The present study showed that AS patients had lower serum OPG levels and a higher RANKL/OPG ratio compared to healthy controls. Previous studies have shown discrepancies in regards to OPG level in AS. Some studies revealed elevated OPG levels in AS patients compared to healthy controls
]. However, a study in a Korean cohort found no differences in serum levels of OPG between AS patients and normal subjects
]. In a cohort of 240 AS patients, Franck et al.
found that AS patients generally had lower serum OPG level and higher RANKL/OPG ratio; they also reported a lack of compensatory increase of OPG with age in AS patients
]. Subgroup analysis of our results also revealed that active disease state (BASDAI
4) was associated with higher OPG levels. This result is in agreement with the findings of Chen et al
., who found OPG to be correlated with poor physical mobility and increased inflammatory state in AS patients; however, in contrast to our results, that study found RANKL and OPG to be elevated compared to controls
]. Osteoprotegerin inhibits osteoclastogenesis by binding RANKL, acting as a decoy receptor to competitively inhibit RANKL interaction with its receptor RANK. Thus, decreased OPG levels in AS patients might have contributed to the lowered BMD detected at femur in our study group
]. On the other hand, hypothetically, the excess production of OPG during active disease state could contribute to the new bone formation. In this study, we also showed that, anti-TNF treated AS patients had significantly lower levels of OPG compared with the conventionally treated patients. This observation is in line with a prospective study performed by Kwon et al. who showed anti-TNF treatment had a negative effect on OPG concentrations
The discrepancies between the results of various studies may be due to the effects of various disease states and treatment types on the RANKL/OPG axis, as well as the complex interaction of various cytokines and signaling molecules. In our study, RANKL was similar in AS patients and healthy controls, was not altered with treatment, and showed no relation with clinical parameters; in contrast, Kim et al
. found increased RANKL level correlating with disease activity markers
]. RANKL is an important cytokine, but osteoclastogenesis is also influenced by TNF, IL-1, IL-6, IL-17, vitamin D3, and prostaglandin E2
]. OPG balances bone resorption, and is induced by IL-4, IFNγ, PTH, BMP, and Wnt signaling
]; all of these cytokines are expressed differently in cases of certain disease activity and treatment. Woo et al
. reported that etanercept therapy didn’t change RANKL/OPG levels, but improved bone metabolic markers and BMD in AS patients
]. In our study, we observed that sRANKL/OPG ratio was significantly higher in patients treated with anti-TNF therapies. Although sRANKL did not change between the treatments groups, this significance was a consequence of lower OPG concentrations in the biological treatment group. The effects of inflammation on bone remodeling have different outcomes in different rheumatic diseases, such as RA and AS
]. In both diseases, decreased bone mineral density is expected, including juxta-articular osteopenia in RA and decreased BMD mainly at vertebras and hip in AS
]. In this study, BMD of femoral neck was significantly decreased in AS patients, but BMD of lumbar spine did not differ from the healthy controls. These observations may be due to be the interference of syndesmophytes and ectopic calcifications with BMD measurement at lumbar spine. Low PTH and OPG in AS patients may be explanatory to the finding of decreased BMD of femoral neck as we noted previously.
In our study, the serum levels of Wnt signaling pathway inhibitors, DKK-1, Sclerostin, and sFRP1, were not different in AS patients from the healthy controls. However, subgroup analysis showed that patients receiving anti-TNFα treatment had higher DKK-1 levels compared to patients taking conventional drugs. Daoussis et al
. recently measured DKK-1 level using two different serum assays; a sandwich Elisa assay that showed circulating DKK-1 indicated that serum DKK-1 was increased in AS patients compared to healthy controls, but a functional ELISA model showed decreased binding of DKK-1 to the LRP-6 receptor
]. Diarra et al.
also found that, in contrast to RA, DKK-1 levels in AS were very low and showed no relation with measures of disease activity
]. Lane et al
. found that higher DKK-1 levels were protective and diminished the risk of radiologic progression for hip OA, another disease associated with bone formation
]. All of these studies suggest that either dysfunction or decreased level of DKK-1 is crucial for new bone formation in AS. In our study, increased DKK-1 level in AS patients who were on anti-TNF treatment are noteworthy, since the balance between DKK-1 and Wnt is important for bone turnover. In Diarra et al
.’s study, DKK-1 levels in RA patients were diminished with anti-TNF drugs, but the effects in AS patients were not clear
]. According to our results, decreased OPG and increased DKK-1 in patients on anti-TNF therapy suggest a trend favoring osteoclastogenesis in these patients. However, prospective studies are needed to determine the net effect of biological therapies on bone metabolism.