Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab.
The bone mass benefits of antiresorbers in postmenopausal osteoporosis are limited by the rapid coupling of decreasing bone resorption with bone formation. Wnt signaling is involved in this coupling process during treatment with bisphosphonates, whereas its role during treatment with the anti-receptor activator of NF-κB ligand (RANKL) antibody denosumab is unknown. The study population includes patients participating in a placebo-controlled trial lasting 36 months: 19 women were on placebo and 24 on subcutaneous 60 mg denosumab every 6 months. All measured parameters (serum C-terminal telopeptide of type I collagen [sCTX], serum bone alkaline phosphatase [bAP], Dickkopf-1 [DKK1], and sclerostin) remained unchanged during the observation period in the placebo group. sCTX and bAP were significantly suppressed by denosumab treatment over the entire follow-up. Denosumab treatment was associated with significant (p < 0.05) increases (28% to 32%) in serum sclerostin over the entire study follow-up. Serum DKK1 significantly decreased within the first 6 months with a trend for further continuous decreases, which reached statistical significance (p < 0.05) versus placebo group from the 18th month onward. The changes in DKK1 were significantly and positively related with the changes in sCTX and bAP and negatively with hip bone mineral density (BMD) changes. The changes in sclerostin were significantly and negatively related only with those of bAP. The changes in bone turnover markers associated with denosumab treatment of postmenopausal osteoporosis is associated with significant increase in sclerostin similar to those seen after long-term treatment with bisphosphonates and significant decrease in DKK1. This latter observation might explain the continuous increase over 5 years in BMD observed during treatment of postmenopausal osteoporosis with denosumab.
Unit of Rheumatology, University of Verona, Verona, Italy.
Davide
D
Gatti
Ombretta
O
Viapiana
Elena
E
Fracassi
Luca
L
Idolazzi
Carmela
C
Dartizio
Maria Rosaria
MR
Povino
Silvano
S
Adami
Maurizio
M
Rossini
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D024042:Collagen Type I / Q000097:blood; D003710:Demography; D000069448:Denosumab; D005260:Female; D005819:Genetic Markers; D006615:Hip / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D010455:Peptides / Q000097:blood; D013131:Spine / Q000187:drug effects / Q000503:physiopathology
D048868:Adaptor Proteins, Signal Transducing; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C422903:SOST protein, human; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D000469:Alkaline Phosphatase