In this large cross-sectional study, we found that dietary calcium intake related to the increment of the risk of hyperuricemia even after adjusting for age, gender, nationality, residence, marriage status, educational level, activity level, smoking status, drinking status, tea status, sleep duration, BMI, triglyceride, total cholesterol, high-density lipoprotein cholesterol, hypertension, diabetes, chronic kidney disease, cardiovascular disease, daily energy, protein, fat, cholesterol, diet fiber intake. Therefore, calcium is an independent risk factor for hyperuricemia. Due to different age, gender, BMI status, whether with hypertension, diabetes or chronic kidney disease, the prevalence of hyperuricemia is very different. Therefore, we conducted a stratified analysis of the above factors, and found similar results in most stratified factors. In addition, sensitivity analysis support above results. All these results indicated that an increased risk of hyperuricemia with increased dietary calcium intake
To the best of our knowledge, this is the first study independently revealing the relationship between dietary calcium intake and hyperuricemia. A multicenter, randomized, double-blind, placebo-controlled study found that the group who received calcium + vitamin D had significantly elevated concentrations of serum uric acid compared with those who received placebo (52.3% vs 37.2%; P = 0.046) which is similar to our study (24). Another study based on the Chinese population seemed also support our research and this study concluded that the concentration of serum calcium was positively with hyperuricemia in both man and women (23). The failure of the current study to find significant result in women may be due to the fact that the previous study was conducted participants aged > 65 years and 40 years old or above respectively, while participant was ≥ 18 years old in our study. Besides, the adjusted OR of hyperuricemia increased with rising serum calcium concentrations in Irish (15). This relationship was also found in kidney transplant recipients with intact graft function and Coates V and Raiment PC had found elevated blood calcium concentrations in gout patients as early as 1924 (33, 34). However, to our knowledge, no study has independently assessed the relationship between hyperuricemia and dietary calcium intake. Additional studies may be required to assess the relationships of hyperuricemia and dietary calcium intake.
However, a study from Korean found that hyperuricemia subjects had significantly a lower intake of calcium (268.7mg vs 300.3mg, p < 0.001) (26). This study adjusted age, gender and BMI merely, whereas, our study adjusted for living habits and dietary nutrient intake besides age, gender, BMI. Lina Zgaga et al. found a significant weak association between calcium intake and urate among 2,037 healthy individuals from the UK (27). Several factors may account for the difference. Firstly, dietary calcium in westerners were mainly derived from dairy products which might be helpful in protection against hyperuricemia (35). Whereas, dietary calcium consumed by the Chinese mainly sourced from soy food, sea food and meat. Secondly, the amount of dietary calcium intake and requirement varies from region to region, which may cause differences in results. The average dietary calcium intake (412.63 mg/day, 437.07 mg/day for men and 391.05 mg/day for women) in our study was much lower than that of westerners. Although calcium intake of Chinese is low, calcium concentration in the body has reached a state of equilibrium and some scholars believe that the demand for calcium of Chinese people may only be half of Western countries (36). Finally, clinical treatment of alkalization of urine is commonly used to promote uric acid excretion and calcium supplements such as calcium carbonate and calcium citrate are also weakly alkaline. We hypothesized that calcium supplements may promote uric acid excretion. Nevertheless, the proportion of Chinese individuals using dietary supplements was quite low compared to the use of calcium supplements in the Western population (37, 38).
The biological mechanism underlying the association between dietary calcium intake and the prevalence of hyperuricemia was not completely understood, but may be related to the inflammatory mechanism. It has been suggested that high levels of serum uric acid may contribute to inflammatory arthritis (39). Some important inflammatory cytokines, such as IL-6, TNF-A and high-sensitivity C-reactive protein, are positively correlated with serum uric acid (40, 41). serum calcium concentration is also positively correlated with inflammation, and hypercalcemia has been recognized to be associated with many inflammatory diseases (42, 43). Thus, the relationship between calcium and hyperuricemia may be mediated by inflammatory mechanisms. In addition, our previous studies have shown that dietary zinc intake is inversely associated with hyperuricemia (21). Whereas, R J Wood and J J Zheng suggested that consumption of a high calcium diet can significantly reduce net zinc absorption and zinc balance and increase the risk of developing negative zinc balance (44). This may be another reason for the relationship between calcium and hyperuricemia.
In addition, a large number of studies have proved that hyperuricemia is an independent risk factor for metabolic diseases, cardiovascular disease and some scholars call hyperuricemia the second largest metabolic disease after diabetes. Calcium may mediate the relationship between uric acid and metabolic syndrome. M K Kim et al showed that excessive dietary calcium may increase the prevalence of metabolic syndrome in men, but for postmenopausal women, calcium intake does not increase the risk of metabolic syndrome (45). A meta-analysis concluded that calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction (46).
The main strengths of our study are as follows. firstly, to our knowledge, this is the first study to independently assess the relationship between dietary calcium and hyperuricemia. In addition, our study adjusted for a wide range of potential confounding variables. Several limitations also need to be acknowledged. First, the 24-h dietary recall method was utilized to obtain dietary intake and may not reflect long-term calcium intake status. To compensate for this, sensitivity analysis was performed using cumulative mean calcium intake, the conclusions were not altered. Second, there is a lack of information on calcium supplementation in this survey, although the proportion of Chinese individuals using dietary supplements was quite low. Third, we considered the effects of hormone therapy (postmenopausal women) on hyperuricemia. Although in the CHNS survey, the questionnaire did not provide information about hormone therapy in postmenopausal women. Analyses were repeated performed among women under the age of 50 and women 50 or older respectively (Table S1 in supplementary material). Fourth, the potential confounders were adjusted to the extent possible, the residual confounding could not be completely ruled out. Five, our study was restricted to persons of Chinese whose average dietary calcium only about 400 mg/d, and it is unknown whether our results can be generalized to other ethnic groups. Finally, due to the limitations of cross-sectional studies, the causal relationship between dietary calcium and hyperuricemia cannot be determined, and even causal inversion may occur. Therefore, further prospective studies are necessary.