The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity

A. Staal, Julie Clare Crockett, M. H. French, J. Swartz, T. Gungor, T. W. Harrity, J. Tamasi, Michael John Rogers, J. H. M. Feyen

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.

Original languageEnglish
Pages (from-to)88-96
Number of pages8
JournalJournal of Bone and Mineral Research
Volume18
Issue number1
DOIs
Publication statusPublished - Jan 2003

Keywords

  • osteoclast
  • statins
  • prenylation
  • mevalonate pathway
  • bone resorption
  • nitrogen-containing bisphosphonates
  • coenzyme-A reductase
  • in-vitro
  • apoptosis
  • cells
  • pravastatin
  • mechanism
  • rats

Cite this

The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. / Staal, A.; Crockett, Julie Clare; French, M. H.; Swartz, J.; Gungor, T.; Harrity, T. W.; Tamasi, J.; Rogers, Michael John; Feyen, J. H. M.

In: Journal of Bone and Mineral Research, Vol. 18, No. 1, 01.2003, p. 88-96.

Research output: Contribution to journalArticle

Staal, A, Crockett, JC, French, MH, Swartz, J, Gungor, T, Harrity, TW, Tamasi, J, Rogers, MJ & Feyen, JHM 2003, 'The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity', Journal of Bone and Mineral Research, vol. 18, no. 1, pp. 88-96. https://doi.org/10.1359/jbmr.2003.18.1.88
Staal, A. ; Crockett, Julie Clare ; French, M. H. ; Swartz, J. ; Gungor, T. ; Harrity, T. W. ; Tamasi, J. ; Rogers, Michael John ; Feyen, J. H. M. / The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. In: Journal of Bone and Mineral Research. 2003 ; Vol. 18, No. 1. pp. 88-96.
@article{9dc2afa2f4034d8c86ea05c58d5335b1,
title = "The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity",
abstract = "Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.",
keywords = "osteoclast, statins, prenylation, mevalonate pathway, bone resorption, nitrogen-containing bisphosphonates, coenzyme-A reductase, in-vitro, apoptosis, cells, pravastatin, mechanism, rats",
author = "A. Staal and Crockett, {Julie Clare} and French, {M. H.} and J. Swartz and T. Gungor and Harrity, {T. W.} and J. Tamasi and Rogers, {Michael John} and Feyen, {J. H. M.}",
year = "2003",
month = "1",
doi = "10.1359/jbmr.2003.18.1.88",
language = "English",
volume = "18",
pages = "88--96",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "WILEY-BLACKWELL",
number = "1",

}

TY - JOUR

T1 - The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity

AU - Staal, A.

AU - Crockett, Julie Clare

AU - French, M. H.

AU - Swartz, J.

AU - Gungor, T.

AU - Harrity, T. W.

AU - Tamasi, J.

AU - Rogers, Michael John

AU - Feyen, J. H. M.

PY - 2003/1

Y1 - 2003/1

N2 - Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.

AB - Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.

KW - osteoclast

KW - statins

KW - prenylation

KW - mevalonate pathway

KW - bone resorption

KW - nitrogen-containing bisphosphonates

KW - coenzyme-A reductase

KW - in-vitro

KW - apoptosis

KW - cells

KW - pravastatin

KW - mechanism

KW - rats

U2 - 10.1359/jbmr.2003.18.1.88

DO - 10.1359/jbmr.2003.18.1.88

M3 - Article

VL - 18

SP - 88

EP - 96

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 1

ER -