The Role of PTH in Bone Remodeling

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The Role of PTH in Bone Remodeling
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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  deposited to or withdrawn from the bones at a
  moments notice to maintain the delicate
  homeostasis of calcium and phosphorus in the
  blood.

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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.

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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, 7-84 PTH,
  Vitamin D and estrogen.

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Osteoblasts

• They are found on the surfaces of newly forming
  trabecular bone.
• When they are completely embedded in the osteoid,
  they are called osteocytes.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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 patients 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 patients initial
  serum calcium value
• 10.5 1.2 11.7 mg/dl (new calcium value which
  would correctly lead to a diagnosis of
  hypercalcemia)

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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.

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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).

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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.

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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.

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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.

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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

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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.

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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.

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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

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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).

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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.

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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.

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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.

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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.

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Ectopic Calcification

• The calcium x phosphorus product is a measure of
  the patients 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.

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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.

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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.

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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.

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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

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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.

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