Case Report

An Unrecognized Cause of Recurrent
Hypercalcemia: Immobilization
Chih-Jen Cheng, MD, Chung-Hsing Chou, MD, and Shih-Hua Lin, MD
Abstract: We report a 66-year-old Chinese man with chronic renal
insufficiency (creatinine 1.7 mg/dL) and gout suffering from slurred
speech and right hemiplegia for 3 days. Acute cerebral infarction
was confirmed by computed tomography. Conscious disturbance
occurred on the tenth hospital day without significant changes on
imaging study when compared with a previous scan. Hypercalcemia
(total calcium 14.1 mg/dL) and acute exacerbation of chronic renal
failure (serum creatinine 2.5 mg/dL) were noticed. Hypercalciuria
(FECa 3.2%), and low serum levels of intact parathyroid hormone
and 1,25(OH)2D3 suggested nonparathyroidal hypercalcemia. An
extensive workup failed to identify any etiology of hypercalcemia.
Hypercalcemia and renal failure were temporarily ameliorated after
aggressive volume expansion and loop diuretic treatment but recurred 2 weeks later. Immobilization hypercalcemia was considered
after the exclusion of other discernible causes and was successfully
treated with rehabilitative exercises and bisphosphonates without
further recurrence during a 2-year follow-up. Clinical alertness to
immobilization as a possible cause of hypercalcemia may avoid
unnecessary and invasive examinations, life-threatening complications and annoying recurrences.
Key Words: Hypercalcemia, immobilization, renal failure, stroke.

H

ypercalcemia, a common electrolyte imbalance, can induce multiple organ dysfunction and diverse manifestations, such as renal symptoms (polyuria, polydipsia), intestinal symptoms (nausea, vomiting, constipation), neurologic
symptoms (weakness, headache, depression), and cardiac
symptoms (tachycardia, hypertension). Hypercalcemic crisis
(especially total calcium [Ca] ⬎ 16 mg/dL) endangers the
patient with encephalopathy, acute renal failure and even
death.1
The commonly encountered causes of hypercalcemia are

From the Division of Nephrology, Department of Medicine, and the Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Reprint requests to Shih-Hua Lin, MD, Division of Nephrology, Department
of Medicine Tri-Service General Hospital No. 325, Section 2, ChengKung Road, Neihu 114, Taipei, Taiwan, R.O.C. Email:
shihhualin@yahoo.com
Accepted January 13, 2006.
Copyright © 2006 by The Southern Medical Association
0038-4348/0⫺2000/9900-0371

Southern Medical Journal • Volume 99, Number 4, April 2006

malignancy (70%), primary hyperparathyroidism (20%) and
chronic granulomatous disorders. Immobilization, a well-established cause of hypercalcemia since 1941, is still under
appreciated due to vague clinical features.2 In most previous
reports, immobilization hypercalcemia occurred in adolescents with normal renal function and a median onset time of
4 weeks.3 There is a paucity of literature describing immobilization hypercalcemia in impaired renal function and in the
elderly.4,5 Herein we describe an elderly patient with chronic
renal insufficiency who developed recurrent hypercalcemia
and acute exacerbation of chronic renal failure following
stroke-related immobilization.

Case Report
A 66-year-old Chinese male presented to our emergency
department with slurred speech and right hemiplegia x 3 days
in October 2003. No head injury or use of sedatives was
noted. His pertinent medical history included hypertension,
gout, and chronic renal insufficiency for 10 years. His family
history was noncontributory.
On physical examination, the patient was alert with a
supine blood pressure of 112/72 mm Hg, heart rate 96 beats/
min, respiratory rate 18 breaths/min, and body temperature
37.0°. Neurologic examination showed dysarthria, right facial
palsy, deviated tongue to the right, right hemiplegia (0/5

Key Points
• Immobilization is a well-established but under appreciated etiology of hypercalcemia.
• A high index of suspicion for immobilization-induced
hypercalcemia can obviate the need to order unnecessary examinations.
• Due to the reduced ability to excrete calcium, patients
with pre-existing renal function impairment are prone
to develop immobilization hypercalcemia in a shorter
time frame.
• In addition to enhancing renal calcium excretion, the
standard treatments for immobilization hypercalcemia
include the use of antiosteoclastic agents, early rehabilitative exercises and control of the underlying
illness.

371

Cheng, Chou, and Lin • Immobilization Hypercalcemia in a Stroke Patient

strength in the right upper and lower extremities), and rightsided positive Babinski sign. The remainder of the physical
examination was unremarkable.
Laboratory values at admission showed a white blood
cell count of 10,700/␮L, platelets 393,000/␮L, alkaline phosphatase 85 U/L, glucose 168 mg/dL, creatinine 1.7 mg/dL,
uric acid 9.7 mg/dL, and albumin 3.2 g/dL. The remainder of
the values are listed in the Table. The urinalysis revealed only
trace proteinuria without hematuria or cast. The estimated
glomerular filtration rate through creatinine clearance rate
was around 20 mL/min. Computed tomography (CT) scan of
the brain showed acute cerebral infarction in the left middle
cerebral artery territory. Aspirin 100 mg and piracetam 800
mg t.i.d. were prescribed. On the 10th hospital day, conscious
disturbance and an elevated serum creatinine (2.5 mg/dL)
were noticed. Repeat CT of the brain did not show new
infarction or intracranial hemorrhage. Cerebrospinal fluid
studies ruled out the possibility of encephalomeningitis. Renal ultrasound revealed relatively small-sized kidneys (right
8.7 cm, left 8.5 cm). The subsequent electrolyte survey revealed hypercalcemia (total/ionized Ca: 14.1/8.2 mg/dL), high
urinary Ca excretion (fraction excretion of Ca (FECa): 3.2%,
normal ⬍ 2%), and low intact parathyroid hormone (iPTH:
0.1 pg/mL). A 1,25(OH)2D3 of 7.7 pg/mL indicated nonparathyroidal hypercalcemia (Table). The patient was on no medication that could lead to hypercalcemia.
A series of examinations, including CT scan of the whole

Table 1. Serial serum biochemical values during
hospitalization
Hospital Day

1

10

17

24

28

40

Total calcium (NR
8.4–10.2 mg/dL)
Ionized calcium (NR
4.5–5.3 mg/dL)
Phosphate (NR 2.7–4.5
mg/dL)
Alkaline phosphatase
(NR 35–104 U/L)
Albumin (NR 3.4–4.8
g/dL)
Urea nitrogen (NR
7–20 mg/dL)
Creatinine (NR 0.5–1.0
mg/dL)
Intact PTH (NR 12.6–
57.5 pg/dL)
1,25-(OH)2D3 (NR
16–42 pg/mL)
25-(OH)D3 (NR 9.7–
41.7 ng/mL)
FECa (%) (NR ⬍ 2%)

8.7

14.1

10.3

15.3

10.1

8.6

–

8.2

5.6

6.8

4.8

3.4

–

4.2

–

4.0

–

–

85

125

–

146

–

–

3.2

3.3

–

3.5

–

–

16

32

27

20

22

17

1.7

2.5

1.4

2.1

1.8

1.5

–

0.1

–

–

1.8

97

–

7.7

–

–

12.8

25.9

–

9.1

–

–

12.9

11.4

–

3.2

–

2.5

–

1.5

NR, normal range; FECa, urinary fraction excretion of calcium; PTH, parathyroid hormone.

372

abdomen, panendoscopy of the upper gastrointestinal tract,
whole body bone scan, tumor markers and Gallium-67 scan
were nonrevealing for malignancy. Bence-Jones protein, skull
film, serum and urine protein electrophoresis and bone marrow biopsy were also not suggestive of multiple myeloma.
Chest film lacked features of sarcoidosis. The serum cortisol
level was also within normal range, at 11.7 ␮g/dL at 8:00 AM.
Saline hydration with 2000 mL per day and IV infusion
of furosemide 40 mg every 4 hours for 7 days had corrected
the serum Ca, renal function and consciousness. Unfortunately, gouty arthritis over the knees occurred, followed by
recurrent hypercalcemia. Renal function deteriorated on the
24th hospital day (Table). Immobilization hypercalcemia was
considered due to the presence of right hemiplegia and lack of
other identifiable causes of hypercalcemia. IV infusion of
pamidronate disodium 90 mg and saline hydration with 2000
mL per day, together with a rehabilitative program, began on
the 25th hospital day. The patient’s consciousness, serum
calcium and renal function recovered within 1 week. The
serial change of serum Ca and creatinine is shown in Figure
1. During a 2-year follow-up period, the patient maintained
steady renal function (creatinine 1.7–1.9 mg/dL) without recurrent hypercalcemic episode.

Discussion
The homeostasis of calcium is complex because the bone,
gastrointestinal tract, and kidney all affect the balance of
calcium. Alteration of calcium homeostasis from any of these
organ systems can lead to serum calcium changes. Therefore,
hypercalcemia can be divided into three categories: accelerated bone calcium resorption (resorptive hypercalcemia), increased gastrointestinal calcium absorption (absorptive hypercalcemia), and enhanced renal calcium reabsorption
(reabsorptive hypercalcemia) (Fig. 2).6,7 In addition to the
comprehensive medical history and physical examinations,
measurement of urinary calcium excretion, serum iPTH and
1,25-(OH)2D3 is very helpful in the rapid differentiation of
these three categories. Urinary calcium excretion (FECa) is
lower in reabsorptive hypercalcemia, whereas it is higher in
resorptive and absorptive hypercalcemia. 1,25-(OH)2D3 is
usually high in absorptive hypercalcemia. The serum iPTH
level can further subdivide resorptive hypercalcemia, the most
common cause of hypercalcemia, into parathyroidal and nonparathyroidal hypercalcemia.
Our patient had recurrent hypercalcemia and acute exacerbation of chronic renal failure during hospitalization. His
high urine FECa excluded reabsorptive hypercalcemia; while
his low serum iPTH and 1,25-(OH)2D3 excluded parathyroidal hypercalcemia and endogenous or exogenous vitamin Drelated hypercalcemia. A detailed review of his medications
ruled out the possibility of milk-alkali syndrome and vitamin
D analogue overdose. Further studies, including serum cortisol, ACTH, Gallium scan, CT scan of whole abdomen, and
© 2006 Southern Medical Association

Case Reports

Fig. 1 A serial change of serum total calcium and creatinine.

Fig. 2 Common causes of hypercalcemia.
whole body bone scan failed to conclude either adrenal insufficiency or occult malignancy. Because of cautious exclusion of other causes and an excellent response to passive
mobility on paralyzed limbs, immobilization was confirmed
as the final cause of hypercalcemia.

Immobilization hypercalcemia mainly results from rapid
bone turnover and may be seen after spinal cord injury or
long bone fracture in children and adolescents.8 In the elderly
population, immobilization hypercalcemia is usually a sequela of cerebrovascular accident and is easily misdiagnosed

Southern Medical Journal • Volume 99, Number 4, April 2006

373

Cheng, Chou, and Lin • Immobilization Hypercalcemia in a Stroke Patient

due to several pitfalls related to poor nutritional and inflammatory status with low serum albumin and 25(OH)D3 levels.
Disturbed consciousness in a recent stroke patient may be
easily attributed to intracranial events, such as a new infarction, hemorrhage, or infection.
The exact mechanisms of immobilization hypercalcemia
remain elusive. Loss of mechanical stress (mechanostat theory) has proven critical for bone loss.9 Another proposed
mechanism is the acidic environment created by low blood
flow that may impair mineralization of bone and increase
PTH activity.10,11 Overall, increased osteoclastic bone resorption and decreased osteoblastic bone formation are hallmarks
in bone biopsy.
The serum calcium level in immobilization hypercalcemia depends on the rate of bone resorption and the capacity
of renal calcium excretion. In the bone resorptive aspect, the
speed of bone mineral density (BMD) loss in first-year stroke
patients is determined by age of onset, severity and duration
of paralysis, baseline serum Ca and 25(OH)D3 concentration.12 Resumption of walking within 2 months after the stroke
may reduce the BMD loss rate.13 In renal calcium handling
aspects, the median interval between initiation of immobilization and onset of hypercalcemia had been reported as 4
weeks, but may extended to 16 weeks in patients with normal
renal function.3 When the capacity of calcium excretion decreases in patients with chronic renal insufficiency or uremia,
the interval is shortened, with a reported range from 3 to 16
days.4,5 Similarly, our patient developed hypercalcemia 10
days following a stroke.
Hypercalcemia itself can induce acute impairment of renal function via afferent glomerular arteriolar vasoconstriction, volume depletion, and nephrocalcinosis and then in turn,
compromise calcium clearance and accentuate the degree of
hypercalcemia.14 Irreversible renal failure can supervene if
the diagnosis is delayed. Hypercalcemia-induced acute exacerbation of chronic renal insufficiency was diagnosed in our
patient due to lack of rhabdomyolysis, nephrotoxic agents, or
other identifiable causes, and when correction of the hypercalcemia stabilized his renal function.
The therapeutic goals of immobilization hypercalcemia
are retardation of bone resorption and enhancement of renal
calcium excretion. Preliminary management includes discontinuation of medications that directly or indirectly lead to
hypercalcemia (eg, calcium tablets, calcitriol, vitamin D, lithium and thiazides), volume repletion and loop diuretic treatment, followed by antiosteoclastic agents. Bisphosphonate
has been proven to effectively reduce serum ionized calcium
and BMD loss in hemiplegic stroke patients.15 A passive
mobility or weight-bearing rehabilitative program is undoubt-

374

edly the curative treatment and should be instituted early.
Control of the underlying illness generating immobilization is
crucial to foster recovery or alleviation of immobilization.

Conclusion
Immobilization hypercalcemia should be kept in mind as
a differential diagnosis for stroke patients with unexplained
altered mentality and deterioration of renal function. Patients
with pre-existent renal function impairment carry a potentially higher risk and a shorter time to develop hypercalcemia.
Early diagnosis and prompt correction of immobilization hypercalcemia results in avoidance of unnecessary investigations, unwanted recurrences and potentially life-threatening
complications.

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