Benjamin A Gartrell1, Robert E Coleman2, Karim Fizazi3, Kurt Miller4, Fred Saad5, Cora N Sternberg6, Matthew D Galsky7. 1. Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: bgartrel@montefiore.org. 2. Academic Unit of Clinical Oncology, Weston Park Hospital, CR-UK/YCR Sheffield Cancer Research Centre, Sheffield, UK. 3. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France. 4. Department of Urology, University Hospital Charité, Berlin, Germany. 5. Division of Urology, Centre Hospitalier de l'Université de Montréal, CRCHUM, Montréal, QC, Canada. 6. Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy. 7. Tisch Cancer Center Institute, Mount Sinai School of Medicine, New York, NY, USA.
Abstract
CONTEXT: Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events. OBJECTIVE: To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events. EVIDENCE ACQUISITION: PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs. EVIDENCE SYNTHESIS: The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed. CONCLUSIONS: Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa.
CONTEXT: Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events. OBJECTIVE: To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events. EVIDENCE ACQUISITION: PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs. EVIDENCE SYNTHESIS: The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed. CONCLUSIONS:Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa.
Authors: N Sathiakumar; E Delzell; M A Morrisey; C Falkson; M Yong; V Chia; J Blackburn; T Arora; M L Kilgore Journal: Prostate Cancer Prostatic Dis Date: 2011-03-15 Impact factor: 5.554
Authors: Steven C Campbell; Nirmala Bhoopalam; Thomas E Moritz; Mona Pandya; Padmini Iyer; Peter Vanveldhuizen; Nancy K Ellis; Lizy Thottapurathu; Harinder Garewal; Stuart R Warren; Nicholas Friedman; Domenic J Reda Journal: Urology Date: 2010-03-19 Impact factor: 2.649
Authors: Jeanny B Aragon-Ching; Yang-Min Ning; Clara C Chen; Lea Latham; Jean-Pierre Guadagnini; James L Gulley; Philip M Arlen; John J Wright; Howard Parnes; William D Figg; William L Dahut Journal: Cancer Invest Date: 2009-02 Impact factor: 2.176
Authors: Nirmala Bhoopalam; Steven C Campbell; Thomas Moritz; William R Broderick; Padmini Iyer; Anthony G Arcenas; Peter J Van Veldhuizen; Nicholas Friedman; Domenic Reda; Stuart Warren; Harinder Garewal Journal: J Urol Date: 2009-09-16 Impact factor: 7.450
Authors: Matthew R Smith; Blair Egerdie; Narciso Hernández Toriz; Robert Feldman; Teuvo L J Tammela; Fred Saad; Jiri Heracek; Maciej Szwedowski; Chunlei Ke; Amy Kupic; Benjamin Z Leder; Carsten Goessl Journal: N Engl J Med Date: 2009-08-11 Impact factor: 91.245