Pharmacotherapy of

Parathyroid Disorder
 Parathyroid Hormone
The parathyroid hormone (PTH) is the most important
regulator of calcium metabolism.
PTH is secreted by the chief cells of the parathyroid glands as
a polypeptide containing 84 aa in response to hypocalcemia
and hyperphosphatemia.
PTH release results in a signal to the bones to release calcium
into the bloodstream and also to the kidneys to resorb calcium
in the collecting system and excrete phosphorus.

Saliba W, and El-Haddad B. 2009

 Parathyroid Hormone
In addition, PTH plays an active role in the intestines 
stimulates the absorption both calcium and phosphorus.
PTH increases the activation of 25-hydroxy vitamin D to 1,25-
dihydroxy vitamin D in the kidneys  activate vitamin D
Simplified overview of the calcium-vitamin D-
PTH axis

van Ballegooijen, 2014

 Parathyroid Hormone

Conversely, if the blood calcium level is elevated, PTH

production is decreased
 This allows for excretion of excess calcium from the body

In the instance of renal disease or parathyroid disease, this

normal mechanism runs awry and the result can be injurious
to multiple body systems, including the bones, muscles,
kidneys, and brain function.
 Parathyroid Hormone

PTH is split into 3 fragments in the parathyroid gland

before systemic release:
 an amino or N-terminal fragment,
 a midregion fragment, and
 a carboxy or C-terminal fragment.

The active intact PTH and the N-terminal fragment

are physiologically active in the body.
 Parathyroid Hormone
The reference range for PTH:
Normal: 10-65 pg/mL or 10-65 ng/L
PTH levels in the blood may be analyzed to identify the
underlying cause of calcium aberrations
 This may delineate hyperparathyroidism, parathyroid tumors,
vitamin D deficiency, renal disease, and some tumors that produce
the hormone.
 Intraoperative PTH assays may be performed during parathyroid tumor
surgery to help determine if the PTH-producing adenoma was correctly
removed.
Primary Hyperparathyroidism
A disorder “originates” from parathyroid gland(s).
Parathyroid gland(s) is overactive  releases too much PTH.
The disorder includes the problems that occur in the rest of
the body as a result of too much PTH e.g osteoporosis.
In the United States, about 100,000 people develop primary
hyperparathyroidism each year; Most often in people between
age 50 and 60, and women are affected about 3x than men.

NIDDK, 2017
Secondary Hyperparathyroidism
Secondary, or reactive, hyperparathyroidism can occur if a
problem such as kidney failure causes the parathyroid
glands to be overactive.
 What are the effects of high
PTH levels?
High PTH levels trigger the bones to release increased
amounts of calcium into the blood, causing blood calcium
levels to rise above normal.
 The loss of calcium from bones may weaken the bones 
Osteoporosis

Also, the small intestine may absorb more calcium from

food, adding to the excess calcium in the blood.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 What are the effects of high
PTH levels?
In response to high blood calcium levels, the kidneys excrete
more calcium in the urine, which can lead to kidney stones.

High blood calcium levels might contribute to other problems,

such as heart disease, high blood pressure, and difficulty with
concentration.
 However, more research is needed to better understand how
primary hyperparathyroidism affects the cardiovascular
system—the heart and blood vessels—and the central nervous
system—the brain and spinal cord.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Why is calcium important?
Calcium is essential for good health.
Calcium plays an important role in bone and tooth
development and, combined with phosphorus,
strengthens bones and teeth.
Calcium also helps muscles contract and nerves
transmit signals.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 What causes primary
hyperparathyroidism?
In about 80% of people with primary hyperparathyroidism, a
benign, or noncancerous, tumor called an adenoma has formed
in one of the parathyroid glands.
 The tumor causes the gland to become overactive.

In most other cases, the excess hormone comes from two or more
overactive parathyroid glands, a condition called multiple
tumors or hyperplasia.

Rarely, primary hyperparathyroidism is caused by cancer of a

parathyroid gland.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
What are the symptoms of primary
hyperparathyroidism?
Most people with primary hyperparathyroidism have no
symptoms.
When symptoms appear, they are often mild and
nonspecific, such as muscle weakness, fatigue and an
increased need for sleep, feelings of depression, aches and
pains in bones and joints
People with more severe disease may have loss of appetite,
nausea, vomiting, constipation, confusion or impaired
thinking and memory, increased thirst and urination
 These symptoms are mainly due to the high blood calcium levels
that result from excessive PTH.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 How is primary
hyperparathyroidism diagnosed?
Diagnose primary hyperparathyroidism when a person has
high blood calcium and PTH levels.
High blood calcium is usually the first sign that leads
health care providers to suspect parathyroid gland
overactivity.
Other diseases can cause high blood calcium levels, but
only in primary hyperparathyroidism is the elevated
calcium the result of too much PTH.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 What tests may be done to check
for possible complications?
Bone mineral density (BMD) test
Dual energy x-ray absorptiometry (DXA or DEXA scan) to measure
bone density. The test can help assess bone loss and risk of
fractures.
Ultrasound
Bounces safe, painless sound waves off organs to create an image of
their structure. The images can show the presence of kidney stones.
Computerized tomography (CT) scan
Combination of x rays and computer technology to create 3D images;
can show the presence of kidney stones.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 What tests may be done to check
for possible complications?
A 24-hour urine collection
To measure selected chemicals, such as calcium and
creatinine, which is a waste product healthy kidneys remove 
may provide information on kidney damage, the risk of
kidney stone formation, and the risk of familial
hypocalciuric hypercalcemia.
25-hydroxy-vitamin D blood test.
This test is recommended because vitamin D deficiency is
common in people with primary hyperparathyroidism.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 How is primary
hyperparathyroidism treated?
Surgery (Parathyroidectomy)

Surgery to remove the overactive parathyroid gland(s) is

the only definitive treatment for the disorder, particularly
if the patient has a very high blood calcium level or has
had a fracture or a kidney stone.
In patients without any symptoms  guidelines
Surgery improve bone density and fewer fractures and
reduce the chance of forming kidney stones.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Bilezikian, 2005
 Parathyroidectomy
Surgery strategies:
 Minimally invasive parathyroidectomy
 Standard neck exploration

Complication
 Rate of 1–3% damage to the nerves controlling the vocal
cords, which can affect speech.
 A small number of patients lose all parathyroid tissue and
develop chronic low calcium levels, requiring lifelong
treatment with calcium and some form of vitamin D. This
complication is called hypoparathyroidism.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Surgery Monitoring
Long-term monitoring should include periodic clinical
evaluations, annual serum calcium & creatinine measurements
to check kidney function, and bone density measurements every
1 to 2 years.
Vitamin D deficiency should be corrected if present.
Medical attention if patient immobilized or dehydrated due to
vomiting or diarrhea  blood calcium levels 

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Medications
Calcimimetics are a new class of medications that
decrease parathyroid gland secretion of PTH.
The calcimimetic, cinacalcet (Sensipar), has been
approved by the U.S. FDA for the treatment of secondary
hyperparathyroidism caused by dialysis and primary
hyperparathyroidism caused by parathyroid cancer.
Cinacalcet has also been approved for the management of
hypercalcemia associated with primary
hyperparathyroidism.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Medications
A number of other medications are being studied, including
bisphosphonates and selective estrogen receptor
modulators.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Eating, Diet, and Nutrition
Eating, diet, and nutrition have not been shown to play a
role in causing or preventing primary
hyperparathyroidism.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Vitamin D
Research is ongoing to determine optimal doses and regimens
of vitamin D supplementation for people with primary
hyperparathyroidism.
 Achieve a serum level of 25-OH Vitamin D > 20 ng/dL.

For the healthy public, the Institute of Medicine (IOM)

guidelines for vitamin D intake are:
 600 IUs for ages 1 - 70 yo and
 800 IUs for older.
 No more than 4,000 IUs of vitamin D be taken per day.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Calcium
People with primary hyperparathyroidism without
symptoms who are being monitored do not need to
restrict calcium in their diet.
People with low calcium levels due to loss of all
parathyroid tissue from surgery will need to take calcium
supplements for the rest of their life.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

 Pharmacological approaches
Oestrogens and SERMs
Oestrogen therapy have beneficial effects of but risks associated
with oestrogen use have been well publicized.
The amount of oestrogen required is higher than most women can
tolerate, although some positive studies have utilized lower doses.
Amongst postmenopausal women who are not candidates for
surgery or refuse this option, can be an option.
The SERM (selective estrogen receptor modulator), raloxifene, is a
potential alternative to estrogen. In a short-term, 8-week trial of
18 postmenopausal women, raloxifene (60 mg/day) reduced the
serum calcium by 0.5 mg/dL) along with reduction in markers of
bone turnover

Bilezikian, 2005
 Pharmacological approaches
Bisphosphonates
By reducing bone turnover, without affecting PTH
secretion directly, bisphosphonates could reduce serum
and urinary calcium levels.
Alendronate leads to substantial gains in lumbar spine
and hipbone density; Calcium and PTH levels do not
change.
Risedronate experience, was an acute, 7-day study of 19
patients with PHPT in which the serum and urinary
calcium fell significantly.

Bilezikian, 2005
 Pharmacological approaches
Calcimimetics
Inhibits the processes associated with the synthesis and secretion of
PTH  most specific approach to PHPT
Molecules interact with the calcium-sensing receptor on the
parathyroid cell  alter the affinity of calcium.
The first calcimimetic, (R)-N(3-methoxy-a-phenylethyl)-3-(2-
chlorophenyl)-1-propylamine (R-568) has been supplanted by
cinacalcet, a second generation ligand.
Cinacalcet normalizes the serum calcium in most patients with mild
hyperparathyroidism.
Interestingly, the PTH concentration falls but not to normal levels.
These data suggest that a drug of this type may become a useful
alternative to parathyroidectomy in patients with PHPT.
Bilezikian, 2005
OSTEOPOROSIS
Wells, 2009
 ANABOLIC THERAPY
Teriparatide
Recombinant product representing the first 34 amino acids in
human PTH.
Mechanism: increases bone formation, the bone remodeling
rate, and osteoblast number and activity.
 Both bone mass and architecture are improved.
Teriparatide is FDA approved for postmenopausal women and
men who are at high risk for fracture.

Wells, 2009
 Teriparatide
Candidates for therapy include patients with a history of
osteoporotic fracture, multiple risk factors for fracture,
very low bone density (e.g., T-score <–3.5), or those who
have failed or are intolerant of previous bisphosphonate
therapy.
The drug reduces fracture risk in postmenopausal women,
but no fracture data are available in men. Lumbar spine BMD
increases are higher than with any other osteoporosis
therapy. Although wrist BMD is decreased, wrist fractures
are not increased.

Wells, 2009
 Teriparatide
Discontinuation of therapy results in a decrease in BMD, but some
antifracture efficacy appears to be maintained. Sequential
therapy with teriparatide followed by an antiresorptive agent
(e.g., bisphosphonate) should be considered to maintain BMD
gains.
The dose is 20 mcg administered subcutaneously in the thigh or
abdominal area. The initial dose should be given with the patient
either lying or sitting, in case orthostatic hypotension occurs. Each
prefilled 3-mL pen device delivers a 20-mcg dose each day for up
to 28 days; the pen device should be kept refrigerated.

Wells, 2009
Wells, 2009
 Teriparatide
Transient hypercalcemia rarely occurs. A trough serum calcium
concentration is recommended 1 month after initiation of therapy.
Teriparatide is contraindicated in patients at baseline increased
risk for osteosarcoma (e.g., Paget’s bone disease, unexplained
alkaline phosphatase elevations, pediatric patients, young adults
with open epiphyses, or patients with prior radiation therapy
involving the skeleton)

Wells, 2009
 SECONDARY HYPERPARATHYROIDISM
AND RENAL OSTEODYSTROPHY

Calcium–phosphorus balance is mediated through a

complex interplay of hormones and their effects on
bone, GI tract, kidney, and parathyroid gland.
As kidney disease progresses, renal activation of
vitamin D is impaired, which reduces gut absorption of
calcium. Low blood calcium concentration stimulates
secretion of PTH.
As renal function declines, serum calcium balance can be
maintained only at the expense of increased bone
resorption, ultimately resulting in renal osteodystrophy
(ROD)
Secondary hyperparathyroidism
Secondary hyperparathyroidism can cause altered lipid
metabolism, altered insulin secretin, resistance to
erythropoietic therapy, impaired neurologic and immune
functions, and increased mortality.
 Treatment
Phosphate-Binding Agents
Phosphate-binding agents decrease phosphorus absorption from the gut
and are first-line agents for controlling both serum phosphorus and
calcium concentrations.
K/DOQI guidelines recommend that elemental calcium from calcium-
containing binders should not exceed 1,500 mg/day and the total daily
intake from all sources should not exceed 2,000 mg. This may necessitate
combination of calcium- and noncalcium-containing products (e.g.,
sevelamer HCL, lanthanum carbonate).
Adverse effects of calcium-containing phosphate binders, include
constipation, diarrhea, nausea, vomiting, and abdominal pain. The risk of
hypercalcemia is also a concern. To avoid potential drug interactions,
phosphate binders should be administered 1 hour before or 3 hours after
other oral medications.
 Vitamin D Therapy
Calcium (less than 9.5 mg/dL) and phosphorus (less than 4.6
mg/dL) must be controlled before vitamin D therapy is initiated.
Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses
PTH synthesis and secretion and upregulates vitamin D
receptors, which ultimately may reduce parathyroid
hyperplasia. The dose depends on the stage of CKD and type of
dialysis
The newer vitamin D analogs paricalcitol and doxercalciferol
may be associated with less hypercalcemia and, for paricalcitol,
hyperphosphatemia. Vitamin D therapy, regardless of agent, is
associated with decreased mortality
Calcimimetics
 LITERATURES
Hanne van Ballegooijen, The role of vitamin D and parathyroid hormone in
cardiovascular health, PhD- hesis of Department of Health Sciences and the
EMGO Institute for Health and Care Research at the VU University, the
Netherlands, 2014
U.S. Department of Health and Human Services, NATIONAL INSTITUTESOF
HEALTH, NIDDK (National Institute of Diabetes and Digestive and Kidney
Disease). https://www.niddk.nih.gov. access date, 14 Nov 2017.
Saliba W, and El-Haddad B. 2009. Secondary Hyperparathyroidism:
Pathophysiology and Treatment. J Am Board Fam Med;22:574–581
Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ. 2005. Primary
Hyperparathyroidism: New Concepts in Clinical, Densitometric and
Biochemical Features, Journal of Internal Medicine; 257: 6–17.
Wells BG, DiPiro JT, Schwinghammer TL, DiPiro CV. Pharmacotherapy
Handbook. Seventh Edition. 2009 by The McGraw-Hill Companies, Inc. New
York. USA.
 Hypocalcemia Medication

Medication Summary
The goals of pharmacotherapy are to reduce morbidity
and to prevent complications.
Patients with hypocalcemia due to resistance to
parathyroid hormone (PTH) generally will require long-
term therapy with vitamin D and calcium
supplementation.
Patients with hypocalcemia associated with chronic renal
failure often require phosphate binders and vitamin D
supplementation.

https://emedicine.medscape.com/article/241893-medication
van Ballegooijen, 2014