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• Through hormonal interplay, these minerals are deposited to or withdrawn from the bones at a moment’s notice to maintain the delicate homeostasis of calcium and phosphorus in the blood.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, 7-84 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.