Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy

R. G. G. Russell, N. B. Watts, F. H. Ebetino, M. J. Rogers

Research output: Contribution to journalLiterature review

816 Citations (Scopus)

Abstract

Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.

Introduction The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts.

Discussion There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction.

Original languageEnglish
Pages (from-to)733-759
Number of pages27
JournalOsteoporosis International
Volume19
Issue number6
DOIs
Publication statusPublished - 2008

Keywords

  • bisphosphonates
  • bone resorption
  • farnesyl pyrophosphate synthase
  • fractures
  • hydroxyapatite
  • osteocytes
  • nitrogen-containing bisphosphonates
  • bone-mineral density
  • farnesyl diphosphate synthase
  • fracture intervention trial
  • intravenous zoledronic acid
  • dose-response relationships
  • activation in-vitro
  • postmenopausal osteoporosis
  • vertebral fractures
  • randomized-trials

Cite this

Mechanisms of action of bisphosphonates : similarities and differences and their potential influence on clinical efficacy. / Russell, R. G. G.; Watts, N. B.; Ebetino, F. H.; Rogers, M. J.

In: Osteoporosis International, Vol. 19, No. 6, 2008, p. 733-759.

Research output: Contribution to journalLiterature review

Russell, R. G. G. ; Watts, N. B. ; Ebetino, F. H. ; Rogers, M. J. / Mechanisms of action of bisphosphonates : similarities and differences and their potential influence on clinical efficacy. In: Osteoporosis International. 2008 ; Vol. 19, No. 6. pp. 733-759.
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AU - Rogers, M. J.

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N2 - Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.Introduction The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts.Discussion There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction.

AB - Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.Introduction The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts.Discussion There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction.

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KW - farnesyl diphosphate synthase

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KW - intravenous zoledronic acid

KW - dose-response relationships

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KW - postmenopausal osteoporosis

KW - vertebral fractures

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JO - Osteoporosis International

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