IOF
Close submenuOsteoporosis
International Osteoporosis Foundation
  • Main menu
  • Home
  • About usOpen submenu
  • What we doOpen submenu
  • Educational hub
  • Thematic menu
  • PatientsOpen submenu
  • Health ProfessionalsOpen submenu
  • Policy MakersOpen submenu
  • Our NetworkOpen submenu
  • IOF Platforms
  • Capture the Fracture®
  • World Osteoporosis Day
  • Fundamentals of Osteoporosis Course
  • Latin America
  • IOF Academy
  • Build Better Bones
Close submenuAbout us
  • About IOF
  • The Board
  • The Executive Committee
  • Regional Representation
  • The Committees
  • The Staff
  • Annual Report
  • Contact us
  • Logo & Brand Guidelines
  • IOF position on conflict zone-collaborations
Close submenuWhat we do
  • Science & ResearchOpen submenu
  • Policy & AdvocacyOpen submenu
  • Meetings & Events
  • Education
Close submenuScience & Research
  • Latest News
  • Capture the Fracture®
  • IOF Academy
  • Latest Projects
  • Working Groups
  • Journals
  • Awards
  • WHO ESCEO Agreement
Close submenuPolicy & Advocacy
  • Latest News
  • World Osteoporosis Day
  • IOF Global Patient Charter
  • Improve your knowledge
  • IOF Compendium of Osteoporosis
  • WHO ESCEO Agreement
Close submenuPatients
  • Patients Homepage
  • IOF Osteoporosis Risk Check
  • About Osteoporosis
  • Prevention
  • Diagnosis
  • Treatment
  • Patient resources
  • Bone Healthy Recipes
  • Facts & Statistics
  • World Osteoporosis Day
  • Patient Stories
  • Find your National Society
  • IOF Global Patient Charter
  • Subscribe to our Newsletter
Close submenuHealth Professionals
  • Health Professionals Homepage
  • Latest News
  • OsteoporosisOpen submenu
  • Fragility FracturesOpen submenu
  • Facts & Statistics
  • Capture the Fracture®
  • Fundamentals of Osteoporosis Course
  • Meetings & Events
  • CSA Working Groups
  • Articles & Position Papers
  • Educational Materials
  • Research Tools
  • Patient Resources
  • Journals
  • Skeletal Rare Disorders
  • Osteoporosis and Covid-19
Close submenuOsteoporosis
  • About Osteoporosis
  • Prevention
  • Diagnosis
  • Treatment
Close submenuFragility Fractures
  • About
  • Epidemiology
  • Vertebral Fractures
  • Treatment & Surgery
  • Models of Care
  • Falls Prevention
Close submenuPolicy Makers
  • Policy Makers Homepage
  • Burden of Osteoporosis
  • Facts & Statistics
  • Fracture Liaison Services (FLS)
  • IOF Global Patient Charter
  • Policy Reports & Audits
  • IOF Alliances
  • World Osteoporosis Day
  • Patient Stories
Close submenuOur Network
  • Our Network Homepage
  • The Committees
  • Fracture Liaison Services (FLS)
  • Latest News
  • IOF Alliances
  • Corporate Partners
  • Subscribe to our Newsletter
  • IOF Universities Network

LOGIN

Sign up for free
Forgot your password?
IOF Cookie Policy -IOF Privacy policy
Skip to main content
IOF International Osteoporosis Foundation
  1. Home
  2. Health professionals
  3. Treatment
  4. Bisphosphonates
Join us !

Social menu

  • Facebook
  • Twitter
  • LinkedIn
  • Instagram
  • YouTube
Donate
Share
  1. Home
  2. Health professionals
  3. Treatment
  4. Bisphosphonates
  • Treatment
  • Bisphosphonates
  • MHT & SERM
  • Denosumab
  • Anabolics
  • Side Effects

Bisphosphonates

Bisphosphonates (BP) are synthetic compounds with a common phosphorus-carbon-phosphorus bond and have a high affinity for the calcium hydroxyapatite of the bone.  Among them, the nitrogenous BPs are potent inhibitors of bone resorption as they inhibit the farnesyl diphosphate synthase (FPPS) osteoclast enzyme in the mevalonate pathway causing its activity to decrease. A decrease of bone formation is then observed secondarily [1]Roelofs, A.J., et al., Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res, 2006. 12(20 Pt 2): p. 6222s-6230s.

. 

The nitrogenous BPs are the most widely studied and prescribed BPs for the treatment of postmenopausal osteoporosis. These include alendronate, ibandronate, risedronate and zoledronic acid and are available in oral and intravenous formulations, with weekly, monthly and annual dosing schedules, depending on the specific agent. 
Orally administered BPs have a poor intestinal absorption, with approximately only 1% of the administered dose bioavailable, and can induce mild gastro-intestinal disturbances. 

The recommendations for the best gastric absorption are strict:  BPs should be taken after an overnight fast, with water only, 30 to 60 minutes prior to any food or other drinks. After a quick clearance by the plasma, about 50% is excreted unchanged by the kidney and the remaining 50% binds to bone mineral with a very high affinity. As such, skeletal retention of BPs is long and can exceed ten years [2]Khan, S.A., et al., Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res, 1997. 12(10): p. 1700-7.

. 

Effects of bisphosphonates

With respect to bone mineral density (BMD), alendronate, ibandronate, risedronate and zoledronic acid have been shown to increase BMD by 5-7% and 1.6-5% in the spine and femoral neck respectively after 3 years of treatment [3]Black, D.M., et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet, 1996. 348(9041): p. 1535-41.

[4]Harris, S.T., et al., Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA, 1999. 282(14): p. 1344-52.

[5]McClung, M.R., et al., Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med, 2001. 344(5): p. 333-40.

[6]Chesnut, C.H., 3rd, et al., Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res, 2004. 19(8): p. 1241-9.

[7]Black, D.M., et al., Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med, 2007. 356(18): p. 1809-22.

.

The same BPs (alendronate, risedronate, ibandronate and zoledronic acid) have been shown to reduce vertebral fracture risk by 60-70% within the first year of treatment. Reductions in non-vertebral fracture risk (20-30%) and hip fracture risk (40-50%) have also been demonstrated for alendronate, risedronate and zoledronic acid, but not for ibandronate[3]Black, D.M., et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet, 1996. 348(9041): p. 1535-41.

[4]Harris, S.T., et al., Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA, 1999. 282(14): p. 1344-52.

[5]McClung, M.R., et al., Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med, 2001. 344(5): p. 333-40.

[7]Black, D.M., et al., Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med, 2007. 356(18): p. 1809-22.

. Results are summarized below in the table below.

Anti-fracture efficacies of commonly used treatments

 

Effect on vertebral fracture risk 

Effect on non-vertebral fracture risk

 

Osteoporosis

Established Osteoporosisa

Osteoporosis

Established Osteoporosisa

Alendronate

+

+

N/A

+ (including hip)

Risedronate

+

+

N/A

+ (including hip)

Ibandronate

N/A

+

N/A

+b

Zoledronic acid

+

+

N/A

+c

N/A no evidence available
+ effective drug
a  women with a prior vertebral fracture
b  in subsets of patients only (post hoc analysis)
c  mixed group of patients with or without prevalent vertebral fractures

Anti-fracture efficacies of the most frequently used bisphosphonate treatments for postmenopausal osteoporosis when given with calcium and vitamin D supplements derived from randomized controlled trials. 
Table adapted from Kanis et al., Osteoporos Int, 2019 [8]Kanis, J.A., et al., European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int, 2019. 30(1): p. 3-44.

. 


Zoledronic acid has been shown to reduce the risk of nonvertebral and vertebral fragility fractures, not only in women with osteoporosis, but also in women with osteopenia [9]Reid, I.R., et al., Fracture Prevention with Zoledronate in Older Women with Osteopenia. N Engl J Med, 2018. 379(25): p. 2407-2416.

. 
In the long-term (5-6 years), alendronate and zoledronic acid have been shown to continuously increase BMD at the lumbar spine, but not at the hip where BMD reaches a plateau. Patients at high risk of fractures, particularly vertebral fractures, are the ones who will benefit of continued treatment [10]Black, D.M., et al., The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res, 2012. 27(2): p. 243-54.

[11]Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA, 2006. 296(24): p. 2927-38.

. Discontinuation of the treatments brings bone turnover markers back to baseline values within 12 months with risedronate and these values remain below baseline for several years upon the stopping the alendronate and zoledronic acid [12]Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA, 2006. 296(24): p. 2927-38.

.

Recommendations and safety

BPs are recommended as a first line treatment for women with post-menopausal osteoporosis, in the absence of contraindications. 

Overall, BPs have been shown to have a very good safety and tolerability profile. Oral BPs can induce mild gastro-intestinal disturbances and intravenous bisphosphonates can induce a transient acute reaction with fever, bone and muscle pain. Concerns about atrial fibrillation with intravenous zoledronic acid and esophageal cancer with oral bisphosphonates have been raised but not confirmed [13]Watts, N.B., et al., Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int, 2008. 19(3): p. 365-72

. 

Two more serious adverse events, atypical subtrochanteric fractures and osteonecrosis of the jaw, have been associated with bisphosphonates. Read more about these two side effects.

REFERENCES

1.

Roelofs, A.J., et al., Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res, 2006. 12(20 Pt 2): p. 6222s-6230s.

2.

Khan, S.A., et al., Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res, 1997. 12(10): p. 1700-7.

3.

Black, D.M., et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet, 1996. 348(9041): p. 1535-41.

4.

Harris, S.T., et al., Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA, 1999. 282(14): p. 1344-52.

5.

McClung, M.R., et al., Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med, 2001. 344(5): p. 333-40.

6.

Chesnut, C.H., 3rd, et al., Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res, 2004. 19(8): p. 1241-9.

7.

Black, D.M., et al., Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med, 2007. 356(18): p. 1809-22.

8.

Kanis, J.A., et al., European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int, 2019. 30(1): p. 3-44.

9.

Reid, I.R., et al., Fracture Prevention with Zoledronate in Older Women with Osteopenia. N Engl J Med, 2018. 379(25): p. 2407-2416.

10.

Black, D.M., et al., The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res, 2012. 27(2): p. 243-54.

11.

Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA, 2006. 296(24): p. 2927-38.

12.

Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA, 2006. 296(24): p. 2927-38.

13.

Watts, N.B., et al., Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int, 2008. 19(3): p. 365-72

9, rue Juste-Olivier
CH-1260 Nyon - Switzerland
+41 22 994 0100
info@osteoporosis.foundation
Follow us
  • Facebook
  • Twitter
  • LinkedIn
  • Instagram
  • YouTube
© 2025 International Osteoporosis Foundation
Cookie Policy - Privacy policy
 
Close menu