Calcium Metabolism Disorders 6.

03b
Lecturer: Dr. Rosario
Date: April 25, 2018

OUTLINE
I. Osteoporosis
A. Definition
B. Epidemiology
C. Different types of fractures
D. Normal Bone process throughout life
E. Pathophysiology
F. Measurement of bone mass
G. Fracture Risk Assessment Tool
H. Preventive and Treatment Measures
II. Hypercalcemic Disorders
A. Manifestations
B. Approach to Hypercalcemia
C. PTH Dependent Hypercalcemia
D. Malignancy Related Hypercalcemia
E. Vitamin D Related Hypercalcemia
F. Hypercalcemia Associated With High Bone Turnover
G. Hypercalcemia Associated with Renal Failure
H. Treatment of Hypercalcemic States
III. Hypocalcemic Disorders
A. Manifestations
B. Transient Hypocalcemia
C. Functional Classifications
D. PTH Absent
E. Pseudohypoparathyroidism
F. PTH Overwhelmed Figure 1. Case 1 Radiograph
IV. Mini Quiz
V. Appendix I. Osteoporosis

Legend: A. Definitions
Remember Previous Trans
Lecturer Book
(Exams) Trans Com 1. Osteoporosis
      Reduction in bone strength with an increased risk for
fractures
CASE 1  Operational Definition: Bone Density that falls 2.5 SD
below the mean for young healthy adults of the same sex.
RR is 40-year old female, Filipino, single, works as a  T score is -2.5
librarian, who currently lives in Malabon City. She was
admitted at our institution for back pain. 2. Osteopenia
1 month PTA, she was riding a tricycle which came across a  Increased risk for developing Osteoporosis and fractures
pothole on the road. She complained of right rib and back
 Bone Density that falls at the lower end of the young
pain after the said incident. She sought consult with an
normal range
Orthopedic Surgeon and thoracic cage and lumbosacral x-
 T score < -1.0
ray were requested revealing old fracture deformities with
 T score is less than -1.0 to -2.5
evidence of callus formation, right 7th lateral and left 4th-6th
lateral rib and compression fracture of L1 and L2 vertebrae.
Patient developed fracture after a low-force trauma. What B. Epidemiology
predisposes her to increased fracture risk? Maybe, she has
osteoporosis.  9 million Osteoporosis versus 48 million Osteopenia
Pertinent Past Medical History: Diagnosed with Cushing’s  More than 50% of fractures occur in osteopenia.
Syndrome Why? There are more cases of osteopenia.
 Risk of osteoporosis increases after age 50 for women
because of decrease in estrogen (menopause)
 Distal radius fractures: before age 50
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 Hip fractures: rates double every 5 years after age 70  Non-Vertebral Fractures
o Wrist: 400,000/year
o Pelvis: 135,000/year
o Fractures of other bones: 675,000/year (estimated)

D. Normal Bone Processes

Figure 2. Epidemiology of vertebral, hip and Colles’ fracture with

age. More fractures at distal area occur before 50 years old. After
70 years old, there is a sharp increase in the hip fractures. This due to
the way we fall. Before age 50, we fall on an outstretched hand but
when we are old, we fall directly on our hip.

C. Risk Factors for Fractures

Figure 4. Mechanism of bone remodeling (from Harrison’s 19th

Figure 3. Factors leading to osteoporotic fractures. What
predisposes a patient to osteoporosis? 1) Propensity to fall from
chronic diseases such as dementia, parkinsons. 2) Poor bone quality
due to chronic diseases such as rheumatoid arthritis and 3) low bone
density which can be due to low peak bone mass (example: decrease
physical activity) and increased bone loss (occurs in menopause and
other risk factors). See Appendix 1 for a table of conditions, diseases,
and medications that contribute to osteoporosis and fractures.
Ed). A. Origination of BMU-lining cells (basic molecular unit) contracts
to expose collagen and attract preosteoclasts. B. Osteoclasts fuse into
multinucleated cells that resorb a cavity. Mononuclear cells continue
resorption, and preosteoblasts are stimulated to proliferate. C.
Osteoblasts align at bottom of cavity and start forming osteoid (black).
D. Osteoblasts continue formation and mineralization. Previous osteoid
starts to mineralize (horizontal lines). E. Osteoblasts begin to flatten. F.
Osteoblasts turn into lining cells

 Vertebral Fractures
o 550,000/year (more common compared to Non-
Vertebral Fractures)
o 1/3 recognized clinically, 2/3 asymptomatic
o Height loss, Kyphosis, secondary back pain
 Suspect a vertebral fracture
o Thoracic fractures may present with restrictive lung
Figure 5. Normal Bone Process throughout life
disease
o Lumbar Fractures presents with abdominal distention,  Pre-puberty: Linear growth and modeling
early satiety, constipation  Puberty: Increased sex hormone production that leads to
skeletal maturation
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 Adulthood: Peak mass achieved; Bone Remodeling and 1. When to Measure Bone Mass
at age 30-45: Resorption predominates formation  Women age 65 and older and men 70 and older,
 Menopause: Decrease in estrogen  resorption further regardless of clinical risk factors
predominates formation  Younger postmenopausal women, women in the
menopausal transition and men age 50-69 with clinical risk
E. Pathophysiology of Osteoporosis factors for fracture
 Adults who have a fracture after age 50
1. Pathophysiology  Adults with a condition (rheumatoid arthritis) or taking a
medication associated with low bone mass or bone loss
o Example: glucocorticoids daily dose > 5 mg of
prednisone (or equivalent) for > 3 months
 This costs around 5,000-10,000 Php, not really cheap so
you have to identify who are at risk.

2. How to Measure Bone Mass

 Single Energy Xray Absorptiometry, CT scan and
Ultrasound
 Dual Energy Xray Absorptiometry
o Standard for measuring bone density at the lumbar
spine and hip
o Bone spurs – false increase in spinal density
o T score below -2.5 in the lumbar spine, femoral neck
Figure 6. Pathophysiology of Osteoporosis.
or total hip
What increases your risk for Osteoporosis? o Vertebral Fracture assessment: to screen for
o Inadequate Calcium and Vitamin D stores undiagnosed Vertebral Fracture
o Low estrogen status  What we usually use.
o No Physical activity
o Presence of Chronic Diseases
o Use of certain medications like steroids and excessive
 Intake of levothyroxine producing iatrogenic
thyrotoxicosis
o Cigarette smoking. If you’re a smoker, you reach
menopause earlier by 2 years

2. Gucocorticoid Induced Osteoporosis

 Bone loss rapid in the early months = increased fracture
risk within 3 months
 Affects trabecular bone more severely but increases
fracture risk in both axial and appendicular
 Bone loss can occur with any route (high dose inhaled and
intra articular) Figure 7. Dual energy X-ray absorbtiometry device
 Pathophysiology:
o Inhibits osteoblast function  The WHO has established the following definitions based
o Promotes osteoblast apoptosis on BMD (bone mass density) measurement at the spine,
o Stimulates bone resorption hip or forearm by DXA devices
o Impairs intestinal absorption of calcium o Normal: BDM is within SD of a young normal adult (T-
o Promotes urinary calcium loss score at -1.0 and above)
o Low bone mass “osteopenia”: BMD is between 1.0
o Suppression of estrogen and androgen secretion
and 2.5 SD below that of a young normal adult (T-
o Induces myopathy – increased risk for falls
score between -1.0 and -2.5)
o Osteoporosis: BMD is 2.5SD or more below that of a
F. Measurement of Bone Mass
young normal adult (T-score at or below -2.5).
Patients in this group who have already experienced
one or more fractures are deemed to have severe or
established osteoporosis
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 o Note that although these definitions are necessary to
establish the presence of osteoporosis, they should
not be used as the sole determinant of treatment
decisions

Table 1. BMD Measurement Summary

T score
Normal -1.0 and above
Osteopenia -1.0 to -2.5
Osteoporosis </= to -2.5

Figure 9. Fracture Risk Assessment Tool.

H. Preventive and Treatment Measures

1. Preventive and Treatment Measures

 Acute Management of Fractures
o Surgical repair
Figure 8. Bone density graph o Pain control
 Risk Factor Identification and Management
G. Fracture Risk Assessment Tool
 Fall Risk assessment and Management
 Encourage Exercise and Lifestyle changes
 Estimates 10 year probability of hip fracture and Major
Osteoporotic Fracture (MOF)
 Nutritional Recommendations
 Applicable for ages 40-90 years old o Calcium:
 Clinical risk factors: Age, sex, weight, height, previous  Preferred source is dairy products and fortified
fracture, parent fractured hip, current smoking, foods
glucocorticoids, rheumatoid arthritis, secondary  Calcium supplements – taken less than 600 mg
osteoporosis, alcohol and Femoral Neck BMD at a time
 Femoral BMD using DXA  Screen for contraindications – kidney stones
 Country specific FRAX prediction algorithms are available o Vitamin D
 National Osteoporosis Foundation Guide  Target serum 25(OH)D of 30 ng/ml
Recommendations (US)  Recommended Daily Intakes
o 10 year risk Hip Fracture > 3% Table 2. Calcium Recommended Daily Intake
o 10 year risk MOF > 20% Age Amount
1-3 years old 500 mg/d
4-8 years old 800 mg/d
9-18 years old 1300 mg/d
19-50 years old 19-50 years old – 1000 mg/d
> 50 years old > 50 years old – 1200 mg/d

Table 3. Vitamin D Recommended Daily Intake

Age Amount
< 50 years old 200 IU
50-70 years old 400 IU
> 70 years old 600 IU

2. Pharmacologic Preventie and Treatment Measures

a. Estrogens
 Fracture Data:
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 o 50% reduction including hip fractures
o Greatest benefit: started replacement early and
continued the treatment
 Mode of action
o Indirect action by decreasing IL-1, IL-6, TNF alpha
and osteocalcin synthesis and increasing IGF1 and
TGF B (promotes anabolic processes)
o May inhibit osteoclast action directly Table 5. Oral Preparations of Different Bisphosphonates

 For the patient case presented: you can give Alendronate

and Risendronate (prevention steroid induced)
 All three can be used for prevention post-menopause
 Prevention of steRoid induced: Risedronate
 Treatment for Men: Alendronate and Risedronate
 Yearly preparation: Zolendronic Acid

c. Other medications
 Calcitonin
o Administration: Nasal Spray
Figure 10. Hormonal control of bone resorption. Proresorptive and o MOA: Acts on calcitonin receptor on the osteoclasts,
calciotropic factors. suppressing its activity (anti-resorptive)
 A study was done and it look at the effect of estrogen o Prevention: not indicated
plus progestin. In about 16,000 postmenopausal o Treatment: only in osteoporosis in women >5 years
women. There was a reduction in hip and clinical post menopause
spine fractures by as much as 34%. How about the o May have analgesic effect for bone pain in acute
adverse effects? For patients on this regimen, they
vertebral fractures
have this additional events, coronary heart
 Denosumab
diseases, stroke, breast cancer, venous
o Administration: Subcutaneous twice a year
thromboembolism  (discuss with your patients).
o MOA: binds to RANKL, inhibiting its ability to initiate
osteoclast maturation (anti-resorptive)
b. Bisphosphonates
o Prevention: not indicated
 What is usually given
o Treatment: indicated in postmenopausal women and
 Mechanism of action
men at high risk
o Structurally related to pyrophosphates, which are
o Effects rapidly reversible and bone lost will occur
incorporated into the bone matrix
once stopped
o Impair osteoclast function
o Induce osteoclast apoptosis
 Parathyroid hormone (Teriparatide)
 Instructions for intake (oral preparations)
o Administration: 20ucg subcutaneous daily for 2 years
o Taken on an empty stomach before breakfast
max
o Given with a full glass of water o MOA: increases bone mass and mediates
o Remain upright for at least 30 minutes after taking architectural improvement; direct action on
the medication to avoid esophageal irritation  it osteoblasts
can produce esophagitis o Treatment: indicated in both men and women at high
o For ibandronate only: No food or drink (other than risk
water) for 1 hour after intake
Table 4. Different Bisphosphonates First 2 agents are antiresorptive, while teriparatide is
anabolic.

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 II. Hypercalcemic Disorders

CASE 2

NN is a 42-year old female

 Elevated calcium levels
o Ionized calcium 1.47; (Normal Value = 1.1-1.35)
 Intact PTH at 113 (NV = up to 85)
 History of recurrent urolithiasis
 Bone mineral density was below normal for her age
 Sestamibi scan showed parathyroid gland enlargement

Figure 11. Algorithm of Hypercalcemia Evaluation

C. Classification of Hypercalcemic Disorders

Table 6. Different causes of Hypercalcemia

A. Manifestations

 Symptoms: Fatigue, depression, mental confusion,

anorexia, nausea, vomiting, constipation, reversible renal
tubular defects, increased urination, short QT interval in
the ECG, and, in some patients, cardiac arrhythmias
 Symptoms maybe non-specific but at certain levels
symptoms occur and may affect the kidneys and
heart)
 Calcium Levels
o >2.9–3 mmol/L (11.5–12.0 mg/dL) – Appearance of
symptoms
o >3.2 mmol/L (13 mg/dL) – Calcification in kidneys,
skin, vessels, lungs, heart, and stomach occurs and
renal insufficiency may develop
o ≥3.7–4.5 mmol/L (15–18 mg/dL) – Medical
emergency; coma and cardiac arrest can occur

B. Approach to Hypercalcemia

 The first thing you have to do when presented with

hypercalcemia  Repeat testing the calcium and make
sure it is truly elevated
 Next, look at the duration. An acute duration with high PTH
levels  Consider primary hyperparathyroidism but if PTH
is low consider malignancy.
 Hyperparathyroidism and cancer account for 90% of cases
(for your initial work-up focus on these entities)
D. PTH Dependent Hypercalcemia

1. Primary Hyperparathyroidism
 Most important out of the three (PTH Dependent
Hypercalcemia). There is increased secretion of PTH. This
leads to elevated levels of calcium and low levels of
phosphate.
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 Increased secretion of PTH leading to hypercalcemia and
hypophosphatemia.
 Classic Hyperparathyroidism vs Asymptomatic
Hyperparathyroidism
o Classic Manifestations: recurrent nephrolithiasis,
peptic ulcers, mental changes, extensive bone
resorption.
o Nowadays, what we are seeing is more of the
asymptomatic hyperparathyroidism. Why? Figure 13. Salt and Pepper X-ray of the skull
Because of increased screening for calcium.
 Annual incidence: as high as 0.2% in patients >60 years, b. Renal Features
with an estimated prevalence of ≥1%
 Renal stones
 Peak incidence between the third and fifth decades; but o Calcium oxalate or calcium phosphate
occurs in young children and in the elderly.
 Clinical manifestations
o Recurrent calcium nephrolithiasis
 Causes:
o Nephrocalcinosis
o Usually benign neoplasm or adenoma and rarely a
o Impaired concentrating ability
parathyroid carcinoma
o Solitary Adenomas
 A single abnormal gland is the cause in ~80% of c. Gastrointestinal Features
patients  Non-specific complaints such as anorexia, nausea,
 Usually a benign neoplasm or adenoma and vomiting, constipation, abdominal pain
rarely a parathyroid carcinoma  Duodenal Ulcers in MEN1 - Excessive Gastrin (ZES)
o Parathyroid Carcinomas rather than HPT
 Most often not aggressive  Peptic ulcer disease
 Clinical clue: higher calcium values 3.5-3.7  Pancreatitis
mmol/L (14-15 mg/dL)
o Hereditary - MEN 1 (Wermer’s syndrome), MEN2A, d. Neuropsychiatric Features
Hyperparathyroidism Syndrome – Jaw Tumor  Correlate poorly with serum calcium concentration
Syndrome  Elderly persons are most likely to exhibit such symptoms
 Neuromuscular signs: proximal muscle weakness or
a. Skeletal Features atrophy, easy fatigability
 Osteitis Fibrosis Cystica o Complete regression after correction of
o Subperiosteal resorption – resorption of phalangeal hyperparathyroidism
tufts and irregular outlines of the digits
 Increase in giant multinucleated osteoclasts on histology e. Medical Management
 Others:  Maintain adequate hydration
o Salt and pepper Xray of the skull o Avoid diuretics
o Subperiosteal resorption of teeth o Seek prompt medical attention for volume-losing
o Radiographic “disapperance” of bones illnesses such as vomiting or diarrhea
o Clinical findings: Bone pain & tenderness, kyphosis,  Avoid prolonged immobilization
loss of height, pigeon breast  Limit dietary calcium to RDA of LESS THAN 800mg/day
 Oral contraceptives
 Selective Estrogen Receptor Modulators
 Bisphophonates
 Cinacalcet (Calcimimetic)
o Allosteric modulator of the calcium-sensing receptor
o Enhances the sensitivity of the CaSR to the prevailing
extracellular calcium

Figure 12. Subperiosteal resoprtion

f. Surgical Management
 Indications for Surgery:
o Kidney stones or nephrocalcinosis
o Fractures
o X-ray finding of osteitis fibrosa cystica

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 o Classic neuromuscular disease Elevated but lower
PTH Elevated
o life threatening or symptomatic hypercalcemia compared to PHPT
(recurrent)
 Indications for Surgery if asymptomatic:
o Serum Calcium: 1mg/dl above upper limit of normal
o Creatinine clearance: <60 ml/min 3. Lithium induced
o Age: <50 years  10% of Li treated patients have hypercalcemia
o Bone Marrow Density: T score < -2.5 at any site  May induce increase in gland size (adenomas)
and/or previous fragility fracture  Induces hypercalcemia by shifting the curve to the right
 Parathyroid Surgery o Higher calcium needed to lower PTH secretion
o Pre op location with Sestamibi scan with SPECT CT o Defect in CaSR
to locate the abnormal gland  Treatment: Replace Lithium
o Intraoperative serial sampling of intact PTH after
removal of suspect gland
o For multiple gland hyperplasia (familial cases)
 Removal of 3 and 1/2 glands OR
 Removal of all glands and transplant a portion of
one gland on the forearm

2. Familial Hypocalciuria Hypercalcemia

Figure 16. Lithium induces hypercalcemia by shifting the curve to

the right.

E. Malignancy Related Hypercalcemia

 Hypercalcemia due to malignancy is common,

occurring in as many as 20% of cancer patients, especially
Figure 15. FHH with certain types of tumor such as lung carcinoma
 It is often severe and difficult to manage, and, on rare
Table 7. PHPT vs FHH
occasions
Primary Familial  Although malignancy is often clinically obvious or readily
Hypoparathyroidism Hypocalciuria
detectable by medical history, hypercalcemia can
(PHPT) Hypercalcemia (FHH)
occasionally be due to an occult tumor
Autonomous secretion
Defect Abnormal CaSR  Hypercalcemia associated with malignancy is known to
of PTH
result from the elaboration by the malignant cells of
Renal
Calcium <99% >99%
humoral mediators of hypercalcemia
Reabsorption o PTHrP is the responsible humoral agent in most solid
 <100mg/day tumors that cause hypercalcemia
 >100mg/day
 Abnormal CaSR in  The histologic character of the tumor is more
24 hour Urine  Excessive calcium
Calcium
tubules leading to important than the extent of skeletal metastases in
overwhelms
increased predicting hypercalcemia
Excretion reabsorption
reabsorption of o Small-cell carcinoma (oat cell) and adenocarcinoma
capabilities
calcium
of the lung, although the most common lung tumors
Detectable in affected
associated with skeletal metastases, rarely cause
Family Rarely occurs before members of the
History 10 kindreds in the first hypercalcemia
decade of life o Squamous cell carcinoma of the lung develop
With previous history hypercalcemia
Past Medical No prior history of
History
of normal calcium
normal calcium levels
 Histologic studies of bone in patients with squamous cell
levels or epidermoid carcinoma of the lung, in sites invaded by
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 tumor as well as areas remote from tumor invasion, reveal the hypercalcemia should be judicious as high
increased bone resorption calcium levels can have a mild sedating effect
 Two main mechanisms of hypercalcemia are operative in  Standard therapies for hypercalcemia (discussed
cancer hypercalcemia below) are applicable to patients with malignancy
 Solid tumors associated with hypercalcemia,
particularly squamous cell and renal tumors, produce
and secrete PTHrP
 PTHrP that causes increased bone resorption
and mediate the hypercalcemia through systemic F. Vitamin D Related Hypercalcemia
actions on the skeleton
o Direct bone marrow invasion occurs with 1. Vitamin D Intoxication
hematologic malignancies such as leukemia,
 Chronic ingestion of 40 – 100 times the normal
lymphoma, and multiple myeloma
physiologic requirement of vitamin D (amounts >
 Lymphokines and cytokines (including PTHrP)
40,000 – 100,000 U/d) is usually required to produce
produced by cells involved in the marrow
significant hypercalcemia in otherwise healthy individuals
response to the tumors promote resorption of
 Upper limit of safe dietary intake is 2,000 U/d (50 μg/d) in
bone through local destruction
adults because of concerns about potential toxic effects of
 The etiologic factor produced by activated normal
cumulative supraphysiologic doses
lymphocytes and by myeloma and lymphoma
 Hypercalcemia in vitamin D intoxication is due to an
cells, originally termed osteoclast activation
excessive biologic action of the vitamin, perhaps the
factor, now appears to represent the biologic
consequence of increased levels of 25(OH)D rather than
action of several different cytokines, probably
merely increased levels of the active metabolite
interleukin 1 and lymphotoxin or tumor necrosis
1,25(OH)2D
factor (TNF)
o An increased level of the active metabolite is not
o In some lymphomas, there is a third mechanism,
necessary to produce this condition
caused by an increased blood level of 1,25(OH)2D,
 25(OH)D has definite, if low, biologic activity in the
produced by the abnormal lymphocytes
intestine and bone
 Humoral hypercalcemia of malignancy o The production of 25(OH)D is less tightly regulated
 Solid tumors (cancers of the lung and kidney, in
than is the production of 1,25(OH)2D
particular); in which bone metastases are absent,
o Concentrations of 25(OH)D are elevated several-fold
minimal, or not detectable clinically; produce and
in patients with excess vitamin D intake
secrete PTHrP measurable by immunoassay
 Secretion by the tumors of the PTH-like factor,
PTHrP, activates the PTH1R, resulting in a
pathophysiology closely resembling
hyperparathyroidism, but with normal or suppressed
PTH levels
 Clinical picture resembles primary
hyperparathyroidism (hypophosphatemia
accompanies hypercalcemia), and elimination or
regression of the primary tumor leads to
disappearance of the hypercalcemia
 Patients have elevated urinary nephrogenous cAMP
excretion, hypophosphatemia, and increased urinary
phosphate clearance; however, immunoreactive PTH
is undetectable or suppressed
 Other features of the disorder differ from those of true Figure 17. Vitamin D metabolism
hyperparathyroidism
 Treatment of Malignancy Related Hypercalcemia  Diagnosis is made by documenting elevated levels of
o First directed to control of tumor; reduction of 25(OH)D > 100 mg/mL
tumor mass usually corrects hypercalcemia  Treatment
 If a patient has severe hypercalcemia yet has a good o Hypercalcemia is usually controlled by restriction of
chance for effective tumor therapy, treatment of the dietary calcium intake and appropriate attention to
hypercalcemia should be vigorous while awaiting the hydration
results of definitive therapy o Discontinuation of vitamin D, usually lead to
 If hypercalcemia occurs in the late stages of a tumor resolution of hypercalcemia
that is resistant to antitumor therapy, the treatment of
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 o Vitamin D stores in fat may be substantial, and
vitamin D intoxication may persist for weeks after
vitamin D ingestion is terminated
 These patients are responsive to
glucocorticoids, such as hydrocortisone 100
mg/day (or its equivalent), which would return
serum calcium levels to normal over several days
2. Sarcoidosis and Other Granulomatous Diseases
(Tuberculosis and Fungal infections)
 Excess 1,25(OH)2D is synthesized in macrophages or
other cells in the granulomas
 Macrophages obtained from granulomatous tissue
convert 25(OH)D to 1,25(OH)2D at an increased rate
 Normally, there is no increase in 1,25(OH)2D with
increasing 25(OH)D levels due to multiple feedback
controls on renal 1α-hydroxylase; however, in
sarcoidosis there is a positive correlation between
25(OH)D levels (reflecting vitamin D intake) and the
circulating concentrations of 1,25(OH)2D
 The usual regulation of active metabolite production by
calcium and phosphate or by PTH does not operate in
these patients
 Clearance of 1,25(OH)2D from blood may be decreased
as well
 PTH levels are usually low and 1,25(OH)2D levels are
elevated, but primary hyperparathyroidism and sarcoidosis
may coexist in some patients
 Treatment:
o Treat primary disorder
 Presumably, the abnormal sensitivity to vitamin D
and abnormal regulation of 1,25(OH)2D synthesis
will persist as long as the disease is active
o Lower vitamin D supply
 Avoid excessive sunlight exposure
 Limit vitamin D and calcium intake
o Glucocorticoids, such as hydrocortisone 100 mg/day
(or its equivalent), may help control hypercalcemia
 Glucocorticoids act by blocking excessive
production of 1,25(OH)2D, as well as the
response to it in target organs
3. Idiopathic Hypercalcemia of Infancy ()
 Usually referred to as Williams’ syndrome
 A rare autosomal dominant disorder characterized by
multiple congenital development defects including
supravalvular aortic stenosis, mental retardation, and an
elfin facies, in association with hypercalcemia due to
abnormal sensitivity to vitamin D
 Levels of 1,25(OH)2D can be elevated, ranging from 150 –
500 pg/mL (46 – 120 nmol/L)
 Mechanism of the abnormal sensitivity to vitamin D and of
the increased circulating levels of 1,25(OH) 2D is still
unclear
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o Genetic mutations involving microdeletions at the
elastin locus and perhaps other genes on
chromosome 7
o 24-hydroxylase deficiency in infants and young
children impairs metabolism of 1,25(OH)2D
G. Hypercalcemia Associated with High Bone Turnover
1. Hyperthyroidism
 20% of hyperthyroid patients have high-normal or mildly
elevated serum calcium concentrations
 Hypercalciuria is common and is due to increased bone
turnover, with bone resorption exceeding bone
formation
 Severe calcium elevations are not typical, and the
presence of such suggests a concomitant disease such as
hyperparathyroidism
 Usually, the diagnosis is obvious, but signs of
hyperthyroidism may occasionally be occult, particularly in
the elderly
 Hypercalcemia is managed by treatment of the
hyperthyroidism
2. Immobilization
 A rarely seen in adults in the absence of an associated
disease
 More common in children and adolescents, particularly
after spinal cord injury and paraplegia or quadriplegia
 With resumption of ambulation, the hypercalcemia in
children usually returns to normal
 The mechanism appears to involve a disproportion
between bone formation and bone resorption; the
former decreased and the latter increased
 Immobilization of an adult with a disease associated with
high bone turnover, however, such as Paget’s disease,
may cause hypercalcemia
3. Thiazides
 Administration of benzothiadiazines (thiazides) can cause
hypercalcemia in patients with high rates of bone turnover
 Thiazides are associated with aggravation of
hypercalcemia in primary hyperparathyroidism, but
this effect can be seen in other high-bone turnover states
as well
 Chronic thiazide administration leads to reduction in
urinary calcium; the hypocalciuric effect appears to
reflect the enhancement of proximal tubular resorption
of sodium and calcium in response to sodium depletion
 Some of this renal effect is due to augmentation of PTH
action and is more pronounced in individuals with intact
PTH secretion
 Thiazides cause hypocalciuria in hypoparathyroid
patients on high-dose vitamin D and oral calcium
replacement if sodium intake is restricted
 Thiazide administration to normal individuals causes a
transient increase in blood calcium, usually within the high-
10 of 20
 normal range, that reverts to preexisting levels after a
week or more of continued administration
o If hormonal function and calcium and bone
metabolism are normal, homeostatic controls are
reset to counteract the calcium-elevating effect of
the thiazides
o In the presence of hyperparathyroidism or
increased bone turnover from another cause,
homeostatic mechanisms are ineffective
 The abnormal effects of the thiazide on calcium
metabolism disappear within days of cessation of the
drug
4. Vitamin A Intoxication
 A rare cause of hypercalcemia and is most commonly a
side effect of dietary faddism
 Calcium levels can be elevated into the 12 – 14 mg/dL (3 –
3.5 mmol/L) range after the ingestion of 50,000 –
100,000 units of vitamin A daily (10 – 20 times the
minimum daily requirement)
 Features of severe hypercalcemia include fatigue,
anorexia, and, in some, severe muscle and bone pain
 Excess vitamin A intake is presumed to increase bone
resorption
 The diagnosis can be established by history and by
measurement of vitamin A levels in serum, and skeletal x-
rays that reveals periosteal calcifications, particularly in the
hands
 Withdrawal of the vitamin is usually associated with
prompt disappearance of the hypercalcemia and reversal
of the skeletal changes
 Administration of 100 mg/d of hydrocortisone or its
equivalent leads to a rapid return of the serum calcium to
normal
H. Hypercalcemia Associated with Renal Failure
1. Severe Secondary Hyperparathyroidism
 Pathophysiology:
o Decreased vitamin D receptor (VDR) and calcium-
sensing receptor (CaSR)
o Elevated phosphate levels
o Low calcium levels
 Resistance to the normal level of PTH is a major
factor contributing to the development of
hypocalcemia, which, in turn, is a stimulus to
parathyroid gland enlargement
 Increase of FGF23 production by osteocytes, and
possibly osteoblasts in bone occurs well before an
elevation in PTH is detected
 FGF23 is a potent inhibitor of the renal 1-
alphahydroxylase
 FGF23-dependent reduction in 1,25(OH)2 vitamin
D seems to be an important stimulus for the
development of secondary hyperparathyroidism
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[MED II[Calcium Metabolism Disorders]
 Secondary hyperparathyroidism occurs not only in patients
with renal failure but also in those with osteomalacia due
to multiple causes, including deficiency of vitamin D action
and pseudohypoparathyroidism
o Hypocalcemia seems to be the common
denominator in initiating the development of
secondary hyperparathyroidism
o In secondary hyperparathyroidism, there is an
adaptive response of the parathyroids, which is
typically reversible; in contrast to primary
hyperparathyroidism, wherein there is autonomous
growth of the parathyroid glands
 Manifestations of secondary hyperparathyroidism include
bone pain, ectopic calcification, and pruritus
o Renal osteodystrophy is the bone disease seen in
patients with secondary hyperparathyroidism and
chronic kidney disease, and it primarily affects bone
turnover
o Osteomalacia is frequently encountered as well and
may be related to the circulating levels of FGF23
 Skeletal disorders have been frequently associated in the
past with chronic kidney disease patients treated by long-
term dialysis, who received aluminum-containing
phosphate binders
o Aluminum deposition in bone leads to an
osteomalacia-like picture
o “Aplastic” or “adynamic” bone disease is a low-
turnover bone disease
 PTH levels are lower than typically observed in
CKD patients with secondary
hyperparathyroidism
 It is believed that the condition is caused, at least
in part, by excessive PTH suppression
2. Aluminum Intoxication ()
 Aluminum intoxication and often hypercalcemia as a
complication of medical treatment occurred in patients on
chronic dialysis
 The disorder is now rare because of the avoidance of
aluminum-containing antacids or aluminum excess in the
dialysis regimen
 Manifestations included acute dementia and
unresponsive and severe osteomalacia; and there may
also be bone pain, multiple non-healing fractures,
particularly of the ribs and pelvis, and a proximal myopathy
 Hypercalcemia develops when these patients are treated
with vitamin D or calcitriol because of impaired skeletal
responsiveness
 Aluminum is present at the site of osteoid
mineralization, osteoblastic activity is minimal, and
calcium incorporation into the skeleton is impaired
3. Milk Alkali Syndrome ()
 Due to excessive ingestion of calcium and absorbable
antacids such as milk or calcium carbonate
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 The increased use of calcium carbonate in the
management of secondary hyperparathyroidism led to
reappearance of the syndrome
 Clinical presentations for acute, subacute, and chronic
disease feature hypercalcemia, alkalosis, and renal failure
o Acute syndromes reverse if the excess calcium and
absorbable alkali are stopped
o Chronic form of the disease, termed Burnett’s
syndrome, is associated with irreversible renal
damage
 Individual susceptibility is important in the pathogenesis,
because
o Some patients are treated with calcium carbonate and 2. Hydration
alkali regimens do not develop the syndrome  The first principle of treatment is to restore normal
o Fractional calcium absorption is important as a hydration
function of calcium intake  Hypercalcemic patients are dehydrated because of
o Some individuals absorb a high fraction of calcium, vomiting, inanition, and/or hypercalcemia-induced defects
even with intakes ≥2 g of elemental calcium per day, in urinary concentrating ability
instead of reducing calcium absorption with high  Dehydration brings about a drop in glomerular
intake filtration rate which is accompanied by an additional
o Resultant mild hypercalcemia after meals in such decrease in renal tubular sodium and calcium clearance
patients is postulated to contribute to the generation  Restoring a normal ECF volume corrects these
of alkalosis abnormalities and increases urine calcium excretion by
 Development of hypercalcemia causes increased sodium 100 – 300 mg/day (2.5 – 7.5 mmol/day)
3. Hydration + Increased Urinary Sodium Excretion
excretion and some depletion of total-body water
 These phenomena and perhaps some suppression of  Increasing urinary sodium excretion to 400 – 500
endogenous PTH secretion due to mild hypercalcemia mmol/day increases urinary calcium excretion even further
lead to increased bicarbonate resorption and to alkalosis than simple rehydration
in the face of continued calcium carbonate ingestion  After rehydration has been achieved, saline can be
administered, or furosemide or ethacrynic acid can be
 Alkalosis selectively enhances calcium resorption in the
given twice daily
distal nephron, thus aggravating the hypercalcemia
o Depresses the tubular reabsorptive mechanism for
 The cycle of mild hypercalcemia  bicarbonate
calcium
retention  alkalosis  renal calcium retention 
o Care must be taken to prevent dehydration
severe hypercalcemia perpetuates and aggravates
hypercalcemia and alkalosis as long as calcium and  Hydration + Saline + Furosemide
absorbable alkali are ingested o Can increase urinary calcium excretion to ≥ 500
mg/day (12.5 mmol/day) in most hypercalcemic
I. Treatment of Hypercalcemic States patients
o Serum calcium concentration usually falls 1 – 3
mg/dL (0.25–0.75 mmol/L) within 24 hours
1. Approach to medical treatment of hypercalcemia
 Precautions should be taken to prevent potassium
 Assess severity of hypocalcemia
and magnesium depletion; calcium-containing renal
 Lower calcium to safe levels
calculi are a potential complication
 Search and treat underlying diosrder
 In extreme situation: NSS (6L daily) + Furosemide (100
 The choice depends on the underlying disease, the
mg ever 1 – 2 hours)
severity of the hypercalcemia, the serum inorganic
o Can increase urinary calcium excretion to 1,000
phosphate level, and the renal, hepatic, and bone marrow
mg/day
function
o Serum calcium concentration usually falls 4
o Mild hypercalcemia (≤ 12 mg/dL [3mmol/L]) can
mg/dL within 24 hours
usually be managed by hydration
o Severe hypercalcemia (≥ 15 mg/dL [3.7 mmol/L])
4. Bisphosphonates
requires rapid correction
 Bisphosphonates are analogues of pyrophosphate, with
high affinity for bone, especially in areas of increased bone
Table 8. Therapies for severe hypercalcemia
turnover, where they are and are taken up by and inhibit
osteoclast action
 Etidronate, the initial bisphosphonate used in clinical
practice
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[MED II[Calcium Metabolism Disorders]
 oDisadvantage/s: Capacity to inhibit bone formation as
well as blocking resorption
 Newer bisphosphonates
o Advantage/s:
 Highly favorable ratio of blocking resorption
versus inhibiting bone formation
 Inhibit osteoclast-mediated skeletal resorption yet
do not cause mineralization defects at ordinary
doses
o Potency of the compounds for inhibition of bone
resorption varies more than 10,000-fold
 Potency (in increasing order): Etidronate,
Tiludronate, Pamidronate, Alendronate,
Risedronate, and Zoledronate
 IV use of pamidronate is approved for the treatment of
hypercalcemia
o Between 30 and 90 mg given as a single IV dose over
a few hours
o Return of serum calcium to normal within 24 – 48
hours with an effect lasts for weeks in 80 – 100% of
patients
 IV use of zoledronate is approved for the treatment of
hypercalcemia
o Given in doses of 4 or 8 mg/5-min infusion
o Has a more rapid and more sustained effect than
pamidronate in direct comparison
 These drugs are used extensively in cancer patients
 Absolute survival improvements are noted with
Pamidronate and Zoledronate in multiple myeloma
 There are reports of jaw necrosis, after dental
surgery, mainly in cancer patients treated with
multiple doses of the more potent bisphosphonates
5.Calcitonin
 Mechanism of action:
o Bone: Principally through receptors on osteoclasts, to
block bone resorption
o Kidneys: Via decreased tubular resporption of calcium
 Calcitonin is no longer effective in lowering calcium after
24 hours of use
o Tachyphylaxis is a known phenomenon with this
drug, seems to explain the results, since the drug is
often effective in the first 24 hours of use
 In life-threatening hypercalcemia:
o Calcitonin can be used effectively within the first 24
hours in combination with rehydration and saline
diuresis while waiting for more sustained effects from
a simultaneously administered bisphosphonate such
as pamidronate
 Usual doses of calcitonin are 2 – 8 U/kg of body weight IV,
SC, or IM every 6 – 12 hours
6. Glucocorticoids
 Glucocorticoids have utility, especially in hypercalcemia
complicating certain malignancies
 Mechanism of action:
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[MED II[Calcium Metabolism Disorders]
o Increase urinary calcium excretion
o Decrease intestinal calcium absorption when given in
pharmacologic doses,
o May also cause negative skeletal calcium balance
 In normal individuals and in patients with primary
hyperparathyroidism, glucocorticoids neither increase
nor decrease the serum calcium concentration
 In patients with hypercalcemia due to certain osteolytic
malignancies, however, glucocorticoids may be effective
as a result of antitumor effects
o Malignancies in which hypercalcemia responds to
glucocorticoids include multiple myeloma, leukemia,
Hodgkin’s disease, other lymphomas, and early
stage carcinoma of the breast
 Glucocorticoids are also effective in treating
hypercalcemia due to vitamin D intoxication and
sarcoidosis
 Glucocorticoids are also useful in the rare form of
hypercalcemia, now recognized in certain autoimmune
disorders in which inactivating antibodies against the
receptor imitate familial hypocalciuric hypercalcemia
(FHH)
o Elevated PTH and calcium levels are effectively
lowered by the glucocorticoids
 Prednisone 40 – 100 mg (or its equivalent) daily in four
divided doses
 Hypocalcemic effect develops over several days
 The side effects of chronic glucocorticoid therapy may
be acceptable in some circumstances
7. Dialysis
 Used as a last resort
 Treatment of choice for severe hypercalcemia
complicated by renal failure
 Peritoneal dialysis with calcium-free dialysis fluid
o Removes 200 – 500 mg (5 – 12.5 mmol) of calcium in
24 – 48 hours
o Lowers the serum calcium concentration by 3 – 12
mg/dL (0.7 – 3 mmol/L)
 Large quantities of phosphate are lost during dialysis, and
serum inorganic phosphate concentration usually falls,
potentially aggravating hypercalcemia
o Serum inorganic phosphate concentration should
be measured after dialysis
o Phosphate supplements should be added to the diet
or to dialysis fluids if necessary
8. Denosumab ()
 An antibody that blocks the RANK ligand (RANKL) and
dramatically reduces osteoclast number and function
 This is approved for therapy of osteoporosis and is an
effective treatment to reverse hypercalcemia of
malignancy, but is not yet approved for this indication
 Plicamycin (formerly mithramycin)
o Inhibits bone resorption, and gallium nitrate, which
exerts a hypocalcemic action also by inhibiting bone
resorption
13 of 20
 o No longer used because of superior alternatives such
as bisphosphonates
9. Phosphate Therapy ()
 PO or IV phosphate therapy has a limited role in certain
circumstances
 Correcting hypophosphatemia lowers the serum calcium
concentration by several mechanisms, including
bone/calcium exchange
 Oral treatment: 1 – 1.5 g of phosphorus per day for several
days, given in divided doses
 Toxicity does not occur if therapy is limited to restoring
serum inorganic phosphate concentrations to normal
 Raising the serum inorganic phosphate concentration
above normal decreases serum calcium levels
 Intravenous phosphate is one of the most dramatically
effective treatments available for severe hypercalcemia
but is toxic and even dangerous (fatal hypocalcemia)
o It is used rarely
o Used only in severely hypercalcemic patients with
cardiac or renal failure where dialysis, the preferable
alternative, is not feasible or is unavailable
III. Hypocalcemic Disorders
A. Manifestations
 Acute rather than chronic hypocalcemia is seen in critically
ill patients or as a consequence of certain medications and
often does not require specific treatment
 Chronic hypocalcemia is less common than hypercalcemia
and is usually symptomatic and requires treatment
o Neuromuscular and neurologic manifestations include
muscle spasms, carpopedal spasm, facial grimacing,
and, in extreme cases, laryngeal spasm and
convulsions
o Respiratory arrest may occur
o Increased intracranial pressure occurs in some
patients with long-standing hypocalcemia, often in
association
o with papilledema
o Mental changes include irritability, depression, and
psychosis
o QT interval on the electrocardiogram is prolonged, in
contrast to its shortening with hypercalcemia
o Arrhythmias occur, and digitalis effectiveness may be
reduced
o Intestinal cramps and chronic malabsorption may
occur
o Chvostek’s or Trousseau’s sign can be used to
confirm latent tetany
B. Transient Hypocalcemia
 This is usually seen in patients with:
o Severe sepsis
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[MED II[Calcium Metabolism Disorders]
o Burns
o Acute renal failure / acute kidney injury
o Extensive transfusions with citrated blood
 The hypocalcemia after repeated transfusions of
citrated blood usually resolves quickly
 So when a patient undergoes a lot of blood
transfusions, we have to check for hypocalcemia
 Patients with severe sepsis may have a decrease in
ionized calcium (true hypocalcemia)
 Other severely ill individuals, hypoalbuminemia is the
primary cause of the reduced total calcium concentration
 Alkalosis increases calcium binding to proteins, and in this
setting, direct measurements of ionized calcium should be
made
 Medications such as protamine, heparin, and glucagon
may cause transient hypocalcemia
o These forms of hypocalcemia are usually not
associated with tetany
o Resolve with improvement in the overall medical
condition
 Acute pancreatitis have hypocalcemia that persists
during the acute inflammation and varies in degree with
disease severity
o Pathogenesis of hypocalcemia remains unclear
o PTH values are reported to be low, normal, or
elevated
o Resistance to PTH and impaired PTH secretion have
been postulated
C. Functional Classification of Hypocalcemic Disorders
 Classification of hypocalcemia shown is based on an
organizationally useful premise that PTH is responsible
for minute-to-minute regulation of plasma calcium
concentration and, therefore, that the occurrence of
hypocalcemia must mean a failure of the homeostatic
action of PTH
 Failure of the PTH response can occur if:
o There is hereditary or acquired parathyroid gland
failure
o PTH is ineffective in target organs,
o The action of the hormone is overwhelmed by the
loss of calcium from the ECF at a rate faster than it
can be replaced
Table 9. Functional classification of hypocalcemia (excluding
neonatal conditions)
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D. PTH Absent
1. Acquired Hypoparathyroidism
 Usually the result of inadvertent surgical removal of all
the parathyroid glands; in some instances, not all the
tissue is removed, but the remainder undergoes vascular
supply compromise secondary to fibrotic changes in
the neck after surgery
 Hypoparathyroidism now usually occurs after surgery for
hyperparathyroidism (thyroidectomy) when the
surgeon, facing the dilemma of removing too little tissue
and thus not curing the hyperparathyroidism, removes too
much
o Parathyroid function may not be totally absent in all
patients with postoperative hypoparathyroidism
 Rare causes of acquired chronic hypoparathyroidism
include:
o Radiation-induced damage subsequent to
radioiodine therapy of hyperthyroidism
o Glandular damage in patients with hemochromatosis
or hemosiderosis after repeated blood transfusions
 Infection may involve one or more of the parathyroids but
usually does not cause hypoparathyroidism because all
four glands are rarely involved
 Transient hypoparathyroidism is frequent following surgery
for hyperparathyroidism
o After a variable period of hypoparathyroidism, normal
parathyroid function may return due to hyperplasia or
recovery of remaining tissue
o Recovery occurs months after surgery
2. Hypomagnesemia
 Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L) is
associated with hypocalcemia, and restoration of the total
body magnesium deficit leads to rapid reversal of
hypocalcemia
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[MED II[Calcium Metabolism Disorders]
 There are at least two causes of the hypocalcemia—
impaired PTH secretion and reduced responsiveness to
PTH
o Hypermagnesemia suppresses and hypomagnesemia
stimulates PTH secretion
 Effects of magnesium on PTH secretion are
normally of little significance, because the
calcium effects dominate
 Greater change in magnesium than in calcium is
needed to influence hormone secretion
o Severe, chronic hypomagnesemia leads to
intracellular magnesium deficiency, which
interferes with secretion and peripheral responses
to PTH (paradoxic effect)
 The mechanism of the cellular abnormalities
caused by hypomagnesemia is unknown
 Effects on adenylate cyclase (for which
magnesium is a cofactor) have been proposed
 PTH levels are undetectable or inappropriately low in
severe hypomagnesemia despite the stimulus of severe
hypocalcemia, and acute repletion of magnesium leads to
a rapid increase in PTH level
 Serum phosphate levels are often not elevated, in
contrast to the situation with acquired or idiopathic
hypoparathyroidism, probably because phosphate
deficiency is often seen in hypomagnesmia
 When acute magnesium repletion is undertaken, the
restoration of PTH levels to normal or supranormal may
precede restoration of normal serum calcium by several
days
 It is important to screen for magnesium levels and correct
3. Hereditary Hypoparathyroidism
 Can occur as an isolated entity without other endocrine or
dermatologic manifestations
 Typically, it occurs in association with other abnormalities
such as defective development of the thymus or failure of
other endocrine organs such as the adrenal, thyroid, or
ovary
 Is often manifest within the first decade but may appear
later
 DiGeorge syndrome or velocardiofacial syndrome
 A form of hypoparathyroidism associated with
defective development of both the thymus and the
parathyroid glands
 Congenital cardiovascular, facial, and other
developmental defects are present, and patients may
die in early childhood with severe infections,
hypocalcemia and seizures, or cardiovascular
complications
 Most cases are sporadic, but an autosomal dominant
form involving microdeletions of chromosome 22q11.2
has been described
 Smaller deletions in chromosome 22 (DSG1) are seen
in incomplete forms of the DiGeorge syndrome,
appearing in childhood or adolescence, that are
manifest primarily by parathyroid gland failure
15 of 20
  Recently, a defect in chromosome 10p (DSG2) is also
recognized
 HDR syndrome
 Autosomal dominant developmental defect, featuring
hypoparathyroidism, deafness, and renal dysplasia
 Cytogenetic abnormalities points to translocation
defects on chromosome 10, as in DiGeorge syndrome
 Transcription factor GATA3, which is important in
embryonic development and is expressed in
developing kidney, ear structures, and the
parathyroids
 HDR syndrome lack immunodeficiency and heart
defects seen in DiGeorge syndrome
 Kenney-Caffey syndrome type I
 Features hypoparathyroidism, short stature,
osteosclerosis, and thick cortical bones
 Involves a chaperone protein, called TBCE, relevant
to tubulin function
 Kenney-Caffey syndrome type II
 Due to a defect in FAM111A
 Sanjad-Sakati syndrome
 Defect seen in Middle Eastern patients, particularly in
Saudi Arabia
 Exhibits growth failure and other dysmorphic features
 Autosomal recessive disorder, which involves a gene
on chromosome 1q42-q43
 Involves a chaperone protein, called TBCE, relevant
to tubulin function
 Autoimmune polyglandular syndrome type 1 /
Polyglandular autoimmune type 1 deficiency
o A complex hereditary autoimmune syndrome
involving failure of the adrenals the ovaries, the
immune system, and the parathyroids in association
with recurrent mucocutaneous candidiasis, alopecia,
vitiligo, and pernicious anemia
 Responsible gene has been identified on
chromosome 21q22.3
 The protein product, which resembles a transcription
factor, has been termed the autoimmune regulator
(AIRE)
 A stop codon mutation occurs in many Finnish
families
 AIRE mutation (Y85C) is typically observed in
Jews of Iraqi and Iranian descent
 Autosomal Dominant Hypocalcemic Hypercalciuria
(ADHH)
 Gain of function mutations in calcium-sensing
receptor (CaSR)
o Opposite of familial hypocalciuric hypercalcemia
(FHH)
o Receptor senses the ambient calcium level as
excessive leading to hypocalcemia
 Leads to low PTH secretion in the parathyroid
gland
 Leads to decreased renal tubule calcium
absorption hence increased calcium excretion
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[MED II[Calcium Metabolism Disorders]
 Hypocalcemia is aggravated by constitutive receptor
activity in the renal tubule causing excretion of
inappropriate amounts of calcium
 Recognition of the syndrome is important because
efforts to treat the hypocalcemia with vitamin D
analogues and increased oral calcium exacerbate
the already excessive urinary calcium excretion
leading to irreversible renal damage from stones and
ectopic calcification
 Bartter’s syndrome
 A group of disorders associated with disturbances in
electrolyte and acid/base balance, sometimes with
nephrocalcinosis and other features
 Several types of ion channels or transporters are
involved
 Bartter’s syndrome type V has the electrolyte and pH
disturbances seen in the other syndromes but
appears to be due to a gain of function in the calcium-
sensing receptor (CaSR)
 The defect may be more severe than in autosomal
dominant hypocalcemic hypercalciuria (ADHH) and
explains the additional features seen beyond
hypocalcemia and hypercalciuria
 Kearns-Sayre syndrome (KSS)
o Associated with mitochondrial dysfunction and
myopathy
o With ophthalmoplegia and pigmentary retinopathy
 MELAS syndrome
o Mitochondrial encephalopathy, lactic acidosis, and
stroke-like episodes
o Associated with mitochondrial dysfunction and
myopathy
4. Treatment for PTH Absent Hypocalcemic Disorders
a.Treatment for Acquired and Hereditary
Hypoparathyroidism
 Treatment involves replacement with vitamin D or
1,25(OH)2D (Calcitriol) combined with a high oral calcium
intake
 High-dose Vitamin D
o Doses of 40,000 – 120,000 U/day (1 – 3 mg/day)
combined with ≥ 1 g elemental calcium
o Regular recommended daily allowance (RDA) of 200
– 800 U/day
 Because of its storage in fat, when vitamin D is
withdrawn, weeks are required for the disappearance
of the biologic effects, compared with a few days for
calcitriol, which has a rapid turnover
 Alternative treatment is with the use of the active
metabolite of vitamin D (Calcitriol)
o Physicians use 0.5–1 μg in the management of
patients that are difficult to control
 Elemental calcium: 1 g/day
16 of 20
 Oral calcium and vitamin D restore the overall calcium-
phosphate balance but do not reverse the lowered urinary
calcium reabsorption typical of hypoparathyroidism
o Care must be taken to avoid excessive urinary
calcium excretion after vitamin D and calcium
replacement therapy
o Nephrocalcinosis and kidney stones can develop, and
the risk of CKD is increased
 Thiazide diuretics lower urine calcium by as much as 100
mg/day in hypoparathyroid patients on vitamin D provided
they are maintained on a low-sodium diet
 Thiazides seems to be of benefit in mitigating
hypercalciuria and easing the daily management of
these patients
b. Treatment for Hypomagnesemia ()
 Repletion of magnesium cures the condition
 Repletion should be parenteral
 Attention must be given to restoring the intracellular deficit,
which may be considerable
 After IV magnesium administration, serum magnesium
may return transiently to the normal range, but unless
replacement therapy is adequate, serum magnesium will
again fall
 If the cause of the hypomagnesemia is renal magnesium
wasting, magnesium may have to be given long-term to
prevent recurrence
E. PTH Ineffective
1. Chronic Renal Failure / Chronic Kidney Disease
 Improved medical management of CKD now allows many
patients to survive for decades and hence allows time
enough to develop features of renal osteodystrophy, which
must be controlled to avoid additional morbidity
 Hyperphosphatemia in CKD lowers blood calcium levels
by several mechanisms
o Extraosseous deposition of calcium and phosphate
(Phosphate retention)
o Impairment of the bone-resorbing action of PTH
(Skeletal resistance to PTH)
o Reduction in 1,25(OH)2D production by remaining
renal tissue (Altered vitamin D metabolism)
 Impaired production of 1,25(OH)2D is now thought to be
the principal factor that causes calcium deficiency,
secondary hyperparathyroidism, and bone disease
hyperphosphatemia typically occurs only in the later
stages of the disease
 Low levels of 1,25(OH)2D due to increased FGF23
production in bone are critical in the development of
hypocalcemia
 Uremic state also causes impairment of intestinal
absorption by mechanisms other than defects in vitamin
D metabolism
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[MED II[Calcium Metabolism Disorders]
 Increased FGF23 levels are seen even in early stages of
CKD and have been reported to correlate with increased
mortality and left ventricular hypertrophy
 Treatment for Chronic Renal Failure
 Aim of therapy is to restore normal calcium balance to
prevent osteomalacia; severe secondary
hyperparathyroidism; and secondary
hyperparathyroidism from becoming autonomous
hyperparathyroidism
 Supraphysiologic amounts of vitamin D or calcitriol
can correct the impaired calcium absorption
o Provision of adequate oral calcium
supplementation, usually 1 – 2 g/day
 Corrects both hyperphosphatemia (acts as
phosphate binders and hypocalcemia
o Restriction of phosphate in the diet
o Supplementation with 0.25 – 1 μg/d calcitriol or
other activated forms of vitamin D
 Avoidance of aluminum-containing phosphate-binding
antacids to prevent the problem of aluminum
intoxication
2. Active Vitamin D Lacking
a. Decreased Intake and/or Decreased sunlight exposure
 May be due to inadequate intake of dairy products
enriched with vitamin D, lack of vitamin
supplementation, and reduced sunlight exposure in
the elderly, particularly during winter in northern latitudes
 Hepatocellular dysfunction can lead to reduction in
25(OH)D levels, as in portal or biliary cirrhosis of the liver,
and malabsorption of vitamin D and its metabolites
 Gastrointestinal diseases can occur with mild
hypocalcemia, secondary hyperparathyroidism, severe
hypophosphatemia and a variety of nutritional deficiencies
o Intestinal malabsorption leading to decreased
apsorption of vitamin D
 Concentrations of 25(OH)D are low or low-normal in these
patients
 PTH hypersecretion compensates for the tendency for the
blood calcium to fall but also increases renal phosphate
excretion and thus causes osteomalacia
 Treatment involves adequate replacement with vitamin
D and calcium until the deficiencies are corrected
b.Vitamin D Dependent Rickets Type I (Pseudo-vitamin
D–resistant rickets)
 Typically less severe than vitamin D–dependent rickets
type II
 Autosomal recessive disorder caused by mutations in the
gene encoding 25(OH) D-1α-hydroxylase
 Clinical features include hypocalcemia, often with tetany or
convulsions, hypophosphatemia, secondary
hyperparathyroidism, and osteomalacia, often associated
with skeletal deformities and increased alkaline
phosphatase
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 Adequate vitamin D supplies but decreased conversion to
active metabolite
 Treatment with appropriate doses of the vitamin’s
active metabolite, 1,25(OH)2D (Calcitriol) reverses the
biochemical and radiographic abnormalities
3. Active Vitamin D Ineffective ()
a. Anticonvulsant Therapy
 Anticonvulsant therapy with any of several agents induces
acquired vitamin D deficiency
 There is an increase in the the conversion of vitamin D to
its inactive compounds and/or resistance to its action
 The more marginal the vitamin D intake in the diet, the
more likely that anticonvulsant therapy will lead to
abnormal mineral and bone metabolism
b. Vitamin D Dependent Rickets Type II (True vitamin D–
resistant rickets)
 Results from end-organ resistance to the active metabolite
1,25(OH)2D
 Clinical features resemble those of the type I disorder and
include hypocalcemia, hypophosphatemia, secondary
hyperparathyroidism, and rickets but also partial or total
alopecia
 Plasma levels of 1,25(OH)2D are elevated, in keeping with
the refractoriness of the end organs
 This disorder is caused by mutations in the gene encoding
the vitamin D receptor
 Treatment is difficult and requires regular, usually
nocturnal calcium infusions, which dramatically improve
growth but do not restore hair growth
4. Pseudohypoparathyroidism (PHP)
 PHP refers to a group of distinct inherited disorders
 The classification scheme is based on the signs of
ineffective PTH action (low calcium and high phosphate),
low or normal urinary cAMP response to exogenous PTH,
the presence or absence of Albright’s hereditary
osteodystrophy (AHO), and assays to measure the
concentration of the Gsα subunit of the adenylate cyclase
enzyme
 PTH is normal but there is an end organ response to PTH,
so the PTH levels here is elevated in an attempt to
overcome the resistance.
Table 10. Classification of Pseudohypoparathyroidism (PHP) and
Pseudopseudohypoparathyroidism (PPHP)
 PHP-I
o The most common of the disorders
Transcribers: Delos Angeles, Delos Santos, Diola, Duque, Espino
Editors: Banaag, Cornelio, Lee, Mallari
[MED II[Calcium Metabolism Disorders]
oShows a deficient urinary cAMP response to
administration of exogenous PTH.
o Patients with PHP-Ia show evidence for AHO and
reduced amounts of Gsα protein/activity, as
determined in readily accessible tissues such as
erythrocytes, lymphocytes, and fibroblasts
 Most patients reveal characteristic features of
AHO, which consist of short stature, round face,
obesity, skeletal anomalies (brachydactyly),
intellectual impairment, and/or heterotopic
calcifications
 Patients have low calcium and high phosphate
levels, as with true hypoparathyroidism
 PTH levels, however, are elevated, reflecting
resistance to hormone action
o Patients with PHP-Ib typically lack evidence for AHO
and they have normal Gsα activity
o PHP-Ic, sometimes listed as a third form of PHP-I, is
really a variant of PHP-Ia, although the mutant Gsα
shows normal activity in certain in vitro assays
 Treatment of PHP is similar to that of hypoparathyroidism,
except that calcium and vitamin D doses are usually
higher
o Patients with PHP show no PTH-resistance in the
distal tubules, hence urinary calcium clearance is
typically reduced, and they are not at risk of
developing nephrocalcinosis
F. PTH Overwhelmemed
1. Severe Acute Hyperphosphatemia
 Associated with extensive tissue damage or cell
destruction
 The combination of increased release of phosphate from
muscle and impaired ability to excrete phosphorus
because of renal failure causes moderate to severe
hyperphosphatemia, the latter causing calcium loss from
the blood and mild to moderate hypocalcemia
 Hypocalcemia is usually reversed with tissue repair and
restoration of renal function as phosphorus and creatinine
values return to normal
 There may even be a mild hypercalcemic period in the
oliguric phase of renal function recovery
 This sequence, severe hypocalcemia followed by mild
hypercalcemia, reflects widespread deposition of calcium
in muscle and subsequent redistribution of some of the
calcium to the ECF after phosphate levels return to normal
 Other causes of hyperphosphatemia include
hypothermia, massive hepatic failure, and hematologic
malignancies, either because of high cell turnover of
malignancy or because of cell destruction by
chemotherapy
 Treatment is directed toward lowering of blood phosphate
by the administration of phosphate-binding antacids or
dialysis, often needed for the management of CKD
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 Calcium administration during the hyperphosphatemic
period tends to increase extraosseous calcium deposition
and aggravate tissue damage
 The levels of 1,25(OH)2D may be low during the
hyperphosphatemic phase and return to normal during the
oliguric phase of recovery
2. Post-parathyroidectomy Hypocalcemia
 In adults, hypoparathyroidism most commonly results from
inadvertent damage to all four glands during thyroid or
parathyroid gland surgery
 History of hyperparathyroidism
 Hungry bone syndrome after parathyroidectomy
o Often occurs in patients who have developed bone
disease preoperatively due to a chronic increase in
bone resorption induced by high levels of PTH
(osteitis fibrosa) [UpToDate]
 Osteitis fibrosa after parathyroidectomy is characterized by
severe hypocalcemia after parathyroid surgery
o This is rare now that osteitis fibrosa cystica is an
infrequent manifestation of hyperparathyroidism
o When osteitis fibrosa cystica is severe, however, bone
mineral deficits can be large
o After parathyroidectomy, hypocalcemia can persist for
days if calcium replacement is inadequate
o Treatment may require parenteral administration of
calcium; addition of calcitriol and oral calcium
supplementation is sometimes needed for weeks to a
month or two until bone defects are filled
 So our patient earlier who underwent the parathyroid
surgery, so with high PTH level, it will produce resorption
of calcium from the bone to increase the calcium levels in
the blood. Now, if you remove that adenoma, your PTH
levels goes down, so now there will be a reversal from
resorption to reabsorption of that calcium inside the bone.
So the calcium levels in the blood may go down. This is
what we call the hungry bone syndrome.
 So after surgery of the parathyroids, we have to screen for
hypocalcemia, usually 24 to 48 hours.
IV. Mini Quiz
1. Which among the following drugs will cause falsely
elevated aldosterone-renin ratio?
A. Verapamil
B. Amiloride
C. Ramipril
D. Bisoprolol
2. A 38-year old hypertensive male came in with a serum
potassium of 2.8 mmol/L (normal value 3.5-5.1 mmol/L).
He was given medication that corrects his potassium level.
Further workup after correction of hypokalemia showed
plasma renin of 0.99 ng/mL/h (normal value 3.2 ± 1
ng/mL/h) and plasma aldosterone of 987 pmol/L (normal
value 140- 560 pmol/L). Aldosterone-renin ratio was 997.
Saline infusion test was done and aldosterone level was
843 pmol/L after the saline infusion. Your next step should
be:
A. Do CT scan of the adrenal glands
Transcribers: Delos Angeles, Delos Santos, Diola, Duque, Espino
Editors: Banaag, Cornelio, Lee, Mallari
[MED II[Calcium Metabolism Disorders]
B. No further diagnostic tests required
C. Do adrenal vein sampling
D. Send patient for adrenalectomy
3. A 51-year old female was diagnosed with Cushing’s
syndrome based on a 24 hour urine cortisol level of 276 ug
(normal value: 3.5-45 ug/24h). Plasma ACTH was drawn
and noted to be <5 pg/mL. Your next step should be:
A. Do a low dose dexamethasone suppression test
B. Do a high dose dexamethasone suppression test
C. Do MRI of the pituitary glands
D. Do CT scan of the adrenal glands
4. A 32-year old female was referred for management of
obesity. Her BMI is 40 and her BP is 160/100. She said
she gained much of her weight during the past 8 months.
You did a screening test that showed a 1 mg
dexamethasone suppression cortisol level of 6 ug/dl
(Normal: <1.5 ug/dl) and a 24-hour urinary free cortisol of
209 ug/dl (Normal: 80-120 ug/dl). ACTH was suppressed
to below normal. Which of the following is correct?
A. She has Cushing’s syndrome and should have a
repeat ACTH
B. She has Cushing’s disease and should have an MRI
of the pituitary
C. She has Cushing’s syndrome and should undergo CT
scan of the adrenal gland
D. She has morbid obesity causing a false positive test
5. A 27-year old female complained of fatigue, nausea,
anorexia and myalgia for the past 3 days. Six months ago,
she had few episodes of asthma for which she was
prescribed prednisone 10 mg daily for 5 days. She was
given 0.25 mg ACTH intramuscularly. Serum cortisol level
went from 15 ug/dL to 29 ug/dL before and after ACTH
administration respectively. She most likely has:
A. Primary adrenal insufficiency
B. Normal glucocorticoid function
C. Secondary adrenal insufficiency
D. Equivocal test results
6. The most common hypersecreted hormone among
patients adrenal incidentaloma is
A. Glucocorticoids
B. Sex hormones
C. Aldosterone
D. Epinephrine
7. A 28-year old male is being evaluated for an abnormal rib
fracture sustained while playing golf. After several tests
that included a parathyroid hormone (PTH), calcium, and
phosphorus, he was told that he had primary
hyperparathyroidism. Which of the following laboratory
values would be expected in this case?
A. High PTH, low calcium, high phosphorus
B. High PTH, high calcium, low phosphorus
C. High PTH, high calcium, high phosphorus
D. High PTH, low calcium, low phosphorus
8. A 40-year old female with an anterior neck mass was
found to have an enlarged thyroid. She is asymptomatic
but decided to have a thyroidectomy and had laboratory
tests done prior to surgery. The results revealed the
following:
Thyroid stimulating hormone (TSH): 1.02 (Normal: 0.55-
4.78 ulU/mL)
Free thyroxine (fT4): 1.13 (Normal: 0.89-1.76 ng/dL)
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 Parathyroid hormone (PTH): 120 (Normal: 11-54 pg/mL)
Calcium: 10.5 (Normal: 8.5-10.2 mg/dL)
Phosphorus: 2.0 (Normal: 2.5-4.5 mg/dL)
As part of the work-up for the above condition, she also
had a bone mineral density measurement done which
revealed a T-score of -2.0. Which of the following features
of this case indicates that the patient is a candidate for
parathyroid surgery?
A. Age
B. PTH level
C. Calcium level
D. T-score
9. A 40-year old male tripped and twisted his ankle. He is
diagnosed with a sprain and is told to rest, use an ice pack
and elevate the affected leg. After 2 weeks however the
pain has not completely subsided and he had an X-ray
done. He is told that his leg bones look curved. His doctor
is concerned and orders X-rays of all his other bones and
there are deformities in the skull, spine, and pelvis. Which
of the following is the laboratory test of choice for this
patient’s condition?
A. Alkaline phosphatase (ALP)
B. Calcium
C. Vitamin D
D. Parathyroid Hormone (PTH)
10. A 25-year old female with elevated serum calcium has
pulmonary tuberculosis. What will be your next step?
A. check if PTH is intact
B. check phosphorus levels
C. perform Vit D assay
D. Repeat test
11. An eldelry male with lung cancer with anorexia, headache,
vomiting, HR=110, BP=90/60, increased Ca levels, and
increased creatinine. What is the management?
A. Bisphosphonates
B. Dialysis
C. Infuse with saline
D. Infuse with saline and furosemide
12. Mr P has had repeatedly high serum calcium. He has a
history of recurrent nephrolithiasis. He comes to you
complaining of muscle weakness and easy fatigability (I’m
not sure if he had these symptoms, can’t remember). He
denies vomiting, nausea, or diarrhea. Sestamibi scan
revealed a solitary enlargement at the right inferior pole of
the thyroid. What is your management?
A. Calcimimetic
B. Remove abnormal parathyroid
C. Remove 3 ½ of the parathyroids
D. Remove all 4 and transplant portion of one gland to
forearm
13. Which of the following is associated with excess Vitamin D
production leading to hypercalcemia?
A. Hyperthyroidism
B. Lithium use
C. Tuberculosis
D. Thiazides
14. Which of the following therapeutics used in the treatment
of severe hypercalcemia has a delayed onset of action?
A. Bisphosphonates
B. Calcitonin
C. Dialysis
D. Hydration
Transcribers: Delos Angeles, Delos Santos, Diola, Duque, Espino
Editors: Banaag, Cornelio, Lee, Mallari
[MED II[Calcium Metabolism Disorders]
15. A 43-year old female underwent thyroidectomy for
multinodular goiter. Within hours after the surgery, she
develops symptoms of perioral numbness and carpopedal
spasms. What is the likely cause of her symptoms?
A. Hypothyroidism
B. Hypoparathyroidism
C. Vitamin D Deficiency
D. Recurrent Laryngeal nerve injury
16. PJ is an asymptomatic 62-year old female who had an
executive check-up. Her laboratory tests revealed a
calcium level of 11.7 mg/dL (N=8.5-10.2). On repeat
testing, her result was 12mg/dL. Her intact PTH was
elevated at 300 ng/L (N=10-65). Her bone mineral density
lowest score was -2 at the lumbar spine. 24 hour urine
calcium was elevated. How should she be managed?
A. Prescribe hydrocortisone
B. Prescribe Calcitonin
C. Prescribe 1, 25a-dihydroxycholecalciferol
D. Refer to surgery for parathyroidectomy
17. TF is a 72-year old male with diabetic kidney disease
stage 4. His calcium is persistently low. What is the cause
of his low calcium?
A. Decreased bone resorption
B. Decreased sunlight exposure
C. Increased circulating parathyroid hormone
D. Decreased circulating 1,25-dihydroxycholecalciferol
18. RG is a 70-year old male diagnosed with lung carcinoma
who presents with persistently elevated serum calcium for
the past year. No intervention has been done to address
the hypercalcemia. Today he presents at the emergency
room with vomiting, abdominal pain, dehydration, and
oliguria. His calcium is markedly elevated. Despite
aggressive hydration and loop diuretics, urine output does
not improve. How should he be managed?
A. Hemodialysis
B. Start zoledronic acid
C. Add thiazide diuretics
D. Add 1,25-dihydroxycholecalciferol
19. PL is a 65-year old female with hypercalcemia secondary
to primary hyperparathyroidsm and vertebral T score <
3.0. She refuses parathyroidectomy. What can you
prescribe her for long-term control of the hypercalcemia?
A. Calcitonin
B. Glucocorticoids
C. Biphosphonates
D. 1,25-dihydroxycholecalciferol
20. RF is a 28-year old female with hyperthyroidism. How
does her condition affect her serum calcium?
A. Serum calcium is decreased due to increased urinary
excretion
B. Serum calcium is decreased due to decreased
intestinal absorption (increased motility)
C. Serum calcium is elevated due to increased
parathyroid activity
D. Serum calcium is elevated due to increased bone
turnover
21. Approved in prevention of osteoporosis in women
A. Calcitonin
B. Denosumab
C. Estrogen
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 D. Teriparatide C. Alendronate
D. Stronium ranelate
22. HA is a 78/F who had a fragility fracture on her left hip
after a fall in her home. According to the 2016 AACE
guidelines, which of the following pharmacologic therapies
is appropriate for her?
A. Calcitonin
B. Denosumab 1A 2A 3D 4C 5B 6A 7B 8A 9A 10D 11D 12B 13C 14B
15C 16D 17D 18A 19C 20D 21C 22B

APPENDIX A. Therapies for severe hypercalcemia

APPENDIX B. Classification of Pseudohypoparathyroidism (PHP) and Pseudopseudohypoparathyroidism (PPHP)

Transcribers: Delos Angeles, Delos Santos, Diola, Duque, Espino 21 of 20

Editors: Banaag, Cornelio, Lee, Mallari
[MED II[Calcium Metabolism Disorders]