AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

The immobilization resulting from acute spinal cord injury (SCI) 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.¹

The onset of hypercalcemia usually is insidious. The patient may present with vague and varied symptoms beginning several weeks after SCI. 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.^{2, 3}

Related Medscape topic:
Resource Center Spinal Disorders

Pathophysiology

Immobilization following SCI triggers an increase in osteoclastic bone resorption. The cascade of events that links the lack of mechanical forces on bone with enhanced resorption may involve altered piezoelectric effects in bone.⁴ 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 SCI, 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 SCI. Reduced PTH is associated with increased serum phosphate concentrations and reduced synthesis of 1,25-dihydroxyvitamin D.⁵

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 SCI, but it can begin as early as 2 weeks or as late as 6 months after the injury.

Frequency

United States

Immobilization hypercalcemia occurs in approximately 10-23% of persons with SCI and affects adolescent and young adult males more commonly than it does other populations.^{6, 7} This disorder is more common in patients with tetraplegia than it is in persons with paraplegia.⁸

Mortality/Morbidity

• The degree of hypercalcemia associated with SCI 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.

Sex

Hypercalcemia is more common in males, possibly because of their greater bone mass.⁶

Age

Increased incidence in older children and adolescents probably is related to the rapid bone turnover that accompanies growth.^{6, 9}

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• The onset of hypercalcemia is often insidious, and presenting symptoms can be vague. The clinician should maintain a high index of suspicion.
• Patients with mild hypercalcemia may be asymptomatic. Symptomatic patients typically have serum calcium levels above 11.5-12 mg/dL.
• Signs and symptoms of hypercalcemia include fatigue, lethargy, apathy, abdominal pain, constipation, anorexia, nausea, vomiting, polydipsia, polyuria, and dehydration.² Patients also may exhibit behavioral changes, lassitude, lethargy, confusion, or an acute psychosis.
• Severity of clinical symptoms is not associated with neurologic level.

Physical

No specific physical findings are associated with hypercalcemia of immobilization.

Causes

Immobilization after SCI 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.⁴ This mechanism is not understood completely.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to Be Considered

Viral syndrome
Primary hyperparathyroidism
Hypercalcemia of malignancy¹⁰
Vitamin D intoxication
Acute abdomen

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Ionized calcium
  • Reference range is 1.16-1.27 mmol/L.
  • This study is the best indicator and may be used as a weekly screen in high-risk patients.
• Corrected serum calcium
  • Reference range is 8.7-10.7 g/dL.
  • The serum calcium must be corrected for albumin concentration, because 40% of serum calcium is protein bound. The following formula is for determining total serum calcium¹¹:

    Corrected calcium = 0.8 X (normal albumin concentration - patient's albumin) + patient's calcium concentration

• Electrolytes
• • Monitor during rehydration, especially if diuretics are used.
  • Hypokalemia can result.
• Creatinine/creatinine clearance¹²
• • Hypercalcemia can cause renal insufficiency.
  • If the creatinine is elevated, obtain a creatinine clearance.
• BUN - Monitor hydration status.
• Urinary excretion - A 24-hour urinary calcium excretion or a spot-urine calcium/creatinine ratio can document the response to therapy and determine when the risk for hypercalcemia has subsided.
• PTH level
• • Measure the PTH level if the patient does not fall within the typical age group for hypercalcemia after SCI; rule out primary hyperparathyroidism.¹¹
  • PTH levels should be low in hypercalcemia due to SCI.
• Thyroid studies
• • Obtain thyroid studies if the patient does not fall within the typical age group for hypercalcemia after SCI; rule out hyperthyroidism.
  • Thyroid levels should be within the reference range in hypercalcemia associated with SCI.
• Vitamin D levels
• • Measure levels of vitamin D if the patient does not fall within the typical age group for hypercalcemia after SCI or if excess vitamin D consumption is suggested.
  • Levels of 1,25-dihydroxyvitamin D typically are low in patients with hypercalcemia after SCI.⁵
• Serum phosphorus - This usually is within the reference range.

Imaging Studies

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

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Rehabilitation Program

Physical Therapy

Ambulation is the most effective treatment for immobilization hypercalcemia in persons who do not have SCI.¹³ Early mobilization is recommended for patients with SCI (eg, tilt table), but there is no supporting evidence for the treatment's effectiveness in these patients.

Medical Issues/Complications

• Medical management is required for symptomatic hypercalcemia.^{2, 6} If the patient has hypercalcemia but is asymptomatic, treatment still may be indicated. Prolonged hypercalcemia can cause nephrocalcinosis.
• • The first step is hydration with IV normal saline. This step can be followed by the use of medications to enhance excretion of calcium in the urine and/or medications to reduce bone resorption.
  • Restriction of dietary intake of calcium is not necessary; 1,25-dihydroxyvitamin D levels already are low, suppressing intestinal absorption of calcium.
  • 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. This measure has not been studied as a way to reduce the risk of nephrocalcinosis in immobilization hypercalcemia.
  • In patients without SCI, oral intake of 500 mg or more of ascorbic acid increases urinary oxalate concentration and the risk of calcium oxalate stones.¹⁴

Consultations

If the clinician is unfamiliar with the medications for reducing bone resorption, consultation with endocrinology may be helpful. In patients with renal complications, consult nephrology.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

The first step in treatment is hydration with 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 input and output is necessary. Administration of IV fluids and the possible need for an indwelling urinary catheter can interfere with rehabilitation treatments. A second line of medications usually is needed to control the hypercalcemia.^{15, 16}

Excretion can be enhanced further by adding furosemide, but this treatment is used in addition to the IV therapy and does not shorten the overall course of hypercalcemia. Prednisone also can enhance urinary calcium excretion, but hypercalcemia recurs after discontinuation of prednisone.

Several medications directly decrease the activity of osteoclasts. Calcitonin may reduce serum calcium temporarily, but tachyphylaxis often develops within 6-10 days of administration. The combination of etidronate and calcitonin also has been used to reduce serum calcium in patients with SCI who have immobilization hypercalcemia.^{11, 17}

Pamidronate disodium is a bisphosphonate approved for treatment of hypercalcemia of malignancy.^{11, 18, 19, 20} This medication acts by inhibiting osteoclast-mediated resorption and by reducing osteoclast viability. The drug is administered as a single IV dose and rapidly lowers serum calcium within 3 days.²¹ 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 the newest 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 have a longer duration.²² However, no reports in the literature have described its use in immobilization hypercalcemia or SCI. Also, a potential risk of renal deterioration exists, which may progress to renal failure.

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

IV saline (with or without furosemide) administered concomitantly with pamidronate is an efficient way to make the patient feel better and to reduce interventions that can interfere with the rehabilitation process. If hypercalcemia is severe, initial administration of calcitonin can be used until the pamidronate takes effect. Several liters of normal saline should be administered each day to expand intracellular volume and to produce immediate increase in renal clearance of calcium. If volume overload is a concern, add furosemide, which also helps to inhibit calcium resorption by the kidney.

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 re-administered as needed.

Drug Category: Loop diuretics

These agents enhance the excretion of calcium in urine.

Drug Category: Bone resorption inhibitors

These agents inhibit osteoclastic activity, thereby reducing bone resorption.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• The gastrointestinal 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.
• 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.

Further Outpatient Care

• Because bone resorption is ongoing for up to 18 months after SCI, hypercalcemia can appear or reappear after discharge from the rehabilitation hospital. Readmission to the hospital for hydration and IV pamidronate is appropriate.

Transfer

• Patients usually can be treated safely in the rehabilitation setting. 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.
• 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.

Complications

• Natriuresis and volume contraction
• Acute, reversible reduction in glomerular filtration rate
• Chronic nephropathy
• Nephrocalcinosis, usually localized to the medulla of the kidney
• Nephrolithiasis
• Dehydration

Prognosis

• As bone resorption diminishes after SCI, 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.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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10. Deftos LJ. Hypercalcemia in malignant and inflammatory diseases. Endocrinol Metab Clin North Am. Mar 2002;31(1):141-58. [Medline].
11. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. May 1 2003;67(9):1959-66. [Medline]. [Full Text].
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14. Urivetzky M, Kessaris D, Smith AD. Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis. J Urol. May 1992;147(5):1215-8. [Medline].
15. Gilchrist NL, Frampton CM, Acland RH, et al. Alendronate prevents bone loss in patients with acute spinal cord injury: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. Apr 2007;92(4):1385-90. [Medline]. [Full Text].
16. Valverde P. Pharmacotherapies to manage bone loss-associated diseases: a quest for the perfect benefit-to-risk ratio. Curr Med Chem. 2008;15(3):284-304. [Medline].
17. Meythaler JM, Tuel SM, Cross LL. Successful treatment of immobilization hypercalcemia using calcitonin and etidronate. Arch Phys Med Rehabil. Mar 1993;74(3):316-9. [Medline].
18. Fitton A, McTavish D. Pamidronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs. Feb 1991;41(2):289-318. [Medline].
19. Gucalp R, Ritch P, Wiernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol. Jan 1992;10(1):134-42. [Medline].
20. Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol. Mar 1996;45(3):175-9. [Medline].
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22. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. Jan 15 2001;19(2):558-67. [Medline].

Article Last Updated: Aug 19, 2008