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Bisphosphonates Mechanism for Low Bioavailability with Oral Administration


  • Bisphosphonates are synthetic analogs of pyrophosphates and have poor oral bioavailability reported at a range of 0.6 to 1.5% of the administered dose.
  • Orally administered medications can cross the gastrointestinal epithelium by either the transcellular route or the paracellular route depending on their physiochemical properties. 
  • Bisphosphonates are a large, hydrophilic molecule that cannot cross the gastrointestinal epithelium via the transcellular route and inefficiently utilize the paracellular route of absorption due to their large size and negative charge, thus lowering absorption and oral bioavailability. 

Bryant B. Summers, PharmD
Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors:
Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed: August 2015


  • Bisphosphonates are synthetic analogs of a naturally occurring compound called pyrophosphate and are currently approved for the treatment of osteoporosis and other metabolic bone disorders.(1,2) They work by binding to the bone matrix and inhibiting osteoclast activity, either through direct induction of apoptosis of osteoclasts or inhibiting the proteins osteoclasts require for their resorptive effects.(1) Their chemical structure contains two phosphate groups and two side chains (R1 and R2) bound to a central carbon (See figure). The side chains affect bisphosphonate skeletal binding and prevent enzymatic breakdown in the gastrointestinal tract by phosphatases. Despite this physiochemical advantage, the oral bioavailability of bisphosphonates remains low at 0.6% to 1.5% of the administered dose.(2,3)

    In general, a drug may be absorbed through the intestine by either the transcellular or paracellular route depending on its physiochemical properties. The transcellular route involves passive diffusion, carrier-mediated transport, and endocytosis; all of which require the drug to be small and lipophilic. The paracellular route requires a drug to be resistant to enzymatic degradation, small, and hydrophilic. Once a drug passes through the epithelial cell layer of the gastrointestinal tract, it is then absorbed into circulation to exert its effects.(4,5,6)

    Bisphosphonates are large, hydrophilic drugs, which prevents diffusion across the gastrointestinal epithelium through the transcellular route.(7) The molecular weight of alendronate is 249 grams/mole and its octanol/buffer partition coefficient is 0.0017 independent of pH, all properties indicating a large, hydrophilic drug. This leaves the paracellular route as a means for bisphosphonates to be absorbed; however, their large size hinders their movement through tight junctions in the gastrointestinal epithelium. Additionally, the brush-border membrane is negatively charged and will often repel the negatively charged phosphate groups on the bisphosphonate from the epithelium and tight junctions. Finally, these negative charges also give bisphosphonates the tendency to bind with cations such as calcium and magnesium present in the intestinal lumen.8 In relation to this, the opening and closing of tight junctions has been linked to shifts in intracellular and extracellular movements of calcium. This additional supply of calcium ions may also interfere with the movement of the bisphosphonate through these junctions.(6,8,9)


    1. Friedman PA. Chapter 44. Agents Affecting Mineral Ion Homeostasis and Bone Turnover. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's: the pharmacological basis of therapeutics. 12nd ed. New York: McGraw-Hill; 2011. 
    2. Khosla S, Bilezikian JP, Dempster DW, Lewiecki ME, Miller PD, Neer RM, Recker RR, Shane E, Shoback D, and Potts JT. Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab. 2012;97(7):2272-82.
    3. Cremers S and Papapoulos. Pharmacology of bisphosphonates. Bone. 2011;49:42-49.
    4. Shargel L, Wu-Pong S, Yu AB. Chapter 13. Physiologic Factors Related to Drug Absorption. In: Shargel L, Wu-Pong S, Yu AB, eds. Applied biopharmaceutics & pharmacokinetics. 6th ed. New York: McGraw-Hill; 2012.
    5. Barthe L, Woodley J, and Houin G. Gastrointestinal absorption of drugs: methods and studies. Fundam Clin Pharmacol. 1999;13:154-68.
    6. Hayashi M and Tomita M. Mechanistic analysis for drug permeation through intestinal membrane. Drug Metab Pharmacokinect. 2007;22(2):67-77.
    7. Porras AH, Holland SD, and Gertz BJ. Pharmacokinetics of alendronate. Clin Pharmacokinet. 1999;36(5):315-28.
    8. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996. 18(2):75-85.
    9. Salama NN, Eddington ND, and Fasano A. Tight junction modulation and its relationship to drug delivery. Adv Drug.

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MESH Terms & Keywords

  • Bisphosphonates, oral administration, bioavailability, alendronate absorption, alendronate bioavailability, why alendronate poor absorption