2Bone FormationThe 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are made up of calcium, phosphorus and magnesium.Through hormonal interplay, these minerals are deposited to or withdrawn from the bones at a moment’s notice to maintain the delicate homeostasis of calcium and phosphorus in the blood.
3Types of BoneThe 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.
4How 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:OsteoblastsOsteoclasts** These have opposite actions and the number of these cells is determined by 1-84 PTH, 7-84 PTH, Vitamin D and estrogen.All bone is formed through the action of bone cells that are….The two main types of bone cells found are**These have opposite actions and the number of these cells found in bone cells are determined by PTH, Vitamin D and estrogen
5OsteoblastsThey are found on the surfaces of newly forming trabecular bone.When they are completely embedded in the osteoid, they are called “osteocytes”.The osteoid is the collagen like scaffolding to which calcium and phosphorus deposit in the mineralization process.
6OsteoblastsOsteoblasts 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.
7OsteoclastsOsteoclasts consume bone. They produce enzymes which break down, or resorb mineralized bone.Osteoclasts are locatedAt the sites of bone formation where bone resorption occursThroughout the trabecular portion of bone.
8Why 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.
9Bone RemodelingIn 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.
10Bone Remodeling1-84 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.
11Bone RemodelingRemodeling 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.
12Functions of CalciumCalcium 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.
13Corrected CalciumEach 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.
14Calculating Corrected Calcium Albumin Corrected Calcium =Serum calcium + [(4 -albumin) X 0.8] Albumin Corrected CalciumExample: Ca of 10.5 mg/dl & Alb of 2.5 g/dl:= [(4 – 2.5) X 0.8] = 11.7 mg/dl
15Calculating 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 0.81.5 X 0.8 = 1.2*Finally add the results to the patient’s initial serum calcium value= 11.7 mg/dl (new calcium value which would correctly lead to a diagnosis of hypercalcemia)
16Functions 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.
17PTHBoth 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 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).
18PTH 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.
19PTH Regulation of Calcium Homeostasis Effects on BonesIn 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.
20PTH Regulation of Phosphorus Homeostasis *KidneysPTH (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.* GIPTH 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.
21Classification of Renal Osteodystrophy In general there are 4 types of renal osteodystrophy:Two are classified as “high turnover”Hyperparathyroid Bone DiseaseMixed Uremic OsteodystrophyTwo are classified as “low turnover”Adynamic or Low Turnover Uremic OsteodystrophyLow Turnover Osteomalacia bone disease
22Hyperparathyroid 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.
23Mixed 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.
24Low 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 DSurgical parathyroidectomyAluminum overload
25Low Turnover Osteomalacia Uremic Osteodystrophy Without 1-84 PTH, bone remodeling is slow and sparse…Decreased number of active remodeling sitesReduced numbers of osteoblasts and osteoclastsReduced mineralizationMuch of the bone surface is covered with osteoid instead of mineralized bone (i.e. the collagen framework is present without mineralization).
26Adynamic 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.
27Aluminum-Related Bone Disease Caused by exposure to aluminumAluminum 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 diseasePerhaps more than any other form of renal osteodystrophy, it causes severe, deep bone pain.
28Others Effects of Aluminum Aluminum accumulation also can be responsible for brain injury or dementia in hemodialysis patients, called “Dialysis Encephalopathy.”Epo-resistant (refractory) AnemiaBone aluminum cannot be removed by dialysis.Chelation therapy can be attempted to remove aluminum.
29Diagnosis of Osteodystrophy The later stages of Renal Osteodystrophy, damage to cortical bone may be evident by X-ray.Subperiosteal resorptionErosion of the bones of the skullBone 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.
30Ectopic 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.
31Ectopic 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.
32Vascular 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.
33Periarticular 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.
34Alternative Sites for Calcification Soft Tissues (extra-skeletal)(calcium deposits almost anywhere)KidneysHeart (arrythmias, CAD, mitral & aortic valves)Lungs- fibrosis-like restrictive lung diseaseJoints
35Calciphylaxis Rare but dangerous consequence of uncontrolled Ca x P productCalcium 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.