Hypercalcemia and Spinal Cord Injury

Hypercalcemia in spinal cord injury (SCI), or immobilization hypercalcemia, occurs in approximately 10-23% of patients with spinal cord injuries and affects adolescent and young adult males more commonly than it does other populations. ^{[1, 2, 3]} The increased incidence in older children and adolescents probably is related to the rapid bone turnover that accompanies growth, ^{[1, 4]} whereas that in males is possibly because of their greater bone mass. ^[1] This disorder is more common in patients with tetraplegia than it is in persons with paraplegia. ^[5]

The immobilization resulting from acute spinal cord injury stimulates osteoclastic bone resorption. This process causes calcium loss from the bones and hypercalciuria. Hypercalcemia results when the efflux of calcium is massive or when the glomerular filtration rate of the kidneys is reduced. ^[6]

The onset of hypercalcemia is usually insidious. The patient may present with vague and varied symptoms beginning several weeks after the spinal cord injury. Clinicians should suspect hypercalcemia in high-risk groups. If untreated, patients may develop dehydration, personality changes, calcium oxalate nephrolithiasis, and renal failure. Treatment is aimed at early mobilization, hydration, and restoration of the balance between calcium excretion and resorption. ^{[7, 8]}

See also Spinal Cord Injuries, Autonomic Dysreflexia in Spinal Cord Injury, Functional Outcomes per Level of Spinal Cord Injury, Heterotopic Ossification in Spinal Cord Injury, Osteoporosis and Spinal Cord Injury, Prevention of Thromboembolism in Spinal Cord Injury, Rehabilitation of Persons With Spinal Cord Injuries, and Spinal Cord Injury and Aging.

Signs and symptoms of hypercalcemia

These include the following ^[6] :

• Fatigue
• Lethargy
• Apathy
• Abdominal pain
• Constipation
• Anorexia
• Nausea
• Vomiting
• Polydipsia
• Polyuria
• Dehydration

Patients may also exhibit behavioral changes, lassitude, lethargy, confusion, or an acute psychosis.

Workup in hypercalcemia

An ionized calcium level is the best indicator for hypercalcemia in patients with spinal cord injury (SCI), or immobilization hypercalcemia, and may be used as a weekly screen in high-risk patients.

Because hypokalemia can result from aggressive management, monitor electrolytes during rehydration, especially if diuretics are used.

Measure levels of vitamin D if the patient does not fall within the typical age group for hypercalcemia after spinal cord injury (SCI) or if excess vitamin D consumption is suggested.

Hypercalcemia can cause renal insufficiency. Creatinine, creatinine clearance, blood urea nitrogen (BUN), and urinary excretion levels, as well as kidney imaging studies, help in the evaluation of the patient's renal function.

Measure the parathyroid hormone (PTH) level and conduct thyroid studies if the patient does not fall within the typical age group for hypercalcemia after spinal cord injury (SCI), to rule out primary hyperparathyroidism ^[9] as well as hyperthyroidism.

Management of hypercalcemia

The first treatment step is hydration with intravenous (IV) normal saline. This can be followed by the use of drugs to enhance excretion of calcium in the urine and/or medications to reduce bone resorption.

Calcitonin may reduce serum calcium temporarily, but tachyphylaxis often develops within 6-10 days of administration.

Pamidronate disodium and zoledronic acid are bisphosphonates approved for treatment of hypercalcemia of malignancy. ^{[10, 11, 12, 13, 14]}

If the hypercalcemia is severe, initial administration of calcitonin can be used until the pamidronate takes effect. ^[15]

Immobilization after spinal cord injury (SCI), or immobilization hypercalcemia, triggers an increase in osteoclastic bone resorption. The cascade of events that link the lack of mechanical forces on bone with enhanced resorption may involve altered piezoelectric effects in bone. ^[16] This mechanism and the specific events are not understood completely.

Muscle activity transmits a bone formation signal through the osteocyte. With immobilization, the mechanical stimulation for bone formation caused by muscle activity is reduced, leaving resorption unopposed. The bone resorption continues for up to 18 months after spinal cord injury, long after patients begin remobilization. The resorption ultimately results in osteoporosis, particularly of the appendicular skeleton.

The calcium released by bone resorption is excreted by the kidneys. Hypercalciuria develops within the first week after injury and continues for 6-18 months. The release of calcium suppresses production of parathyroid hormone (PTH) within several weeks of spinal cord injury. Reduced PTH is associated with increased serum phosphate concentrations and reduced synthesis of 1,25-dihydroxyvitamin D. ^[17]

If the rate of calcium resorption exceeds the capacity of urinary excretion, hypercalcemia results. This condition is most likely to occur in children, adolescents, and persons with impaired renal function. Hypercalcemia usually appears 4-8 weeks after spinal cord injury, but it can begin as early as 2 weeks or as late as 6 months after the injury.

The onset of hypercalcemia is often insidious, and the presenting symptoms can be vague. Patients with mild hypercalcemia may also be asymptomatic. In addition, no specific physical findings are associated with hypercalcemia of immobilization due to spinal cord injury (SCI). Therefore, the clinician should maintain a high index of suspicion.

Symptomatic patients typically have serum calcium levels above 11.5-12 mg/dL. However, the severity of clinical symptoms is not associated with neurologic level.

Signs and symptoms of hypercalcemia include fatigue, lethargy, apathy, abdominal pain, constipation, anorexia, nausea, vomiting, polydipsia, polyuria, and dehydration. ^[7] Patients may also exhibit behavioral changes, lassitude, lethargy, confusion, or an acute psychosis.

When evaluating a patient with spinal cord injury (SCI) and hypercalcemia, or immobilization hypercalcemia, other conditions to consider include hypercalcemia of malignancy, ^[9] viral syndrome, vitamin D intoxication, and acute abdomen.

The following are also considered in the differential diagnosis:

• Adrenal Insufficiency

• Chronic Renal Failure

• Depression

• Hyperthyroidism

• Paget Disease

• Primary hyperparathyroidism

• Urinary Tract Infection in Females

• Urinary Tract Infection in Males

An ionized calcium level is the best indicator for hypercalcemia in patients with spinal cord injury (SCI), or immobilization hypercalcemia, and may be used as a weekly screen in high-risk patients. The reference range is 1.16-1.27 mmol/L.

A corrected serum calcium level is used to adjust for albumin concentration, because 40% of serum calcium is protein bound.

The following formula is for determining total serum calcium ^[10] (reference range is 8.7-10.7 g/dL):

• Corrected calcium = 0.8 × (normal albumin concentration – patient's albumin) + patient's calcium concentration

Because hypokalemia can result from aggressive management, monitor electrolytes during rehydration, especially if diuretics are used. Serum phosphorus is usually within the reference range.

Measure levels of vitamin D if the patient does not fall within the typical age group for hypercalcemia after spinal cord injury (SCI) or if excess vitamin D consumption is suggested. Typically, levels of 1,25-dihydroxyvitamin D are low in patients with hypercalcemia after spinal cord injury. ^{[17, 18, 19]}

Hypercalcemia can cause renal insufficiency. Creatinine, creatinine clearance, blood urea nitrogen (BUN), and urinary excretion levels, as well as kidney imaging studies, help in the evaluation of the patient's renal function.

If the creatinine level is elevated, obtain a creatinine clearance result. ^[20] Monitor hydration status with BUN levels.

A 24-hour urinary calcium excretion or a spot-urine calcium/creatinine ratio can document the patient's response to therapy and determine when the risk for hypercalcemia has subsided.

Consider renal ultrasonography to rule out nephrolithiasis, especially if reduced renal function is present.

Measure the parathyroid hormone (PTH) level and conduct thyroid studies, if the patient does not fall within the typical age group for hypercalcemia after spinal cord injury (SCI), or immobilization hypercalcemia, to rule out primary hyperparathyroidism ^[10] as well as hyperthyroidism.

PTH levels should be low in hypercalcemia due to spinal cord injury. However, thyroid levels should be within the reference range in patients with hypercalcemia that is associated with spinal cord injury.

Medical management is required for symptomatic hypercalcemia. ^{[7, 1]} If the patient has hypercalcemia but is asymptomatic, treatment may still be indicated. Prolonged hypercalcemia can cause nephrocalcinosis.

Patients can usually be treated safely in the rehabilitation setting. If the clinician is unfamiliar with the medications for reducing bone resorption, consultation with an endocrinology specialist may be helpful. In patients with renal complications, consult a nephrology specialist.

Treatment approach

The first treatment step is hydration with intravenous (IV) normal saline. Monitor for volume overload during the initial hydration. Because of the young age of most patients, volume overload is not usually a concern. Atypical older patients, who may have hypercalcemia due to renal insufficiency, may not be able to handle a vigorous hydration.

Hydration can then be followed by the use of medications to enhance excretion of calcium in the urine and/or medications to reduce bone resorption.

The gastrointestinal (GI) complaints of nausea, anorexia, and vomiting resolve quickly as the serum calcium level drops. The same is true for the symptoms of lethargy, apathy, and depressed affect.

Dietary restrictions

It is not necessary to restrict dietary intake of calcium; 1,25-dihydroxyvitamin D levels are already low, thereby suppressing intestinal absorption of calcium. ^[21]

Restriction of vitamin C intake may be prudent; the patient may want to avoid eating excessive amounts of green, leafy vegetables, which are sources of oxalate. However, this measure has not been studied as a way to reduce the risk of nephrocalcinosis in hypercalcemia in patients with spinal cord injury (SCI), or immobilization hypercalcemia.

In patients without spinal cord injury, oral intake of 500 mg or more of ascorbic acid increases urinary oxalate concentration and the risk of calcium oxalate stones. ^[22]

Initiate hydration with intravenous (IV) normal saline. Saline expands the extracellular fluid volume, increases the glomerular filtration rate, and increases the excretion of calcium in the urine. Saline administration alone can control hypercalcemia in some patients, but it needs to be used for the duration of the increased mobilization from bone, which could last weeks.

Careful monitoring of urinary input and output is necessary. Administration of IV fluids and the possible need for an indwelling urinary catheter can interfere with rehabilitation treatments. IV saline (with or without furosemide) administered concomitantly with pamidronate, a bisphosphonate, is an efficient way to make the patient feel better and to reduce interventions that can interfere with the rehabilitation process.

A second line of medications is usually is needed to control the hypercalcemia. ^{[23, 24]} If the hypercalcemia is severe, initial administration of calcitonin can be used until the pamidronate takes effect. ^[15] Several liters of normal saline should be administered each day to expand intracellular volume and to produce immediate increase in renal clearance of calcium.

Thiazide diuretics should never be used because of their hypercalcemic effects. A single dose of pamidronate should be administered with the start of hydration. When the pamidronate takes effect 2-3 days later, the IV fluids can be discontinued. Hypercalcemia may reappear several weeks later, and pamidronate can be readministered as needed.

Loop diuretics agents enhance the excretion of calcium in urine. Thus, adding furosemide (also used if volume overload is a concern) helps to inhibit calcium resorption by the kidney. However, this treatment is used in addition to the IV therapy and does not shorten the overall course of hypercalcemia.

Prednisone can also enhance urinary calcium excretion, but hypercalcemia recurs after discontinuation of prednisone.

The gastrointestinal and psychiatric symptoms should resolve quickly with resolution of the hypercalcemia. Patients should not miss more than a few days of rehabilitation treatments.

Several medications directly decrease the activity of osteoclasts. Bone resorption inhibitors inhibit osteoclastic activity, thereby reducing bone resorption.

Calcitonin may reduce serum calcium temporarily, but tachyphylaxis often develops within 6-10 days of administration. The combination of etidronate, a bisphosphonate, and calcitonin has also been used to reduce serum calcium in patients with spinal cord injury (SCI) who have immobilization hypercalcemia. ^{[10, 25]}

Bisphosphonates

Pamidronate disodium is a bisphosphonate approved for treatment of hypercalcemia of malignancy. ^{[10, 11, 12, 13]} This medication acts by inhibiting osteoclast-mediated resorption and by reducing osteoclast viability. The drug is administered as a single intravenous (IV) dose and rapidly lowers serum calcium within 3 days. ^[26] The serum calcium level falls to a nadir within 7 days and may remain normal for several weeks or longer. Additional doses can be repeated if needed.

Zoledronic acid is another bisphosphonate approved for treatment of hypercalcemia of malignancy. In randomized clinical trials, zoledronic acid was more effective at lowering serum calcium levels than was pamidronate, and the effects had a longer duration. ^[14] However, no reports in the literature have described its use in immobilization hypercalcemia or spinal cord injury (SCI). Also, a potential risk of renal deterioration exists, which may progress to renal failure.

Other

Gallium and plicamycin have been used to treat hypercalcemia of malignancy, but these compounds have not been used in immobilization hypercalcemia after spinal cord injury. The other inhibitors of bone resorption (calcitonin, etidronate, and pamidronate) are characterized by significantly less toxicity.

A case study by de Beus and Boer described the successful use of the antiresorptive drug denosumab, a monoclonal antibody, in the treatment of immobilization hypercalcemia in a young adult. Advanced renal insufficiency in the patient discouraged use of a sufficient dose of bisphosphonate, with rapid and sustained reduction in serum calcium levels instead resulting after a single dose of denosumab. ^[27]

Because bone resorption is ongoing for up to 18 months after spinal cord injury, hypercalcemia can appear or reappear after discharge from the rehabilitation hospital. Readmission to the hospital for hydration and intravenous (IV) pamidronate is appropriate.

Patients should have periodic screening for hypercalcemia after treatment or with the recurrence of presenting symptoms. If a reduction in creatinine or creatinine clearance is noted, screen for nephrocalcinosis.

The degree of hypercalcemia associated with spinal cord injury (SCI), or immobilization hypercalcemia, has not been reported to reach the life-threatening levels that may occur in hypercalcemia of malignancy.

Acute hypercalcemia induces natriuresis (nephrogenic diabetes insipidus) and polyuria, possibly resulting in extracellular fluid contraction and dehydration. Chronic hypercalcemia can reduce renal concentrating ability, further exacerbating polyuria and polydipsia. The disorder also causes urinary stones, nephrocalcinosis, and chronic renal failure.

As bone resorption diminishes after spinal cord injury, hypercalcemia resolves. Eventually the hypercalciuria also resolves.

During the period of increased excretion, hypercalcemia can recur weeks to months after the initial episode, particularly if the patient is dehydrated.

Ambulation is the most effective treatment for immobilization hypercalcemia in persons who do not have spinal cord injury (SCI). ^[28] Early mobilization is recommended for patients with spinal cord injury (eg, tilt table), but there is no supporting evidence for the treatment's effectiveness in these patients.

Complications of hypercalcemia may include the following:

• Natriuresis and volume contraction

• Acute, reversible reduction in glomerular filtration rate

• Chronic nephropathy

• Nephrocalcinosis, usually localized to the medulla of the kidney

• Nephrolithiasis

• Dehydration