Objective: To analyze the association between serum uric acid (UA) levels and bone turnover markers. Methods: 62 ankylosing spondylitis (AS) and 50 healthy controls were enrolled. Bone turnover markers were detected by electrochemiluminescence method. The laboratory measurements of AS were collected. The relationship between UA and bone turnover markers were analyzed.
Results: The mean level of serum UA was 409.96±93.06 umol/L in healthy controls, and 348.89±68.95 umol/L in AS patents. The levels of UA were significantly higher in healthy controls than in AS patients(P=0.000). In healthy controls, UA was significantly negative correlated with osteocalcin (OC) and C-terminal crosslaps of type I collagen (β-CTX) (P<0.05). However, UA was significantly positive correlated with β-CTX in AS patients with low bone mineral density (BMD).
Conclusion: UA could reflect bone resorption in AS patients with low BMD. UA could be used as a marker for the treatment of AS with low BMD and following-up.
Ankylosing spondylitis (AS) is a chronic inflammatory disease, which is associated with human leukocyte antigen B27. It mostly occurs in young adults and is accompanied by heterotopic ossification of spine and systemic bone loss. Furthermore, abnormal bone metabolism occurs in the early stage of the disease. Studies[1,2] found that the prevalence of osteoporosis and osteopenia in AS was significantly higher than that in healthy people of the same age. Recently, biochemical bone turnover markers(BTM) were employed as an indication of osteoblast and osteoclast activities in bone remodeling. Gamez-Nava et al. reported that BTM levels were associated with the severity of spinal damage, and they should be included as tools to determine the prognosis and progression of spinal damage in AS patients. In AS patients, heterotopic ossification and osteoporosis coexist, and the mechanism is complex, which has not been clarified.
Uric acid (UA) is a final product of purine catabolism, and is soluble in blood under normal condition. Although hyperuricemia was reported to be associated with gout, renal disease and cardiovascular, it was found to have antiosteoporotic properties[5,6]. Many studies found that higher serum UA levels were associated with higher bone mineral density(BMD) and lower nonspinal fracture rate[7,8]. Chen et al. found that serum uric acid showed inverted “U” type correlation with osteoporosis in Chinese ankylosing spondylitis patients. It revealed that uric acid value between 300-600umol/L had the highest BMD. However, another report found lower levels of serum UA levels were associated with lower BMD in young male patients with AS. The mechanism of UA in the abnormal bone metabolism of AS patients was unknown. Serum UA is a common clinical laboratory data. Can serum UA provide a reference for the treatment of osteoporosis (or osteopenia) or follow-up in patients with AS? Therefore, our study was designed to analyze the association between the serum UA levels and BTMs, and to reveal the role of UA in the bone metabolism of AS.
In this study, we enrolled 62 AS patients who meet the modified New York criteria in 1984, and 50 matched healthy controls with the age between 18 and 45 years old. The All the subjects were male, and subjects with other bone metabolic diseases (endocrine diseases, metabolic diseases, abnormal renal function, digestive system diseases, etc.) or drug effects were excluded. Fasting venous blood was collected for uric acid and bone metabolism index detection. The laboratory measurements of UA, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were obtained in the same day. All the subjects were examined for BMD. BMD of lumbar spine (L1-4) and hip were detected by dual energy X-ray absorptiometry. According to the definition of the World Health Organization, osteoporosis is defined as T value less than − 2.5, osteopenia is defined as T value less than between − 1.0 and − 2.5, and normal bone density is defined as T value greater than − 1. These 62 AS patients were divided into normal BMD group and low BMD group. All 50 healthy controls had normal BMD.
The BTMs we tested were C-terminal crosslaps of type I collagen(β-CTX), osteocalcin (OC), procollagen type 1 N-terminal propeptide(P1NP) and parathyroid hormone (PTH). They were detected by electrochemiluminescence method according to the detection process of corresponding diagnostic kit (Roche Diagnostics GmbH, Germany). Firstly, the appropriate dose of samples, biotinylated anti-β-CTX (or anti-OC or anti-P1NP or anti-PTH) monoclonal antibody and ruthenium (RU)-labeled anti-β-CTX (or anti-OC or anti-P1NP or anti-PTH) monoclonal antibody were mixed to form a sandwich complex. Then, the particles coated with streptavidin were added. The complex was bound to the particles through the reaction between biotin and streptavidin. The reaction mixture was absorbed into the measuring cell, and the particles were adsorbed to the electrode through a magnet. After the voltage was applied to the electrode, chemiluminescence was generated and measured by a photomultiplier tube.
All the data were analyzed by SPSS 17.0. Quantitative parameters were expressed as means ± standard deviation (SD). Pearson’s correlation analysis was used for relationship between two groups of data with normally distributed. P-values less than 0.05 indicated statistical significance(P < 0.05).
The mean age was 33.16±6.06 years in healthy controls, and 31.50±7.35 years in AS patients. There was no significant difference in ages(P>0.05). The mean level of serum UA was 409.96±93.06 umol/L in healthy controls, and 348.89±68.95 umol/L in AS patients (Figure 1). The levels of UA were significantly higher in healthy controls than in AS patients(P=0.000).
In healthy controls, UA was significantly negative correlated with OC and β-CTX (Table 1, Figure 2, 3). However, in AS patients, UA had no significant relationship with BTMs(P>0.05). UA also had no significant relationship with ESR, CRP or T values of BMD(P>0.05). According to BMD, there were 29 with low BMD, and 33 with normal BMD in AS patients. 46.77% AS patients had low BMD. There was no significant difference in UA between normal BMD group and low BMD group(P>0.05). In low BMD group, UA was significantly positive correlated with β-CTX (Table 2, Figure 4). Other BTMs had no significant relationship with UA(P>0.05).
As is a chronic inflammatory disease, mainly involving sacroiliac joint and spine, but also involving peripheral joints. It is characterized by inflammation of tendon and ligament attachment points, and then, leads to bone destruction and heterotopic ossification. The prevalence rate of AS is about 0.25%, and the age of onset is 20-30years old. Epidemiological investigations found that the prevalence of osteoporosis and osteopenia of AS was more than 60%. The risk of vertebral fracture in AS patients caused by osteoporosis and osteopenia was significantly increased. Malochet-Guinamand et al. found that: about 6.2% of AS patients had at least one vertebral fracture. In the 2-year follow-up study, 6% of AS patients had new fractures during the follow-up period. As a result of abnormal bone metabolism in the early stage of AS, it is particularly important to identify the changes of bone metabolism early to prevent the occurrence of osteoporosis and fracture. In this study, all objects enrolled were man with the age between 18 and 45 years, in order to eliminate interference factors.
Bone remodeling was an equilibrium process, which involved bone resorption by osteoclasts and bone formation by osteoblasts. Vasikaran et al.found that BTMs could be used to rapidly indicate the condition of bone loss or formation. BTMs were generally subdivided into bone resorption markers, bone formation markers and osteoclast regulatory proteins. The representative marker of bone resorption was β-CTX. While bone formation markers were OC and P1NP. Studies were reported that BTMs were used to understand bone metabolism, predict fracture risk and bone healing. However, BTMs were not tested routinely, and they were expensive to evaluate or treatment monitoring in osteoporosis or osteopenia in AS patients. Therefore, UA was a convenient and economical laboratory index. UA was reported to closely related to bone metabolism, and played an important role in the pathogenesis of osteoporosis. Most reports found an increased serum UA level was associated with a lower risk of fracture. In our study, we found that the levels of UA were significantly higher in healthy controls than in AS patients. It showed that UA played an important role in osteoporosis of AS patients. Yan et al. reported that serum UA levels were significantly associated with osteoporosis, and serum UA levels were positively correlated with the BMD of the femoral neck, total hip, and L1-4 in females. Furthermore, UA was negatively correlated with OC and β-CTX in females. However, there was no relationship between UA and BTMs in males. We found that UA was significantly negative correlated with OC and β-CTX in healthy young males. Bone resorption and bone formation are the process of dynamic balance. It again confirmed that serum UA levels were closely associated with bone metabolism.
In low BMD group of AS patients, UA was significantly positive correlated with β-CTX which was the marker of bone resorption. The mechanism of bone metabolism is complex in AS. It is characterized by both abnormal bone formation and bone resorption. Therefore, UA played an important role in bone resorption of AS patients with low BMD. UA could reflect bone resorption in AS patients with low BMD, and could be used as a marker for the treatment of osteoporosis (or osteopenia) and following-up. Whether reducing UA can improve osteoporosis in AS with low BMD remains to be further studied.
In conclusion, UA was associated with bone metabolism, and it could reflect bone resorption in AS patients with low BMD. UA could be used as a marker for the treatment of AS with low BMD and following-up.
Ethics Approval and Consent to Participate
All methods were carried out in accordance with relevant guidelines and regulations of Zhejiang Provincial People’s Hospital. All experimental protocols were approved by the ethics committees of Zhejiang Provincial People’s Hospital. Informed consent was obtained from all the participants.
Consent for publication
Availability of Data and Materials
The datasets generated and analyzed during the current study are available in the upload supplementary file.
All authors have declared that no conflict of interest exists.
We thank the support of Zhejiang TCM Science and Technology Project(2020ZB023).
Yu-Qiong Zou and Juan-Juan Li discovered the phenomenon of relationship between bone mineral density and serum uric acid. Then we collected the data of the patients and analysis. Yu-Qiong Zou wrote the main manuscript text. All authors reviewed the manuscript.
We thank all the patients involved in the study.
1Center for General Practice Medicine, Department of Rheumatology and Immunology, Zhejiang Provincial People's Hospital（Affiliated People's Hospital, Hangzhou Medical College）, Hangzhou, Zhejiang, China 310014. 2Emergency and Critical Care Center, Intensive Care Unit, Wang-Jiang-Shan Branch of Zhejiang Provincial People's Hospital（Affiliated People's Hospital, Hangzhou Medical College）, Hangzhou, Zhejiang, China 310014.
Table 1 correlation between UA and BTMs in healthy controls
OC P1NP β-CTX PTH
UA r -0.314 -0.174 -0.264 0.075
P 0.026 0.113 0.032 0.606
Table 2 correlation between UA and BTMs in low BMD AS patients
OC P1NP β-CTX PTH
UA r 0.014 0.089 0.385 -0.342
P 0.941 0.644 0.039 0.069