Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM).
OBJECTIVE
Several observational studies indicate that estrogen deficiency increases the incidence of osteoarthritis in postmenopausal women. To validate this observation, we investigated the effects of ovariectomy (OVX) on cartilage erosion in rats using histology and an established bio-assay of cartilage-specific collagen type II degradation products (CTX-II). Furthermore, we investigated whether estrogen and levormeloxifene, a selective estrogen-receptor modulator (SERM), can prevent the OVX-induced changes in cartilage degradation. The clinical relevance was assessed in postmenopausal women by measuring the changes in CTX-II during 12-month treatment with levormeloxifene versus placebo.


METHODS
Sixty 6-month-old rats were divided in five groups. One group was subjected to sham and the others to OVX, followed by treatment with vehicle alone, estradiol or 0.2 mg/kg/day or 5 mg/kg/day of levormeloxifene. The rats were treated for 9 weeks with biweekly blood and urine sampling for measurement of bone resorption and cartilage turnover. After study termination, hind knees were removed for histological analysis of erosions. The effect of levormeloxifene in post-menopausal women was assessed by measuring CTX-II in samples from 301 women who were participating in a phase II study of this SERM.


RESULTS
OVX rats showed significant increases in the urinary excretion of CTX-II. After 9 weeks this was manifested as increased surface erosion of knee articular cartilage compared with sham-operated rats. Treatment with estrogen or levormeloxifene prevented the OVX-induced changes. There was a significant correlation between the 4-week changes in CTX-II and cartilage erosion at week 9 (r = 0.64, P < 0.001). In postmenopausal women treated with levormeloxifene, the urinary excretion of CTX-II was decreased by approximately 50% and restored CTX-II levels to the premenopausal range.


CONCLUSIONS
This study is the first to demonstrate that a SERM suppresses cartilage degradation in both rodents and humans, suggesting potential therapeutical benefits in the prevention of destructive joint diseases such as osteoarthritis.
Christgau
Stephan
S
Nordic Bioscience, Herlev, Denmark. sc@nordicbioscience.com
Tankó
László B
LB
Cloos
Paul A C
PA
Mouritzen
Ulrik
U
Christiansen
Claus
C
Delaissé
Jean-Marie
JM
Høegh-Andersen
Pernille
P
D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D015914:Estrogen Replacement Therapy / Q000379:methods*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000517:prevention & control*; D010052:Ovariectomy; D017698:Postmenopause; D011336:Probability; D011379:Prognosis; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; C108255:levormeloxifene