Osteoarthritis (OA) is a degenerative disease of the joints which is characterized by degradation of articular cartilage, synovitis, and changes to subchondral bone which exhibits altered remodeling.1 It is a major public concern as it is one of the leading causes of morbidity and disability, thereby laying a huge medical and economic burden on health resources.2 Despite these concerns, the pathogenesis of OA remains unclear. A combination of local joint-specific factors acting in the context of systemic susceptibility may contribute to the development of OA. There seem to be many factors contributing to the occurrence and extent of the OA process including obesity, joint injury, metabolic diseases, bone and joint malformations, and genetic factors.3

It is hypothesized that nutritional imbalance is also involved in the pathogenesis of OA. The importance of nutrition in the maintenance of joint health is now widely recognized.4 In recent studies, our investigative group found that serum magnesium (Mg) concentration may have an inverse relationship with radiographic OA of the knee.5 Calcium, which belongs to the same family in the periodic table as Mg, shares the same homeostatic regulating system that involves calcium sensing receptor and (re)absorption with calcium.6,7Meanwhile, Mg and calcium antagonize each other in many physiological activities.7–10 So the relationship of the prevalence of radiographic knee OA with serum calcium concentration is also worth studying. Calcium is an essential nutrient which plays a key role in regulating a great diversity of physiology processes, including muscle contraction, neurotransmitter release, endocrine and exocrine secretion, and blood clotting.11,12 In healthy individuals, serum levels of calcium are regulated by homeostatic mechanisms involving the calcium-sensing receptor, 1,25-dihydroxyvitamin D, and parathyroid hormone. Disorders of calcium homeostasis are related to an increased risk disease, such as cardiovascular disease, metabolic syndrome, and prostate cancer.13–18 There have been studies reporting associations between serum calcium and OA. However, no association was found between OA and serum calcium concentration in these studies.19–21 It is notable that these studies have been performed on Western population, the lifestyle and eating habits of which are different from Asian people. Differences may exist among populations from the different regions. For example, a multicenter hospital-based case-control study conducted in Asian revealed an inverse association between serum concentrations of calcium and the risk of prostate cancer,18 while no association was found in Western populations.22,23

Hence, thorough investigation of serum calcium concentration in Asian countries such as China can potentially reveal further insight concerning probable association between OA and serum calcium in a different geographic setting. We, therefore, designed a cross-sectional study aimed to further evaluate the association of the prevalence of radiographic knee OA with serum calcium concentration.

The characteristics of the study population (2855 subjects) based on quartiles of serum calcium concentration are shown in Table ​Table1.1. There were 1623 men and 1232 women, and the prevalence of radiographic OA of the knee in the present cross-sectional study (age ≥40 years, with an average age of 52.26 ± 7.16 years) was 30.0%. Serum calcium concentration of 570 subjects (20.0% of the study population) were below 2.25 mmol/L. Significant differences were observed across all quartiles of serum calcium concentration in terms of female ratio, alcohol drinking ratio, the ratio of diabetes, and the ratio of hypertension. There was no significant difference in terms of age (P = 0.12), sex (P = 0.14), or BMI (P = 0.96) between those included in the main analysis and those excluded as a result of missing health-related behavior data (n = 2023).

A negative association between serum calcium concentration and radiographic OA of the knee was observed in a model after adjustment for age, sex, and BMI, and also in a multivariable model adjusted for age, BMI, sex, educational level, smoking status, activity level, alcohol drinking status, diabetes, and hypertension (Table ​(Table2).2). The relative odds of radiographic OA of the knee were decreased by 0.79 times (OR = 0.79, 95% CI: 0.62–1.00) in the fourth quartile of serum calcium concentration compared with those in the lowest quartile after adjusted by age, sex, and BMI. A trend approached to be statistically significant (P = 0.07). The multivariable-adjusted ORs (95% CI) for radiographic OA of the knee from the first to the fourth serum calcium concentration quartiles were 1 (reference), 1.05 (95% CI: 0.83–1.31), 1.01 (95% CI: 0.80–1.27), and 0.79 (95% CI: 0.62–1.00) respectively, and a trend was also approached to be statistically significant (P = 0.06). The relative odds of radiographic OA of the knee were decreased by 0.79 times in the fourth quartile of serum calcium concentration compared with the lowest quartile. Subgroup analysis was also conducted to evaluate the association between serum calcium and radiographic OA in male and female population, respectively. The results suggested that the negative association still existed in the female population (multivariable adjusted OR = 0.66, 95% CI: 0.46–0.97 in the fourth quartile compared with the reference), but not in the male population.

In this population-based cross-sectional study, an inverse relationship between serum calcium and prevalence of radiographic OA of the knee was shown independent of some major confounding factors.

Yazmalar et al19 found that serum calcium levels were not significantly different between 74 knee osteoarthritis patients and 70 controls. The authors state that there were statistically significant differences between groups in terms of age, sex, and BMI (P < 0.05). However, these potential confounding factors were not adjusted, which may compromise the accuracy of the research results. In a case-control study conducted by Zoli et al,20 no statistically significant difference in calcium serum levels was found among hand osteoarthritis patients and healthy controls. Site difference may explain the different results observed. Hunter et al21 also failed to report an association between serum calcium and radiological features of knee OA in the cotwins with OA from 229 female white twin pairs aged from 24 to 79 years. Different from our study that measured serum calcium in patients with different K–L grades, this study compared serum calcium with radiological evidence of knee osteophytes with those without osteophytes, which may lead to the different results. What is more, the inconsistency between our study with previous study could also be due to difference of geographic setting. Moreover, previous studies are limited by a relatively small sample size.

The inverse relationship between serum calcium concentration and radiographic OA of the knee is biologically plausiable. In vitro studies have investigated the pathophysiological mechanism of calcium on chondrocyte. For chondrocytes, calcium is involved in matrix synthesis, cytoskeletal remodeling, cell hyperpolarization, and cell death. Intracellular calcium release has been implicated for aggrecan gene upregulation in response to static compression in cartilage explants.27 Cell experiment also has shown a requirement for calcium to complete post-translational modifications of glycosylation and export of secretory proteins.28,29 Amin’s study suggested that extracellular calcium may be important for maintaining calcium homeostasis and cell viability over time.30 Even though there is no direct evidence found that calcium plays a role in the pathogenesis of OA, these studies support that calcium is involved in physiological and pathological processes of chondrocyte. Chondrocytes functions may be impaired under conditions of calcium insufficiency. Certainly, studies are still required to clearly understand the mechanisms of efficacy and action of calcium. In addition, significant differences were observed across all quartiles of serum calcium concentration in terms of female ratio, alcohol drinking ratio, the ratio of diabetes, and the ratio of hypertension. These findings were in accordance with some previous studies that indicated that serum calcium levels are associated with alcohol drinking,31,32 sex difference,33,34 diabetes,35,36 and hypertension,37,38 and need future studies to elaborate further.

It is well known that Mg and calcium antagonize each other in various physiological activities. And they may directly or indirectly compete for intestinal absorption. A high calcium intake consistently leads to significantly increased excretion of Mg via urine.6,39,40 It should be mentioned that serum Mg concentration may also have an inverse relationship with knee OA which was indicated by our previous study.5 However, to our best knowledge, there was no study reported that serum calcium level is negatively associated with serum Mg level. Thus, our findings may not contradict previous researches. In addition, the association between dietary Mg intake and serum Mg level may be influenced by some factors, such as renal function and diabetes.41,42 So maybe lower serum Mg level does not necessarily lead to increased calcium reabsorption. Furthermore, Nielsen et al reported that Mg deficiency-induced calcium retention most likely did not increase the amount of calcium as bone mineral and did not increase extracellular calcium, but instead increased soft tissue calcium concentrations.43 So Mg deficiency does not necessarily lead to increased serum calcium level. Overall, serum calcium and Mg levels are influenced by a lot of factors and the findings of our studies are worth exploring by further studies.

Our present study has several strengths. To the best of our knowledge, this is the first study that examined the association between serum calcium concentration and radiographic OA of the knee in a large sample in Asia. Second, the multivariable model was adjusted for a considerable number of potentially confounding factors, which greatly improves the reliability of the results.

Several limitations of this study must be taken into account when interpreting the results. First, because it was an observational study, a definitive causal relation could not be drawn. We anticipate that future prospective studies and intervention trials will help to clarify a causal association between serum calcium concentration and knee OA. Second, the serum level of parathyroid hormone (PTH) and vitamin D was not measured. Both PTH and vitamin D play a crucial role in calcium metabolism, so it is impossible to absolutely exclude confounding factors such as primary hyperparathyroidism and secondary hyperparathyroidism due to vitamin D deficiency. Third, there was no repeat calcium measurement during follow-up. A single measurement of plasma calcium levels could merely reflect a snapshot at a particular time, and long-term calcium status is not certain. We cannot comment on serum concentration before OA developed either. Fourth, we did not examine the association between serum calcium level and knee OA among participants younger than 40 years. However, middle-aged and older adults are considered at high risk of knee OA, and the prevalence of knee OA among participants younger than 40 years may be relatively low. Last, other factors (including pain and functional level) potentially related to serum calcium were not available for all the participants. Thus, we are unable to take these factors into account.

In conclusion, the present study found that serum calcium concentration has an inverse relationship with radiographic OA of the knee. High level of calcium may possibly exert a protective role in the control of radiographic knee OA.

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