title: Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events.
abstract: OBJECTIVE
  Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies.
  
  
  METHODS
  As part of a comprehensive pharmacovigilance plan, developed with regulators' input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to-follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naïve patients, zoledronic acid-naïve patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA(®) clinical trials program.
  
  
  CONCLUSIONS
  This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies.
authors: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors: John
authors: J
authors: Acquavella
authors: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Vera
authors: V
authors: Ehrenstein
authors: Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen, Denmark.
authors: Morten
authors: M
authors: Schiødt
authors: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Uffe
authors: U
authors: Heide-Jørgensen
authors: Department of Urology, Karolinska University Hospital; Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
authors: Anders
authors: A
authors: Kjellman
authors: Cancer Registry of Norway, Oslo University Hospital, Oslo, Norway.
authors: Svein
authors: S
authors: Hansen
authors: Department of Oral and Maxillofacial Surgery, Södra Älvsborg Hospital, Borås, Sweden; Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Cecilia
authors: C
authors: Larsson Wexell
authors: Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo, Norway.
authors: Bente Brokstad
authors: BB
authors: Herlofson
authors: Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors: Sven Erik
authors: SE
authors: Noerholt
authors: Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA.
authors: Haijun
authors: H
authors: Ma
authors: Clinical Development, Amgen Inc., Thousand Oaks, CA, USA.
authors: Katarina
authors: K
authors: Öhrling
authors: Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA.
authors: Rohini K
authors: RK
authors: Hernandez
authors: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Henrik Toft
authors: HT
authors: Sørensen
keywords: cohort study; denosumab; osteonecrosis of the jaw; pharmacovigilance; postmarketing drug surveillance; zoledronic acid