comply with a set
dosing schedule of the antiresorptive
medications, which may require onceweekly (Fosamax and Actonel) or
once-monthly (Boniva) oral ingestion,4
a new once a year intravenous (IV)
infusion of zoledronic acid (Reclast,
Novartis Pharmaceuticals, East Hanover,
NJ; Aclasta, Novartis Pharma) was
approved by the FDA in 2007.10 At a dose
of 5 mg once per year, it has demonstrated antifracture properties in
postmenopausal women and men with
osteoporosis.10,11 During a 3-year
period, an annual infusion of 5 mg of
zoledronic acid significantly reduced
the risk of fracture of all major osteoporotic anatomic sites, especially vertebral
and hip fractures.2 Once per year infusion of zoledronic acid may be more
appealing to the osteoporotic patient,
as strict adherence to a weekly or monthly
regimen of oral dosing for 12 months
can be challenging and lead to patient’s
noncompliance.12–14 Medication-related
osteonecrosis of the jaw (MRONJ) due
to long-term oral antiresorptive therapy
has been well documented.1,15–21 This
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228
INTRAVENOUS ZOLEDRONIC ACID (RECLAST): REPORT
OF
4 CASES
LEE
Table 1. MRONJ Patient Data
Patient Sex Age
AK
JK
BS
F
F
F
87
72
70
JS
F
89
Time to
Event (wk) Stage
Complication
Maxillary infection
Mandible infection
Sinusitis of right
maxillary sinus
Mandible fracture
1
5
2
2
2
2
2 (infection)
4 (fracture)
2
3
Procedure
Extraction of teeth
Extraction of teeth
Sinus lift elevation with
bone grafting
Extraction of teeth
Average age: 79.5 years.
Time to Event: From day of surgery to first observed postoperative signs and symptoms of MRONJ based on 2014 AAOMS
classification.
Stage: Clinical signs and symptoms of MRONJ based on 2014 AAOMS classification.
disease entity was formerly known as bisphosphonate-related osteonecrosis of the
jaws and antiresorptive-related osteonecrosis of the jaws.1 But, because of the vast
amount of recent cases of osteonecrosis
of the jaws from other antiresorptive and
antiangiogenic treatment strategies, the
American Association of Oral and
Maxillofacial Surgeons (AAOMS) has
recommended the change in nomenclature.15 Since the first reports by Marx16
in 2003 who described 36 patients with
ONJ while receiving IV antiresorptive
agents and Ruggiero et al17 who presented an additional 63 cases in 2004,
multiple reports of MRONJ have
appeared in the medical and dental literature.18–20 Development of soft and hard
tissue lesions is usually because of an
inciting event, such as tooth extraction,
bone grafting of the jaws in preparation
for dental implants, and implant
surgery.16,17,21
MRONJ has been reported in patients with cancer treated with multiple
doses of IV zoledronic acid.22,23 The
incidence of MRONJ for patients taking the IV form of this medication is
estimated at 2% to 18%.24,25 In contrast, Merck et al estimate the risk of
developing MRONJ for patients taking
the oral form of antiresorptive agents is
0.7 cases per 100,000 person-years of
exposure.16 The AAOMS position
paper on MRONJ estimate the incidence of ONJ cases for patients taking
the oral form as 0.01% to 0.04%.15,26
However, there are very few reports
in the English literature of this occurring with the once-yearly infusion of
Table 2. MRONJ Staging and Treatment Strategies
Stage
0
1
2
3
Description
Treatment
Nonspecific clinical findings,
radiographic findings, and
symptoms. No clinical evidence of
necrotic bone
Asymptomatic, but exposed, necrotic
bone or fistulas are present. No
evidence of infection
Systemic management. Use of
analgesics and antibiotics
Use of chlorhexidine mouth rinse,
close monitoring of patient on
quarterly basis. Provide patient
education
Symptomatic treatment with
antibiotics, oral bacterial mouth
rinse, pain control, debridement of
infected area
Exposed necrotic bone or fistulas that
probes to bone in area of infection.
Clinical signs of infection, such as
pain, erythema with or without
purulent discharge
All of the above treatment with more
Exposed necrotic bone or fistulas
aggressive surgical intervention,
present that probes to bone and
such as debridement and resection
extends beyond region of alveolar
of jaw
bone, such as to inferior border of
mandible, ramus of mandible, and
zygoma in maxilla. Fracture of jaw
or osteolysis present in jaws
Staging and treatment strategy of MRONJ according to the position paper of the 2014 AAOMS.
AND
SUZUKI
zoledronic acid (Reclast, Novartis
Pharmaceuticals; Aclasta, Novartis
Pharma) for the management of osteoporosis.27,28 It is estimated that the risk
of developing MRONJ from IV zoledronic acid in the management of osteoporosis is approximately 0.017% (1.7
cases per 10,000 patients).28 In this article, we report 4 cases of patients who
had a history of long-term oral antiresorptive therapy and now were taking
the once-yearly IV zoledronic acid (Reclast) and soon developed MRONJ
after completing surgery of the maxilla
and mandible.
PATIENTS
AND
METHODS
For all clinicians, it is important to
obtain a complete health history regarding patient exposure to antiresorptive
agents.29 A prospective chart review of
4 patients was completed. Data
included gender, age, systemic factors,
duration of antiresorptive therapy (oral
and IV) prescribed by their physician,
jaw location of osteonecrosis, surgical
treatment (debridement, sequestrectomy, platelet-rich plasma), and overall
outcome. The study group consisted of
4 female patients whose age ranged
from 70 years to 89 years. The mean
age was 79.5 years (Table 1).
We adhere to the classification of
the AAOMS15,26 to define MRONJ
that consist of 4 stages (0–3) (Table 2).
This clinical staging system has been
established to define the severity of
MRONJ and guide the clinician in
the management of this surgical problem. Biopsy specimens were obtained
from all 4 patients that were histopathologically diagnosed with actinomyces (Fig. 1). Of the 4 patients, 3
presented with stage 2 disease and 1
(mandible fracture) with stage 3 disease. One patient completed the sinus
lift elevation procedure with bone
graft augmentation of the right maxillary sinus in preparation for implant
placement that became infected 2
weeks after the surgical procedure.
Acute sinusitis and fistula formation
were present upon initial examination.
The other 3 patients had molar teeth
extracted from the posterior maxilla
and mandible. Oroantral communication was observed in the patient who
had teeth extracted from the left
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IMPLANT DENTISTRY / VOLUME 24, NUMBER 2 2015
Fig. 1. Diffuse purple staining filamentous bacteria identified as actinomyces in nonvital bone
specimen. Microbes are not surface contaminants but established deep in the bone that may
represent biofilms. Hematoxylin and eosin (3100).
Fig. 2. Displaced fracture of left posterior mandible that occurred 4-week postextraction of
teeth and surgical debridement in this 89-year-old Asian woman. Mandible fracture due to
long-term use of alendronate (greater than 10 years) and recent use of IV zoledronic acid.
posterior maxilla as the floor of the
maxillary sinus was eroded. The
89-year-old patient sustained a mandible fracture 4 weeks (Fig. 2) after
extraction of the teeth and a debridement procedure. All 4 patients (including the patient with the mandible
fracture) were treated with surgical
debridement that consisted of excision of all necrotic-appearing bone
cellular therapy consisting of platelet-rich plasma and long-term oral
antibiotic therapy for a period of 4 to
12 months prescribed by an infectious
disease specialist.
DISCUSSION
Antiresorptive agents decrease
bone resorption and skeletal fracture
by chemically binding to calcium
hydroxyapatite in the mineral phase of
bone. They are attracted to areas of bone
remodeling, where osteoclast activity is
high and concentrating in the lacunae of
the osteoclast. Therefore, the osteoclastic cell is the main target for antiresorptive agents and prevents osteoclasts
from binding to the surfaces of bone,
which prevents bone resorption and
increases bone mineral density.30–33
229
IV infusion of zoledronic acid
(Reclast) 5 mg over a 15-minute interval is used in the management of
osteoporosis.2,10,11,34 It is considered
as the most potent of the antiresorptive
medications with a long half-life.10 In
several human and animal studies,
yearly IV doses of zoledronic acid had
a greater effect on bone remodeling
compared with oral antiresorptive medications and may be responsible for one
of the many proposed mechanisms of
MRONJ.34–36 However, clinical data
regarding the incidence of MRONJ
from once a year infusion of zoledronic
acid (Reclast) is sparse.28,37 Data
regarding our case series are presented
in Table 1. All 4 patients were Asian
women, with an average age of 79.5
years. They all had a positive history
of long-term Fosamax (Merck, Whitehouse Station, NJ) use for over 10 years
before treatment with IV zoledronic
acid. Three of the 4 patients received 2
doses of zoledronic acid. The woman
who developed a mandible fracture
received only a single dose of zoledronic acid.
We hypothesize that all of our
patients developed MRONJ while on
IV zoledronic acid. Based on past
clinical experience, it is the authors’
opinion that compared with the oral
form of MRONJ, osteonecrosis of the
jaws from the IV form of bisphosphonates presents with greater challenges.
Of the 4 patients, 1 developed an infection that progressed to a mandible fracture 4 weeks after the teeth were
extracted. The infection was refractory
to surgical treatment, which ultimately
required application of a reconstruction
bone plate to stabilize the fracture segments once the fracture was identified.
Currently, it remains unclear if
actinomyces is primarily involved in
the pathogenesis of osteonecrosis in the
patient on antiresorptive therapy.38–42
In Marx’s series of 30 consecutive
MRONJ cases, they demonstrated high
number of actinomyces species, but the
clinical significance of this observation
was not addressed.39 In a study by
O’Ryan et al,43 actinomyces was present
in greater than 75% of histologic specimens. When histopathology was available, Lazarovici et al38 reported that
actinomyces colonies were identified
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230
INTRAVENOUS ZOLEDRONIC ACID (RECLAST): REPORT
93% of the time. In our opinion, recognition of actinomycosis is critical. The
reasons for the use of the term “critical”
are the facts that in the presence of signs
and symptoms of soft tissue edema,
erythema, orocutaneous fistulas, and
suppuration in the MRONJ patient, actinomycosis should be recognized as a primary diagnosis and specific treatment
directed at eradication of this bacterial
pathogen. Therefore, our treatment regimen consists of penicillin VK at a dose of
1 g 3 to 4 times per day over a 4- to
12-month duration. If patients are younger than 65 years, probenecid, 500 mg 3
to 4 times per day is added to decrease
antibiotic renal clearance. For patients
who are allergic to penicillin, an alternative regimen such as doxycycline 100 mg
twice daily, erythromycin 500 mg or clindamycin 300 mg 4 times per day is
acceptable over 6- to 12-month duration.
Based on our surgical experience
and that of others,43–52 surgical intervention should be considered early in
the course of management of MRONJ.
It has been demonstrated that conservative management in many advanced
cases (Stage 2 and 3) results in only
a 50% resolution defined as closure
of the oral mucosa and remains refractory to conservative treatment. Surgical intervention may result in a more
definitive treatment and resolution of
MRONJ.45–52
CONCLUSION
In this report, we describe 4 patients with a medical history of longterm oral antiresorptive therapy who
were now taking the once-yearly infusion of IV zoledronic acid who soon
developed MRONJ after completing
surgery of the jaws. We anticipate that
the dental practitioner will increasingly
encounter patients not only prescribed
the oral form of antiresorptive agents
but also the IV form as well and should
be able to anticipate the potential complications from this medication.
DISCLOSURE
The authors claim to have no
financial interest, either directly or indirectly, in the products or information
listed in the article.
OF
4 CASES
LEE
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