Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients

Abstract

BACKGROUND:

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is a relatively new disease. The aim of this study was to evaluate the prevalence of BP-ONJ in breast cancer patients with osseous metastasis and bisphosphonate therapy.

METHODS:

A retrospective study was conducted in a EUSOMA accredited breast unit in Germany. All patients treated from January of 2000 to March of 2006 with metastatic breast cancer and bisphosphonate therapy were reviewed. All patients were contacted, and missing data were completed through structured interviews with their dentists and physicians (n = 75). Primary outcome was the development of BP-ONJ and the detection of possible additional trigger factors for the development of BP-ONJ.

RESULTS:

A total of 117 patients with breast cancer fulfilled the inclusion criteria, and data for 75 still living patients were included. Of these 75, 4 patients developed a BP-ONJ, resulting in a prevalence of 5.3%: 3 patients received zoledronate only; 1 patient had first pamidronate followed by zoledronate and ibandronate. A tooth extraction could be identified as an additional trigger factor for 2 patients.

CONCLUSIONS:

With a prevalence of 5.3%, BP-ONJ in breast cancer patients has become a relevant disease that should be discussed with patients for whom bisphosphonates have been recommended. Appropriate dental care before bisphosphonate therapy commences has been advised to reduce the occurrence of BP-ONJ. Cancer 2009. © 2009 American Cancer Society.

Breast cancer is the most common cancer and the most common cause of cancer death in women worldwide. The skeleton is the most frequent site of distant metastasis in breast cancer patients.1 The metastases cause severe morbidity including pain, impaired mobility, hypercalcemia, pathological fractures, spinal cord compression, and bone marrow infiltration.2

Bisphosphonates play an important role in the therapy of breast cancer patients with osseous metastases. Depending on the ligands, bisphosphonates are separated into nitrogen-containing and non-nitrogen-containing bisphosphonates. The former inhibit the mevalonate pathway, and the latter are integrated into the ATP molecule. Both mechanisms result in a cytotoxic effect on the osteoclasts.3, 4 There is further evidence that bisphosphonates reduce and delay skeletal-related events and reduce pain and thereby improve quality of life.1 Further effects of bisphosphonates are listed in Table 1.

Table 1. Effects of Bisphosphonates (↑ Increased; ↓ Decreased)

Sphere of Activity	Effect	Reference
Osteoclast	Recruitment ↓	Hughes 199529
	Life span ↓
	Activity ↓	Green & Clezardin 200230
Osteoblast	Prostaglandin E2 ↓	Igarashi 199731
	Alkaline phosphatase activity ↑
	IL 6 ↓	Green & Clezardin 200230
	Osteoblast precursors ↑	Giuliani 199832
	Apoptosis ↓	Abe 200033
	Differentiation ↑ (clodronate and etidronate)	Itoh 200334
	RANKL expression ↓ (zoledronate)	Pan 200435
Osteocyte	Metabolic activity ↓	Im 200436
	Apoptosis ↓ (etidronate, aledronate, pamidronate)	Plotkin 199937
Vessels	Angiogenesis ↓	Green & Clezardin 200230
	Endothelial growth factor ↓
Tumor cell	Apoptosis ↑	Green & Clezardin 200230
	Proliferation ↓
	Invasion ↓
	Adhesion ↓
γδ T-Lymphocytes	Function ↑ (risedronate)	Green & Clezardin 200230

Adverse side effects are acute-phase-reactions, affection of the upper aerodigestive tract and renal toxicity.5 In 2003, a new adverse side effect was described for the first time6 and has since increased in frequency, probably due to increased awareness, namely bisphosphonate associated osteonecrosis of the jaws (BP-ONJ).7 At first, causality was questioned and the appearance of the osteonecrosis was explained by the higher incidence of osteonecrosis already associated with cancer patients, radiation, chemotherapy, co-medications such as steroids, infections of dental or sinus origin, dental procedures, anemia, and local anesthetics with vasoconstrictor.8 Recently, BP-ONJ has been included in the summary of product characteristics.

Patients with BP-ONJ mainly suffer from pain and infection of the soft tissue and the bone. In general, the bone is exposed to the oral cavity or a fistula can be detected. Usually these patients have an additional trigger factor such as previous tooth extraction, surgical dental procedures, periodontal diseases with odontososis, or denture pressure sores.7 There is evidence that patients with an additional risk factor for osteonecrosis, such as radiation of the head and neck area, have an increased risk of developing BP-ONJ.9

Regarding pathogenesis, several theories are being discussed. In addition to the death of osteoclasts with consequential reduced bone remodeling,10 the antiangiogenetic potency and the development of an avascular bone necrosis,11 and the impact of bisphosphonates on the mucosal layer over a proapoptotic effect on keratinocytes are implicated.12

Because bone remodeling is affected by bisphosphonates, a typical radiological sign in dental x-rays is persistent alveolar sockets.13

Therapy for the manifest BP-ONJ is difficult.14, 15 Depending on the stage of the disease, therapy ranges from mouth rinses, debridement, to huge resections of the affected area with a broad influence on the quality of life for these patients. Independent from any form of therapy mastication, the possibility of wearing dentures and nutritional intake are affected. The incidence, prevalence, and etiology of the BP-ONJ and risk factors triggering BP-ONJ are largely unknown. In most BP-ONJ case series and case reports, the authors report a previous dental surgical procedure.7, 16 Therefore, guidelines have been established that recommend introducing patients to a dentist or an oral and maxillofacial surgeon before bisphosphonate therapy starts, with the goal of restoring and/ or extracting teeth before treatment. This regimen is already routinely practice for patients with forthcoming radiation.17 Only a few studies have been published about BP-ONJ in breast cancer patients. The study by Durie et al was a Web-based survey without strictly defined inclusion criteria and, therefore, may be hampered by events-based bias.18 The studies of Bamias et al19 and Wang et al20 reported an incidence of 2.5% and 2.9%, respectively. Aguiar Bujanda et al21 describe in a smaller study 4 BP-ONJ cases out of 35 breast cancer patients receiving zoledronate only, resulting in an incidence of 11.4%. Sanna et al22 report an incidence of 6.2% in breast cancer patients receiving pamidronate and zoledronate. Overall, the available amount of data regarding BP-ONJ compared with the widespread use of bisphosphonates seems remarkably sparse. Therefore, we conducted this retrospective study in a dedicated breast unit. Our aim was to evaluate the prevalence of BP-ONJ and to investigate predictive or prognostic factors that might be related to the development of the BP-ONJ.

MATERIALS AND METHODS

This retrospective study was performed at the breast unit of the HSK, Dr. Horst Schmidt Hospital, Wiesbaden, Germany. The protocol was approved by the local ethics committee (837.099.06 (5197)), and every patient gave written informed consent.

Data were primarily derived from the in-house cancer registry. All patients treated in the breast unit from January 2000 to March 2006 with breast cancer were identified. Patients with osseous metastasis and bisphosphonate therapy were enrolled. The living patients were contacted by mail and, if the patient agreed, by phone. Further information was extracted from the medical records. Additional data were gained by structured interview with the family physicians and dentists of patients who agreed. Data collected included age, breast cancer characteristics, applied bisphosphonate, co-morbidity and co-medication, radiation of the head and neck area, and dentist consultation frequency. Due to its retrospective character, statistical analysis was restricted to a descriptive analysis only.

RESULTS

A total of 117 patients with osseous metastases due to breast cancer were identified and 88 were still alive at the time of this analysis. Thirteen patients could not be included because they either refused participation or we failed to locate them. All together, 75 patients (64.1% of the 117 patients) with a median age of 60 years (range, 30-92 years) could be included. The median age at breast cancer diagnosis was 58 years (range, 27-89 years). Median duration of bisphosphonate therapy was 28 months (range, 6 months to 93 months). Bisphosphonates were either given orally or applied intravenously every 3 or 4 weeks. The bisphosphonates administered were as follows: exclusively zoledronate in 26 patients, exclusively coldronate in 24 patients, exclusively ibandronate in 7 patients, and exclusively pamidronate only in 3 patients. Seven more patients had combinations of different bisphosphonates sequentially with zoledronate. The other 8 patients had different bisphosphonate combinations but without zoledronate (Table 2).

Table 2. Demographic Data From All Patients Included in This Study

	All Patients	BP-ONJ	No BP-ONJ
BP-ONJ indicates bisphosphonate-associated osteonecrosis of the jaws; mam ca, mammary cancer; iban, ibandronate; zol, zoledronate; clo, clodronate; pam, pamidronate.
Patients (n)	75	4	71
Average age mam ca diagnosed (y)	58.6 (±12.3)	55.8 (±8.6)	58.8 (±12.6)
Average age at study (y)	63.5 (±12.4)	64.8 (±10.4)	63.4 (±12.6)
Bisphosphonates administered
Zoledronate	26	3	23
Ibandronate	7	-	7
Clodronate	24	-	24
Pamidronate	3	-	3
Iban + zol	2	-	2
Clo + iban	4	-	4
Clo + zol	4	-	4
Pam + zol + iban	1	1	-
Clo + pam	4	-	4
Further medication
Chemotherapy	48	4	44
Head + neck radiation	2	-	2
Further diseases
Diabetes mellitus	4	1	3
Hypertension	9	1	8
Coronary heart disease	1	1	-
Thrombosis	4	-	4
Ovarian cancer	1	-	1
Melanoma	1	1	-

Of 75 patients, 4 developed a BP-ONJ (5.3%). In these patients, the bisphosphonate had been applied for a median of 42 months (range, 16 months to 74 months). In all BP-ONJ cases, zoledronate had been used. One of the BP-ONJ patients had also received pamidronate and ibandronate sequentially (Table 3). In contrast, no patient receiving clodronate only developed BP-ONJ in our cohort.

Table 3. Patients With Bisphosphonate-associated Osteonecrosis of the Jaws

No.	Bisphosphonate	Application	BP App. Frequency	Site	Trigger Factor
BP app. indicates bisphosphonate application.
1	Zoledronate	16 months	Every 3 weeks	Mandible	Unknown
2	Pamidronate	74 months	Every 4	Maxilla	Tooth extraction
	Zoledronate		3 and
	Ibandronate		4 weeks
3	Zoledronate	55 months	Every 4 weeks	Mandible	Unknown
4	Zoledronate	29 months	Every 4 weeks	Mandible	Tooth extraction

All affected patients had received prior chemotherapy, whereas patients without prior chemotherapy in our cohort did not develop BP-ONJ. Eighteen patients were treated with aromatase inhibitors only, 4 patients received antiestrogens, 43 patients received aromatase inhibitors and antiestrogens sequentially, and 10 patients had no additional endocrine therapy. All patients with BP-ONJ had a treatment consisting of sequential tamoxifen and aromatase inhibitors.

One BP-ONJ patient had melanoma and renal insufficiency. None of the BP-ONJ patients had prior radiation of the head and neck region, 2 of the affected patients reported prior smoking.

Two patients with BP-ONJ were treated in the Department for Oral and Maxillofacial Surgery in the HSK, Dr. Horst Schmidt Hospital, Wiesbaden. A patient with necrosis in the maxilla had a hemimaxillectomy and developed half a year later relapse and had an extended second resection of the maxilla. In the second patient, a partial resection of the left mandible was planned, but the patient cancelled the appointment and was lost to follow-up. The third patient did not have infected osteonecrosis in the mandible and was treated without surgery. The fourth patient was lost to follow-up shortly after BP-ONJ diagnosis.

DISCUSSION

This study was conducted for evaluation of the prevalence of bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) in breast cancer patients treated with bisphosphonate in a tertiary breast center.

Of 75 breast cancer patients, 4 developed BP-ONJ, resulting in a prevalence of 5.3%. These findings are a higher than most of the reported incidences in the literature of 2.9 % (2 of 7019), 4.3 % (13 of 29918) and 2,5 % (2 of 8120). A reason for this higher incidence in our cohort might be that anticancer therapy such as chemotherapy or endocrine therapy was different in our population. Of interest, all our affected patients had not only received bisphosphonate therapy but also had been administered prior chemotherapy and aromatase inhibitors. Both chemotherapy and aromatase inhibitors have a negative impact on the bone mineral density.23, 24 Therefore, an additional impact on the risk for BP-ONJ cannot be ruled out. Unfortunately, anticancer medication accompanying bisphosphonate therapy had not been fully reported in most other series.

The study by Sanna et al22 reports a little higher incidence possibly because of the study design. It was a prospective study, and every patient had an oral examination so that even asymptomatic BP-ONJ cases were recorded.

The bisphosphonates that are related to BP-ONJ development in other studies were nitrogen-containing bisphosphonates such as zoledronate, pamidronate, and ibandronate.6, 7 This observation was also true in our cohort. All affected patients had been administered zoledronate, the most potent bisphosphonate. However, our trial was not designed to compare BP-ONJ risks among different bisphosphonates, and conclusions should be withheld until prospective comparisons have been performed. The bisphosphonates used in this study are typically used in breast cancer patients.1

In 3 of the 4 BP-ONJ patients, the osteonecrosis developed in the mandible. This is similar to the pattern of osteoradionecrosis, of which the mandible is also more often affected. This observation had been explained by the more critical blood perfusion of the mandible compared with the maxilla25 and the antiangiogenetic effect of the bisphosphonates.26 In 2 of the patients, a previous tooth extraction shortly preceded the onset of BP-ONJ, a phenomenon that has been described as a risk factor several times.7, 11 Because the possible adverse effects of bisphosphonates are not really well known, there might be no difference as to whether a patient developed BP-ONJ due to a tooth extraction or to periodontal disease. Awareness of BP-ONJ on behalf of the bisphosphonate-prescribing or -applying physicians and dentists could reasonably lead to prevention.

No potential dental status-related additional risk factors could be identified in the 2 other patients with BP-ONJ. However, no prospective dental evaluation had been performed prospectively. Predispositions for BP-ONJ might have been missed in these 2 patients, thus underlining the limitation of retrospective studies as always bearing the potential of missing data. Furthermore, the latter accounts not only for potential prognostic or predictive factors, we may have also missed BP-ONJ cases because we could not contact all patients, especially those who had already died.

The incidence of BP-ONJ in breast cancer patients seems to be lower than in patients with prostate cancer or patients with multiple myeloma, with reported incidence rates ranging from 3.8% to 11.0% (Table 4). This first observations might suggest that not only co-medication but also the underlying malignant disease may influence the occurrence of BP-ONJ. However, non-cancer-related patient characteristics might add to different incidence rates in different populations, eg, breast cancer patients on average are younger compared with patients with prostate cancer (around 70 years of age).27 Age (and gender) had been reported as prognostic factors for treatment needs for conservative dental treatment, tooth extractions, and prostheses.28 Younger and female patients may have better motivation or manual abilities needed for oral hygiene. Thus, better oral hygiene may suggest fewer possible trigger factors for the development of BP-ONJ in younger women, resulting in a lower prevalence of BP-ONJ.

Table 4. Published Incidences of Bisphosphonate-associated Osteonecrosis of the Jaws*

Disease	Study, year	Patients (n)	BP-ONJ (n)	Incidence (%)
BP-ONJ indicates bisphosphonate-associated osteonecrosis of the jaws; * In Durie's study, based on a Web survey, the cases are separated in BP-ONJ (first number) and suspicious findings without further explanation.
Breast cancer Total n=2172	Aguiar Bujanda 200721	35	4	11.4
	Bamias 200519	70	2	2.9
	Durie 200518	299	13/ 36	4.3/ 12.0
	Guarneri 200538	48	3	6.3
	Hoff 2006/200839	1338	16	1.2
	Ibrahim 200840	220	5	2.3
	Sanna 200622	81	5	6.2
	Wang 200720	81	2	2.5
Multiple myeloma Total n=3408	Badros 200641	340	11	3.2
	Bamias 200519	111	11	9.9
	Boonyapakorn 200842	58	10	17.2
	Calvo-Villas 200643	64	7	10.9
	Corso 200744	106	8	7.6
	Dimopoulos 200645	202	15	7.4
	Durie 200518	904	62	6.9
	Hoff 2006/ 200839	448	14	3.1
	Ibrahim 200840	59	2	3.4
	Petrucci 200746	311	22	7.1
	Tosi 200647	259	9	3.5
	Wang 200720	292	11	3.8
	Zervas 200648	254	28	11.0
Prostate cancer total n=245	Bamias 200519	46	3	6.5
	García Sáenz 200749	104	3	2.9
	Ortega 200750	52	6	11.5
	Walter 200816	43	8	18.6

Further prospectively designed subprojects associated with prospective trials evaluating bisphosphonates should focus on BP-ONJ to better define risk populations and strategies for prevention.

Conflict of Interest Disclosures

Conflict of interest: Christian Walter received funding for scientific research from a bisphosphonate-producing company.