Hypercalcemia and

hypocalcemia
Skugor Mario M.D. FACE
Cleveland Clinic Foundation
IM Board Review, 2012
Case 1

Patient is 64-year-old CC male.

He was found to have serum Ca of 11.3 and
11.1 mg/dL on routine lab.
Albumin was 3.9 g/dL.
He has no complaints.
No history of kidney stones, PUD, HTN or
psychiatric difficulties.
Question 1

Which of the following labs you want

first?

A - PTH rp
B - iPTH
C - 25(OH) Vitamin D
D - Ionized Ca
E - 24 hour urine for Ca.
Hypercalcemia:

In outpatient setting most common reason

is primary HPT.
In inpatient setting most common cause is
HHM.

iPTH is most important initial lab that will

guide further management.
Case 1

iPTH was 35 ng/mL

Normal is 10-64 ng/mL

Question 2

What is the next best step?

A - Refer for parathyroidectomy

B - Order PTHrp
C - Order 1,25(OH) Vitamin D
D - Order parathyroid SESTAMIBI scan
E - Order 24 hour urine for Ca
Question 2

Patients iPTH is inappropriately normal.

He has primary HPT.
However, he needs further evaluation before
decision is made regarding need for
parathyroidectomy.
Case 1

Daily urinary excretion was measured at

474 mg/d (normal 150-300 mg/d).
His BMD showed hip T-score of -2.2 and
lumbar spine T-score of -1.8.
Indications for
parathyroidectomy
All patients younger than 50 years of age.
Patients with serum Ca level over 12 mg/dL.
Patients with complications (nephrolythiasis, PUD,
pancreatitis, nephrocalcinosis, hypercalcemic crisis).
Patients with hypercalciuria (>400 mg/d).
Creatinine clearance reduced >30% than age-matched
controls.
Reduction in BMD of the femoral neck, lumbar spine or
distal radius of more than 2.0 standard deviations below
age, sex and ethnically matched population(Z score < -
2.0).
Patients for whom medical surveillance is not possible
Asymptomatic primary
HPT Conservative treatment is for

All asymptomatic patients older than 50

years of age whose serum Ca level is
under 12 mg/dL.

Patients who are medically unfit for

surgical intervention.
Asymptomatic primary
HPT Conservative management
Avoid factors that aggravate hypercalcemia
Thiazides
Dehydration
Immobilization and prolonged bed rest
High calcium dietary intake
Promote moderate physical activity
Encourage hydration (6-8 glasses of water daily)
Follow serum Ca and urinary Ca every 6 months
Follow BMD every 12 months
Case 1

Patient underwent uneventful surgery.

Question 3

What is the most likely finding during the

surgery?
A - Four glands hyperplasia
B - Ectopic parathyroid adenoma
C - Adenoma of parathyroid in usual position
D - Parathyroid carcinoma
Question 3

Causes of primary HPT

85% have adenoma of the gland in usual

anatomic position.
10-12% have four gland hyperplasia.
<1% have parathyroid carcinoma
Rest are ectopic disease
Case 1

Day after parathyroidectomy patients

developed perioral tingling and
numbness in his fingertips.
Ca was checked and was 7.4 mg/dL
Ionized Ca was 1.03 mmol/L
Question 4

What is the most likely reason for his

hypocalcemia?

A - Post surgical hypoparathyroidism

B - Preexisting vitamin D deficiency
C - Hungry bone syndrome
D - Soft tissue calcifications
Laboratory evaluation
Intact PTH assay

Suppressed Elevated/high normal

Primary HPT
PTH-rP
FHH
Elevated Not elevated
Malignancy Lithium
Vitamin D metabolites

Elevated 1,25 OH D Elevated 25 OH D Low 1,25 OH D

Granulomatous disease Vit D intoxication Malignancy
1,25 OH D intake Thyrotoxicosis
Lymphoma Pagets disease
Immobilization
Milk-alkali syndrome
Humoral hypercalcemia
of malignancy
Usually, it is related to PTH related peptide (elevated
in about 90% of patients with solid tumors and HHM.)
Others have multiple myeloma or osteolytic
metastases.
PTH-rp has close homology with PTH (AA 1-13)
It binds to PTH receptor and stimulates adenylate
cyclase activity
Levels are undetectable in normal individuals (and in
primary HPT).
Intestinal hyperabsorption
of Ca
Vitamin D overdose (25 OH D)
Calcitriol overdose (1,25 OH D)
Milk-alkali syndrome
Granulomatous disorders
Sarcoidosis
Tuberculosis
Beryliosis
Histoplasmosis
Coccidioidomycosis
Lymphomas
Vitamin D intoxication

Calcidiol - 25(OH) Vitamin D.

Calcidiol is biologically active and if taken in large
quantities it can directly increase intestinal Ca
absorption.

It also displaces calcitriol from proteins and

increases its free level

It is fat soluble and causes prolonged

hypercalcemia.
Vitamin D intoxication

Calcitriol 1,25(OH) Vitamin D

Calcitriol is short acting and hypercalcemia lasts

2-3 days.

Hydration and stopping the calcitriol is usually all

that is needed for therapy.
Granulomatous diseases

Macrophages express the same 1- hydroxylase that

produces calcitriol as kidneys have.
However, it is not regulated by PTH or calcium levels.
Uncontrolled production causes Vit D intoxication.

Treatment consists of steroid administration.

30 mg/d of prednisone for benign diseases
60 mg/day for cases caused by lymphomas.
Effect seen in 7-10 days.
Familial hypocalciuric
hypercalcemia (FHH)
Rare but important clinically.

Inactivating mutation of CSR gene.

This results in higher set point for serum Ca

(higher Ca is needed to suppress PTH).

Higher Ca is needed to reduce Ca

reabsorption in collecting tubule.
Familial hypocalciuric
hypercalcemia (FHH)
Condition is typically asymptomatic
Hypercalcemia is not sensed by target organs
PTH is usually normal or minimally elevated
And this is the problem they are diagnosed
as primary HPT and sent for
parathyroidectomy, which, of course, cannot
cure hypercalcemia.
Some patients undergo several surgeries.
Treatment of
symptomatic hypercalcemia
Initial therapy

Begin saline infusion (1-3 L per day)

Administer salmon calcitonin (4 U/kg)
every 12 hours
Begin infusion of bisphosphonate
(Pamidronate or Zolendronate)
Treatment of
symptomatic hypercalcemia
Continuation of therapy
Check serum Ca++ after 4 hours
If falling, continue salmon calcitonin (4
U/kg) every 12 hours for 72 hours.
If unchanged, add furosemide (80 mg IV
every 12 hours) and replace urine volume
alternating 0.9% and 0.45% saline with
10-20 meq/L of potassium.
Bisphsphonate treatment
Pamidronate - 30-90 mg IV over 4-24 hours.
Mild hypercalcemia (<13 mg/dL) - 30 mg
Moderate hyperCa (13-15 mg/dL) - 60 mg
Severe hyperCa (>15 mg/dL) - 90 mg

Zoledronate 4 mg IV over 15 minutes.

Dose should be reduced by 50% in patients with renal

insufficiency.
In HHM doses may need to be given every 3-4 weeks.
Hypocalcemia
More common causes are:

Hypoparathyroidism
Deficiency of abnormal metabolism of Vit.D.
Hypomagnesemia
Renal failure
Because of hyperphosphatemia and inability to
activate vitamin D.
Hyperphosphatemia of any cause
Hypocalcemia
Other causes are:
Intravascular binding (chelation)
Citrate, EDTA, foscarnet, lactate
Pancreatitis (saponification)
Sepsis (Ca++ is usually normal)
Chemotherapy
Cisplatin, 5FU, leucovorin
Hypocalcemia
Symptoms
Tetany (repetitive discharges after single stimulus)
Seizures (even without tetany)
Extrapyramidal symptoms
Papilledema
Psychiatric symptoms
Myopathy
Prolonged QT interval, hypotnesion, CHF
Achlorhydria
Hypoparathyroidism
Lack of PTH glands
Idiopathic (usually autoimmune)
Isolated
As a part of autoimmune polyglandular syndrome.
Post-surgical (the most common form)
After radiation therapy
Metal overload syndromes (Cu, Fe)
Granulomatous or neoplastic infilration.
Relative hypoparathyroidism (hungry bone
syndrome).
Aplasia of parathyroid glands
Hypoparathyroidism due
to impaired PTH action
Hypomagnesemia
Pseudohypoparathyroidism
Postreceptor resistance to PTH action
Several variants exist
Clinical picture of hypocalcemia is associated with
normal or elevated PTH levels.
Hypoparathyroidism

Hypocalcemia
Hyperphosphatemia
Low or low-normal 1,25(OH)VitD
Low or absent iPTH (except in PTH resistance
syndromes)
24 hour Ca excretion is low but higher than
expected for the level of hypocalcemia.
Hypoparathyroidism
treatment
Main therapy consist of administration of Ca
and Vitamin D.
1 hydroxylated forms of Vitamin D (1(OH)Vit-
D and 1,25(OH)Vit-D) are preferred because
of:
Relatively short duration of action
No need for PTH dependent hydroxylation
Hypoparathyroidism
treatment
Typical doses are:

0.25-1.0 mcg of calcitriol per day

1000-3000 mg of Ca per day

THIS ARE ONLY ROUGH GUIDELINES

Increasing calcitriol dose is more effective

than increasing Calcium dose.
Hypoparathyroidism
treatment
Calcium level needs to be as close to
normal as possible while avoiding
hypercalciuria.
Risk of nephrolithiasis and
nephrocalcinosis.
Hypoparathyroidism
treatment
Goal is to maintain Calcium level as close as
possible to 8.0 mg/dl.
Urinary calcium excretion should be
measured when Ca is satisfactory.
If hypercalciuria is detected thiazide diuretic
may be added to diminish Ca excretion and
further raise serum Ca level (may decrease
Ca excretion up to 150 mg per day).
Hypocalcemia associated
with Vitamin D deficiency
Vitamin D deficiency rarely causes
hypocalcemia.
Reason is development of secondary
HPT.
This causes increased renal tubular Ca
reabsorption and increased mobilization
of Ca from the skeleton.
Hypocalcemia associated
with Vitamin D deficiency
This results in:
Normal Ca level
Low phosphorus
Elevated alkaline phosphatase
Increased iPTH
Low 25(OH)Vitamin D
Normal 1,25(OH)Vitamin D
It is important to recognize this and not to mix
with primary HPT.
Hypocalcemia associated
with Vitamin D deficiency
Hypocalcemia develops only if Vit D
deficiency is long lasting and associated with
prolonged dietary Ca deficiency.

Treatment is Vit D and calcium

supplementation
Any form of Vit D can be used.
Question 5

A 64-years-old Caucasian female had a

non-traumatic compressive vertebral
fracture.
2 months before fracture DEXA showed
her LS-spine t-score to be -1.2 and left
hip t-score to be -0.9.
Question 5:

Labs:

iPTH - 42 ng/mL (10-64 ng/mL)

Corrected Ca 9.1 mg/dL (8.5-10.5 mg/dL)
25(OH)Vit D 48 ng/mL (9-52 ng/mL)
24-hour-ur Ca 212 mg/d (100-250 mg/d)
Question 5:

What is most likely diagnosis?

A. Osteomalacia
B. Primary hyperparathyroidism
C. Postmenopausal osteoporosis
D. Low bone mineral density secondary to
sprue disease
E. Primary hypercalciuria
Primary osteoporosis is a systemic skeletal
disease characterized by low bone mass and
micro-architectural deterioration of bone tissue,
with a consequent increase in bone fragility and
susceptibility to fracture.
Pathophysiology:
Moderate
Pathophysiology: Severe
Normal Osteoporosis Osteoporosis
high
highmetabolic
metabolicactivity
activityfrom
fromloss
lossof
ofestrogen
estrogenprotection
protection

increased
increasednumbers
numbersand
andactivity
activityof
ofosteoclasts
osteoclasts

bone
bonedestruction
destruction

Definition: Consensus Development Conference. Am J Med. 1993;94:646-650

Images: Courtesy Dr. A. Boyde, London
Diagnosing primary
osteoporosis
Clinical diagnosis is based on two
data streams
radiological data
non-invasive measurement of bone mass
(bone mineral densitometry)

laboratory data
Normal Ca, iPTH, Vitamin D etc.
Low bone mass -most
accurate predictor of
increased risk of fracture
Osteoporosis:

Heel US.
Screening tool

T-score - 0.5 or
less need DEXA.
Bone Measurement Techniques

Significant
Technique Precision (%) change (%)

Spine DEXA 1 3
Hip DEXA 1.5 4
Q-CT 3 8
p-DEXA 2 5
Ultrasound 4 11
Interpreting T-scores
(WHO) Young normal scores

OSTEOPOROSIS LOW BONE MASS NORMAL

("Osteopenia") BONE MASS

-4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 +0.5 +1

T-score
 Vertebral Fracture Rates
by T-score
50
Fracture Rate Per 1,000 Person-Years

45

40

35

30

25

20

15

10

0
> 1.0 1.0 to 0.5 to 0.0 to 0.5 to 1.0 to 1.5 to 2.0 to 2.5 to 3.0 to <3.5
0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Caucasian women; BMD at all sites combined.
*Defined by the World Health Organization (WHO).
T-score
WHO technical report series 843, Geneva 1994.
 Hip Fracture Rate by T-
score
14
Fractures Per 1,000 Person-Years
12

10

0
1.25 0.75 0.25 0.25 0.75 1.25 1.75 2.25 2.75 3.25

Caucasian women; BMD at all sites combined.

BMD Groups
Data available on request from Merck & Co., Inc. Please
specify DA-FOS72(1).
Caveats about the T-
score
surrogate marker for destroyed bone
applicable only to population it was derived from

misleading in other circumstances (pre menopausal women,

secondary diseases, etc.)

t-score - 2.5 s.d.

equals
T-scores and Z-scores

Compared to young normal individuals

(T-scores) identify patient at risk for
osteoporosis
Age-related scores ( Z-scores) identify
patients who lost bone mass to a greater
degree than accounted for by age alone.
It is referenced to age matched peers.
Usually implies a secondary cause.
 160 T = -2.5

Fracture risk per 1000 person-years

Age (years)

80+
140
Hui et al., J
Clin Invest,
1988
120
75-79
100

80 70-74

60 65-69

40 60-64

55-59
20 50-54
45-49
<45
0
>1.0 0.90 0.80 0.70 0.60 <0.60
-0.99 -0.89 -0.79 -0.69
Bone mass (g/cm2)
Secondary causes of
osteoporosis
Endocrine - Cushings disease,
hyperparathryoidism, hypogonadism

Gastrointestinal - malabsorption, cirrhosis, IBD

Renal - insufficiency and failure

Pulmonary - treatment or disease

Drugs - steroids, anti-gonadotrophins,

anticonvulsants
Secondary causes of
osteoporosis
Nutritional - alcohol, tobacco, eating disorders

Neoplasia - blood derived malignancies

Neurological - atrophy/weakness

Metabolic

Genetic
Question 6:

Three months after start of treatment for

osteoporosis markers of bone turnover
were checked and following changes
were noted:
Urinary N-telopeptide did not changed
significantly.
Bone specific alkaline phosphatase elevated
significantly.
Osteocalcin level increased significantly
Question 6:

Which of the following compounds used

for treatment of osteoporosis is most
consistent with these changes?
A. Intravenous bisphosphonates.
B. Oral bisphosphonates
C. Estrogen
D. Calcitonin
E. Recombinant human PTH(1-34)
Therapy for primary
osteoporosis
anti-resorptive and anabolic
drugs
Drug classes
Anti-resorptives Anabolic agents

calcium/ vit D PTH (1-34)

estrogens
PTH (1-84)
SERM-s
PTH rp
bisphosphonates
etc.
calcitonin
denosumab
Bone remodeling cycle
Resorption phase antiresorptive agents act by decreasing size
of resorption cavity formed by activated osteoclasts.

Lining cells

Osteoclasts

Resorption depth

Bone tissue
Bone remodeling cycle
Formation phase

Osteoblasts

Newly synthesized osteoid

Bone tissue
Bone remodeling cycle
Formation phase

Osteoblasts

Uncalcified osteoid
Newly calcified osteoid
Bone remodeling Cycle
End of remodeling cycle Anabolic agents increase formation
and produce net increase in bone mass instead of deficit with
each remodeling cycle
Lining cells

Osteoporotic filling deficit

Newly formed bone

Bone tissue
Antiresorptives and
Fracture Reduction
Calcium and vitamin D
analogs
SERMs
Estrogens
Calcitonin
Bisphosphonates
Denosumab
Ca and Vit D analogs:

In elderly women with osteoporosis 1200

mg of Ca per day and Vit D 800 IU/d for
18 months:

43% fewer hip fractures

32% fewer non-vertebral fractures

Benefits were maintained at 36 months

Chapuy MC, Arlot ME, Duboeuf PD, et al. NEJM 327:1637-42, 1994.
 How Much Calcium is
Enough?
Children Adolescents Adults Elderly
US RDA 800 mg/d 1200 mg/d 800 mg/d 800 mg /d
Consensus None 1200 mg/d 1000 1500 mg/d
conference provided mg/d
Ca
NIH 800-1200 1200-1500 1000 <65 on
consensus mg/d mg/d mg/d HRT 1000
conference mg, all
others
1500 mg/d
SERMs (Raloxifene):

Selective estrogen receptor modulators

Not a hormone
No effect on breast or uterine receptors
Reduction in vertebral fractures
May prevent breast cancer and cardiovascular
disease
Does not prevent hot flashes, leg aches
Daily, 120 mg PO dose with or without food
SERM-s (Raloxifene):

Dose of 120 mg/d in 2277

postmenopausal osteoporotic women
over 36 months reduced vertebral
fractures.
40% in those with no preexisting vertebral
fracture.
50% in those with prevalent vertebral
fracture.

Ettinger B, et al. JAMA. 1999;282:637-645.

Estrogen:
In 1976 Estrogen was shown to increase
metacarpal bone mineral content.
Lindsay R et al, Lancet 1976 May 15;1(7968):1038.

Fracture reduction of about 35% has been

shown at hip and lumbar spine.

FHI study revealed unexpected risks and

estrogen should not be used for osteoporosis
prevention or treatment.
Risks of Estrogen Replacement

FHI study results*:

Placebo HRT
Vertebral fx 16 10
Hip fx 15 10
CVA 21 29
Breast cancer 30 37
Coronary events 30 37
Vasc. Thrombosis 16 34

*events per 10,000 women/years.

 Vertebral Fracture Reduction
with Calcitonin
Fracture
Study (yr) Calcitonin Placebo

PROOF 3 33/270* 50/253

(12%) (20%)
Overgaard 2 4/124 6/40
(3%) (15%)
Gennari 1 10/30 11/15
(33%) (73%)
*p<0.01
Calcitonin:

Most commonly administered as a nasal

spray.
SC injection is available, too (used
uncommonly)

Calcitonin has analgesic effect on bone

pain.
Bisphosphonates
Alendronate, Risedronate, Ibandronate,
Zoledronte, Pamidronate are available
Used orally (first three), daily weekly and
monthly.
Used IV Zoledronate 5 mg IV over 15
min once a year.
Prevention and treatment, reduction of
vertebral and hip fractures
Used in GIOP, and in men
GI side effects with PO administration
Bisphosphonate -
fractures
Alendronate in pts with low hip BMD and
prevalent vertebral fx:
55% reduction in clinically apparent vertebral fx.
51% reduction in hip fractures.
48% reduction in wrist fractures.

Risedronate reduced vertebral fractures:

65% in all patients. Black DM et al, Lancet 1996;348:1535.
74% in high risk patients.

Zoledronate reduced fractures:

77% vertebral fractures in all patients
41% hip fractures in all patients
Harris ST, et al. JAMA. 1999;282:1344-1352
Denosumab

Binds to the RANKL and prevents its

binding to RANK which inhibits
octeoclasts activation.
Mimic the action of OPG
(osteoprotegerin)
Fracture risk reduction is similar to
zoledronic acid and teriparatide.
Given by SC injection twice a year
Anabolic agents increase
bone formation and
remodeling

hrPTH (1-34) Forteo

hrPTH (1-84)

PTHrp
 3-D Structural Indices
P<0.001
Trabecular bone volume
Increases

P<0.025
Structure model index Decreases

P<0.034
Connectivity density
Increases

P<0.012
Cortical thickness
Increases

Eriksen et al. ACR 2002

rhPTH and fx reduction:

In 1637 postmenopausal osteoporotic

females 20 mg of rhPTH daily by SC
injection over 21 months in average:

65% reduction in vertebral fractures.

53% reduction in nonvertebral fractures.

Neer RM, et al. N Engl J Med. 2001;344:1434-1441.