Abstract
Despite several decades of progress, bone-specific delivery is still limited by the unique anatomical features of bone, which mainly consists of inorganic hydroxyapatite. A practical approach to this problem is to produce targeted drugs that have a high affinity for hydroxyapatite. Bisphosphonates are a class of synthetic compounds structurally related to pyrophosphate. Bisphosphonates rapidly localise on the bone surface after being administered either intravenously or orally, since the P-C-P portion of the bisphosphonate structure has high affinity for hydroxyapatite. Therefore, bisphosphonate modification might be a promising method for targeting drugs selectively to the bone.
Bisphosphonate-conjugated drugs are hydrophilic and highly water-soluble due to the acidic nature of the bisphosphonate moiety at physiological pH, and therefore they hardly permeate through the biological membrane of soft tissues. These physicochemical changes also reduce the intrinsic susceptibility of the drug to metabolism, promoting urinary or biliary excretion as unchanged drug. All these physicochemical and pharmacokinetic alterations contribute to the exceptional skeletal disposition of bisphosphonate-conjugated drugs.
Bisphosphonate conjugation is based on chemical modification of the targeting molecule, and therapeutically optimised bisphosphonate derivatives have to be custom-developed on a case-by-case basis. The bisphosphonate moiety is usually coupled with the targeting drug through a specific linkage. The high affinity of bisphosphonate conjugates for the bone is not simply dependent on the bisphosphonate moiety but on the resultant molecule as a whole, including the linker and the linked drug. Lipophilicity (represented as log P) appears to be an appropriate index for predicting the osteotropic properties of bisphosphonate derivatives.
Several strategies using bisphosphonate-conjugated drugs have been investigated at a laboratory level with the aim of obtaining therapeutically optimised treatments for conditions such as osteoporosis, osteoarthritis and bone cancer. In each case, the intention is to achieve prolonged local exposure to high concentrations of the targeting drug, thereby improving therapeutic index by enhancing pharmacological efficacy and minimising systemic adverse effects.
Although most examples of bone-specific drug delivery via bone-seeking agents still remain in preclinical studies, several phosphonate-coupled radiopharmaceuticals, such as samarium-153 complexed to tetraphosphonate, are expected to be an effective pain palliation therapies for metastatic bone cancer and are currently being developed in clinical trials. Furthermore, recent reports on bisphosphonate-modified proteins have illustrated the feasibility of bone-specific delivery of biologically active protein drugs, such as cytokines and growth factors.
Similar content being viewed by others
Notes
Use of tradenames is for product identification only and does not imply endorsement.
References
Abbott III TA, Lawrence BJ, Wallach S. Osteoporosis: the need for comprehensive treatment guidelines. Clin Ther 1996; 18(1): 127–49
Hoerger TJ, Downs KE, Lakshmanan MC, et al. Healthcare use among US women aged 45 and older: total costs and costs for selected postmenopausal health risks. J Womens Health Gend Based Med 1999; 8(8): 1077–89
Tahara Y, Ishii Y. Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation. J Orthop Sci 2001; 6(6): 556–65
Kato H, Neo M, Tamura J, et al. Bone bonding in bioactive glass ceramics combined with a new synthesized agent TAK-778. J Biomed Mater Res 2001; 57(2): 291–9
Sánchez E, Baro M, Soriano I, et al. In vivo-in vitro study of biodegradable and osteointegrable gentamicin bone implants. Eur J Pharm Biopharm 2001; 52(2): 151–8
Woo BH, Fink BF, Page R, et al. Enhancement of bone growth by sustained delivery of recombinant human bone morphogenetic protein-2 in a polymeric matrix. Pharm Res 2001; 18(12): 1747–53
Talmage RV. Morphological and physiological consideration in a new concept of calcium transport in bone. Am J Anat 1970; 129(4): 467–76
Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996; 18(2): 75–85
Cantrill JA, Anderson DC. Treatment of Pagets’s disease of bone. Clin Endocrinol (Oxf) 1990; 32(4): 507–18
Heath D. The treatment of hypercalcaemia of malignancy. Clin Endocrinol (Oxf) 1991; 34(2): 155–7
van Holten-Verzantvoort AT, Bijvoet OL, Cleton FJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet 1987; II (8566): 983–5
Storm T, Thamsborg G, Steiniche T, et al. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990; 322(18): 1265–71
Myers HM. Structure-activity relationships (SAR) of hydroxyapatite-binding molecules. Calcif Tissue Int 1987; 40(6): 344–8
Bisaz S, Jung A, Fleisch H. Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives. Clin Sci Mol Med 1978; 54(3): 265–72
Fleisch H. Bisphosphonates: a new class of drugs in diseases of bone and calcium metabolism. In: Baker PF, editor. Handbook of experimental pharmacology. Vol. 83. Berlin-Heidelberg: Springer, 1988: 441–66
Fujisaki J, Tokunaga Y, Takahashi T, et al. Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. I: synthesis and in vivo characterization of osteotropic carboxyfluorescein. J Drug Target 1995; 3(4): 273–82
Tsushima N, Yabuki M, Harada H, et al. Tissue distribution and pharmacological potential of SM-16896, a novel oestrogenbisphosphonate hybrid compound. J Pharm Pharmacol 2000; 52(1): 27–37
Hirabayashi H, Takahashi T, Fujisaki J, et al. Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the Osteotropic Drug Delivery System (ODDS). J Control Release 2001; 70 (1–2): 183–91
Boulenc X, Marti E, Joyeux H, et al. Importance of the paracellular pathway for the transport of a new bisphosphonate using the human CACO-2 monolayers model. Biochem Pharmacol 1993; 46(9): 1591–600
Lin JH, Chen I-W, de Luna FA, et al. Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats. Drug Metab Dispos 1992; 20(4): 473–8
Lin JH, Duggan DE, Chen I-W, et al. Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals. Drug Metab Dispos 1991; 19(5): 926–32
Fujisaki J, Tokunaga Y, Takahashi T, et al. Physicochemical characterization of bisphosphonic carboxyfluorescein for osteotropic drug delivery. J Pharm Pharmacol 1996; 48(8): 798–800
Fujisaki J, Tokunaga Y, Sawamoto T, et al. Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein. J Drug Target 1996; 4(2): 117–23
Smith RL. Excretion of drugs in bile. In: Brodie BB, Gillette JR, editors. Handbook of experimental pharmacology: concepts in biochemical pharmacology. Vol. 28. Berlin: Springer, 1971: 354–89
Mönkkönen J, Urtti A, Paronen P, et al. The uptake of clodronate (dichloromethylene bisphosphonate) by macrophages in vivo and in vitro. Drug Metab Dispos 1989; 17(6): 690–3
Mönkkönen J, Ylitalo P. The tissue distribution of clodronate (dichloromethylene bisphosphonate) in mice: the effects of vehicle and the route of administration. Eur J Drug Metab Pharmacokinet 1990; 15(3): 239–43
Mönkkönen J, Rooijen N, Ylitalo P. Effects of clodronate and pamidronate on splenic and hepatic phagocytic cells of mice. Pharmacol Toxicol 1991; 68(4): 284–6
Hirabayashi H, Sawamoto T, Fujisaki J, et al. Dose dependent pharmacokinetics and disposition of bisphosphonic prodrug of diclofenac based on Osteotropic Drug Delivery System (ODDS). Biopharm Drug Dispos 2002; 23(8): 307–15
Hirabayashi H, Sawamoto T, Fujisaki J, et al. Relationship between physicochemical and osteotropic properties of bisphosphonic derivatives: rational design for osteotropic drug delivery system (ODDS). Pharm Res 2001; 18(5): 646–51
Fleisch H. Diphosphonates: history and mechanisms of action. Metab Bone Dis Relat Res 1981; 3 (4–5): 279–87
van Beek E, Hoekstra M, van de Ruit M, et al. Structure requirement of bisphosphonate actions in vitro. J Bone Miner Res 1994; 9(12): 1875–82
Sunberg R, Ebetino FH, Mosher CT, et al. Designing drugs for stronger bones. Chemtech 1991; 21: 304–9
Cohen H, Solomon V, Alferiev IS, et al. Bisphosphonates and tetracycline: experimental models for their evaluation in calcium-related disorders. Pharm Res 1998; 15(4): 606–13
Cohen H, Alferiev IS, Mönkkönen J, et al. Synthesis and preclinical pharmacology of 2-(2-aminopyrimidinio) ethylene-1,1-bisphosphonic acid betaine (ISA-13-1), a novel bisphosphonate. Pharm Res 1999; 16(9): 1399–406
Hoffman A, Stepensky D, Ezra A, et al. Mode of administration-dependent pharmacokinetics of bisphosphonate and bio-availability determination. Int J Pharm 2001; 220 (1–2): 1–11
Gil L, Han Y, Opas EE, et al. Prostaglandin E2-bisphosphonate conjugates: potential agents for treatment of osteoporosis. Bioorg Med Chem 1999; 7(5): 901–19
Bauss F, Esswein A, Reiff K, et al. Effect of 17β-estradiol-bisphosphonate conjugates, potential bone-seeking estrogen pro-drugs, on 17β-estradiol serum kinetics and bone mass in rats. Calcif Tissue Int 1996; 59(3): 168–73
Fujisaki J, Tokunaga Y, Takahashi T, et al. Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. IV: effects of osteotropic estradiol on bone mineral density and uterine weight in ovariectomized rats. J Drug Target 1998; 5(2): 129–38
Fujisaki J, Tokunaga Y, Takahashi T, et al. Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. V: biological disposition and targeting characteristics of osteotropic estradiol. Biol Pharm Bull 1997; 20(11): 1183–7
Herczegh P, Buxton TB, McPherson III JC, et al. Osteoadsorptive bisphosphonate derivatives of fluoroquinolone antibacterials. J Med Chem 2002; 45(11): 2338–41
Klenner T, Valenzuela-Paz P, Keppler BK, et al. Cisplatin-linked phosphonates in the treatment of the transplantable osteosarcoma in vitro and in vivo. Cancer Treat Rev 1990; 17 (2–3): 253–9
Klenner T, Wingen F, Keppler BK, et al. Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies? J Cancer Res Clin Oncol 1990; 116(4): 341–50
Klenner T, Wingen F, Keppler B, et al. Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat. Clin Exp Metastasis 1990; 8(4): 345–59
Sturtz G, Couthon H, Fabulet O, et al. Synthesis of gembisphosphonic methotrexate conjugates and their biological response towards Walkers’s osteosarcoma. Eur J Med Chem 1993; 28: 899–903
Hosain F, Spencer RP, Couthon HM, et al. Targeted delivery of antineoplastic agent to bone: biodistribution studies of technetium-99m-labeled gem-bisphosphonate conjugate of methotrexate. J Nucl Med 1996; 37(1): 105–7
Serafini AN. Systemic metabolic radiotherapy with samarium-153 EDTMP for the treatment of painful bone metastasis. Q J Nucl Med 2001; 45(1): 91–9
Lamb HM, Faulds D. Samarium 153Sm lexidronam. Drugs Aging 1997; 11(5): 413–8
Eary JF, Collins C, Stabin M, et al. Samarium-153-EDTMP biodistribution and dosimetry estimation. J Nucl Med 1993; 34(7): 1031–6
Lewington VJ. Cancer therapy using bone-seeking isotopes. Phys Med Biol 1996; 41(10): 2027–42
Mundy GR. Pathogenesis of osteoporosis and challenges for drug delivery. Adv Drug Deliv Rev 2000; 42(3): 165–73
Gambrell Jr RD. The menopause: benefits and risks of estrogen-progestogen replacement therapy. Fertil Steril 1982; 37(4): 457–74
Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332(24): 1589–93
Pardridge WM, Mietus LJ. Transport of steroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. J Clin Invest 1979; 64(1): 145–54
Orme MW, Labroo VM. Synthesis of β-estradiol-3-benzoate-17-(succinyl-12A-tetracycline): a potential bone-seeking estrogen. Bioorg Med Chem Lett 1994; 4(11): 1375–80
Yokogawa K, Miya K, Sekido T, et al. Selective delivery of estradiol to bone by aspartic acid oligopeptide and its effects on ovariectomized mice. Endocrinology 2001; 142(3): 1228–33
Sekido T, Sakura N, Higashi Y, et al. Novel drug delivery system to bone using acidic oligopeptide: pharmacokinetic characteristics and pharmacological potential. J Drug Target 2001; 9(2): 111–21
Uludag H, Kousinioris N, Gao T, et al. Bisphosphonate conjugation to proteins as a means to impart bone affinity. Biotechnol Prog 2000; 16(2): 258–67
Uludag H, Gao T, Wohl GR, et al. Bone affinity of a bisphosphonate-conjugated protein in vivo. Biotechnol Prog 2000; 16(6): 1115–8
Uludag H, Yang J. Targeting systemically administered proteins to bone by bisphosphonate conjugation. Biotechnol Prog 2002; 18(3): 604–11
Acknowledgements
Financial support for this manuscript was provided by Fujisawa Pharmaceutical Co. Ltd. The authors wish to thank Bindu Gadani, M.S., for critical reading and reviewing of the manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hirabayashi, H., Fujisaki, J. Bone-Specific Drug Delivery Systems. Clin Pharmacokinet 42, 1319–1330 (2003). https://doi.org/10.2165/00003088-200342150-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200342150-00002