Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab

Abstract

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.

Sclerostin Blood Levels Before and After Kidney Transplantation

“…1C). In contrast to our finding, Gatti et al found a significant increase in sclerostin levels in postmenopausal women treated with denosumab for osteoporosis compared with the placebo group [28]. The reasons for this discrepancy need to be elucidated.…”

Insight into the WNT system and its drug related response

“…This effect of bisphosphonates on WNTantagonist appears to be different from that we found in patients treated with denosumab (95), an antiresorptive drug that, suppressing RANKL activity, lowers the number not only of actively resorbing osteoclasts (as bisphosphonates do) but also of osteoclast precursors. In our study denosumab therapy was found to be associated with increasing SCL levels (as bisphosphonates treatment) but it was also associated with declining serum levels of DKK1 (95) and this might explain the apparent persistent slight positive unbalance between suppressed bone resorption and formation during denosumab treatment (96). The WNT-pathway is also involved in the response to bone anabolic agents.…”

Letter regarding “Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts”

“…Denosumab, a monoclonal RANKL antibody, not only effectively inhibits RANKL, which can lead to significant reduction of osteoclasts, but also increases osteoblastogenesis via inhibition of DKK1, which is antagonist of WNT/b-catenin pathway [4]. Therefore, these important mechanisms should be borne in mind as the major mechanisms for Denosumab for treatment of bone cyst.…”