Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland.

The secretory vesicles (brown) contain hormones.

From: Seeleys Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

Learning Objectives
Pharmacology of Calcium Metabolism
1. The role of key organs involved in regulation of plasma calcium concentration
2. The endocrine regulation of calcium homeostasis and mechanisms involved
3. The principles underlying the treatment of both hyper- and hypocalcemia.
4. The indications, mechanism of action, adverse effects and contraindications
of the drugs used in therapy of hypo- and hypercalcemia.

Drugs That Affect Calcium Levels

DRUGS THAT DECREASE CALCIUM LEVELS
DRUGS THAT INCREASE CALCIUM LEVELS

Calcium citrate (many other salts)

Calcium gluconate
Teriparatide
Vitamin D Analogues
Calcitriol
Cholecalciferol
Dihydrotachysterol
Doxercalciferol
Ergocalciferol
Paricalcitol

Marc Imhotep Cray, MD

Bisphosphonates
Alendronate
Ibandronate
Pamidronate
Etidronate
Risedronate
Tiludronate
Zoledronic acid
Calcitonin
Calcimimetics
Cinacalcet
Clodronate
Estrogens and raloxifene
Gallium nitrate
Phosphate

Parathyroid Gland Disorders &

Agents Affecting Calcium
Homeostasis

Marc Imhotep Cray, MD

Marc Imhotep Cray, MD

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

Hypoparathyroidism
Definition
Low PTH levels, usually due to destruction of parathyroid
glands (acquired)
Etiology
Common causes:
- Surgery
- Infiltration and destruction of parathyroid glands (Wilson
disease, hemachromatosis, and radiation)
- PTH production may be suppressed in hypomagnesemia
(magnesium important for PTH homeostasis)
Marc Imhotep Cray, MD

Hypoparathyroidism (2)
Clinical Presentation
Laboratory
Decreased serum PTH
Hypocalcemia
Hyperphosphatemia
Normal 25-hydroxyvitamin D level
Decreased 1,25- dihydroxyvitamin D levels

Marc Imhotep Cray, MD

Hypoparathyroidism (3)
Diagnosis
Increased urine: calcium to creatinine ratio and
hypophosphaturia
ECG: prolonged Q-T interval (hypocalcemia)
Treatment
Supplementation with calcium and 1,25-dihydroxyvitamin D
Caution with intravenous calcium administration

Marc Imhotep Cray, MD

Hypoparathyroidism (4)
Symptoms (most due to hypocalcemia)
Seizures
Constipation
Muscle cramps
Hyperreflexia
Tetany
Abdominal pain
Lethargy
Cardiac dysrhythmia
Chvosteks sign (facial twitching when the zygomatic arch is tapped)
Trousseaus sign (forearm spasms induced by inflating BP cuff on upper
arm)
Marc Imhotep Cray, MD

Hyperparathyroidism
Definition
High levels of PTH levels, usually due to excessive release
Types of HPT
Primary Hyperparathyroidism
Secondary Hyperparathyroidism
Tertiary Hyperparathyroidism

Marc Imhotep Cray, MD

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Primary Hyperparathyroidism
Parathyroid adenoma is the most common cause
(85% of all hyperparathyroid cases)

Hyperplasia of the parathyroid glands

Parathyroid carcinoma (rare)

Primary Hyperparathyroidism
Feedback response to hypocalcemia stimulates parathyroid
glands leading to hyperplasia and excessive PTH production
Causes of hypocalcemia:
- Renal failure is most common cause
- Vitamin D deficiency
- Malabsorption of intestinal calcium
Marc Imhotep Cray, MD

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Tertiary Hyperparathyroidism
Constant stimulation of parathyroids in secondary
hyperparathyroidism causes autonomous secretion of PTH by gland
End result is hypercalcemia because feedback response is
functional
Correction of hypercalcemia associated with tertiary HPT
requires surgical resection of most of four parathyroid glands

Marc Imhotep Cray, MD

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Clinical Presentation of HPT

Laboratory
Elevated serum PTH levels
Elevated 1,25-dihydroxyvitamin D
levels
Hypercalcemia
Hypophosphatemia

Marc Imhotep Cray, MD

Symptoms
(most due to hypercalcemia)
Stones, groans, and psychic moans

Kidney stones
Abdominal pain
Bone pain
Depression
Nausea & Vomiting
Weakness
Lethargy
Hypertension
13

Diagnosis & Treatment of HPT

Dx
Urine: decreased calcium to creatinine ratio
and hyperphosphaturia
ECG: short Q-T interval (hypercalcemia)
Tx
Calcium binding agents
Treat underlying etiology

Marc Imhotep Cray, MD

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Drugs That Affect Calcium Levels

DRUGS THAT INCREASE CALCIUM LEVELS

Calcium citrate (many other salts)

Calcium gluconate
Teriparatide
Vitamin D Analogues
Calcitriol
Cholecalciferol
Dihydrotachysterol
Doxercalciferol
Ergocalciferol
Paricalcitol

Marc Imhotep Cray, MD

DRUGS THAT DECREASE CALCIUM LEVELS

Bisphosphonates
Alendronate
Ibandronate
Pamidronate
Etidronate
Risedronate
Tiludronate
Zoledronic acid
Calcitonin
Calcimimetics
Cinacalcet
Clodronate
Estrogens and raloxifene
Gallium nitrate
Phosphate

15

Case 44
Agents Affecting Calcium Homeostasis
A 66-year-old woman presents for an annual health maintenance visit. She is generally feeling
well and has no specific complaints. She takes hydrochlorothiazide for hypertension,
levothyroxine sodium for hypothyroidism, and a multivitamin. She went through menopause
at age 48 and never took hormone replacement therapy. She is a former cigarette smoker,
having a 30 pack-year history and having quit 20 years ago. She occasionally has a glass of
wine with dinner and walks three or four times a week for exercise. On examination you note
that her height is 1 inch less than it was 3 years ago. Her vital signs are normal. She has a
prominent kyphoscoliosis of the spine. Her examination is otherwise unremarkable.
Blood work reveals normal electrolytes, renal function, blood count, calcium, and thyroidstimulating hormone (TSH) levels. You order a bone density test, which shows a significant
reduction of density in the spine and hips. You diagnose her with osteoporosis and start her
on alendronate sodium.
_ What is the mechanism of action of parathyroid hormone (PTH) on the bone and in the
kidney?
_ What is the mechanism of action of alendronate sodium?
Marc Imhotep Cray, MD

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What are the three hormones that regulate calcium levels in

the blood and tissues and their origin of secretion?
1. PTH is secreted from chief cells in parathyroid glands
PTH is released in response to low serum calcium, and its purpose is to
raise serum calcium level
2. Vitamin D is produced from diet as well as from synthesis through
cholesterol with help of ultraviolet (UV) light
Its purpose is to raise serum calcium level
3. Calcitonin comes from parafollicular cells in thyroid gland
Calcitonin is secreted in response to high serum calcium and will lower
serum calcium level

Marc Imhotep Cray, MD

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Parathyroid Hormone (PTH)

Biosynthesis
PTH secreted by chief cells of parathyroid gland
Mode of Action
PTH binds PTH receptor activation of guanyl nucleotide regulatory
protein activation of adenylate cyclase increased cAMP production
Regulation
Increased serum calcium and increased 1,25-(OH) 2D3 levels decreased
PTH secretion
PTH secretion
Decreased serum calcium increased PTH secretion
Marc Imhotep Cray, MD

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Parathyroid Hormone (PTH) cont.

Function:
Overall effect is to increase serum calcium and decrease serum phosphate
levels
Effects on bone:
Promotes osteoclastic activity
Increases rate of skeletal remodeling
Effects on kidney:
Promotes calcium reabsorption in distal tubule of nephron
Increases phosphate excretion
Increases formation of 1,25-(OH) 2D3 (activated vitamin D)
Effects on intestine:
Increased 1,25-(OH) 2D3 results in increased intestinal calcium and
phosphate absorption
Marc Imhotep Cray, MD

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Calcium homeostasis: PTH & Vit D

Marc Imhotep Cray, MD

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

20

Calcium homeostasis:
PTH & Vit D (2)

Marc Imhotep Cray, MD

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

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Calcium Regulation by Parathyroid Hormone

and Vitamin D Summary Table

Miksad RA, Meyer GK & DeLaMora PA. Last Minute Internal Medicine. New York: McGraw-Hill, 2008

Marc Imhotep Cray, MD

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Vitamin D
Vitamin D3 (cholecalciferol) is absorbed by small intestine as part of diet
(e.g. dairy food) or is synthesized from cholesterol in skin
VitaminD3 synthesis requires ultraviolet B (UVB) light the sun it is
then converted into calcitriol Calcitriol is biologically active form of
vitamin D and is a major determinant of intestinal calcium and phosphate
reabsorption.
Activation
Human vitamin D is an inactive steroid called
cholecalciferol (or vitamin D3)
o It is a fat-soluble steroid is stored in adipose tissue

Two reactions must take place in different organs

to activate vitamin D
o Activated vitamin D (1,25-dihydroxycholecalciferol)
Marc Imhotep Cray, MD

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Activation of Vitamin D

Actions of vitamin D on GIT, bone

(PTH, parathyroid hormone) and
kidney

Horton-Szar D. Crash Course: Endocrinology, 4th Ed. Elsevier, 2012

Marc Imhotep Cray, MD

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Calcium-relate Diseases & Disorders

Osteoporosis, Paget disease, and osteomalacia are disorders of the bone
Osteoporosis is characterized by progressive loss of bone mass and
skeletal fragility
Patients with osteoporosis have an increased risk of fractures, which
can cause significant morbidity
Osteoporosis occurs in older men and women but is most pronounced
in postmenopausal women
Paget disease is a disorder of bone remodeling that results in disorganized
bone formation and enlarged or misshapen bones
Unlike osteoporosis, Paget disease is usually limited to one or a few
bones
Patients may experience bone pain, bone deformities, or fractures
Osteomalacia is softening of bones that is most often attributed to
vitamin D deficiency Osteomalacia in children is referred to as rickets
Marc Imhotep Cray, MD

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Changes in bone morphology seen in

osteoporosis

Whalen K. Lippincott Illustrated Reviews: Pharmacology 6th Ed. Wolters Kluwer, 2015
Marc Imhotep Cray, MD

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Treatment of Osteoporosis
Nondrug strategies to reduce bone loss in
postmenopausal women include
adequate dietary intake of calcium and
vitamin D
weight-bearing exercise, and
smoking cessation
In addition, patients at risk for osteoporosis
should avoid drugs that increase bone loss
such as glucocorticoids
[Note: Use of glucocorticoids (for example,
prednisone 5 mg/day or equivalent) for 3 months or
more is a significant risk factor for osteoporosis.]

Marc Imhotep Cray, MD

Drugs that can contribute to bone

loss or increased fracture risk.

Aluminum antacids
Anticonvulsants (e.g.,
phenytoin)
Aromatase inhibitors
Furosemide
Glucocorticoids
Heparin
Medroxyprogesterone acetate
Proton pump inhibitors
SSRIs
Thiazolidinediones
Thyroid (excessive replacement)

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Treatment of Osteoporosis cont.

Pharmacologic therapy for osteoporosis is warranted in postmenopausal
women and men aged 50 years or over who have a previous osteoporotic
fracture, a bone mineral density that is 2.5 standard deviations or more
below that of a young adult, or a low bone mass with a high probability of
future fractures
Common agents used include:
Bisphosphonates:
o Alendronate, Ibandronate, Risedronate, Zoledronic acid
Selective estrogen receptor modulators
Calcitonin
Denosumab
Teriparatide
Marc Imhotep Cray, MD

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Bisphosphonates*
Mechanism of action
Bind to hydroxyapatite in bone,
inhibiting osteoclast activity
Uses
Postmenopausal bone loss
1. Alendronate (oral; once a week)
2. Risedronate (oral; once a week)
Osteoporosis and compression
fractures
1. Alendronate (oral; once a week)
2. Risedronate (oral; once a week)
3. Ibandronate (oral; once a month)
4. Zoledronic acid (IV; once a year)
Marc Imhotep Cray, MD

Uses cont.
Hypercalcemia due to malignancy
1. Clodronate
2. Etidronate
3. Tiludronate
4. Zoledronic acid
Pagets disease
1. Clodronate
2. Etidronate
3. Tiludronate
4. Zoledronic acid
*Note common ending -dronate
for all bisphosphonates.

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Bisphosphonates cont.
Adverse effects
Reflux esophagitis (gastroesophageal reflux disease; GERD) when
taken orally; avoid this by:
1. Taking these drugs on an empty stomach, with at least 8 oz. water,
immediately upon awakening
2. Remaining in an upright position for at least 30 minutes after
taking drug
3. Avoiding food or drink for 30 minutes after taking drug
Musculoskeletal pain
Hypocalcemia
Hypophosphatemia
Osteonecrosis (jaw)
Marc Imhotep Cray, MD

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Bisphosphonates cont.
Pharmacokinetics
Food and other medications decrease absorption of
bisphosphonates, which are already poorly absorbed (less than
1%) after oral administration

Bisphosphonates are cleared from plasma by binding to bone and

being cleared by kidney
not metabolized by CYP450 system
Elimination half-life may be years
Marc Imhotep Cray, MD

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Selective estrogen receptor modulators

(SERMs)
Raloxifene
MOA
Agonist in bone
Antagonist in breast
Antagonist in uterus
Uses
Prevention and treatment of osteoporosis in
postmenopausal women
Risk reduction for invasive breast cancer in
postmenopausal women with osteoporosis
Risk reduction in postmenopausal women
with high risk for invasive breast cancer
Marc Imhotep Cray, MD

Adverse effects
Thromboembolism
Peripheral edema
Hot flashes
Headache
Depression
Vaginal bleeding

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Denosumab

MOA
A monoclonal antibody that targets receptor activator of nuclear factor
kappa-B ligand and inhibits osteoclast formation and function
Use
Denosumab is approved for treatment of postmenopausal osteoporosis in
women at high risk of fracture
It is administered via subcutaneous injection every 6 months
Adverse Effects
increased risk of infections
dermatological reactions
hypocalcemia
osteonecrosis of the jaw
atypical fractures
Reserved for women at high risk of fracture and those who are intolerant
of or unresponsive to other osteoporosis therapies

Marc Imhotep Cray, MD

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Calcitonin
Uses
Administered parenterally to treat
hypercalcemia
Pagets disease of bone
Postmenopausal osteoporosis
(intranasal)
Adverse effects
a. Rhinitis
b. Flushing
c. Back pain

Marc Imhotep Cray, MD

Teriparatide (a PTH analogue)

A recombinant segment of human
parathyroid hormone administered
subcutaneously for Tx of osteoporosis
MOA
Causes dissolution of bone but can
more commonly cause bone formation
Uses
Osteoporosis in postmenopausal
women at high risk of fracture
Primary or hypogonadal osteoporosis
in men at high risk of fracture
Adverse effects
Hypercalcemia
Hyperuricemia
Arthralgia
Respiratory effects

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Vitamin D analogues
Examples
Calcitriol
Cholecalciferol
Dihydrotachysterol
Doxercalciferol
Ergocalciferol
Paricalcitol

Marc Imhotep Cray, MD

Uses
Treatment of vitamin D deficiency
Prophylaxis against vitamin D deficiency
Rickets prevention
o Given with calcium to supplement diet of
infants
Hypoparathyroidism (with calcium
supplements)
Osteoporosis
o Prevention and treatment
Chronic renal disease
1. Calcitriol
2. Paricalcitol (Oral and IV)
35

Question
OP is a 65-year-old female who has been diagnosed with postmenopausal
osteoporosis. She has no history of fractures and no other pertinent medical
conditions.
Which of the following would be most appropriate for management of her
osteoporosis?
A. Alendronate
B. Calcitonin
C. Denosumab
D. Raloxifene
E. Teriparatide

Marc Imhotep Cray, MD

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Correct answer = A
Bisphosphonates are first-line therapy for osteoporosis in postmenopausal
women without contraindications.
Calcitonin and raloxifene are alternatives but may be less efficacious
(especially for nonvertebral fractures).
Teriparatide and denosumab should be reserved for patients at high risk or
those who fail other therapies.

Marc Imhotep Cray, MD

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Estrogen or hormonal replacement therapy (HRT)

Evidence-based medicine (EBM) states that overall health risks from HRT in
postmenopausal women appear to exceed possible benefits
Mechanism of action
Reduces bone resorption
Uses
Postmenopausal osteoporosis (reduces bone loss)
Cannot restore bone
Adverse effects
Similar to oral contraceptives but to a lesser extent because of lower
estrogen content
The Womens Health Initiative (WHI) Trial reported an increase in incidence
of strokes in both estrogen-alone and the estrogen-progestin subgroups as
compared with placebo groups.
Thromboembolism
Marc Imhotep Cray, MD

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Case 44 Answers
Agents Affecting Calcium Homeostasis
Summary: A 66-year-old woman with osteoporosis is prescribed
alendronate.
Mechanism of action of PTH on the bone: Pulsatile administration, the
normal physiologic mode, enhances bone formation. Continuous delivery, for
example, as a consequence of a parathyroid tumor, results in bone resorption.
Mechanism of action of PTH in the kidney: Increases reabsorption of Ca 2+
and Mg2+ and increases production of vitamin D and the active metabolite
calcitriol and decreases reabsorption of phosphate, bicarbonate, amino acids,
sulfate, sodium, and chloride.
Mechanism of action of alendronate sodium: Inhibition of osteoclastic
activity in bone, which reduces bone reabsorption.
Marc Imhotep Cray, MD

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Case 44 Answers
Agents Affecting Calcium Homeostasis cont.
CLINICAL CORRELATION
PTH has multiple actions on bone. Chronic elevations in PTH, for example, from
a tumor, stimulate the resorption of bone via its stimulation of the number and
activity of osteoclasts. This is mediated by specific PTH receptors in the bone,
coupled to an
increase in cyclic adenosine monophosphate (cAMP). Intermittent
administration of PTH stimulates bone growth. Estrogen is an indirect inhibitor
of PTH activity in the bone. This effect allows premenopausal women to
maintain higher levels of bone density. Following menopause, with the resultant
decrease in circulating estrogen levels, there is a relative increase in osteoclastic
activity and resorption of bone, with a net loss of bone mineral density.

Marc Imhotep Cray, MD

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Case 44 Answers
Agents Affecting Calcium Homeostasis cont.
Alendronate sodium is an analog of pyrophosphate that directly binds to
bone. It inhibits osteoclastic activity, reducing the resorption of bone. This
retards the progression of bone density loss and may allow for increases in
density, because osteoblastic activity is not affected. It is administered orally,
and its most common adverse effects are gastrointestinal (GI).
It may produce esophagitis, and even esophageal perforation, if the pill were
to get caught in the esophagus while swallowing. For that reason, patients
taking alendronate are instructed to take it on an empty stomach with a full
glass of water and to remain upright for at least 30 minutes after ingesting the
medication.

Marc Imhotep Cray, MD

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THE END

See next slide for further study.

Marc Imhotep Cray, MD

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Sources and further study:

eLearning
Endocrine cloud folder tools and resources
MedPharm Guidebook:
Unit 5 Drugs Used In Disorders of Endocrine System
Endocrine and Reproductive System Pharmacology eNotes
Clinical Pharmacology Cases 39 to 44 (Learning Triggers)
Textbooks
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmans The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill,
2012
Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.
Marc Imhotep Cray, MD

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