Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review.

Abstract

Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1-2years in duration. A systematic review on the risk-benefit of BMA use for > 2years in breast cancer or castrate-resistant prostate cancer was conducted. MEDLINE, Embase, and Cochrane databases were searched (1970-February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2years. Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0-24months) to 15.5% (> 24months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2years to 3.8-18% after 2years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare. Evidence informing the use of BMA beyond 2years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed. CRD42019126813.