The decrease of soluble RAGE levels in rheumatoid arthritis patients following hormone replacement therapy is associated with increased bone mineral density and diminished bone/cartilage turnover: a randomized controlled trial.
OBJECTIVE
The aim of the study was to prospectively investigate the effects of HRT on serum soluble receptor for advanced glycation end product (sRAGE) levels in RA patients and to determine whether sRAGE production is related to bone/cartilage metabolism.


METHODS
Eighty-eight post-menopausal RA patients were randomized to receive vitamin D3 and calcium supplementation with or without HRT (oestradiol plus noretisterone acetate). The levels of total sRAGE in sera were measured before, 1 and 2 years after treatment initiation. Potential associations between sRAGE levels, bone/cartilage metabolic markers and BMD were investigated.


RESULTS
Patients receiving HRT displayed significantly decreased levels of serum sRAGE at 1 and 2 years as compared with levels at study entry. The increase in serum oestradiol was associated with the decline in sRAGE levels. Importantly, sRAGE levels at baseline significantly correlated with bone/cartilage turnover markers including C-terminal propeptide of type I procollagen, carboxyterminal telopeptide of type I collagen and cartilage oligomeric matrix protein, and the decrease of sRAGE levels paralleled with diminished concentration of these molecules. BMD in hip and femoral neck and progression of Larsen score at 1 year were associated with baseline sRAGE levels. The decline in sRAGE levels significantly correlated with an increase in total BMD following 2 years of treatment in patients receiving HRT but not in the control group.


CONCLUSIONS
Our findings suggest that HRT decreases the levels of endogenous sRAGE in post-menopausal RA patients implicating its role in sRAGE regulation. In addition, serum sRAGE was associated with BMD and markers of bone/cartilage metabolism. These data suggest that sRAGE is involved directly or indirectly in bone metabolism. Trial registration. Current Controlled Trials, ISRCTN46523456, http://www.controlled-trials.com/isrctn/search.html?srch=ISRCTN46523456.
Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden. rille.pullerits@rheuma.gu.se
Rille
R
Pullerits
Helena Forsblad
HF
d'Elia
Andrej
A
Tarkowski
Hans
H
Carlsten
D000469:Alkaline Phosphatase / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000008:administration & dosage; D002356:Cartilage / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D002762:Cholecalciferol / Q000008:administration & dosage; D004958:Estradiol / Q000008:administration & dosage; D015914:Estrogen Replacement Therapy; D016326:Extracellular Matrix Proteins / Q000097:blood; D005260:Female; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D064235:Matrilin Proteins; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077563:Norethindrone Acetate; D010446:Peptide Fragments / Q000097:blood; D017698:Postmenopause / Q000378:metabolism*; D011347:Procollagen / Q000097:blood; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*; D018709:Statistics, Nonparametric
D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; D010446:Peptide Fragments; D011347:Procollagen; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C577553:TSP5 protein, human; C042813:procollagen type I carboxy terminal peptide; D002762:Cholecalciferol; D004958:Estradiol; D000077563:Norethindrone Acetate; D000469:Alkaline Phosphatase; D002118:Calcium; D009640:Norethindrone