Duration of Bisphosphonate Drug Holidays in Osteoporosis Patients: A Narrative Review of the Evidence and Considerations for Decision-Making

Abstract

Bisphosphonates are first-line therapy for osteoporosis, with alendronate, risedronate, and zoledronate as the main treatments used globally. After one year of therapy, bisphosphonates are retained in bone for extended periods with extended anti-fracture effects after discontinuation. Due to this continued fracture protection and the potential for rare adverse events associated with long-term use (atypical femoral fractures and osteonecrosis of the jaw), a drug holiday of two to three years is recommended for most patients after long-term bisphosphonate therapy. The recommendation for a drug holiday up to three years is derived primarily from extensions of pivotal trials with alendronate and zoledronate and select surrogate marker studies. However, certain factors may modify the duration of bisphosphonate effects on a drug holiday and warrant consideration when determining an appropriate time off-therapy. In this narrative review, we recall what is currently known about drug holidays and discuss what we believe to be the primary considerations and areas for future research regarding drug holiday duration: total bisphosphonate exposure, type of bisphosphonate used, bone mineral density and falls risk, and patient sex and body weight.

Bone Mineral Density Loss and Fracture Risk After Discontinuation of Anti-osteoporotic Drug Treatment: A Narrative Review

“…Since the data are too limited, it is not possible to draw any conclusions on etidronate. Another issue is the difference between oral bisphosphonates: depending on farnesyl pyrophosphate synthase (FPPS) inhibitory potency, the binding affinity to hydroxyapatite and the accumulation and saturation potential, a drug holiday or discontinuation of therapy of 1-2 years for risedronate and 2-3 years for alendronate and zoledronic acid are currently recommended [28]. There were few data on fracture risk after discontinuation of therapy.…”

Are secondary effects of bisphosphonates on the vascular system of bone contributing to increased risk for atypical femoral fractures in osteoporosis?

“…Further, it also means that the changes occurring in the lead up to the AFF is a chronic process that occurs over months to years. The reports that indicate episodic discontinuation of BPs, or drug “holiday,” can lower AFF risk, [ 17,18 ] indicate that the alterations contributing to AFF risk are potentially reversible. Not all of the BPs commercially available exhibit the same risk for AFF or other prominent side‐effects. Therefore, the chemical structure plays a role in the risk for secondary effects of the drugs.…”

“…Further, it also means that the changes occurring in the lead up to the AFF is a chronic process that occurs over months to years. The reports that indicate episodic discontinuation of BPs, or drug "holiday," can lower AFF risk, [17,18] indicate that the alterations contributing to AFF risk are potentially reversible.…”

Zoledronic acid for osteoporosis and associated low-energy fractures

“…В целом показания к выбору длительной непрерывной терапии или прерывистых курсов, сроков проведения и критериев прекращения/возобновления лечения требуют дальнейшего изучения ввиду сравнительно небольшого числа доказательных исследований и, соответственно, довольно ограниченной имеющейся на сегодня достоверной информации [38].…”