Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women.
After acute estrogen withdrawal in postmenopausal women, administration of anakinra or etanercept, specific blockers of IL-1 and TNF-alpha, respectively, reduced the rise in bone resorption markers to about one half of that in controls. This is consistent with an important role for these immune cytokines in mediating the effect of estrogen deficiency on bone.


BACKGROUND
Studies in rodents have implicated increased production of interleukin (IL)-1 beta and TNF-alpha as mediators of bone loss after ovariectomy, but their roles are unclear in humans whose immune system differs markedly from that of rodents.


METHODS
We administered transdermal estradiol, 0.1 mg/d, for 60 days to 42 early postmenopausal women. Estrogen treatment was discontinued, and subjects were randomly assigned to intervention groups receiving 3 wk of injections with 0.9% saline, anakinra 100 mg/d, or etanercept 25 mg/twice weekly. Bone turnover was assessed by measuring serum carboxyl-terminal telopeptide of type 1 collagen (CTX) and amino-terminal telopeptide of type 1 collagen (NTX), markers for bone resorption, and serum amino-terminal propeptide of type 1 collagen (P1NP), a marker for bone formation. Results were expressed as percent change in markers from baseline (last 2 days of estrogen treatment and days 20 and 21 of intervention).


RESULTS
The percent changes from baseline during intervention for serum CTX, urine NTX, and serum PINP, respectively, were 43.3 +/- 8.0%, 12.0 +/- 7.1%, and -41.0 +/- 2.5% for the control group; 25.9 +/- 6.3%, 9.5 +/- 4.0%, and -37.8 +/- 3.0% for the anakinra group; and 21.7 +/- 5.0%, 0.32 +/- 3.82%, and -34.5 +/- 3.9% for the etanercept group. Compared with the control group, the blunting of the increase in serum CTX fell just below the level of significance (p=0.10) after anakinra treatment, whereas the blunting of the increase in serum CTX (p=0.034) and in urine NTX (p=0.048) were significant after etanercept treatment. Other changes were not significant.


CONCLUSIONS
The data are consistent with a role for TNF-alpha, and possibly for IL-1 beta, in mediating increased bone resorption during estrogen deficiency in women. Although either cytokine blocker reduced serum CTX by about one half, the effect of combined blockade could not be tested because of concerns about toxicity. The data do not exclude direct or indirect contributory roles for RANKL or for other cytokines.
Charatcharoenwitthaya
Natthinee
N
Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Khosla
Sundeep
S
Atkinson
Elizabeth J
EJ
McCready
Louise K
LK
Riggs
B Lawrence
BL
D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004967:Estrogens / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage* / Q000009:adverse effects; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood / Q000187:drug effects / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
D015415:Biomarkers; D004967:Estrogens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept