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bisphosphonate

Group of compounds that bind to hydroxyapatite & inhibits osteoclast activity. Indications: 1) osteoporosis a) post-menopausal women b) chronic glucocorticoid use, > 5 mg/day (prednisone) for more than 3 months [8] c) hypogonadism - androgen-deprivation therapy for prostate cancer d) bone mineral density < -2.5 (i.e. -2.6 or -2.8)* e) prior fracture (vertebral fracture, hip fracture, fragility fracture) f) high-risk by FRAX g) 10 year risk of hip fracture >= 3% [15] h) 10 year probability of major osteoporotic fracture >= 20% [15] 2) osteopenia with high risk factors (see FRAX risk assessment tool) - bisphosphonate cost-effective when 10 year risk of major osteoporotic fracture is >= 20% or risk of hip fracture is >= 3% [8] 3) excessive or disordered osteoclastic activity associated with a) Paget's disease of bone b) hypercalcemia c) bone metastases [18] 1] osteolytic bone metastases of breast cancer 2] osteolytic bone lesions of multiple myeloma 4) dystrophic calcification [18] 5) bisphosphates lower breast cancer recurrence & mortality in postmenopausal women [23] - bisphosphates do not reduce risk of breast cancer [20] Contraindications: (cautions) - limit therapy to 3-5 years (saturation of benefit) [3,9] - use with caution in premenopausal women [8] - use controversial in patients with chronic renal failure stage 3 or greater (GFR < 30 mL/min/1.73 m2) [8] - use to treat osteoporosis not associated with lower mortality [33] - IV bisphosphonates contraindicated in patients with hypocalcemia [8] - oral bisphosphates contraindicated in patients with esophageal varices - vitamin D deficiency (osteoporosis) Benefit/risk: - postmenopausal women with prior fracture or very low bone density - number needed to treat (NNT) - 20 women for 3 years to prevent 1 vertebral fracture [21] - 100 women for 3 years to prevent 1 hip fracture [21] - 100 postmenopausal women with osteoporosis for 12.4 months to prevent one nonvertebral fracture [36] - number needed to harm - a small number of women are harmed - harms not well studied [21] - postmenopausal women without prior fracture or very low bone density - no benefit for preventing fractures within 3 years [22] - a small number of women are harmed - treatment of osteoporosis with a bisphosphonate has an expected time-to-benefit of 1-2 years [15] Dosage: - separate from calcium supplement - duration of therapy: 3-5 years for most patients [12,17] - discontinue bisphosphonate therapy after 2-5 years [32] - 5 years for alendronate, 3 years for zoledronate [17]* - continue alendronate 10 years in women with history of osteoporotic fracture (high-risk) with stable bone density [8,37] - 5 years for bisphosphonates [31] - no benefit for >5-7 years of therapy [35] - reassess fracture risk after 5 years for alendronate, 3 years for zoledronate [24] - for women at high risk (low T score, previous osteoporotic fracture), oral therapy may be continued for up to 10 years or IV therapy for up to 6 years [24] - continued treatment can prevent bone loss & reduce risk for vertebral fractures [17,24] - no data to support continued bisphosphonate therapy > 5 years for risk reduction of hip fracture [17] - fracture risk should be reassessed every 2-3 years during this extended treatment [24] * correct vitamin D deficiency prior to administration for osteoporosis * bone loss after discontinuation of therapy may be greater for risedronate than alendronate or zoledronate [17] * no data to guide duration of ibandronate therapy Pharmacokinetics: 1) poorly absorbed orally, 1-5% of oral dose - food interferes with absorption 2) plasma 1/2life of 1 hour 3) eliminated in urine (80%) 4) 20% of absorbed dose taken up by bone 5) bisphosphonate may persist in bone for lifetime Monitor: - routine monitoring of bone mineral density after initiating bisphosphonate therapy is costly & unwarranted [7,31] Adverse effects: 1) nausea/vomiting [15] 2) erosive esophagitis 3) ocular inflammation a) conjunctivitis, blurred vision, eye pain (uncommon) b) uveitis (RR=1.45) & scleritis (RR=1.51) [16] 4) osteonecrosis of the jaw (especially IV administration) [2,19] 5) inhibition of normal bone repair of microdamage that occurs during activities of daily living [3] - despite this, IV zoledronate recommended within 14-90 days after hip fracture surgery [37] 6) long-term therapy (> 5 years) may increase risk of minimal trauma fractures of the femur [9,10] - atypical subtrochanteric stress fracture [15] - > 70% of patients with weight-bearing pain prior to atypical fracture [15] - 277 atypical femur fractures observed in 196,129 women over 10 years [34] - benefit exceeds risk 149:2 (whites) vs 91:8 (Asians) [34] 7) severe joint pain [6], musculoskeletal pain (intravenous & oral) uncommon 8) duration of therapy - after 3-5 years of bisphosphonate therapy, risk may exceed benefit [12]* - benefit/risk ratio remains favorable for > 10 years in postmenopausal women with osteoporosis [30] 9) increases bone mineral density, but also increases risk of hip fracture in primary hyperparathyroidism relative to observation (RR=1.5) [25] * American Board of Internal Medical appears to endorse long term bisphosphonate use, citing [14] Mechanism of action: 1) binds to hydroxyapatite & inhibits osteoclast activity 2) reduces osteoclast number 3) stimulates formation of osteoblast precursors 4) 97% of patients show clinically beneficial increases in bone mineral density at the hip density after 3 years of treatment Notes: - possible association with bisphosphonates & reduced risk of breast cancer [11] - bisphosphonate use is associated with a lower rate of revision after hip arthroplasty & knee arthroplasty & longer implant survival [14]

Interactions

drug interactions drug adverse effects of bisphosphonates

Specific

alendronate (Fosamax, Fosamax Plus D, Binosto) clodronate; clodronic acid (Clodronsaeure, Clasteon, Bonefos, Loron) etidronate (Didronel) ibandronate; ibandronic acid (Boniva, Bondronat) pamidronate (Aredia) risedronate (Actonel) tiludronate (Skelid) zoledronate (Zometa, Reclast)

General

endocrine agent musculoskeletal system agent

References

  1. Prescriber's Letter 10(5):26 2003
  2. Prescriber's Letter 12(5): 2005 Bisphosphonate-associated Jaw Osteonecrosis Detail-Document#: 210511 (subscription needed) http://www.prescribersletter.com - Favia G et al. Osteonecrosis of the jaw correlated to bisphosphonate therapy in non-oncologic patients: Clinicopathological features of 24 patients. J Rheumatol 2009 Dec; 36:2780 http://dx.doi.org/10.3899/jrheum.090455 PMID: 19884275
  3. Journal Watch 25(9):69, 2005 Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005 Mar;90(3):1294-301. Epub 2004 Dec 14. PMID: 15598694 - Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab. 2005 Mar;90(3):1897-9. PMID: 15758064
  4. UpToDate 13.3 http://www.utdol.com
  5. Use of Bisphosphonates In Metabolic Bone Diseases http://www.osteo.org/newfile.asp?doc=p128i&doctitle=Use+of+Bisphosphonates+in+Metabolic+Bone+Diseases&doctype=HTML+Fact+Sheet
  6. FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#Bisphosphonates
  7. Bell KJL Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data BMJ 2009;338:b2266 http://www.bmj.com/cgi/content/full/338/jun23_2/b2266
  8. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  9. Prescriber's Letter 16(12): 2009 Safety of Long-Term Bisphosphonate Therapy COMMENTARY: Safety of Long-Term Bisphosphonate Therapy GUIDELINES: Prevention and Treatment of Osteoporosis (NOF) GUIDELINES: Diagnosis and Treatment of Osteoporosis (ICSI) GUIDELINES: NAMS Position Statement on the Management of Osteoporosis in Postmenopausal Women GUIDELINES: Prevention and Treatment of Postmenopausal Osteoporosis (AACE) GUIDELINES: Menopause and Osteoporosis Update (Canadian) Detail-Document#: 251205 (subscription needed) http://www.prescribersletter.com
  10. Capeci CM and Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am 2009 Nov; 91:2556. PMID: 19884427 - Lenart BA et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: A case control study. Osteoporos Int 2009 Aug; 20:1353. PMID: 19066707
  11. Prescriber's Letter 17(1): 2010 Bisphosphonates and Breast Cancer Prevention Detail-Document#: 260106 (subscription needed) http://www.prescribersletter.com
  12. Park-Wyllie LY Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women JAMA. 2011;305(8):783-789 PMID: 21343577 http://jama.ama-assn.org/content/305/8/783.full - Prescriber's Letter 18(11): 2011 COMMENTARY: Safety of Long-Term Bisphosphonate Therapy PATIENT HANDOUT: What I Need to Know About My Bisphosphonate PATIENT HANDOUT SPANISH VERSION: Lo Que Necesito Saber Acerca De Mi Bifosfonato Detail-Document#: 271122 (subscription needed) http://www.prescribersletter.com
  13. Prieto-Alhambra D et al. Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: Population based retrospective cohort study. BMJ 2011 Dec 6; 343:d7222 PMID: 22147909
  14. Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010; 363:2027-2035. PMID: 21083387
  15. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  16. Etminan M et al Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study CMAJ April 2, 2012 PMID: 22470169 http://www.cmaj.ca/content/early/2012/04/02/cmaj.111752.full.pdf+html
  17. Whitaker M et al Bisphosphonates for Osteoporosis - Where Do We Go from Here? N Engl J Med 2012 May 9, PMID: 22571168 http://www.nejm.org/doi/full/10.1056/NEJMp1202619 - Black DM et al Continuing Bisphosphonate Treatment for Osteoporosis - For Whom and for How Long? N Engl J Med 2012 May 9, PMID: 22571169 http://www.nejm.org/doi/full/10.1056/NEJMp1202623 - McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: Benefits, risks, and drug holiday. Am J Med. 2013;126:13-20. PMID: 23177553
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  20. Hue TF, Cummings SR, Cauley JA et al Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer. Results From the Randomized Clinical Trials of Alendronate and Zoledronic Acid. JAMA Intern Med. Published online August 11, 2014. PMID: 25111880 http://archinte.jamanetwork.com/article.aspx?articleid=1893923
  21. The NNT: Bisphosphonates for Fracture Prevention in Post- Menopausal Women With Prior Fractures or With Very Low Bone Density. http://www.thennt.com/nnt/bisphosphonates-for-fracture-prevention-in-post-menopausal-women-with-prior-fractures-or-very-low-bone-density/
  22. The NNT: Bisphosphonates for Fracture Prevention in Post- Menopausal Women Without Prior Fractures. http://www.thennt.com/nnt/bisphosphonates-for-fracture-prevention-in-post-menopausal-women-without-prior-fractures/
  23. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. Published Online: 23 July 2015 PMID: 26211824 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2960908-4/abstract - Brufsky A, Mathew A Bisphosphonates, bone, and breast cancer recurrence. Lancet. Published Online: 23 July 2015 PMID: 26211825 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2961163-1/abstract
  24. Adler RA et al Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2015 Sep 9. [Epub ahead of print] PMID: 26350171 http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2708/epdf
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  30. Abrahamsen B, Eiken P, Prieto-Alhambra D, Eastell R. Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: Nationwide cohort and nested case-control study. BMJ 2016 Jun 28; 353:i3365 PMID: 27353596 Free PMC Article
  31. Qaseem A, Forciea MA, McLean RM et al Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians. Ann Intern Med. 2017. May 9. PMID: 28492856 http://annals.org/aim/article/2625385/treatment-low-bone-density-osteoporosis-prevent-fractures-men-women-clinical - Orwoll ES Clinical Practice Guidelines for Osteoporosis: Translating Data to Patients? Ann Intern Med. 2017. May 9. PMID: 28492858 http://annals.org/aim/article/2625389/clinical-practice-guidelines-osteoporosis-translating-data-patients
  32. Drieling RL, LaCroix AZ, Beresford SAA et al. Long-term oral bisphosphonate therapy and fractures in older women: The Women's Health Initiative. J Am Geriatr Soc 2017 Sep; 65:1924. PMID: 28555811 - Lyles KW. Have we learned how to use bisphosphonates yet? J Am Geriatr Soc 2017 Sep; 65:1902. PMID: 28555749
  33. Cummings SR, Lui LY, Eastell R et al Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates. A Meta-analysis. JAMA Intern Med. Published online August 19, 2019. PMID: 31424486 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2747869
  34. Black DM et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med 2020 Aug 20; 383:743. PMID: 32813950 https://www.nejm.org/doi/10.1056/NEJMoa1916525
  35. Izano MA, Lo JC, Adams AL et al Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women. JAMA Netw Open. 2020;3(12):e2025190. Dec 7. PMID: 33284336 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.25190
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  37. NEJM Knowledge+ Endocrinology