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.
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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.
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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.
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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.
|
|
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 |
||||
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.
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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.
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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.
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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
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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.