The Role of PTH in Bone
Remodeling
Bone Formation
• The human skeleton is a flexible, lightweight
structural support system for the body.
• Bones also serve as a reservoir of minerals
essential to the proper functioning of every cell in
the human body.
• These minerals are made up of calcium, phosphorus
and magnesium.
• Through hormonal interplay, these minerals are
deposited to or withdrawn from the bones at a
moment’s notice to maintain the delicate
homeostasis of calcium and phosphorus in the
blood.
Types of Bone
• The human skeleton is composed of two types
of bone: cortical and trabecular.
• Cortical bone is also known as compact bone. It
forms a protective outer shell around every bone
in the body.
• Trabecular bone can be found directly beneath
the cortical bone. It forms the interior scaffolding
that helps bones maintain their shape despite
compressive forces.
How is Bone Formed?
• All bone is formed through the action of
bone cells that are distributed sparsely
throughout the bone tissue. The two main
types of bone cells found are:
– Osteoblasts
– Osteoclasts
** These have opposite actions and the number
of these cells is determined by 1-84 PTH, 784 PTH, Vitamin D and estrogen.
Osteoblasts
• They are found on the surfaces of newly
forming trabecular bone.
• When they are completely embedded in
the osteoid, they are called “osteocytes”.
Osteoblasts
• Osteoblasts build bone; they synthesize and
secrete collagen fibrils. The collagen strands
combine to form osteoid.
• They also cause calcium salts and phosphorus
to precipitate from the blood and bond with the
newly formed osteoid to mineralize the bone
tissue.
• Alkaline phosphatase is contained in osteoblasts
and is secreted during osteoblastic activity –
bone formation.
Osteoclasts
• Osteoclasts consume bone. They
produce enzymes which break down, or
resorb mineralized bone.
• Osteoclasts are located
– At the sites of bone formation where bone
resorption occurs
– Throughout the trabecular portion of bone.
Why Does Bone Remodel?
• Bone is a living tissue. It is continuously created
and re-created by the remodeling actions of
osteoblasts and osteoclasts.
• Because the bones are constantly under
changing stresses and need construction, the
remodeling process allows for both the repair of
damaged bones and adaptation of bone to
different tangential & support stresses. It also
facilitates the release of minerals to the blood.
Bone Remodeling
• In normal adult bones, the actions of
osteoclastic resorption and osteoblastic
formation are coupled together – occurring
at the same rate – to maintain bone mass
at a constant level.
• About 10% of bone is replaced through
this remodeling process each year.
Bone Remodeling
• 1-84 PTH signals osteoclasts to attach
themselves and tunnel into the bone, bringing
about the resorption of the bone.
• Recent data indicates that 7-84 PTH inhibits
osteoclast formation and bone resorption.
• Osteoblasts are attracted to the cavities and
secrete collagen to form osteoid. This is then
mineralized to form a new bone layer.
Bone Remodeling
• Remodeling begins with the resorption process
initiated in part by 1-84 PTH, which signals
osteoclasts to attach themselves securely to
bone surfaces and tunnel into the bone, bringing
about the resorption of the bone. The next step
is bone formation.
• Osteoblasts are attracted to the new cavities and
secrete collagen to form osteoid. This osteoid is
then mineralized to form a smooth layer of new
bone.
Functions of Calcium
• Calcium is the most abundant positively charged
ion in the human body (1Kg) and serves many
purposes:
– Helps form the rigid structure of bone as long, flat,
plate-like crystals that are deposited into the bone.
– Regulates muscle contraction.
– Makes nerve conduction possible.
– Facilitates blood clotting – as factor IV, it is necessary
to the formulation of thrombin.
– Is a cofactor necessary for many enzyme reactions to
take place in the body.
Corrected Calcium
• Each one gram change in serum albumin per
deciliter changes the serum calcium
concentration by 0.8 mg/dl.
• Normal serum albumin levels range from about
3.5 to 5.0 g/dl.
• In patients with below normal albumin levels,
obtaining a corrected calcium value can make
the difference between recognizing or missing
an accurate diagnosis of hypercalcemia.
Calculating Corrected Calcium
Albumin Corrected Calcium =
Serum calcium + [(4 -albumin) X 0.8]
Albumin Corrected Calcium
Example: Ca of 10.5 mg/dl & Alb of 2.5 g/dl:
= 10.5 + [(4 – 2.5) X 0.8] = 11.7 mg/dl
Calculating Corrected Calcium
• Example: Jane Doe has a serum calcium value
of 10.5 mg/dl. and a serum albumin of 2.5 g/dl
*First, subtract the patient’s albumin value from the low
normal albumin value: 4 g/dl – 2.5 g/dl = 1.5 g/dl
*Second, multiply the value obtained by 0.8
1.5 X 0.8 = 1.2
*Finally add the results to the patient’s initial serum
calcium value
10.5 + 1.2 = 11.7 mg/dl (new calcium value which would
correctly lead to a diagnosis of hypercalcemia)
Functions of Phosphorus
• Widely available in many foods, phosphorus is
vital to energy production and is stored in the
bone of the human body.
• Is a structural component of fats, proteins and
cell membranes.
• Stimulates the secretions of selected hormones.
• As calcium phosphate, phosphorus is a
component of the mineralized crystals of bone.
• Normal range should be between 3.5 and 5.5
mg/dl.
PTH
• Both 1-84 PTH & 7-84 PTH are synthesized in the four
parathyroid glands which are found deep within the thyroid
gland.
• 1-84 PTH has a half life of 5-10 minutes & 7-84 PTH has a
half life of 10-20 minutes.
• 1-84 PTH is a protein of 84 amino acids.
• 7-84 PTH is a protein of 78 amino acids.
• In secondary hyperparathyroidism the parathyroid gland
cells enlarge early and the gland enlarges late
(hyperplasia)
• 1-84 PTH has an amino terminal end at the first amino acid
(n-terminal) and a carboxy terminal at the other end or the
amino acid #84 (c-terminal).
PTH Regulation of Calcium
Homeostasis
• PTH (1-84 PTH) has effects on calcium
regulation to raise serum calcium through three
target organs.
– * Effect on kidneys (decreasing Ca excretion)
• * PTH stimulates renal tubule resorption to conserve calcium
and stimulates the kidneys to produce calcitriol (vitamin D).
• Effect on GI tract (increasing Ca absorption)
• * PTH increases calcium absorption from the gut indirectly by
stimulating the release of vitamin D. This release acts as a
feedback mechanism on the glands to shut off PTH secretion.
PTH Regulation of Calcium
Homeostasis
• Effects on Bones
– In the short term, PTH (1-84 PTH) promotes the
movement of calcium into the extracellular fluid by
prompting the transfer of readily available bone
calcium to the extracellular fluid.
– In the long term over days or weeks, PTH is secreted
in response to chronic hypocalcemia which stimulates
osteoclasts and increases bone resorption (to raise
serum calcium).
– 7-84 PTH lowers serum calcium.
PTH Regulation of Phosphorus
Homeostasis
*Kidneys
– PTH (1-84 PTH) secretion is triggered by high serum
phosphorus levels and reduced calcium levels.
– PTH reduces renal phosphorus resorption so more phosphorus
is removed from the body.
* GI
- PTH stimulates the production of vitamin D, which increases
calcium and phosphorus absorption from the gut.
* Bones
- PTH increases the solubility of bone calcium by triggering an
increased rate of bone remodeling for the release of both
phosphorus and calcium into the blood.
Classification of Renal
Osteodystrophy
• In general there are 4 types of renal
osteodystrophy:
• Two are classified as “high turnover”
– Hyperparathyroid Bone Disease
– Mixed Uremic Osteodystrophy
• Two are classified as “low turnover”
– Adynamic or Low Turnover Uremic
Osteodystrophy
– Low Turnover Osteomalacia bone disease
Hyperparathyroid Bone Disease
• Called “Osteitis Fibrosa”, it is a high turnover disease-the result of the vicious cycle of secondary
hyperparathyroidism. This can be caused by prolonged
exposure to high 1-84 PTH levels (with low levels of 7-84
PTH) which increases the overall rate of bone
remodeling and alters the structure of the bones.
• These are new, soft bones. The cells are high in number,
and irregular in shape and arrangement.
• Leading to increased fractures and bone pain.
• Leading to abnormal soft tissue calcium loads not being
absorbed into bones and causing metastatic calcification.
Mixed Uremic Osteodystrophy
• Bone remodeling is uncoupled.
• Some areas show rapid remodeling like
Hyperparathyroid Bone Disease.
• Overall the bones are hyperparathyroid, but
there are areas with marked accumulations of
osteoid as typically observed in Low Turnover
Osteomalacia.
• Structurally, the bones are weakened, and bone
volume is variable.
Low Turnover/Adynamic Uremic
Osteodystrophy
• The generally accepted cause of this
disease is over suppression of 1-84 PTH
which can be caused by:
– Calcium load (Ca in dialysate bath, Ca
containing binder, diet)
– Excessive use of vitamin D
– Surgical parathyroidectomy
– Aluminum overload
Low Turnover Osteomalacia
Uremic Osteodystrophy
• Without 1-84 PTH, bone remodeling is
slow and sparse…
– Decreased number of active remodeling sites
– Reduced numbers of osteoblasts and
osteoclasts
– Reduced mineralization
– Much of the bone surface is covered with
osteoid instead of mineralized bone (i.e. the
collagen framework is present without
mineralization).
Adynamic Low Turnover Uremic
Osteodystrophy
• When bone formation has almost
completely stopped, the disease is called
“Adynamic Uremic Bone Disease”.
• When collagen production is normal, but it
outpaces mineralization, the condition is
called “Low Turnover Osteomalacia.”
• In either case, the bones are prone to
injury, bowing and fractures.
Aluminum-Related Bone Disease
• Caused by exposure to aluminum
• Aluminum related bone disease can be superimposed on
any of the previous types of bone disease.
• Sources of aluminum include under treated water used
for dialysate and/or aluminum containing phosphate
binders.
• Aluminum bonds chemically to the bone itself, interfering
with bone cell activity.
• Aluminum also interferes with the effects of calcitriol
(vitamin D) and PTH – low turnover bone disease
• Perhaps more than any other form of renal
osteodystrophy, it causes severe, deep bone pain.
Others Effects of Aluminum
• Aluminum accumulation also can be
responsible for brain injury or dementia in
hemodialysis patients, called “Dialysis
Encephalopathy.”
• Epo-resistant (refractory) Anemia
• Bone aluminum cannot be removed by
dialysis.
• Chelation therapy can be attempted to
remove aluminum.
Diagnosis of Osteodystrophy
• The later stages of Renal Osteodystrophy, damage to
cortical bone may be evident by X-ray.
• Subperiosteal resorption
• Erosion of the bones of the skull
• Bone density cannot be accurately determined by
radiography.
• Bone mineral density of the spine and/or femoral neck can
be semi-quantitated by several methods:
– Dual-energy X-ray absorptiometry (DEXA)
– Dual photon absorptiometry (DPA)
• Double tetracycline labeled bone biopsy is the gold standard
for the diagnosis of renal osteodystrophy. Unfortunately, the
procedure is invasive and not always easily available.
Ectopic Calcification
The calcium x phosphorus product is a
measure of the patient’s risk of metastatic
calcification.
* Levels should be monitored monthly.
* A product over 55 indicates an increased
risk of this complication.
* Even patients receiving vitamin D should
always have a product of below 55.
Ectopic Calcification
• Deposits of calcium phosphate in the skin
which may be one of the factors causing
severe Pruritis.
• Calcium deposits may occur in nearly any
portion of the body.
• Different types are:
– vascular calcification, periarticular or tumoral
calcification, and calciphylaxis.
Vascular Calcification
• Calcification may occur in all small and medium-sized
arteries and even in the aorta.
• A continuous layer of calcium may overlay the vessel walls.
• Calcium deposits to these sites can make it difficult to create
or maintain vascular access.
• On X-ray, the deposits can be seen as a lacy pattern of
calcium surrounding the vessels.
• It can interfere with successful kidney transplant as there
may be no suturable vessels to attach the new organ if the
recipient's vessels are occluded.
• If the calcifications are extensive enough to completely
occlude blood supply to a region, gangrene can occur.
Periarticular or Tumoral
Calcification
• When calcium phosphate is deposited into
the joints, severe pain, redness and
swelling that develop are very much like
Arthritis or Gout.
“Periarticular calcification” is calcification
that surrounds a joint.
Alternative Sites for Calcification
• Soft Tissues (extra-skeletal)
(calcium deposits almost anywhere)
– Kidneys
– Heart (arrythmias, CAD, mitral & aortic valves)
– Lungs- fibrosis-like restrictive lung disease
– Joints
Calciphylaxis
• Rare but dangerous consequence of uncontrolled
Ca x P product
• Calcium deposits to the blood vessels and skin prevent
blood flow to the affected areas and cause tissue death.
• Typically affects the fingers, toes, ankles or the fat and
muscles of the thighs and/or buttocks.
• Condition begins as painful, purple mottled areas.
• The skin over these areas then ulcerates.
• The ulcerations do not heal, Gangrene can occur and
the extensive infection can be fatal.