Reported calcium levels can be influenced by many factors, such as patient's age, comorbidities, lifestyle, gender, medical therapies, and conditions during specimen retrieval. For example, if the sample was poor quality due to it being lipemic or hemolyzed, then calcium levels can be inaccurate.[16] Exercise immediately prior to specimen retrieval has also been shown to increase calcium levels.

Certain medications may precipitate inaccurate measurements of calcium levels. Perchlorate has been reported to cause discrepancies in ionized calcium measurements, leading to false diagnoses of hypo- or hypercalcemia.[17] Medications known to increase serum calcium levels are thiazide diuretics, lithium, antacids, and vitamin D supplements. 

Urine calcium excretion is highly related to sodium excretion, as such dietary sodium can influence reported levels. Diets high in sodium yield higher calcium excretion, and similarly low sodium diets equal lower calcium excretion.[18] Among children, the provider should keep in mind that children have increased calcium to creatinine ratio, and might be falsely determined to be hypercalciuric if following adult guidelines.

Albumin is a carrier protein for calcium and can result in an inaccurately reported serum calcium level. It is important to evaluate albumin levels to correct for total calcium and differentiate true versus factitious calcium dysregulation. The equation is as follows:

Albumin Correction:

True Calcium (mg/dL) = reported total calcium (mg/dL) + 0.8 (4.0 – serum albumin (g/dL))

If the corrected serum total calcium levels are between the normal levels of 8.8 mg/dL to 10.4 mg/dL, then the laboratory reported calcium is fictitious and due to impaired serum albumin levels.[19]

Hypercalcemia

Hypercalcemia is defined as calcium levels elevated above 10.4 mg/dL or ionized serum calcium above 5.2 mg/dL.[19] Patients with hypercalcemia may experience an array of symptoms, some of which include increased calcium stones, bone fragility/fractures, abdominal pain, constipation, thirst, frequent urination, and altered mentation in severe cases. Clinical findings may show tongue fasciculations, bradycardia, or hyperreflexia.[20] The first step after identifying hypercalcemia is to confirm by albumin correction. After confirming hypercalcemia, the next step is to measure the PTH level. If PTH is elevated, then the patient’s hypercalcemia is PTH-dependent and can be caused by primary hyperparathyroidism, familial hypocalciuric hypercalcemia, or medication side-effect. If PTH is suppressed, it is PTH-independent with a much broader differential, and lab values for parathyroid related protein (PTHrP), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels should be evaluated. The differential diagnosis for PTH-independent hypercalcemia includes immobilization, malignancy, medication-induced, thyrotoxicosis, and vitamin D toxicity.[21]

Patients who are asymptomatic with albumin-corrected calcium levels less than 12 mg/dL are advised to avoid precipitating factors such as dehydration, inactivity, calcium diet greater than 1000 mg/day, and certain medications (lithium carbonate, thiazides). Patients with albumin-corrected calcium levels greater than 12 mg/dL may present with mild, moderate, or severe symptoms. Patients with chronic and mild symptoms of hypercalcemia may not require immediate treatment. However, patients with albumin-corrected calcium greater than 14 mg/dL require more urgent attention. 

Treatment with normal saline is the most beneficial early management of these patients.[22] The addition of calcitonin should result in a significant reduction of serum calcium within 48 hours. Furthermore, the administration of bisphosphonates will provide a more sustained effect that will reduce calcium levels in two to four days. Patients with renal failure or refractory to treatment with bisphosphonates can be managed with Denosumab.[23]. Denosumab suppresses bone remodeling and may cause hypocalcemia; therefore, patients should be monitored for serum calcium and serum 25-hydroxyvitamin D. As a last resort to the treatment of severe hypercalcemia, hemodialysis is indicated for patients with malignancy-associated hypercalcemia and renal insufficiency.[24] Careful monitoring is required to avoid fluid overload, especially among patients with a compromised cardiac reserve and renal insufficiency. 

Hypocalcemia

Hypocalcemia is defined as total serum calcium levels below 8.8 mg/dL or ionized serum calcium below 4.7 mg/dL.[25] Due to multiple causal factors, patients with hypocalcemia must be carefully assessed based on laboratory values, clinical presentation, symptoms, medications, and comorbidities.[26]. The first step to diagnose hypocalcemia is to confirm by albumin correction. One of the first signs of hypocalcemia is neuromuscular irritability, which presents with symptoms such as tingling and numbness around the mouth and at the fingertips, paresthesia of the extremities, and painful muscle cramps. The physical exam could likely demonstrate contraction of facial muscles ipsilaterally by tapping on the skin overlying the facial nerve (Chvostek sign) and painful carpal spasms with wrist flexion and interphalangeal joint extension while the blood pressure cuff is set 20 mmHg above the patient’s systolic pressure (Trousseau’s signs).[26] Acute versus chronic hypocalcemia can present differently. Acute hypocalcemia is more likely to present with cardiac dysfunctions such as QT-prolongation and T-wave abnormalities. Chronic hypocalcemia can present with skin manifestations, such as dry skin, coarse hair, and brittle nails and neurologic problems such as calcification of brain parenchyma.[26]

Hypocalcemia can occur due to diseases, treatments, medications, and electrolyte abnormalities. Metabolic alkalosis can cause decreased serum ionized calcium due to calcium-binding albumin more readily during alkalotic states. Chronic diseases of note are hypoparathyroidism, chronic kidney disease, liver disease, and vitamin D deficiency. Acute illnesses such as sepsis, pancreatitis (due to fat saponification), and acute kidney injury can also result in hypocalcemia. Severe hypomagnesemia can secondarily cause hypocalcemia, as is sometimes seen in proton-pump inhibitor (PPI) therapy.[27] PPI therapy also decreases stomach acidity, decreasing calcium absorption via the intestinal tract. A case report in 2017 discussed two children on dialysis for chronic kidney disease (CKD), who experienced acute hypocalcemia and alkalotic episodes a week after starting sodium polystyrene sulfonate (SPS) for treatment of hyperkalemia.[28] Other medications of note that can result in hypocalcemia are long-term use of corticosteroids, antiepileptics, aminoglycosides, cisplatin, and bisphosphonates.[25][27] Acute hypocalcemia is common among patients receiving large transfusions, such as during treatment of traumatic hemorrhage, due to citrate and chelation products. As calcium is vital for proper coagulation, trauma patients receiving blood transfusions should be monitored closely to avoid severe hypocalcemic events.[29]

Treatment for hypocalcemia depends on the severity of the symptoms. Patients experiencing mild symptoms should be treated with calcitriol 0.5 mcg oral twice daily and calcium in the combined form of calcium carbonate taken with the dose of 500 mg orally four times daily to achieve optimal absorption. There are several options in which calcium can be administered. Calcium carbonate can be taken orally via pill, or it can be crushed and mixed with liquid. The absorption of calcium carbonate is dependent on stomach acidity. For better absorption, it may be taken with food or substituted with calcium citrate to stimulate an acidic environment.[30] If serum calcium levels are persistently low, possible hypomagnesemia must be evaluated and corrected to normalize serum calcium levels.[26]

On the other hand, calcium gluconate is available in liquid form. In severely symptomatic patients with hypocalcemia, it is essential to maintain a calcium level above 8 mg/dL (2 mmol/L). Hence calcium gluconate can be administered by continuous intravenous drip infused over 10-20 minutes to avoid cardiac complications such as arrhythmias.[26][31] Serum calcium should be evaluated every 3-6 months, and 24-hour urine calcium should be evaluated annually. If the patient has comorbid hyperphosphatemia, phosphate binders should be provided to avoid calcium phosphate precipitation and soft-tissue calcification.[26]

Hypocalciuria

Hypocalciuria can occur due to medications, diseases, and genetic disorders. Common medications that result in reduced urine calcium are thiazides and estrogen. Genetic diseases such as familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disease that decreases the sensitivity of calcium-sensing receptors (CaSRs) of the parathyroid gland, maintains serum calcium levels at an elevated baseline with resulting hypocalciuria.[32] Another possible genetic cause is Gitelman syndrome, a salt-wasting tubulopathy that presents with spasms, muscle weakness, and salt cravings with multiple electrolyte derangements, including hypocalciuria.[33] Differential diagnosis also includes hypoparathyroidism, pseudohypoparathyroidism, intestinal malabsorption, rickets, and hypothyroidism are other diseases implicated in hypocalciuria.[34]

Hypercalciuria

Hypercalciuria can occur as an effect of medications, diseases, and genetic disorders. Common medications involved are spironolactone, corticosteroids, and acetazolamide. Supplements containing extra calcium should also be considered. Differential diagnosis includes hyperparathyroidism, malignancy, multiple myeloma, sarcoidosis, Paget disease, increased intestinal absorption, and osteoporosis.

Calcium dysregulation can be a sign of many diseases, just as much as dysregulation can cause many adverse effects. This section will highlight various areas throughout the body in which calcium is related to pathologies.

Bone Health and Osteoporosis

Osteoporosis is a disorder that influences bone composition, affecting both density and mineralization. The consequences can be dire as gradual bone loss can result in bone fragility, and ultimately in bone fracture. There are an estimated 1.5 million fractures each year due to osteoporosis, as this disorder affects more than 10 million U.S. adults, the vast majority of whom are women.[35] However, men affected with osteoporosis are often unidentified and undertreated, with higher mortality rates due to hip fractures.[35] Consumption of both dietary calcium and vitamin D from childhood to early adulthood helps patients reach peak bone mass and delay severe bone loss during aging. For osteoporosis prevention, The American College of Obstetricians and Gynecologists have released recommendations for calcium and vitamin D supplementation for women starting as early as nine-years-old, with dosage varying according to age.[36] Furthermore, calcium supplements reduce the risk of fractures and fall in adults age 65 and higher.[37] The United States Food and Drug Administration (FDA) association has approved a health claim suggesting that sufficient calcium and vitamin D intake, with consistent physical activity, might reduce the risk of osteoporosis later in life.[38] However, in contrast to this view, in 2018, the U.S. Preventive Services Task Force (USPSTF) maintains there is insufficient evidence to suggest that supplementation with calcium and vitamin D has greater benefits than potential harm. Thus, the 2018 USPSTF guidelines recommend against supplementation vitamin D and calcium for the prevention of fractures among "community-dwelling, asymptomatic adults." This recommendation does not apply to symptomatic patients with a history of osteoporosis or vitamin-D deficiency.

Gastrointestinal Malignancy

Calcium binds to bile acids and fatty acids to form insoluble complexes that protect the cell lining of the gastrointestinal tract from acids and their metabolites. Also, calcium is involved in improving signaling within the cells, which may reduce cell proliferation by promoting cells to undergo differentiation and or apoptosis.[39] Although studies are inconsistent, conclusions from data collections suggest that calcium may play a role in the prevention of colorectal cancer. The association with daily calcium intake and prevention of colorectal cancer showed an inverse association most strongly among older women and the distal colon.[40] However, more trials are needed to conclude different studies on this topic further. Currently, there is no FDA indication for calcium and cancer of the colon and rectum as further studies are under current investigation.

Hypoparathyroidism

Low levels of PTH occurs due to autoimmune or surgical destruction, abnormal congenital development, impaired PTH regulation, or muted PTH effect. The systemic effect is hypocalcemia, which can range from mild to severe symptoms.

Surgical destruction most often occurs during thyroid, parathyroid, or neck surgery. For example, it is the most common complication following a thyroidectomy, in which patients experience acute symptoms of seizures, laryngospasm, prolonged QT, or tetany.[41] Postsurgical symptoms can be transient, due to glandular stress or partial parathyroid excision, or permanent due to accidental excision.[42][43] Thus, patients should start taking supplements of calcium and vitamin D after thyroid surgery and then taper slowly three to six weeks to avoid symptoms of hypocalcemia.[41]

Autoimmune destruction is another acquired cause and typically begins during childhood or adolescence. The destruction that happens in permanent hypoparathyroidism is a part of autoimmune polyglandular syndrome type 1(APS 1) due to mutations of the autoimmune regulator (AIRE) gene.[44] Further, activating CaSR antibodies can develop, causing factitious negative feedback and decreased PTH secretion.[45]

Abnormal parathyroid development in utero can be a cause of hypoparathyroidism identified in infants and children. An example of this is DiGeorge Syndrome that happens due to a 22q11 deletion resulting in defective development of the pharyngeal pouch and its derivatives. The effects are cardiac anomalies, hypocalcemia, hypoplastic thymus, and immunodeficiency.[46]

Peripartum Effects

Professional organizations such as the American College of Obstetrics and Gynecology (ACOG) recommend 1,500 mg to 2,000 mg calcium to prevent the risk of preeclampsia in pregnant women with a baseline calcium intake of 600 mg or less. Similarly, the World Health Organization (WHO) also recommends the same dosage of 1,500 mg to 2,000 mg for pregnant women with low dietary calcium intake and high risk of gestational hypertension.[47] In a 2020 study, mouse models revealed that placental efficiency was improved among mice receiving adequate amounts of vitamin D, and further showed that deficiencies resulted in altered placental morphogenesis and microstructure.[48] Calcitonin has also been shown to increase during pregnancy as well as among lactating mothers and is thought to be a protective measure to suppress maternal bone loss.[6]

Neonatal hypocalcemia can occur within the first few days of life. Prematurity is the most common factor predisposing a neonate to the development of neonatal hypocalcemia. Other conditions that increase the risk include maternal diabetes, maternal hyperparathyroidism, and being small for gestational age. Early-onset neonatal hypocalcemia is often asymptomatic and occurs within the first few days of life. Neonates at high risk for hypocalcemia should be monitored for the first 72-hours for possible hypocalcemia.[49] Late-onset, which occurs after 72-hours, is generally symptomatic, and the neonate may show tachycardia, tachypnea, episodes of apnea, and seizures.[49]

Chronic Kidney Disease

During chronic kidney disease, the effect of PTH can be decreased due to poor renal response. As such, hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism can occur.[7] Due to elevated serum phosphate levels, the parathyroid glands will be activated to secrete more PTH, and the diseased kidney will continue to be unresponsive. Calcium-containing phosphate binders may be used to lower phosphate levels. Calciphylaxis is a rare complication from calcium-phosphate complexes due to rapid calcification of subcutaneous tissues causing necrotic skin ulcers, and most commonly occurs during advanced renal failure.[50] The use of calcium citrate should be avoided in such patients due to increased intestinal aluminum absorption leading to neurotoxicity and onset of osteomalacia.[51]

Clinicians should consider the potential consequences of oral calcium intake among patients with chronic kidney disease. Increased oral calcium intake is associated with an increased risk of vascular calcification, especially among patients on dialysis receiving calcium-containing phosphate binders versus non-calcium containing phosphate binders. According to research analysis, treatment with calcium phosphate binders increased the progression of coronary and aortic calcification in patients with chronic kidney disease concomitantly undergoing hemodialysis.[52] 

Conversely, the Dallas Heart Study examined the association between coronary artery calcification (CAC) in adults with end-stage kidney disease in the presence of diabetes. The study concluded that adults with comorbid diabetes and chronic kidney disease had increased risk of coronary artery calcification as opposed to patients with chronic kidney disease alone.[53] 

Calcium Nephrolithiasis

Increased calcium excretion contributes to the development of renal stones, comprised of either calcium oxalate or calcium phosphate.[3] In the past, patients were counseled to decrease their calcium intake to prevent hypercalciuria. However, according to research studies, dietary calcium intake appears to decrease the risk of kidney stone formation.[3] It is believed to be related to oxalate absorption through the intestinal tract. When calcium is ingested, a complex with oxalate can be formed, which limits the intestinal absorption of both molecules. However, with dietary calcium restriction, oxalate is more freely absorbed through the intestinal tract and subsequently excreted in greater quantity by the kidneys. As more oxalate is present in the renal system, there is increased calcium-oxalate complex formation leading to kidney stones. A 2012 study evaluated this effect among 5400 women, and it was observed that women with a history of kidney stones had higher levels of calcium absorption and similarly found that increasing calcium intake resulted in lower levels of absorption.[3] Thiazide diuretics increase renal calcium reabsorption, removing calcium from the renal system, and can be prescribed for calcium stone prevention in the absence of primary hyperthyroidism.[54]

Laboratory errors during retrieval and analysis can provide inaccurate information to the medical team. Errors in calcium measurements have been reported when anticoagulant-containing collecting tubes are inadequately filled.[55] The method and quality of the sample can also affect calcium levels, especially among lipemic or hemolyzed samples, due to hemoglobin interference. Lipemia should be removed from the specimen before testing, as it is a source of many laboratory errors. A 2018 study analyzed methods used to recover lipemic samples and promote removal by ultracentrifugation as the best method to maintain specimen integrity without exceeding the limit for clinically significant interference.[56] It has also been reported that venous occlusion during retrieval can mildly elevate calcium levels at the site due to hemodynamic changes.[16] Suspicion of a lab error requires that a new sample be retrieved and evaluated.

Patients should be managed appropriately to receive the best possible care to improve outcomes and lower morbidity. Provided that calcium is implicated in a variety of biochemical pathways, it is important to understand how it can be affected by various diseases and medical therapies. An interprofessional approach is recommended to tailor each patient’s needs and treatment accordingly. For example, patients taking bisphosphonates should receive continuous follow-up for the adverse effects that accompany long-term use such as osteonecrosis of the jaw, particularly in patients with multiple myeloma or metastatic bone disease.[57] Many medical therapies and interventions can affect calcium homeostasis, which necessitates that medical teams coordinate and communicate to discuss recommendations and assure patient safety.