Metabolic Disorders of the Bone

Understand the difference between skeletal modeling and remodeling.

 * Bone remodeling is a continuous process of breakdown and renewal that occurs throughout life; bone formation and bone resorption. Every year about 20-30% of trabecular bone and 3-10% of cortical bone undergoes remodeling.  An uncoupling of bone resorption and bone formation leads to loss of bone mass, loss of bone connectivity, increased fragility of the bones, and increased fracture risk.  This is the essence of osteopenia and osteoporosis.  Remodeling is important to repair microfractures that occur over time and can grow into larger fractures.
 * Bone modeling only occurs in the first two decades of life when formation proceeds and exceeds bone resorption; bone growth. It is a process that establishes the ultimate architecture of the skeleton at the macroscopic level.  Environmental factors affecting bone modeling include: physical activity, nutrition (particularly vitamin D and Ca++), and not drinking EtOH or smoking.

Be able to describe how modeling and remodeling contribute to the three phases of skeletal development and maintenance
Phase I is age 0-20 years. Phase II is 20-50 years. Phase III is over 50 years old.
 * Phase I is designated as the bone modeling stage, while stages II and III are bone remodeling stages.
 * In Phase I, bone formation precedes bone resorption (obviously). In phase II, the opposite is true.  In Phase III, bone resorption greatly precedes bone formation (i.e. little occurs anymore).
 * In Phase I, bone formation is greater than bone resorption. They are equal in Phase II.  In Phase III, bone resorption is greater than bone formation.
 * Bone formation and resorption are uncoupled in Phases I and III. They are only coupled in Phase II.  Uncoupled means that the amount of bone formation doesn't equal the amount of bone resorption.

Understand how metabolic bone disease is a result of “uncoupling” of the normal remodeling process.

 * The normal remodeling process is equilibrium state where the activity of osteoclasts are opposed by osteoblasts. Metabolic bone disease can occur when either cell type becomes relatively overabundant or when either cell looses function.
 * If bone resorption is not followed by equal bone formation, then there will be lose of bone architecture and density. In this case, the bone that remains is strong, but there is not enough bone, leading to overall weakness/fragility and an increased risk of fracture.  This is the basis for osteoporosis.
 * There are also cases when bone formation may be greater than bone resorption, as in acromegaly and in certain areas of the skeleton in Paget's disease. This is also an example of uncoupling.

Comprehend how changes in bone density (or mass) reflect the variations in modeling and remodeling through life.

 * In Phase I, bone density is increasing, reflecting greater osteoblastic activity than osteoclastic activity, as is the characteristic of the modeling stage.
 * In Phase II, bone density remains stable, as remodeling is coupled, and the activities of osteoclasts are paired to those of osteoblasts.
 * In Phase III, bone density is decreased due to increased activity of osteoclasts, that is not coupled to that of osteoblasts. This uncoupling has many causes.

Know the clinical and laboratory definitions of osteoporosis.
Clinical Definition: Osteopenia, such that the remaining bone mass is normally mineralized. Bone is decreased in amount per unit volume, but normal in composition (as opposed to osteomalacia). Patients are at increased risk of fractures.

Laboratory Definition: Unclear what is wanted here. There are four main pathophysical processes that may contribute to osteoporosis, either alone or in combination. These are:
 * 1) Decreased rate of bone formation
 * 2) Increased rate of bone resorption
 * 3) Decreased GI absorption of Ca++
 * 4) Increased urinary excretion of Ca++
 * With this in mind, there are several laboratory studies that may inform a dx.
 * First, you may actually measure the rate of bone formation by giving back-to-back doses of radio-labeled tetracycline, which will lay down linearly in areas of bone that are undergoing remodeling/formation. You must follow up with a bone biopsy to measure the distance between the now visible lines of tetracycline to estimate the rate of bone formation.
 * Next there are several biochemical markers of bone remodeling activity. These include: urine N-telopeptides, 24hr measure of urine Ca++, serum alkaline phosphatase, and osteocalcin.
 * To rule out an absorptive problem, you could do an anti-endomysial antibody screen for Celiac, or even an upper GI endoscopy. This would probably only be appropriate after eliciting evidence of GI distress with a good history.

Radiographs, bone densitometry and bone histomorphometry all can diagnose osteopenia. Appraise the relative merits and disadvantages of these three techniques in the clinical assessment of osteopenia.

 * Radiographs: They are cheap and widely available. But, they only detect mineral loss of more than 40%, which is not good for detecting mild or moderate osteopenia.
 * Bone Densitometry (DEXA most popular): More sensitive, optimal method for precisely determining the bone mineral content of clinically relevant sites, correlates with bone strength and fracture risk, low radiation. But, it is more expensive, not necessarily available everywhere, and it gives you no information on the histology.
 * Bone histomorphometry: Allows you to examine architecture of the bone, and to stain the quality of the mineralization (i.e. distinguish between osteoporosis and osteomalacia). But it is painful and unnecessary in most cases.

Identify the major risk factors for osteoporosis.

 * Never reached genetic potential of peak bone density (often due to excessive childhood illness, especially if it effects absorption, i.e. Celiac sprue, anorexia nervosa, bulimia)
 * Inactivity
 * EtOH and smoking
 * Osteotoxic drugs (glucocorticoids)
 * Poor diet
 * Low estrogen

===Hormonal regulation of mineral balance depends primarily upon Diagram the expected changes PTH, 1,25 (OH)2 (calcitriol), vitamin D3 (cholecalciferol) and calcitonin and resultant effects on skeletal Ca balance in===
 * 40 yo woman immediately after bilateral oophorectomy before estrogen replacement is instituted
 * Increased Ca++ mobilization by osteoclasts, but balanced initially by increased vitamin D3, which can maintain the balance for a short time. Eventually she would experience significant to extreme loss of bone density.
 * PTH decreases, due to increased serum Ca++ levels
 * 1,25 (OH)2 Vitamin D3 decreases, due to a decrease in PTH, (note there is not Ca++ deficiency)
 * Calcitonin increases due to increased serum Ca++, which will oppose the action of osteoclasts (minor role).
 * Results in decreased skeletal balance of 20 to 60mg Ca++ per day.
 * 25 yo man after thyroidectomy for severe Grave's disease
 * No PTH, calcitonin due to thyroidectomy. Decreased 1,25 (OH)2, as PTH regulates renal production of calcitriol.  No change in D3.  Will lead to tetany in short term.
 * 85 yo woman with severe osteoporosis after initiation of bisphosphonate therapy
 * Because she has osteoporosis, she inherently has a negative Ca++ balance in her bones. The bisphosphonates will prevent further loss of bone, but will not increase bone mass, only slow the decline.
 * PTH will likely be normal, because the bisphosphonates are inhibiting all bone remodeling, serum Ca++ levels will likely be stable, and PTH will be too.
 * Vitamin D3 levels will be stable
 * Calcitonin levels will be stable

Defend the following statement:

 * "Peak bone mass is the most important determinant of osteoporotic fracture risk".
 * If you do not reach your peak bone mass, you are undeniably at an increased risk of developing osteoporosis, and experiencing a fracture.

Criticize the following statement:

 * "Peak bone mass is the most important determinant of osteoporotic fracture risk".
 * If one were able to maintain one's peak bone mass throughout a lifetime, there would be no osteoporosis
 * There are other factors that occur after the second phase of bone development (in which modeling and remodeling are coupled) that lead to bone resorption and osteopenia.
 * If we could eliminate the factors that cause uncoupled remodeling in the third phase of life, there would be no osteoporosis, so the peak bone mass wouldn't matter as much.

Relate the major available treatments for osteoporosis to their effects on the remodeling process.

 * Vitamin D and Calcium supplementation
 * Bisphosphonates: potent inhibitors of bone remodeling, both osteoclasts and osteoblasts. This is good if treating osteoporosis, but these are contraindicated in osteomalacia, since this will inhibit mineralization as well.
 * Estrogen: prevents reduction in bone density by increasing levels of osteoprotegerin, which binds to RANKL and prevents activation of osteoclasts. Estrogen deprivation has also been linked to IL-6 synthesis, which activates osteoclasts.  In effect, estrogen replacement prevents the resorption of bone.
 * Calcitonin: endogenous inhibitor of bone resorption
 * Thiazides: stimulate retention of Ca++ in the circulation by reducing urinary losses, and thus may have a positive effect on bone density.
 * PTH: Paradoxically, daily injection of intermediate levels of PTH results in trabecular bone formation, and reduced fractures. This is in contrast to PTH's effects due to primary hyperparathyroidism, which are to increase bone resorption.

Describe the beneficial effects of estrogen at the level of the kidney, gut and bone that may lead to a reduction in osteoporosis risk in a postmenopausal woman.
The effects of estrogen on gut and kidney are more direct. But resorption of Ca++ falls in the face of estrogen deficiency. In addition, renal tubular resorption of Ca++ declines with loss of estrogen. So both effects result in a negative Ca++ balance, thus leading to bone loss.

The effect of estrogen deficiency on serum calcium is minimal. There may be an increased bone sensitivity to PTH which adds to the increased osteoclast activity. This would be expected to raise serum calcium levels. However, this effect is the decline in but calcium resorption and renal tubular calcium resorption described above. So bottom line is that serum calcium changes little in menopause.

Also, direct estrogen effects on the osteoblast have been hard to demonstrate. Most of the estrogen action on bone is thought to be due to osteoclasts.

===You have recently been elected health czar on your sole campaign promise to wipeout osteoporosis. What are the major public health recommendations of your platform? Justify each plank of your platform with your understanding of skeletal physiology.=== I appreciate the nomination, but I decline the position.


 * Improve childhood and adolescent bone growth: exercise, eliminate soda, improve calcium and vitamin D update.
 * Reduce bone resorption: hormone therapy in women willing to take low doses of estrogen, or estrogen analogues.

Characterize the clinical presentation of osteomalacia and differentiate it from that of osteoporosis.

 * Osteomalacia is an abnormality in the quality of the bone. There is an overt defect in bone formation.  The major causes are low vitamin D and hypophosphatemia.  Specifically, osteoblasts lay down a protein matrix, but it is poorly mineralized.
 * Osteoporosis is a reduction in the quantity of the bone. Bone resorption is exceeding bone formation.  Major causes include age, low estrogen.  Bone is not poorly mineralized.

Disorders of skeletal mineralization are lumped into the general category of osteomalacia. However, rickets is a term reserved for a particular clinical situation. Why?
Osteomalacia occurs in bone that is finished growing. Rickets is osteomalacia in children whose bones are still forming.

Know the major causes of osteomalacia.

 * Vitamin D deficiency and hypophosphatemia. Vitamin D deficiency can be caused by malabsorption syndromes (vit D is a fat soluble vitamin), low intake, low sunlight, deficient biosynthesis due to renal disease or liver disease, hormone resistance or increased metabolism or excretion.
 * Hypophosphatemia can be caused by renal disease (Fanconi Syndrome), excessive antacid use or oncogenous osteomalacia.
 * OTHER: Hypocalcemia can be due to diet. Hypophosphatemia is an error of inborn metabolism when alk phos levels are low. Drugs that induce osteomalacia are etidronate, NA F, NAAL, anticonvulsants, and antacids.

Describe the radiographic findings in osteomalacia.
Looks exactly like osteoporosis, unless advanced in which case one might see a pseudofracture. This is where a minor stress fracture has not healed because there is no mineralization.

Identify the principles of therapy in osteomalacia.
Replace whatever mineral is missing. Note that calcium carbonate is the substance the delivers the most essential calcium.

Provide a clinical situation for the use of each form of vitamin D and explain why the use of the other two forms of vitamin D would be inappropriate in the given setting.

 * Cholecalciferol (D3)
 * Supplementation of a health patient or patient with low bone mass and no other health problems. It is the most cost effective and has the highest therapeutic index.


 * Calcifediol (25-OH Vitamin D)
 * Liver failure. Although this form is most expensive, it has a higher therapeutic index than 1,25 OH D.


 * Calcitriol (1,25, (OH)2 vitamin d
 * Renal osteodystrophy. Normally, calcitriol is synthesized by the kidneys.  Other forms of vitamin D could not be converted to calcitriol.

Know the presenting features of Paget's Disease of the Bone

 * Most commonly presents asymptomatically and, in fact, many people have this and don't know it. Can have skeletal abnormality that is warm to the touch.
 * Can have fractures, deafness, cauda equina syndrome, radiculopathy
 * Legs can be different lengths, loss of ROM in the joint, rarely cardiac status may be compromised
 * Radiographic findings include Saber Shin (thinned bone looks like sword), enlargement or expansion of the bone in certain areas and fractures
 * A bone scan will show areas of non-continuous involvement, i.e. tibia on the left, a scapula on the right

Describe the characteristic remodeling abnormalities observed in Paget's disease. What are the consequences of these pagetic changes at the organ level (i.e. bone as an organ of mechanical support)?

 * The bone is no longer able to support body structures once it begins to seriously deform

Know the principal therapeutic options for Paget's Disease

 * There is very little you can do to change the disease
 * If symptomatic, you can offer surgery to relieve neuro issues
 * Pain can be controlled with analgesics, treat the hypercalcemia and treat kidney stones
 * There are specific anti-osteoclastic meds: calcitonin, bisphosphonates and mitramycin.