Mineral Biomarkers: Total Calcium

Optimal Takeaways

Calcium is an essential mineral that supports bone health, nerve transmission, muscle function, vascular contraction and dilation, hormone secretion, and cell-to-cell signaling. Most calcium is stored in the bones, while a small percentage is found in the blood and tissues throughout the body. Blood levels are maintained in a fairly tight range. Increases in blood calcium are associated with hyperparathyroidism, hyperthyroidism, vitamin D overdose, and certain medications. Lower serum calcium is associated with hypoparathyroidism, kidney failure, vitamin D deficiency, and physical immobility. Low levels in the blood can be increased by breaking down bone and releasing calcium into circulation.

Standard Range: 8.6 –10.40 mg/dL (2.15 - 2.6 mmol/L)

The ODX Range: 8.9 – 9.5 mg/dL (2.23 – 2.38 mmol/L)  

Low serum calcium is associated with hypoparathyroidism, renal failure, hyperphosphatemia, vitamin D deficiency, rickets, alkalosis, fat embolism, blood transfusion, and hypoalbuminemia. Drugs that can decrease calcium include anticonvulsants, aspirin, calcitonin, corticosteroids, diuretics, heparin, laxatives, estrogen, oral contraceptives, and magnesium salts (Pagana 2021).

Hypocalcemia may also be associated with menopause (Bhattarai 2014), acute pancreatitis, sepsis, seizures, tetany, and low serum magnesium because of increased resistance to PTH (Goyal 2021).

High serum calcium is associated with osteoporosis due to bone breakdown (Baird 2011, Sadiq 2023), hyperparathyroidism, hyperthyroidism, cancer, prolonged immobilization, milk-alkali syndrome, vitamin D intoxication, Paget’s disease, granulomatous infection, acromegaly, and decreased serum pH. Drugs that can increase calcium levels include alkaline antacids, calcium salts, PTH, lithium, androgens, ergocalciferol, thyroid hormone, vitamin D, hydralazine, and thiazide diuretics (Pagana 2021).

Higher total serum calcium has been associated with hypertension (Sabanayagam 2020), CVD, stroke (Reid 2016, Slinin 2011), diabetes, insulin resistance (Hagstrom 2007), and increased brachial‐ankle pulse wave velocity and Framingham Risk Score (Park 2019).

Overview

Calcium is an essential mineral in the diet and the most abundant mineral in the body, with 99% of calcium found primarily in the bones and teeth. A relatively small amount of calcium participates in critical functions, including nerve transmission, muscle function, vascular contraction, vasodilation, hormonal secretion, and intracellular signaling. Surprisingly, calcium intake has little relative effect on serum calcium as the body employs multiple mechanisms for maintaining a relatively tight and consistent level in blood and intercellular fluids. If dietary intake is too low, bone can be broken down and calcium released to restore serum levels to normal (Raymond 2021). The loss of calcium from bone during this repletion is associated with osteoporosis (Shahida 2021).

Calcitonin also plays a role in maintaining serum calcium levels and can reduce serum calcium by inhibiting the activity of osteoclasts that break down bone tissue (Goyal 2021). Calcium is also essential to the coagulation pathway and may contribute to kidney stones, atheromatous plaque, and soft tissue calcification (Reid 2016).

Total serum calcium represents both the bound and free/ionized form. Approximately 45% of circulating calcium is bound to protein, primarily albumin, 15% to anions such as citrate and phosphate, and 40% circulates freely in its ionized state. The strength of the bond between calcium and albumin is affected by pH and acid-base disturbances. An acidic environment or metabolic acidosis will decrease the bond and increase circulating ionized calcium, while an alkaline environment or alkalosis will strengthen the bond, reducing ionized calcium in circulation. A decrease in albumin can make the value of total calcium appear lower than it is and should be corrected for by adding 0.8 mg/dL (0.20 mmol/L) to the calcium value for every 1 g/dL decrease in albumin below 4 g/dL (Goyal 2021).

Calcium levels can be increased by several mechanisms, including increasing parathyroid hormone. Elevated PTH increases GI absorption of calcium with a subsequent increase in serum calcium. Parathyroid hormone also increases bone resorption/breakdown and decreases urinary excretion of calcium, increasing serum calcium. Vitamin D can also increase GI calcium absorption, potentially increasing serum calcium (Pagana 2021).

True hypercalcemia, most often caused by hyperparathyroidism, may be characterized by bone pain, constipation, depression, excess thirst and urination, fatigue, and kidney stones. Decreased calcium may be characterized by nerve hyperexcitability, muscle cramps, numbness, and tingling (Khan 2021).

Higher total serum calcium has been associated with higher blood pressure, despite higher dietary calcium intake being associated with lower blood pressure. A review of NHANES data found that the highest quartile of total calcium, e.g., above 9.48 mg/dL (2.37 mmol/L), was associated with the most elevated blood pressure of 122.7/75.1 compared to a calcium of 9 mg/dL (2.25 mmol/L) and below associated with the lowest blood pressure of 120.98/73.2. The group with the highest blood pressure tended to be younger, had higher HDL, phosphorus, albumin, and vitamin D, and lower BMI and CRP, which are primarily favorable characteristics. Since the study did not further categorize the higher serum calcium group, blood pressure was close to normal for all groups, and ionized calcium was not significantly related to blood pressure, further evaluation of the relationship between serum calcium and blood pressure is needed (Sabanayagam 2020).  

Calcium supplementation has been associated with an increased risk of MI and may be associated with stroke as well, prompting more research into serum calcium and CVD. One systematic review of the literature found an increased risk of CVD and MI and, in one study, an increase in mortality when calcium rose above 9.48 mg/dL (2.37 mmol/L). Researchers note that elevated blood pressure, weight, lipids, and glucose may contribute to this association (Reid 2016).

Significantly higher calcium was also seen in patients with severe aortic stenosis at a mean level of 9.52 mg/dL (2.38 mmol/L) versus 9.0 (2.25 mmol/L) in the control group (Alsancak 2019). Increasing serum calcium within the conventional range was associated with increasing brachial‐ankle pulse wave velocity, a measure of arterial stiffness, and Framingham Risk Score, a reflection of 10-year cardiovascular risk (Park 2019).

A double-blind placebo-controlled study of 7,259 post-menopausal women with osteoporosis randomly assigned to treatment with raloxifene at two different doses or placebo found that higher baseline calcium of 9.2 mg/dL (2.3 mmol/L) or above was associated with increased risk of adverse cardiovascular outcomes but was also associated with greater use of medications (lipid-lowering drugs, ACE inhibitors, diuretics, beta and calcium channel blockers, aspirin), higher blood pressure, and higher cholesterol and triglycerides, hemoglobin, creatinine, 25(OH) vitamin D, albumin, and phosphorus. Cardiovascular risk increased by 17% for each standard deviation increase in serum calcium. All subjects, including the placebo group, were supplemented with 500 mg of calcium and 400-600 IU/day of vitamin D (Slinin 2011).

Individuals with diabetes tend to have higher serum total calcium than those without, and diabetes is more prevalent in individuals with hyperparathyroidism, suggesting an association between insulin sensitivity and calcium status. In this study, those with lower total serum calcium had a higher dietary calcium intake of 975 versus 943 mg/day, highlighting the complexity of calcium homeostasis (Hagstrom 2007). The relationship between low dietary intake, increased bone breakdown, and serum calcium should be further evaluated.

Low serum calcium can be associated with vitamin D insufficiency and related complications. In a retrospective study of patients hospitalized with COVID-19. A low serum total calcium was associated with lower vitamin D, higher PTH, and worse clinical parameters, including septic shock, increased multiple organ failure, and increased 28-day mortality, especially with a serum calcium of 8.00 mg/dL (2 mmol/L) or below (Sun 2020).

Lead can interfere with calcium metabolism as it competes for binding and transport sites, interferes with GI absorption and kidney reabsorption, displaces calcium in bone, and negatively affects parathyroid hormone and vitamin D activation (Shahida 2021).

References

ALSANCAK, YAKUP, et al. "Can the Ratio of Calcium to Albumin Predict the Severity of Aortic Stenosis?." European Journal of Therapeutics 25.1 (2019): 44-50.

Baird, Geoffrey S. “Ionized calcium.” Clinica chimica acta; international journal of clinical chemistry vol. 412,9-10 (2011): 696-701. doi:10.1016/j.cca.2011.01.004

Bhattarai, Tirtha et al. “Correlation of common biochemical markers for bone turnover, serum calcium, and alkaline phosphatase in post-menopausal women.” The Malaysian journal of medical sciences : MJMS vol. 21,1 (2014): 58-61.

Goyal, Abhinav, et al. “Hypocalcemia.” StatPearls, StatPearls Publishing, 8 August 2021.

Hagstrom, E et al. “Serum calcium is independently associated with insulin sensitivity measured with euglycaemic-hyperinsulinaemic clamp in a community-based cohort.” Diabetologia vol. 50,2 (2007): 317-24. doi:10.1007/s00125-006-0532-9

Khan, Maqsood, et al. “Physiology, Parathyroid Hormone.” StatPearls, StatPearls Publishing, 27 September 2021.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Park, Byoungjin, and Yong-Jae Lee. “Borderline high serum calcium levels are associated with arterial stiffness and 10-year cardiovascular disease risk determined by Framingham risk score.” Journal of clinical hypertension (Greenwich, Conn.) vol. 21,5 (2019): 668-673. doi:10.1111/jch.13532

Raymond, Janice L., et al. Krause and Mahan's Food & the Nutrition Care Process. Elsevier, 2021.

Reid, I R et al. “Circulating calcium concentrations, vascular disease and mortality: a systematic review.” Journal of internal medicine vol. 279,6 (2016): 524-40. doi:10.1111/joim.12464

Sabanayagam, Charumathi, and Anoop Shankar. “Serum calcium levels and hypertension among U.S. adults.” Journal of clinical hypertension (Greenwich, Conn.) vol. 13,10 (2011): 716-21. doi:10.1111/j.1751-7176.2011.00503.x

Sadiq, Nazia M., et al. “Hypercalcemia.” StatPearls, StatPearls Publishing, 4 September 2023.

Shahida, Shabnam et al. “Determination of Blood Calcium and Lead Concentrations in Osteoporotic and Osteopenic Patients in Pakistan.” ACS omega vol. 6,42 28373-28378. 12 Oct. 2021, doi:10.1021/acsomega.1c04565

Slinin, Yelena et al. “Serum calcium, phosphorus and cardiovascular events in post-menopausal women.” International journal of cardiology vol. 149,3 (2011): 335-40. doi:10.1016/j.ijcard.2010.02.013

Sun, Jia-Kui et al. “Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019.” Aging vol. 12,12 (2020): 11287-11295. doi:10.18632/aging.103526