Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

P. S. Narayana Murthy, S. Sengupta, S. Sharma, M. M. Singh

Research output: Contribution to journalArticlepeer-review


Effect of ormeloxifene, a multifunctional selective estrogen receptor modulator, on prevention of ovariectomy-induced bone resorption in retired breeder female rats, osteoclastogenesis using bone marrow cells from adult Balb/c mice cultured in presence of M-CSF and RANKL, osteoclast apoptosis using terminal deoxynucleotidyl transferase fragment end labeling and TGF beta-3 expression were investigated. Raloxifene, a benzothiophene reported to mimic effects of estrogen in bone, and estradiol were used for comparison. Ormeloxifene (10-6 and 10-8 M) significantly inhibited osteoclastogenesis (P < 0.001 versus vehicle control) as evidenced by lower number of TRAP-positive osteoclasts in bone marrow cultures and caused apoptosis of osteoclasts. The effect was almost equivalent to that observed in presence of estradiol-17 beta, except that significant number of cells undergoing apoptosis was evident even at 10-9 M concentration of estradiol-17 beta (P < 0.001). Raloxifene, though inhibited osteoclastogenesis at much lower concentrations (10-8 to 10-12 M; P < 0.001), failed to cause apoptosis of osteoclasts at any of the concentrations used. While ormeloxifene, raloxifene and ethynylestradiol significantly prevented ovariectomy-induced bone loss in vivo in retired breeder female rats, prevention of ovariectomy-induced decrease in BMD and trabecular network of proximal tibia, calcium and phosphorus levels in femur and tibia and prevention of ovariectomy-induced down-regulation of TGF beta-3 expression in lumbar vertebrae was of lower order in raloxifene- than ormeloxifene- or ethynylestradiol-supplemented females. Both the SERMs, however, produced considerable estrogenic effects at the uterine level as evidenced by increase in weight, total and endometrial area and luminal epithelial cell height; the effect being generally greater in raloxifene- than ormeloxifene-treated rats. Findings demonstrate that inhibition of estrogen-deficiency osteoporosis by ormeloxifene, as in case of estradiol, was mediated via inhibition of osteoclastogenesis, apoptosis of osteoclasts and up-regulation of TGF beta-3 expression. Raloxifene, though effective in inhibiting osteoclastogenesis in vitro at much lower concentrations, was not only less potent in preventing ovariectomy-induced bone loss in retired breeder female rats in vivo but also appeared to have a different mechanism of action than ormeloxifene and estradiol.

Original languageEnglish (US)
Pages (from-to)117-128
Number of pages12
JournalJournal of Steroid Biochemistry and Molecular Biology
Issue number4-5
StatePublished - Aug 2006
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Mr. P.K. Dasgupta for help in osteoclast culture, Prof. Kartar Singh, Director, Dr. V.L. Bhatia and Mr. Manoj Dubey, Sanjay Gandhi PostGraduate Institute of Medical Sciences, Lucknow for BMD measurements, M/s. Cadila Healthcare Ltd., Ahmedabad, for generous gift of raloxifene and the Ministry of Health & Family Welfare, Govt. of India, for financial support. One of us (PSN) thanks the CSIR, New Delhi, for award of Senior Research Fellowship. CDRI communication no. 6697.


  • Antiresorptive
  • Bone mineral content
  • Bone mineral density
  • Ethynylestradiol
  • Ormeloxifene
  • Osteoclast apoptosis
  • Osteoclastogenesis
  • Raloxifene
  • Retired breeder rats
  • SERM
  • TGF beta-3


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