Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real‐World Studies

Abstract

Bisphosphonates (BPs) are commonly used in the treatment of osteoporosis and are effective in the prevention of fragility fracture. Long‐term use has been associated with the development of atypical femur fractures (AFFs) and osteonecrosis of the jaw (ONJ). Drug holidays seek to reduce the risk of insufficiency fractures (AFFs) while maintaining durable effects of long‐term treatment in the prevention of fragility fracture. Guidelines suggest that BP drug holidays be considered after 3 to 5 years. However individual factors impacting this decision and outcomes are unclear. This review examines key factors in the planning of a safe BP drug holiday and surrogate markers of fracture risk in patients discontinuing treatment. Fifteen randomized control trials and 19 real‐world studies were included, including nationwide prospective studies from several countries. Increases in bone turnover markers (BTMs) and reductions in bone mineral density (BMD) were generally observed during BP drug holidays. Resurgent bone turnover was problematic in high‐risk patients in whom fractures recurred as early as 12 months following a drug holiday. Risk factors for holiday‐related fractures included older age, low hip BMD, underweight, low medication adherence, and prevalent/incident fractures. Zoledronic acid conferred the most durable reduction in fractures, particularly after six annual infusions. Five years of alendronate was insufficient in preventing vertebral fractures in high‐risk patients embarking on a drug holiday. Relatively faster offset of antiresorptive effect was seen in risedronate users with more frequent fractures than alendronate during a drug holiday. Studies directly counterbalancing effects of long‐term treatment on AFF risk versus drug holiday outcomes in the same population were lacking. In the absence of persistently high fracture risk and following a specific treatment duration dependent on the BP used, drug holidays are safe and mitigate the risk of AFF. However, anti‐resorptive effects diminish over time; ongoing monitoring and careful planning of BP resumption is necessary. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Phylobone: A comprehensive database of bone extracellular matrix proteins in human and model organisms

“…However, these treatments have limitations and problems with side effects and serious risks. For instance, bisphosphonates have been reported to have higher fracture rates after long-term use, characterized as more than six years and requiring a "bisphosphonate holiday" 74 . RANKL antibodies have been reported to have some side effects, such as skin eczema, flatulence, cellulitis, and osteonecrosis of the jaw 75 .…”

Relationship of the occurrence and main approaches to osteonecrosis of the jaw with the use of bisphosphonates: a concise systematic review

“…ONJ has also been defined using a variety of terms, including: "bisphosphonateinduced osteonecrosis of the jaw (BIONJ)", "bisphosphonate-associated osteonecrosis of the jaw (BAONJ)", "bisphosphonateassociated osteomyelitis of the jaw (BAOMJ)" and "bisphosphonate-related osteomyelitis of the jaw (BROMJ)" [1,16]. The cited terms were recently denominated by the term "antiresorptive drug-related osteonecrosis of the jaw (ARONJ)" and currently consolidated as "Medication-related osteonecrosis of the Jaws (MRONJ)" due to clinical reports of osteonecrosis of the jaw related to anti-inflammatory drugs resorptive [2,3].…”

“…To reduce the excessive resorption observed in these pathologies, it has been studied more rigorously in pre-clinical and clinical studies to improve antiresorptive drugs that allow for treating or preventing pathologies of bone metabolism [3][4][5][6]. In this sense, anti-resorptive agents, such as bisphosphonates (BP) and denosumab (DN), as well as some angiogenesis inhibitors, can induce osteonecrosis of the mandible (ONJ).…”

“…In general, the mechanism of action of clodronate and etidronate and alendronate, pamidronate, zoledronate, risedronate, and ibandronate involves the replacement of the oxygen atom by a backbone carbon atom makes the molecule unable to decompose by hydrolysis and binds it tightly to the circulating calcium or calcium from hydroxyapatite crystals in bone [1][2][3]. Once BP is internalized by osteoclasts, the farnesyl synthetase enzyme of the mevalonate pathway is inhibited.…”

Synthesis and Antitumor Activity of a GSH Inert Bisphosphonate Platinum (II) Complex

“…e most widely known bone-targeting agents used in the formation of Pt complexes are bisphosphonates (BPs), which have been used to treat bone diseases such as osteoporosis, bone metastases, and multiple myeloma [21][22][23][24]. In view of these fascinating effects, Pt-BPs complexes with appealing characteristics have been explored.…”