Osteonecrosis of the jaw under palbociclib: A case series description

Abstract

Introduction

Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses.

Materials and methods

A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors.

Results

We identified eight cases, most of them at stages 0–1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug’s half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific.

Conclusion

We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

Keywords

Cyclin-dependent kinase inhibitor palbociclib osteonecrosis of the jaw adverse drug reaction

Introduction

Osteonecrosis of the jaw (ONJ) is a well-known complication among patients receiving antiresorptive drugs, such as bisphosphonates and denosumab.^1,2 In order to prevent, detect early or treat medication-related osteonecrosis of the jaw (MRONJ), especially linked to denosumab 120 mg, regular dental monitoring is provided (pre-denosumab and every 4 months after initiation) at the Dental Care Center of Rennes University Hospital, France.³ In the last few years, dental surgeons have reported to the Rennes Pharmacovigilance center a few cases of ONJ among patients treated with palbociclib and concomitantly exposed to denosumab 120 mg. Although this was not expected with palbociclib,⁴ a safety signal was filed alongside a French pharmacovigilance database analysis between 2017 and 2019.⁵

Palbociclib is a selective cyclin-dependent kinase inhibitor (CKI) of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) approved in late 2016 in Europe for the treatment of women with estrogen-dependent HER2-negative advanced or metastatic breast cancer.⁴

The most expected adverse drug reactions are neutropenia and stomatitis.^6,7 As neutropenia and stomatitis are known risk factors for oral infections, we hypothesized that palbociclib, and more widely CKIs (abemaciclib, ribociclib), could trigger ONJ. Direct toxicity has also been hypothesized. However, there is a lack of data regarding the link between CKIs and ONJ occurrence. The European Medicines Agency summary of product characteristics for palbociclib makes no mention of an ONJ risk; however, bone changes and abnormal incisor growth have been observed in rats after 27 weeks of treatment, without further clarification.^4,6

Using a single-center case series, the aim of our study was to describe ONJ cases among patients exposed to CKIs in order to identify any specific patterns that might suggest a triggering role for CKIs, and to discuss pathophysiological hypotheses in the light of the known pathophysiological mechanisms of MRONJ.

Materials and methods

Building on a collaboration between pharmacovigilance staff, dental surgeons, and oncologists, a retrospective case series study was formed between January 2016 and December 2020, implementing an individual medical record analysis.

The inclusion criteria were women with hormonal metastatic breast cancer treated with CKIs who had developed ONJ, and whose cancer and dental follow-up was provided at the Eugène Marquis Cancer Center and the Rennes Dental Care Center, respectively. All the cases of ONJ were reported to the Rennes pharmacovigilance center and assessed according to the French imputability method.⁸ Cases of ONJ occurring before palbociclib initiation were excluded.

Descriptive analyses were conducted using individual patient medical records. They were reviewed to collect data on patient demographics, breast cancer characteristics (stage, previous and concomitant treatments), ONJ characteristics (stage, area, time to onset after palbociclib initiation), pathology (with a second pathologist's post hoc review) and biological data around the period of ONJ onset. We specifically targeted neutrophil counts to assess neutropenia, in accordance with our hypothesis. We also collected data on CKI treatment characteristics (duration and reported adverse drug reactions before ONJ occurrence). Patients were considered drug-exposed taking into account the drug elimination half-life and specifically five elimination half-lives.

Ethics approval was granted by the University Hospital research ethics committee (#21.47). The study also received a favorable review from the Eugene Marquis Cancer Center's Review of Studies and Data Access Committee (Comité de Revue des Etudes et des Accès aux Données, “CREDO”). Informed consent was obtained from each patient. Participants were fully and fairly informed, in understandable terms, of the study objectives, participants’ right to refuse to participate in the study, or the ability to withdraw at any time.

Results

Between 2016 and 2020, we identified 13 cases of ONJs among patients treated with CKIs involving only palbociclib (Ibrance®, Pfizer Europe MA EEIG, Belgium). After excluding the five cases occurring before palbociclib initiation, eight cases were analyzed.

These baseline patient characteristics are described in Table 1. The median age was 69.5 years (min-max: 50–85 years), and all were menopausal. All patients had bone metastases requiring the use of denosumab.

Table 1.

Baseline patient characteristics.

		n	Percentage
Age (years)	Median	69.5
	Min-max	50–85
Weight (kg)	Median	60.5
	Min-max	46–72
Breast cancer type	Invasive ductal carcinoma	5	62.5
	Invasive lobular carcinoma	2	25
	Well-differentiated adenocarcinoma	1	12.5
Scarff-Bloom-Richardson grade^a	II	6	75
	III	1	12.5
	No grade	1	12.5
Metastasis localization^b	Bone	8	100
	Liver	4	50
	Lymph node	2	25
	Lung/Pleura	1	12.5
Comorbidities^b	Dyslipidemia	2	25
	High blood pressure	2	25
	Hypothyroidism	3	37.5
	Diabetes mellitus	1	12.5
	Tobacco	1	12.5
	Osteoporosis	1	12.5

Histological grading system evaluating tubule formation, nuclear pleomorphism, and mitotic index.

Metastatic sites and comorbidities are not mutually exclusive.

Regarding the ONJ characteristics, half were mandibular and half were maxillary, the majority were ONJ stages 0 or 1 (n = 5; 62.5%). Surgical treatment was performed in five cases (62.5%) with anatomopathological analyses: the necrotic bone tissue was consistent with osteonecrosis associated with nonspecific reactive inflammatory remodeling of the mucosa border in all cases.

All patients had at least one dental risk factor before ONJ diagnosis, including periodontal disease (n = 5; 62.5%), dentures (n = 6; 75%) with four cases of unstable or compressive dentures, tooth extraction (n = 6; 75%) and mucositis (n = 5; 62.5%; two related to palbociclib use and four related to other anticancer drugs). These patients developed mucositis before ONJ onset, but there was no information on the persistence of mucositis at the time of ONJ diagnosis.

The chronological treatment sequences and the dental risk factors are illustrated individually in Figure 1. Since the denosumab half-life is 28 days, all patients were considered to be exposed to denosumab at the time of ONJ diagnosis.

The median time to ONJ onset following denosumab initiation was 18 months (min-max: 4–29 months, Q1-Q3: 13.3–21.3 months). Regarding palbociclib, 4 patients were still exposed to palbociclib at the time of the ONJ diagnosis (cases #1 to #4); the median ONJ onset time from palbociclib initiation was 12.5 months (Q1-Q3: 6.8–16.8 months, min-max: 2–21 months); the four remaining patients discontinued palbociclib prior to their ONJ diagnosis (cases #5 to #8) and were no longer considered exposed at the time of the ONJ diagnosis; the median time from palbociclib discontinuation to the ONJ diagnosis was 6.5 months (min-max: 1–16 months, Q1-Q3: 1.8–12.3 months).

The general and ONJ characteristics of patients in the case series are summarized in Table 2.

Table 2.

General and osteonecrosis of the jaw (ONJ) characteristics of patients under palbociclib.

Case number	#1	#2	#3	#4	#5	#6	#7	#8
Age (years)	85	69	50	69	62	72	70	71
Dental follow-up every 4 months at dental care center	Yes	Yes	No	Yes	Yes	No	No	Yes
Comorbidities	Hypothyroidism	Diabetes	Chronic maxillary sinusitis	Dyslipidemia +high blood pressure	Hypothyroidism + high blood pressure	None	Dyslipidemia	Hypothyroidism
Time to ONJ diagnosis since initiation of denosumab (months)	29	16	11	20	21	24	4	14
Number of denosumab injections	24	8^a	10	20	20	17	28^b	12
Time to ONJ diagnosis following palbociclib initiation (months)	16	21	2	3	8	14	19	11
ONJ onset following of palbociclib discontinuation (months)	Not applicable	Not applicable	Not applicable	Not applicable	2	7	16	1
Palbociclib exposure at the time of ONJ diagnosis	Yes	Yes	Yes	Yes	No	No	No	No
Anticancer drugs at the time of ONJ diagnosis	Palbociclib + fulvestrant	Palbociclib + létrozole	Palbociclib + fulvestrant	Palbociclib + fulvestrant	Capecitabine	Cyclophosphamide	Eribuline	Capecitabine (palbociclib stopped 1 month before ONJ diagnosis)
Neutropenia reported at the time of ONJ	Yes	Yes	Yes	Yes	Not known	No	No	Yes
Periodontal disease	No	No	Yes	Yes	Yes	Yes	No	Yes
Removable dentures	Maxillary and mandibular	Mandibular compression	None	None	Maxillary non-compressive	Maxillary non-compressive	Maxillary compression	Maxillary and mandibular unstable denture
Number of dental extractions	44	x	Debridement on 31–41	38	15, 16, 25, 35	16	x	42, 13
Time-lapse from tooth extractions to initiation of denosumab (months)	3	x	With denosumab^c	2	3	Unknown	x	6 and 3 (2 tooth extractions 3 months apart)
Date of ONJ diagnosis	July 2019	April 2020	April 2018	January 2019	February 2019	June 2019	August 2019	May 2019
ONJ site	Maxillary	Mandibular	Mandibular	Mandibular	Maxillary	Maxillary	Maxillary	Mandibular
Stage of ONJ	1	2	1	1	0	3	2	0
Treament of ONJ	Medical	Surgical	Surgical	Surgical	Surgical	Medical	Surgical	Medical
ONJ evolution (up to the end of 2020)	Stabilization	No cure	Healing	Healing	Healing	Stabilization	Healing	Stabilization

There was a 3-month treatment interruption during denosumab treatment, but at the time of ONJ diagnosis, the patient was exposed to denosumab.

There was a 9-month treatment interruption during denosumab therapy; at the time of ONJ diagnosis, the patient was exposed to denosumab, reintroduced 4 months earlier.

Tooth extraction by a private dentist while the patient was treated by denosumab.

Regarding the analysis of biological data according to toxicity grade, hematological toxicity was observed in all patients, mostly leuko-neutropenia. According to the proportion of patients with/without neutropenia within 12 months before ONJ diagnosis, per month, we observed that the percentage of patients with neutropenia was highly variable (Figure 2). Palbociclib was temporarily discontinued for six out of eight patients because of grades II or III neutropenia. It was reintroduced when neutrophil counts were above 1G/L.

Discussion

Two subgroups can be distinguished in this series of eight cases of ONJ among patients treated with palbociclib: The first group of four patients exposed to palbociclib at the time of ONJ onset, which raises the question of direct palbociclib toxicity and/or the emergence of ONJ risk factors related to palbociclib use and the second group of four patients previously exposed to palbociclib but no longer exposed at the time of ONJ diagnosis. For these, we hypothesized that palbociclib could trigger ONJ onset through its impact on clinical and biological parameters that are ONJ risk factors.

From a pharmacovigilance point of view, considering the palbociclib half-life and the 4-month interval for regular dental monitoring for most patients, the chronological imputability of palbociclib in ONJ onset was considered compatible for four patients and could not be excluded for two patients who had recently discontinued palbociclib. For the last two patients for whom ONJ diagnosis was made more than 10 months after discontinuing palbociclib, chronological imputability could not be excluded because the dental monitoring was irregular.

All patients were exposed to denosumab at the time of ONJ onset and the ONJ characteristics appeared to be similar to those of ONJ under denosumab described in the literature.^9,10 Indeed, we identified similar risk factors, ONJ location, time to diagnosis, and anatomopathological characteristics. It is worth noting that all patients had at least one oral risk factor (tooth extraction, periodontal disease) at the time of ONJ diagnosis.

The baseline characteristics of our case series were also similar to the literature data. The women were on average over 60 years old, postmenopausal, treated with CKIs in combination with an aromatase inhibitor or fulvestrant and an antiresorptive drug for metastatic hormone-dependent breast cancer with bone lesions, as recommended in the palbociclib market authorization.^4,6

ONJ associated with palbociclib exposure has been only occasionally reported in the literature. Marcianò et al. reported six ONJ cases among patients (stages I to III) concomitantly exposed to CKIs (five to palbociclib and one to abemaciclib) and antiresorptive drugs among a total of 16 patients with ONJ diagnosis; the mean time from CKI initiation to ONJ diagnosis was 24 months.¹¹ In this article, critical information was lacking, such as dental risk factors, medication history, and duration of antiresorptive drug and CKI exposure. With the exception of one patient for whom the disease deteriorated, the others fully recovered. From a pharmacological point of view, palbociclib is a CKI preventing cell cycle transition from phases G1 to S and therefore blocking the cell proliferation cycle.⁴ Drawing an analogy with drugs with antiangiogenic properties known to induce ONJ, Marcianò et al. suggested that CKIs might be related to MRONJ, even though no clear pathophysiological mechanism is provided.¹¹ Supported by in vivo and in vitro data, the same authors also suggested that CKIs could be involved in osteoclast differentiation.¹² Fusco et al. discussed these results, considering the lack of evidence in favor of a causal link between MRONJ and CKI.¹³ In their local experience, among 24 patients under CKIs and antiresorptive drugs, 2 presented MRONJ after 30 to 36 months of palbociclib exposure. No information was available on the frequency of dental monitoring nor on ONJ risk factors. On the other hand, they highlighted the fact that no ONJ occurred among 40 other patients receiving CKI inhibitors without antiresorptive agents. Finally, Marcianò et al. mentioned the potential contribution of new cancer therapies as a trigger for ONJ among patients concomitantly exposed to antiresorptive drugs.¹²

The main mechanistic hypotheses regarding MRONJ occurrence involve a decrease in bone remodeling, angiogenesis inhibition, and a considerable role of inflammation and immunity in ONJ occurrence, including neutrophil function alteration.^14–26 We did not identify clinical data suggesting CKI action on bone remodeling. In vitro data from animal studies has shown a pro-angiogenic effect of CDK-6 inducing VEGF-A and CDK-4 inducing VEGF-B. This could suggest an anti-angiogenic effect of CKIs, but this effect has not been identified in clinical data on humans.²⁷

We also hypothesized that palbociclib-related neutropenia could be a risk factor for ONJ. Indeed, the cytostatic effect of palbociclib could affect rapid cell turnover, for instance in hematopoietic or gastrointestinal cells, which could explain palbociclib's neutropenic effect. Neutropenia is the most frequent adverse drug reaction (mainly grade 3) described in clinical studies.^6,7,27–36 It should be noted that neutropenia and agranulocytosis have been well documented as favoring oral infections, leading to oral lesions and delayed healing, which are also described as being among the ONJ risk factors.^15,37–39 The monthly neutrophil count analysis in the year before ONJ diagnosis suggested that neutropenia duration was highly variable in our study. All patients exposed to palbociclib around the time of the ONJ diagnosis were neutropenic but most had non-severe neutropenia. Nor did we identify any studies suggesting a possible link between neutropenia and ONJ occurrence.

On the other hand, palbociclib has also been reported to induce mucositis, and oral stomatitis is a well-known ONJ risk factor. Oral stomatitis is reported to involve between 13% and 15% of patients in palbociclib clinical studies.^6,28,40 In our study, mucositis was reported in the history of 63% of our patients (without information on its presence or absence at the time of ONJ diagnosis) but no specific patterns were identified.

Observation of the anatomopathological characteristics of the bone necrosis evidenced a nonspecific inflammatory process in the mucosa, and we did not find data enabling differentiation of the anatomopathological patterns in palbociclib-exposed patients. It should be noted that two patients presented unusual features noted from histological examination of the mucosa, with the presence of siderophages, suggesting a hemorrhagic transformation. Dental surgeons had thus wondered about a possible effect of palbociclib on the mucosa.⁴¹

Among the limitations of our study, the data was not always exhaustive, at once for the biological results, palbociclib dosage and adjustments, and the discontinuation dates. The exact date of ONJ onset was not known (only the date for the dental follow-up visit where the diagnosis was signaled; but five patients had regular dental follow-up every 4 months, enabling approximations for the ONJ onset date). The anatomopathological examinations were standard, while other more specific analyses such as p53, MDM2, or CDK4 immunomarking were in some cases envisaged at a later date. A single-center study design was chosen because of administrative constraints. Palbociclib, launched about 5 years ago, is used in a restricted target population, that is to say, women with hormone receptor-positive metastatic breast cancer; considering that ONJ is a rare adverse event, a very small number of observed cases was expected, which could have led to variability in the population characteristics.

Overall, on the basis of our case series and the literature, there is no strong evidence to confirm the pharmacovigilance signal for ONJ under palbociclib and, more widely under CKIs. There are no criteria suggesting a causal relationship between palbociclib and ONJ. This study demonstrates the value of a pharmacovigilance evaluation of a safety signal, including a thorough analysis of chronological, semiological, and pharmacological data.

Conclusion

Using a series of eight cases of ONJ among patients exposed to palbociclib, a CKI used in metastatic breast cancer, our in-depth analysis of the medical records evidenced nonspecific patterns of ONJ occurrence and several concomitant ONJ risk factors. Furthermore, despite our several pathophysiological hypotheses, we did not identify any ONJ mechanism that could be related to palbociclib use. Therefore, we cannot confirm the imputability of palbociclib in our case series. It nevertheless seems wise to continue the pharmacovigilance surveillance.

Footnotes

Author’s contributions

Dr Yosofi had full access to all of the data that was used to generate the case series population. Conception and design: Scailteux and Triquet; Acquisition, analysis, and interpretation of the data: All authors; Drafting of the manuscript: Yosofi, Scailteux and Triquet; Critical revision of the manuscript for version to be published: All authors.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Obtained funding

Not applicable.

Administrative, technical, or material support: Scailteux and Triquet.

ORCID iD

Lucie-Marie Scailteux

Supervision

Scailteux and Triquet.

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