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Calcium is a prominent molecule in the body involved in many biochemical processes. This mineral is essential for proper cardiac function, the structural integrity of bone, muscular contraction, and acts as an enzymatic signal in biochemical pathways.[1] Calcium is tightly regulated by the parathyroid hormone (PTH), calcitonin, and calcitriol, which regulate serum calcium levels. Calcium must be ingested endogenously, and absorption in the gastrointestinal system is influenced by hormones PTH and calcitriol (1,25-dihydroxyvitamin D).[2] Serum calcium can be measured by a venous sample, with physiologic levels ranging from 8.8 mg/dL to 10.4 mg/dL for total calcium and 4.7 mg/dL to 5.2 mg/dL for ionized calcium.[3] Total calcium values should be corrected for current albumin concentrations, which act as a carrier protein and can affect the reported results. Calcium can also be analyzed from urine by calcium concentration, urine calcium to creatinine ratio (UCa: UCr), or fractional excretion of calcium (FeCa). Calcium derangements can result from many diseases or therapies that affect hormone secretion, receptor sensitivities, intestinal absorption, and renal effectiveness.[4] Laboratory error can cause inaccurately reported calcium levels, and preventive measures should be included in specimen collection and analysis.

Calcium is tightly regulated and rarely varies from physiologic levels within the body.[9] Homeostasis must be maintained as calcium is critical in many principal cellular functions. The parathyroid hormone (PTH), calcitonin, and calcitriol actively manage calcium levels. The PTH is an essential regulator of calcium homeostasis, which acts on the renal, skeletal, and gastrointestinal systems to increase serum calcium levels. First, PTH promotes calcium absorption in the gut by stimulating the formation of renal-derived calcitriol (1,25-dihydroxyvitamin D), which targets the intestines to increase calcium absorption.[11][13] Second, PTH stimulates calcium resorption from bone by increasing osteoclast number and activity.[14] Lastly, PTH promotes calcium absorption in the kidney by activating adenylyl cyclase in the distal nephron.[15] PTH is regulated by serum calcium via negative feedback, preventing excess PTH secretion when calcium is at the physiological level (10 mg/dL).[14] Calcium-sensing receptors (CaSRs) of the parathyroid gland (to control PTH secretion) continuously monitor calcium levels. Genetic mutations of CaSRs, such as those found in familial hypocalciuric hypercalcemia (FHH), can affect the sensitivity of the receptors to serum calcium levels, resulting in hypo- or hypercalcemia.[9] Calcitonin is secreted by the parafollicular C-cells of the thyroid gland in response to elevated serum calcium levels and acts to inhibit osteoclast activity and decrease calcium absorption in the intestines and kidneys.[16] The overall result is lower serum calcium levels. Calcium and the Renal System The PTH acts on the renal system by activating adenylyl cyclase and 1- alpha-hydroxylase to increase calcium reabsorption and phosphate excretion. Adenylyl cyclase increases calcium reabsorption at the distal convoluted tubules. The enzyme 1-alpha-hydroxylase increases the conversion of vitamin D to its active form, 1,25-dihydroxyvitamin D, resulting in increased calcium absorption in the intestine.[17] In chronic kidney disease, the effect of PTH can become muted, leading to hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism.[5] Calcium and the Gastrointestinal System

The PTH acts on the renal system by activating adenylyl cyclase and 1- alpha-hydroxylase to increase calcium reabsorption and phosphate excretion. Adenylyl cyclase increases calcium reabsorption at the distal convoluted tubules. The enzyme 1-alpha-hydroxylase increases the conversion of vitamin D to its active form, 1,25-dihydroxyvitamin D, resulting in increased calcium absorption in the intestine.[17] In chronic kidney disease, the effect of PTH can become muted, leading to hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism.[5] Calcium and the Gastrointestinal System Humans do not endogenously create calcium, so this mineral must be ingested and absorbed in the gastrointestinal tract. Calcium levels and 1,25-dihydroxyvitamin D (calcitriol) influence calcium absorption in the small intestine. Other factors such as age, gender, race, and comorbidities can affect calcium absorption. Calcitriol is increased in response to low serum calcium and triggers an active process in the duodenum to absorb more calcium.[13] Elevated serum calcium levels shut off the active process, and calcium absorption occurs passively at the jejunum and ileum, resulting in lower calcium absorption rates.[5] Since calcium is absorbed in ionic form, dietary intake of compounds that interact with calcium will reduce the amount of calcium available for absorption. These are primarily oxalate, phosphate, sulfate, citrate, fiber, and fats.[13] Calcium and the Musculoskeletal System Bone tissue stores calcium as hydroxyapatite, deposited when serum calcium levels are elevated and released when levels are low. This process is linked with the endocrine system via the thyroid and parathyroid glands. When serum calcium levels are elevated, the thyroid gland releases calcitonin, which inhibits bone resorption by halting osteoclast activity. The PTH effect on bone tissue is dependent on continuous versus intermittent exposure.[14] In continuous exposure, PTH activates osteoclasts more readily by enhancing RANKL, which increases calcium resorption and bone loss, promoting an osteoporotic state.[17] Intermittent PTH exposure favors osteoblast activation, which promotes bone formation. However, chronically reduced PTH levels precipitate decreased bone remodeling and, subsequently, weak and brittle bones.[18]

Bone tissue stores calcium as hydroxyapatite, deposited when serum calcium levels are elevated and released when levels are low. This process is linked with the endocrine system via the thyroid and parathyroid glands. When serum calcium levels are elevated, the thyroid gland releases calcitonin, which inhibits bone resorption by halting osteoclast activity. The PTH effect on bone tissue is dependent on continuous versus intermittent exposure.[14] In continuous exposure, PTH activates osteoclasts more readily by enhancing RANKL, which increases calcium resorption and bone loss, promoting an osteoporotic state.[17] Intermittent PTH exposure favors osteoblast activation, which promotes bone formation. However, chronically reduced PTH levels precipitate decreased bone remodeling and, subsequently, weak and brittle bones.[18] Calcium is necessary for muscle contraction. Actin and myosin subunits interact to initiate contraction, and two regulatory subunits, troponin and tropomyosin, actively inhibit this process. Tropomyosin obstructs the actin-myosin binding site, which prevents contraction by blocking actin and myosin interaction.[19] Muscle contraction occurs when calcium, released from the sarcoplasmic reticulum, binds troponin to force tropomyosin out of the binding site, thus allowing for actin and myosin interaction.[20] Calcium and the Cardiovascular System Calcium in the heart muscle cells stabilizes the membrane potential.[9] Calcium influx during the plateau phase of myocardial contractility sets the speed of pacemaker potential. Dysregulation of either calcium or potassium can affect this delicate balance. For example, if a patient presents with severe hyperkalemia, order an electrocardiogram to evaluate for abnormal changes, and administration of calcium gluconate is the initial step to stabilize the myocardium and prevent arrhythmias.[21] Prospective cohort studies have shown no relationship between dietary calcium intake and the risk of heart disease, death, or myocardial infarction.[22] Study results conclude an unclear interpretation of whether absorption of dietary calcium versus calcium supplements has any indications regarding cardiovascular risks. Therefore, further investigations are recommended to discover the role of these supplements in cardiovascular prevention.[23]

Prospective cohort studies have shown no relationship between dietary calcium intake and the risk of heart disease, death, or myocardial infarction.[22] Study results conclude an unclear interpretation of whether absorption of dietary calcium versus calcium supplements has any indications regarding cardiovascular risks. Therefore, further investigations are recommended to discover the role of these supplements in cardiovascular prevention.[23] Calcium is a key cofactor in the coagulation cascade and is necessary for appropriate coagulability. During primary hemostasis, von Willebrand Factor (vWF) is released from injured tissue to act as a bridge for the endothelium and platelet GpIb receptors for proper platelet adhesion. After a platelet adheres to the endothelium, calcium is released to assist with other coagulation factors of the clotting cascade.[24] The tissue factor released from subendothelial tissue binds to calcium and factor VII to promote thrombin formation. Calcium is also involved in forming the prothrombinase complex, which converts prothrombin to thrombin and further creates insoluble fibrin.[25] Results from a study of intracerebral hemorrhage among 2103 patients showed that hypocalcemia was associated with subtle coagulopathy and correlated with increased bleeding in patients with intracerebral hemorrhage.[26]

Manage patient care appropriately to provide the best treatment to improve outcomes and reduce morbidity. Calcium is implicated in various biochemical pathways; therefore, understanding how this mineral can be affected by various diseases and medical therapies is essential. An interprofessional approach is recommended to tailor each patient’s needs and treatment. For example, patients taking bisphosphonates should receive continuous follow-ups for the adverse effects of long-term use, such as osteonecrosis of the jaw, particularly in patients with multiple myeloma or metastatic bone disease.[99] Many medical therapies and interventions can affect calcium homeostasis, necessitating medical teams to coordinate and communicate to discuss recommendations and assure patient safety.[100] Interprofessional patient care involving clinicians, nursing staff, pharmacists, and possibly dieticians can address calcium levels and coordinate activity to provide corrective actions when necessary, leading to optimal patient outcomes.