Hypocalcemia in the Older Adult: Pathophysiology, Diagnosis, and Treatment

Ravi Kant, MD 1,2 • Barbara Zelesnick, BA 3 • Bikram Saini, MD 1 • Steven R. Gambert, MD, AGSF, MACP 1 1Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Maryland School of Medicine, University of Maryland Medical Center, and GRECC, Baltimore VA Medical Center 2Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, University of Maryland School of Medicine, University of Maryland Medical Center, and Baltimore VA Medical Center3Scientific Division, Ipsen Pharmaceuticals, Basking Ridge, NJ

Key words: Hypocalcemia, hypoparathyroidism, vitamin D deficiency, hungry bone syndrome, primary hypoparathyroidism.

Calcium is the third most abundant ion in the body and plays a significant role in maintaining normal cellular function, neural transmission, cell membrane stability, blood coagulation, intracellular signaling, and integrity of bone structure. In plasma, calcium takes three forms: (1) ionized (the biologically active form), accounting for 50% of total serum calcium, (2) bound to plasma proteins, typically albumin, accounting for 40% to 45% of total serum calcium, and (3) complexed to anions, including bicarbonate, lactate, phosphate, and citrate, accounting for the remaining 5% to 10% of total serum calcium.1 When calcium levels drop below normal levels, hypocalcemia results. Hypocalcemia is defined as a total serum calcium level lower than 8.5 mg/dL or an ionized serum calcium level lower than 4.7 mg/dL.2 It is a relatively common electrolyte disturbance, and it is not uncommonly observed in a broad spectrum of older adults, from asymptomatic persons to those who are critically ill. Although values of total calcium in the serum may be below what is considered normal based on reference ranges, it is important to remember that it is the ionized calcium and not the total (bound and unbound) that is associated with symptoms of deficiency, such as fragile bones, bone and joint pain, kidney stones, excessive urination, fatigue, nausea, vomiting, and loss of appetite.

Approximately 80% of the protein-bound fraction of calcium is bound to albumin; thus, persons with abnormally high or low levels of albumin will have either a falsely high or low value of total serum calcium, respectively. In hyperalbuminemic or hypoalbuminemic states, a formula is commonly used to “correct” for high or low levels of serum albumin: subtracting or adding 0.8 mg/dL (0.2 mmol/L) for every 1 g change in serum albumin above or below the mean reference value for these laboratory assessments, respectively.3 Since the accuracy of this method of estimating the true value of serum calcium is poor, an ionized calcium concentration should be obtained whenever there is concern. Normal levels of serum ionized calcium are 4.65 mg/dL to 5.25 mg/dL (1.16-1.31 mmol/L). When abnormal serum ionized calcium levels are found, corrective measures should be taken. This article discusses the clinical manifestations of hypocalcemia, the underlying pathophysiological mechanisms that lead to abnormally low calcium levels, and how patients should be assessed and treated when hypocalcemia is observed.

Clinical Manifestations of Hypocalcemia

Hypocalcemia results whenever there is a net efflux of calcium from the extracellular fluid in greater quantities than the intestines or bones can replace. Symptoms are primarily neurological, with the inadequate calcium levels causing hyperexcitability of neuronal membranes. Neurological symptoms may include an altered mental status, confusion, depression, psychosis, gait disturbances, muscle twitching, paresthesias, tremors, seizures, muscle rigidity, or tetany. Clinical signs of latent tetany may include the Trousseau sign, in which a carpopedal spasm occurs when an inflated blood pressure cuff is left on the arm for several minutes, thereby creating ischemia of the nerves in the upper arm.3 The Trousseau sign is usually achieved by inflating a sphygmomanometer cuff to 20 mm Hg above the systolic blood pressure for 3 to 5 minutes. The result is thumb adduction, metacarpophalangeal joint flexion and interphalangeal joint extension, and the Chvostek sign, which occurs when one taps on the facial nerve in front of the ear causing a contraction of the muscles of the eye, mouth, and nose.4 Tetany may be associated with numbness, cramps, carpopedal spasm, laryngeal stridor, and generalized convulsions.

Hypocalcemia may also cause cardiac effects, including prolongation of the QT interval, which is typically one of the condition’s earliest manifestations. Other signs and symptoms may include subcapsular cataracts in those with prolonged hypocalcemia, and calcifications in areas of the brain, such as the basal ganglia, cerebral cortex, and cerebellum, as noted on computed tomography scans. In rare cases, Parkinsonism, choreoathetosis, and even dysphonic spasms may be noted.

Pathophysiological Mechanisms of Hypocalcemia

common causes of hypocalcemiaNumerous conditions can cause hypocalcemia (Table). What follows is a review of some of the most common causes of hypocalcemia.

The four parathyroid glands, lying on the outer corners of the thyroid gland, produce and secrete parathyroid hormone (PTH). Along with the hormone vitamin D, PTH regulates the body’s calcium and phosphate levels and activates the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active form of vitamin D that stimulates calcium and phosphate absorption from the gastrointestinal tract. When the parathyroid glands fail to secrete sufficient quantities of PTH, hypoparathyroidism develops, which is a low calcium level paired with a high phosphorus level. In patients with hypoparathyroidism, PTH is either undetectable or inappropriately normal in the setting of low serum calcium levels. This helps distinguish this entity from pseudohypoparathyroidism, a rare familial disorder with target tissue resistance to PTH, in which hypocalcemia is associated with hyperphosphatemia and elevated PTH levels.

Hypoparathyroidism can occur sporadically or from a primary disorder caused by a genetic mutation that is either autosomal dominant (eg, Barakat syndrome), autosomal recessive (eg, Wilson’s disease), or X-linked with or without other polyglandular failure.3 Activating mutations of the parathyroid and renal calcium-sensing receptor leads to inhibition of parathyroid hormone secretion and, hence, hypocalcemia and hypercalciuria. The hypocalcemia is usually mild and asymptomatic and may escape detection until late in life.3 Autoimmune hypoparathyroidism may occur in isolation or in patients with one or more other autoimmune disorders, such as autoimmune polyendocrine syndrome type 1. Idiopathic hypoparathyroidism is an uncommon condition characterized by the absence of, fatty replacement of, or atrophy of the parathyroid glands. It may be familial or sporadic. To diagnosis idiopathic hypoparathyroidism, the following criteria are necessary: low serum calcium levels; high serum phosphorous levels; and the absence of renal insufficiency, steatorrhea, chronic diarrhea, and alkalosis. Rickets and osteomalacia must also be excluded and patients must not have recently received transfusions or chelating agents. While idiopathic or autoimmune hypoparathyroidism is usually diagnosed earlier in life, it may not be diagnosed until maturity is reached and should always be considered if other causes of hypocalcemia have not been found. With proper treatment, individuals may attain normal levels of serum calcium and be able to lead normal lives.

Hypoparathyroidism may also have a variety of other etiologies. Injury to or removal of the parathyroid glands during neck surgery is the most common cause of hypoparathyroidism. With advancement in surgical techniques and improved medical care, more elderly patients are undergoing neck surgeries, resulting in a rising incidence and prevalence of acquired hypoparathyroidism in this population. Postsurgical hypoparathyroidism is usually transient, but it can be permanent due to irreversible damage to the parathyroid glands. Other possible etiologies of hypoparathyroidism include immune-mediated destruction of parathyroid glands; defective regulation of parathyroid hormone secretion, activating mutations of calcium-sensing receptors; infiltration of the parathyroid glands by iron, copper, amyloid protein, or metastasis; defects in the parathyroid hormone molecule; reduced parathyroid function due to chemical or drug toxicity; sarcoidosis; radiation or mechanical injury; or infection.3,5 Hypoparathyroidism may exist for many years without any clinical signs or symptoms and may only be diagnosed after another condition further lowers the patient’s calcium level.

Any decrease in extracellular calcium stimulates PTH secretion via activation of the calcium sensor receptor on parathyroid gland cells. PTH in turn enhances tubular reabsorption of calcium by the kidneys, increases calcium resorption from the bones, and stimulates the production of 1,25-dihydroxycholecalciferol (1,25 [OH]2 D3) in the kidneys. Vitamin D stimulates intestinal absorption of calcium, regulates PTH release in the parathyroid glands, and mediates PTH-stimulated bone reabsorption. These collective homeostatic mechanisms serve to restore serum calcium levels to normal. Deficiencies in circulating levels of vitamin D increase serum PTH levels, often leading the non-astute observer into wrongly diagnosing hyperparathyroidism; thus, caution is advised to not evaluate levels of PTH in isolation. It is essential to confirm that circulating levels of vitamin D are within the normal range.

Vitamin D Deficiency
Vitamin D, a lipid-soluble vitamin that acts as a hormone, is responsible for intestinal absorption of calcium and phosphate. It is important in maintaining adequate levels of calcium and phosphate for bone mineralization, bone growth, and remodeling. Alone or in combination with calcium, vitamin D has been shown to reduce the risk of fractures in elderly men and postmenopausal women and to reduce the risk of falling in older persons living in the community.6 Vitamin D can be obtained through ultraviolet light from sun exposure, which acts upon cholesterol in the skin to initiate vitamin D synthesis; it can also be obtained through diet. Dietary forms include cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). As vitamin D2 and D3 travel through the body, they are first hydroxylated at the 25 position in the liver and then additionally hydroxylated at the 1 position in the kidneys, each multiplying the potency of that vitamin D analogue by five-fold.7

Vitamin D deficiency is a common finding in older adults, with a prevalence of 5% to 25% in independent community-dwelling elders and 48% to 80% for those who are institutionalized.6 Most experts agree that a serum 25(OH)D level between 30 ng/mL and 50 ng/mL is desirable. Individuals who have renal failure have a decreased ability to hydroxylate 25(OH)D to its active form (1,25 [OH]2 vitamin D); thus, PTH levels should be measured to identify vitamin D deficiency. If PTH is elevated above physiological range, treatment with calcitriol is warranted.

Vitamin D deficiency has been associated with an increased rate of morbidity and frailty and is an established risk factor for osteoporosis, fractures, and osteomalacia.8 A meta-analysis published in 2008 demonstrated that vitamin D supplementation reduced the risk of falling by 22% for older adults.8 Although the exact mechanism for this effect is unknown, vitamin D is thought to play a role in neuromuscular function in addition to its influence on bone metabolism.8

Etiologies for vitamin D deficiency are multifactorial and include inadequate nutritional intake, lack of exposure to sunlight (this impacts activation of precursors of vitamin D), and renal or hepatic dysfunction (this prevents conversion to more physiologically active vitamin D analogues). Additionally, several medications may cause vitamin D to be shunted into inactive pathways. These include phenytoin, phenobarbital, carbamazepine, isoniazid, theophylline, and rifampin.9,10 Individuals on glucocorticoids also have higher requirements for vitamin D because these agents inhibit intestinal vitamin D-dependent calcium absorption. Ketoconazole and other antifungal medications are also capable of inhibiting vitamin D activity by blocking hydroxylation of the vitamin in the kidneys.

is an abnormally high concentration of phosphates in the blood, generally higher than 5 mg/dL. Patients who have impaired renal function, increased intake of phosphate either orally or through the use of phosphate-containing enemas, or those with excess tissue breakdown from conditions such as rhabdomyolysis or tumor lysis may have high levels of phosphorous. A serum phosphorous level of more than 6 mg/dL is of particular concern and may result in hypocalcemia as the body strives to maintain a balance between calcium and phosphorous. Hyperphosphatemia may be induced by the ingestion of large amounts of phosphate-containing laxatives, such as Fleet Phospho-Soda, which contains 4.25 mmoL of inorganic phosphate per milliliter.11 As a result, even 20 mL taken over 3 to 6 hours can cause severe, even fatal, hyperphosphatemia and hypocalcemia. Phosphate excretion may be increased by infusing saline, provided the patient’s renal function is normal.12 Hemodialysis may be indicated in patients with symptomatic hypocalcemia in the setting of renal failure, but dialysis is not that effective in removing excess quantities of phosphorous. For this reason, phosphate binders (calcium
acetate) are often prescribed to reduce the absorption of phosphate obtained through diet. While the first response to the finding of a low calcium level may be to increase the intake of calcium-rich dairy products, these foods are also rich in phosphate and are therefore best avoided under these circumstances.

Hungry Bone Syndrome
A decline in levels of serum calcium has been observed after successful parathyroidectomy in patients with primary or tertiary hyperparathyroidism. Regardless of the gland size or pathological diagnosis, the decrease in serum calcium levels usually does not last more than 2 to 4 days after surgery.13 If hypocalcemia persists beyond 4 days, it could be due to an accidental removal of excessive parathyroid tissue, devascularization of or trauma to residual parathyroid glands, or long-term suppression of residual nonpathological parathyroid glands.13 This state of profound and prolonged hypocalcemia is called hungry bone syndrome (HBS). Prevalence data of HBS have been conflicting, ranging from 13% to 87% in different reports.13 HBS occurs more commonly in persons with preoperative indices of high bone turnover, osteitis fibrosa cystica, and/or brown tumors of the bone. Suboptimal 25(OH)D levels before surgery is another important risk factor for the development of HBS. Ensuring 25(OH)D levels are more than 30 ng/mL can greatly reduce the incidence of postparathyroidectomy hypocalcemia. When severe hypocalcemia occurs, it is thought to result from a greatly increased use of calcium by the skeleton as a result of a rapid decline in circulating PTH levels and its effect on bone. The best treatment is to be observant after parathyroid surgery and promptly replete levels of calcium and vitamin D as necessary.

Blood Transfusion
Blood products are usually preserved in citrate phosphate dextrose adenine. Massive blood transfusion (transfusion of more than 50% of a patient’s blood volume in 12 to 24 hours) can lead to elevated citrate levels in the blood, which causes hypocalcemia by forming a calcium-citrate complex.14 Transfusion of as few as 5 units, however, may also be associated with hypocalcemia due to calcium-citrate complexes and caution is advised to observe serum calcium levels. Because the liver plays a major role in metabolizing calcium-citrate complex, patients with end-stage liver disease who require massive blood transfusions are at an increased risk of hypocalcemia. Patients with liver dysfunction develop more prolonged and severe hypocalcemia after rapid transfusion,14 requiring higher vigilance and, in some cases, prompt calcium supplementation.

Magnesium Metabolism Disorders
Prevalence of hypomagnesemia varies from 7% to 11% in hospitalized patients and is frequently undetected.15 Serum magnesium levels are not part of a complete metabolic profile and, therefore, need to be requested separately. Hypocalcemia is a common presentation of hypomagnesemia. Magnesium depletion can cause hypocalcemia by causing functional hypoparathyroidism. Low serum magnesium levels decreases PTH secretion, increases PTH metabolism, and induces PTH resistance.15 Hypomagnesemia-induced hypocalcemia is refractory to treatment with exogenous calcium and vitamin D supplementation, and magnesium therapy alone results in normalization of serum calcium. Hypermagnesemia may occur with excess oral intake or reduced clearance due to renal failure, which may also be associated with hypocalcemia due to its effects on PTH secretion and is reversible with correction of the hypermagnesemia.


As noted previously, it is essential to make sure true hypocalcemia exists. If so, any causative medication should be discontinued and treatment initiation should be guided by symptoms and the acuity of the hypocalcemia. The main treatment available for hypocalcemia is calcium salts and vitamin D or its analogues. The goal of treatment is to maintain serum calcium levels (corrected for albumin) within the normal range with calcium-phosphate product levels less than 55 mg/dL. In patients with hypoparathyroidism, lack of PTH promotes renal calcium reabsorption, results in hypercalciuria with increased serum calcium levels, and increases the risk of kidney stones and renal complications. This effect is more prominent in patients with hypocalcemia due to activating mutations in the calcium-sensing receptor.16 Therefore, 24-hour urine calcium should be monitored at least biannually in these patients and thiazide should be used when 24-hour urine calcium is 250 mg or more.3

Treatment with calcium and vitamin D is recommended in patients with symptoms of hypocalcemia. Patients with chronic hypocalcemia can be asymptomatic or have subtle symptoms; on the other hand, even acute mild reduction in serum calcium levels can precipitate severe symptoms. In asymptomatic patients, outpatient treatment can be initiated, but the presence of severe hypocalcemic symptoms warrants hospital admission because intravenous calcium therapy, which is usually followed by continuous calcium infusion, is warranted. Oral calcium with vitamin D should be started in these patients as soon as feasible.

Choice of vitamin D preparation depends on the etiology of the hypocalcemia. Treatment with calciferol (vitamin D2 or vitamin D3) is recommended in patients with vitamin D deficiency.3 Parathyroid hormone stimulates 25-hydroxyvitamin D3-1alpha-hydroxylase and production of 1,25-dihydroxyvitamin D, the active vitamin D metabolite. Therefore, most patients with hypoparathyroidism are treated with active vitamin D analogues (eg, calcitriol). Calcitriol can be started at a dose of 0.25 µg to 0.50 µg daily, and further titration should be done to attain the goal of low normal serum calcium levels. Calcitriol has a rapid onset of action (1-2 days); thus, its use warrants close monitoring of serum calcium levels. Because of its short half-life, patients usually develop symptoms of hypocalcemia even after missing one or two doses, which is a common occurrence in elderly patients with cognitive deficits and multiple comorbidities. Pharmacological doses of calciferol can be used, but this usually requires treatment with high doses in patients with hypoparathyroidism due to decreased 1-alpha-hydroxylation of vitamin D2 or D3 to active vitamin D.3 Calciferol has a slow onset of action (10-14 days) and a long half-life, which is a concern if the patient develops vitamin D toxicity; however, some experts indicate that, due to decreased 1-alpha-hydroxylase activity in patients with hypoparathyroidism, their risk of developing vitamin D toxicity with use of calciferol is low. Further research is needed to shed light on this issue, but in the meantime, the choice of vitamin D should be individualized on a case-by-case basis in older adults with hypoparathyroidism.

Serum creatinine, serum phosphate, and 24-hour urine calcium should be routinely monitored in patients with hypoparathyroidism.3 There is no role of monitoring PTH in patients with a definitive diagnosis of hypoparathyroidism. Thiazide diuretics and a low-salt diet should be added if 24-hour urine calcium is 250 mg or above to decrease the risk of renal complications. Hypocalcemia can cause a prolonged QT interval that warrants urgent treatment with intravenous calcium to avoid arrhythmias. Therefore, an electrocardiogram is recommended in all patients with hypocalcemia even in the absence of symptoms. It is important to maintain serum magnesium levels in the normal range, as hypomagnesemia and hypermagnesemia can both cause functional hypoparathyroidism.15

Hypoparathyroidism is the one of the few endocrinopathies for which hormone replacement therapy (ie, PTH) is not yet approved. Two formulations of PTH—teriparatide (human PTH 1-34) and a full-length molecule known as Natpara (recombinant human PTH 1-84)17—are under investigation and may turn out to be standard therapy for treatment of hypoparathyroidism in the near future. Natpara is due to be submitted for US Food and Drug Administration approval in mid-2013 by NPS Pharmaceuticals.18 A positive outcome from its phase 3 trial, known as REPLACE, resulted in the primary efficacy end point being met with a statistically higher responder rate versus placebo. REPLACE was an intent-to-treat analysis in which 54% of Natpara-treated patients reached the primary end point versus only 2% of those treated with placebo. The primary endpoint was defined as a 50% or greater reduction in the amount of oral calcium supplements and active vitamin D therapy required and total serum calcium concentration that was normalized or maintained in comparison to baseline after 24 weeks of therapy. Because Natpara imitates the action of natural PTH it is a very promising hypoparathyroidism treatment that exhibits a more physiological treatment outcome than currently available therapies.18


Hypocalcemia is fairly commonly observed in older adults. When a total serum calcium level shows abnormally low calcium levels, further investigation is warranted before any treatments ensue. A more accurate measurement of calcium levels can be obtained by performing a serum ionized calcium test. When this test reveals that a patient truly has low serum calcium levels, the etiology of the patient’s hypocalcemia should be investigated, even if he or she is asymptomatic. Numerous conditions can cause hypocalcemia, such as genetic abnormalities, injuries or other factors affecting the parathyroid glands, electrolyte imbalances, low vitamin D levels, and various medications. Management of hypocalcemia hinges on identifying its underlying cause, correcting it (eg, by discontinuing medications that are affecting calcium levels), and striving to maintain serum calcium levels (corrected for albumin) in the normal range.


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The authors report no relevant financial relationships.

Address correspondence to:
Steven R. Gambert, MD
University of Maryland Medical Center
N3E09, 22 S. Greene Street
Baltimore, MD 21201