Bisphosphonates: From the laboratory to the clinic and back again

R G G Russell, M J Rogers

Research output: Contribution to journalLiterature review

715 Citations (Scopus)

Abstract

Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occurring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains.

Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. Is addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of nea bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures.

The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs, oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood.

Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects.

In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradually being realized. (C) 1999 by Elsevier Science Inc. All rights reserved.

Original languageEnglish
Pages (from-to)97-106
Number of pages10
JournalBone
Volume25
Publication statusPublished - 1999

Keywords

  • bone resorption
  • osteoclast
  • bisphosphonates
  • protein prenylation
  • bone metastases
  • myeloma
  • osteoporosis
  • MOLD DICTYOSTELIUM-DISCOIDEUM
  • GTP-BINDING PROTEIN
  • HETEROCYCLE-CONTAINING BISPHOSPHONATES
  • CYCLICAL ETIDRONATE THERAPY
  • ACUTE-PHASE RESPONSE
  • BONE-RESORPTION
  • IN-VITRO
  • PAGETS-DISEASE
  • DICHLOROMETHYLENE DIPHOSPHONATE
  • POSTMENOPAUSAL OSTEOPOROSIS

Cite this

Russell, R. G. G., & Rogers, M. J. (1999). Bisphosphonates: From the laboratory to the clinic and back again. Bone, 25, 97-106.

Bisphosphonates: From the laboratory to the clinic and back again. / Russell, R G G ; Rogers, M J .

In: Bone, Vol. 25, 1999, p. 97-106.

Research output: Contribution to journalLiterature review

Russell, RGG & Rogers, MJ 1999, 'Bisphosphonates: From the laboratory to the clinic and back again' Bone, vol. 25, pp. 97-106.
Russell, R G G ; Rogers, M J . / Bisphosphonates: From the laboratory to the clinic and back again. In: Bone. 1999 ; Vol. 25. pp. 97-106.
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T1 - Bisphosphonates: From the laboratory to the clinic and back again

AU - Russell, R G G

AU - Rogers, M J

PY - 1999

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N2 - Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occurring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains.Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. Is addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of nea bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures.The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs, oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood.Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects.In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradually being realized. (C) 1999 by Elsevier Science Inc. All rights reserved.

AB - Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occurring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains.Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. Is addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of nea bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures.The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs, oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood.Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects.In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradually being realized. (C) 1999 by Elsevier Science Inc. All rights reserved.

KW - bone resorption

KW - osteoclast

KW - bisphosphonates

KW - protein prenylation

KW - bone metastases

KW - myeloma

KW - osteoporosis

KW - MOLD DICTYOSTELIUM-DISCOIDEUM

KW - GTP-BINDING PROTEIN

KW - HETEROCYCLE-CONTAINING BISPHOSPHONATES

KW - CYCLICAL ETIDRONATE THERAPY

KW - ACUTE-PHASE RESPONSE

KW - BONE-RESORPTION

KW - IN-VITRO

KW - PAGETS-DISEASE

KW - DICHLOROMETHYLENE DIPHOSPHONATE

KW - POSTMENOPAUSAL OSTEOPOROSIS

M3 - Literature review

VL - 25

SP - 97

EP - 106

JO - Bone

JF - Bone

SN - 8756-3282

ER -