Bisphosphonate holiday

Data suggest that following after bisphosphonate exposure of 3 to 5 years in postmenopausal women with osteoporosis:

• the protection from fractures persists for an unknown interval of time in selected patients when therapy is withdrawn; that the protection wanes within 3 to 5 years of discontinuation; and that the risk of atypical femoral fractures increases with the duration of therapy but may decrease upon withdrawal of treatment
  
  
• bisphosphonates is analogs of pyrophosphate having a three-dimensional structure capable of chelating divalent cations such as Ca2+
  • bisphosphonates have a strong affinity for bone, targeting especially bone surfaces undergoing remodelingand binds strongly to hydroxyapatite and remains inactive until the bone containing BP are reabsorbed half-life after incorporation into mineralized bone nearly 10 years (1)

A. Determination of the duration for bisphosphonate therapy (2,3)

• i. Drug holiday from alendronate and risedronate may be considered after 5 years
  
  
• ii. Drug holiday from zoledronic acid may be considered after 3 years

B. Selection of the appropriate candidates for the drug holiday

• i. Consider a drug holiday after 5 years of alendronate and risedronate treatment, and after 3 years of zoledronic acid, in individuals without high risk.
  
  
• ii. Consider the continued treatment in individuals with high risk.
  • 1) T-score at any site still <=-2.5 after bisphosphonate therapy (5 years for alendronate and risedronate, and 3 years for zoledronic acid).
  • 2) Previous fracture of the hip or spine.
  • 3) High risk of fracture because of secondary osteoporosis from chronic diseases or medication.
    
    
• iii. Alternative therapy may be used for individuals with high risk
  
  
• iv. Factors guiding the determination of a drug holiday are the variable anti-resorptive potency and binding affinity of each bisphosphonate, as well as a demonstration of compliance with the therapy

Duration and Monitoring during a drug holiday (2,3,4)

Duration of treatment and the length of the 'holiday' should be tailored to individual patient circumstances and based on individual assessments of risk and benefit

• it has been stated that "..a drug holiday of 1-2 years should be considered after 3-5 years of bisphosphonate therapy except in those patients who remain at very high fracture risk.." (4)

A. Parameter for monitoring during a drug holiday

• i. Consider the annual measurement of BMD using dual energy X-ray absorptiometry.

B. Restart therapy after a drug holiday

• i. Consider re-treatment if there is a significant decrease in BMD.
• ii. Consider re-treatment if T-score reaches <= -2.5 or a new osteoporotic fracture occurs

Notes:

• a review states (5):
  • the 2016 American Society of Bone and Mineral Research (ASBMR) guidance on drug holidays for patients on long-term bisphosphonates offers emphasizes the balance between the benefits of fracture prevention with bisphosphonate and the need to reassess fracture risk over time
    • high-risk patients, such as persons age >70 years, those with a low hip T score (less than −2.5), those who have had a major osteoporotic fracture, or those who continue to fracture while on therapy, may benefit from extended treatment for up to 10 years with oral bisphosphonates or 6 years with intravenous zoledronic acid
    • for patients deemed to be at low or moderate fracture risk after the initial treatment period, a drug holiday of two to three years may be considered
  • many consider a slightly longer drug holiday duration for zoledronic acid (18–24 months) compared to oral bisphosphonates (no more than 12–24 months for alendronate and perhaps even less for risedronate)

Reference:

1. Friedman PA. Agents affecting mineral ion homeostasis and bone turnover. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman's the Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2006. Ch 16.
2. Lee SH et al. Position Statement: Drug Holiday in Osteoporosis Treatment with Bisphosphonates in South Korea. J Bone Metab. 2015 Nov;22(4):167-74
3. Diab DL, Watts NB. Bisphosphonate drug holiday: who, when and how long.Ther Adv Musculoskel Dis. 2013;5(3):107-111
4. McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, et al. Bisphosphonate therapy for osteoporosis: Benefits, risks, and drug holiday. Am J Med. 2013;126:13-20.
5. Adami, G. and Saag, K.G. (2025), Expert Perspective: How, When, and Why to Potentially Stop Antiresorptive Drugs in Osteoporosis. Arthritis Rheumatol, 77: 1294-1304.