Osteoperosis and Metabolic Bone Disorders Flashcards
Bone Remodeling
a. Body can recognize when bone is older
i. Osteoclasts will bind to older bone (can recognize a rough border of older bone)
b. Osteoclasts will secrete proteolytic enzymes and acid—> Release Ca and Phosphate
i. will also release stimulatory factors for osteoblasts
c. Osteoblasts will come in (attracted by stimulatory factors of osteoclast)
i. osteoblast will secrete Osteoid–> collagen for building new blood
d. Need adequate Ca and PO4 for with Oseoid to form a new bone
i. this process is calcifying and mineralizing the new bone
e. The osteoblasts will get trapped in the new bone, will become Osteocytes
i. Osteocytes are mechanoreceptors, will sense stress and remodel/strengthen new bone!
Bone Resportion
a. RANK-Ligand (RANK-L) is the main controller of bone resportion
i. will be secreted by osteoblasts
b. Osteoblasts will secrete RANK-L while they are in old bone, the RANK-L will bind to RANK on Osteoclasts
i. RANK activation will lead to increased stimulation of osteoclasts and bone breakdown
c. Decoy receptor is called OPG, will prevent RANK-L from binding to RANK
i. OPG will decrease the amount of osteoabsorption
d. RANK and OPG will battle for the amount of RANK-L that is secreted by Osteoblasts
i. More RANK activation means more bone resportion (breakdown and release of Ca and PO4)
ii. More OPG binding by RANK-L means LESS resportion
RANK-L: Rank Ligand
RANK: Receptor Activator of Nuclear Factor kb
OPG: Osteoprotegerin (decoy receptor for RANK-L)
Bone Formation
a. WNT pathway is the protein pathway that leads to osteoblasts forming new bones
i. Wnt, Frizzled / LRP-5, B-Catenin are major proteins of the WNT pathway for forming new bone
b. Sclerostin will inhibit the WNT pathway, and decrease new bone formation
Osteoperosis
a. Compromised Bone Strength
b. Predisposing to Increased Risk of FRAGILITY FRACTURES
i. think low trauma fractures (should not normally happen)
c. Fragility fracture is a type of pathologic fracture that occurs as result of normal activities, such as a fall from standing height or less. There are three fracture sites said to be typical of fragility fractures: vertebral fractures, fractures of the neck of the femur, and Colles fracture of the wrist. This definition arises because a normal human being ought to be able to fall from standing height without breaking any bones, and a fracture therefore suggests weakness of the skeleton
Osteoporosis Fragility Fractures (Low Trauma)
a. Most common areas of fragility fractures
Spine ~ 700,000/year in US
Hip ~ 300,000/year in US
Wrist ~ 250,000/year in US
b. Total Fragility Fractures: 1.5 million
c. Fragility Fractures = Osteoporosis
d. A pathologic fracture is a bone fracture caused by disease that led to weakness of the bone structure.
i. This process is most commonly due to osteoporosis
Fragility Fractures (Osteoporosis) Risk Factors
Biggest risk factors
- Age
- Falls
- Low Bone Mass
- Previous Fractures
Low Bone Mass and Fracture Risk
- Osteoporosis
i. Very low bone mass - Osteopenia
i. fairly low bone mass
Fracture Risk
Effect of Previous Vertebral Fracture
Found that patients are at greater risk for fractures if they had previous fractures
Vertebral Fracture
Fragility Fracture
Most common type of fragility fracture
Abnormal Bone Remodeling
Resorption > Formation
a. Osteoclast activity is greater than osteoblast activity
i. will exceed bone formation
b. Bone mass is overall lost
Risk Factors for Low Bone Mass
a. Non-Modifiable: Age Race Gender Family History Early Menopause
b. Modifiable: Low Calcium Intake Low Vitamin D Intake Estrogen Deficiency Sedentary Lifestyle Cigarette Smoking Excess Alcohol (> 2/day) Excess Caffeine (> 2/day) Medications
Differential Diagnosis of Low Bone Mass
Low bone mass is not always osteoperosis
Osteoporosis
i. the most common cause by far
Osteomalacia Osteogenesis Imperfecta Hyperparathyroidism Hyperthyroidism Hyperprolactinemia Hypogonadism Cushing’s Syndrome Eating/Exercise Disorders
Celiac Disease Inflammatory Bowel Dz Primary Biliary Cirrhosis Multiple Myeloma Rheumatoid Arthritis Chronic Renal Failure Renal Tubular Acidosis Idiopathic Hypercalciuria Systemic Mastocytosis
High Risk Medications*
i. Well Established: Glucocorticoids, Excess Thyroid Hormone, Anticonvulsants
ii. Probable/Possible: Thiazolidinediones, SGLT2-I’s, SSRI’s, PPI’s
Osteoporosis Prevention and Treatment
a. Calcium: 1000-1500 mg/day
b. Dairy Products (CaPO4): ~ 300 mg/serving
c. Supplements if Dairy Intake Insufficient
d. Vitamin D: 1000 units/day
e. Exercise: Aerobic and Resistance
f. Falls: Assessment and Prevention
Osteoporosis Treatment Strategy
Alter Bone Remodeling
Medications that
1. Decrease Bone Resorption
OR
2. Increase Bone Formation
Osteomalacia and Rickets
a. Impaired Bone Mineralization Resulting in Soft, Weak Bones
b. Not mineralizing properly (unlike osteoporosis, where there is net loss)
Osteomalacia - Adults
Rickets - Children
Osteomalacia and Rickets
Pathophysiology
a. Inadequate Calcium x Phosphate
i. Product for Bone Mineralization
b. Have more Unmineralized Osteoid
i. soft bone that is weak
[Ca x PO4 < 24]
Vitamin D Disorders
Can lead to osteomalacia
a. Acquired Vitamin D Deficiency
i. Poor Oral Intake / Malabsorption
ii. Inadequate Sunlight
b. Acquired 1,25 (OH)2 Vitamin D Deficiency
i. Renal Disease
ii. Hypoparathyroidism
c. Congenital 1 Alpha Hydroxylase Deficiency
i. “Vitamin D Dependent Rickets Type 1”
d. Congenital Vitamin D Receptor Deficiency
i. “Vitamin D Dependent Rickets Type 2”
Phosphate Disorders
Can lead to osteomalacia
a. Acquired Hypophosphatemia
i. Poor Oral Intake
ii. Renal Phosphate Wasting
b. Congenital Hypophosphatemic Rickets
“Vitamin D Resistant Rickets”
i. Renal Phosphate Wasting
ii. Impaired 1,25 (OH)2 Vitamin D Formation
Clinical Features of Osteomalacia and Rickets
a. Osteomalacia:
Pain
Deformities
Fractures
b. Rickets: Pain Deformities Muscle Weakness Short Stature
Rickets
a. Rickets is defective mineralization or calcification of bones before epiphyseal closure in immature mammals due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium potentially leading to fractures and deformity.
b. An X-ray or radiograph of an advanced sufferer from rickets tends to present in a classic way: bow legs (outward curve of long bone of the legs) and a deformed chest.
i. Changes in the skull also occur causing a distinctive “square headed” appearance (Caput Quadratum).
ii. These deformities persist into adult life if not treated. Long-term consequences include permanent bends or disfiguration of the long bones, and a curved back.
Osteomalacia is a similar condition occurring in adults, generally due to a deficiency of vitamin D but occurs after epiphyseal closur
Osteomalacia
Radiology
a. Fractures
b. Pseudofractures–> areas of bone demineralization, no actual fracture of bone
i. Milkman’s Fractures
ii. Looser’s Lines
Rickets
Radiology
a. Deformities
i. Bowing of Long Bones
ii. Flaring Ends of Long Bones
b. Delayed Epiphyseal Calcification
Rickets
Before and After Therapy
Bowing of Long Bones
Flaring of Ends of Long Bones
Delayed Epiphyseal Calcification
Paget’s Disease of Bone
An Idiopathic Bone Condition Characterized by Excessive/Unregulated Bone Resorption and Formation
Paget’s Disease
Etiology
- Genetic Predisposition
2. Chronic Paramyxovirus Infection
Paget’s Disease of Bone
Evidence for a Genetic Disorder
a. Familial Aggregation
15-40% Family History
b. 18q Linkage
Familial Expansile Osteolysis
Some Paget’s Families
c. Mutation of Osteoprotegerin Gene
Juvenile Paget’s Disease
d. Mutation of Sequestosome 1/P62 Gene
40-80% of Paget’s Families
Sequestosome I (SQSTM I/ p 62)
SQSTMI: ubiquitin binding protein. Forms ubiquitinated chains that function as protein scaffolds for IL-1 and TNF induced NF-B activation, which regulates RANK signaling that controls osteoclast differentiation, activity and survival.
SQSTMI mutations: linked to Paget’s Disease in many families with familial Paget’s Disease.
Paget’s Disease of BoneEvidence for a Viral Disorder
Geographic
Variation
Dog Ownership
Link
Time Trends
Viral Studies
Paget’s Disease of BoneGeographic Variation
a. High Prevalence: US, UK, France, Germany, Australia, New Zealand
b. Low Prevalence: Ireland, Scandinavia, Southern Europe
c. Rare: Asia, Africa
Paget’s Disease of Bone
Dog Ownership Link
Dogs…. Paget?!?
Paget’s Disease
Paramyxovirus
Paramyxovirus-like Inclusions in Nuclei + Cytoplasm of Osteoclasts
Paget’s DiseaseUnifying Hypothesis
Development of Paget’s Disease Requires:
1. Genetic Component: enhances osteoclast formation/reactivity
- Paramyxovirus Infection: induces changes in osteoclast precursors
Paget’s Disease
Clinical Features
Skeletal: Pain Deformity Fractures *these 3 are most common
Others: Osteoarthritis Hypervascularity Acetabular Protrusion Osteogenic Sarcoma
Paget’s Disease
Common Sites of Involvement
Common Sites Monostotic or Polyostotic 1. Pelvis 2. Skull 3. Vertebrae 4. Femur 5. Tibia
Paget’s DiseaseClinical Features
Neurological:
- Deafness (8th Nerve, Ossicles)
- Cranial Nerve Compression (Bony)
- Spinal Cord Compression (Vascular)
Paget’s Disease
Clinical Features
Cardiovascular:
1. Atherosclerosis
2. Aortic Stenosis
3. Congestive Heart Failure
(High Output)Paget’s Disease
Diagnosis
- Remodeling Markers - Elevated
- X-Ray Features – Very Specific
- Bone Scan – Very Sensitive
- Bone Biopsy - Occasionally Needed
Paget’s Disease
Radiology
a. Osteolytic Lesions
i. “Blade of Grass” Sign in Long Bones
ii. Resorption Front in Flat Bones (~1 cm/yr)
b. Osteosclerotic Lesions near Lytic Areas
c. Thickened, Disorganized Trabeculae
d. Thickened, Expanded Cortex
e. Expansion of Bone Size
Paget’s Disease
Histology
a. Increased Osteoclast Numbers
b. Increased Osteoclast Nuclei (20-100 per cell)
c. Increased Osteoblasts in Periphery
d. Disorganized, Mosaic, Woven Bone
Summary of Paget disease Clinical
a. Skeletal:
i. Pain
ii. Deformity
iii. Fractures
*these 3 are most common
iv. Others:
Osteoarthritis
Hypervascularity
Acetabular Protrusion
Osteogenic Sarcoma
b. Common Sites of involvement
1. Pelvis
2. Skull
3. Vertebrae
4. Femur
5. Tibia
c. Neurological:
1. Deafness (8th Nerve, Ossicles)
2. Cranial Nerve Compression (Bony)
3. Spinal Cord Compression (Vascular)
d. Cardiovascular:
1. Atherosclerosis
2. Aortic Stenosis
3. Congestive Heart Failure
(High Output)
Paget’s Disease-
OCL Phenotype in Paget Disease
a. Increased number and size of Osteoclasts
b. Increased Nuclei/OCL
c. Increased Bone Resorbing Capacity
Great Summary of Bone Remodeling
a. Bone remodeling is the process by which old bone is removed and new bone is formed.
i. Normal bone remodeling is accomplished by 3 cell types: osteoclasts, osteoblasts and osteocytes.
b. Osteoclasts are multinucleated giant cells that attach to bone surfaces where they secrete acid and proteolytic enzymes that dissolve underlying bone, leaving a resorption pit.
i. Osteoblasts then receive a signal to move in and secrete osteoid, a bone specific collagen, which is subsequently mineralized with calcium and phosphate crystals (hydroxyapatite), refilling the resorption pit with new bone.
c. Osteocytes are cells that reside in the bone matrix and function as mechanoreceptors, sensing areas of mechanical stress in bone and orchestrating the rate and sites of bone remodeling by sending signals to osteoclasts and osteoblasts.
d. A key regulator of bone remodeling is the receptor activator of nuclear factor K-Beta (RANK) and RANK ligand (RANK-L) system.
i. RANK-L is an endogenous ligand that binds to and activates RANK to initiate/ promote bone resorption.
e. Osteoprotegerin is a decoy receptor that binds to RANK-L and prevents it from attaching to RANK; it is therefore a major endogenous inhibitor of bone remodeling.
f. Another more recently identified regulator is the Wnt- Frizzled / LRP 5-βCatenin system, which activates osteoblasts, and this activation is blocked by another compound called sclerostin.
Osteocytes, Osteoblasts, Osteoclasts, and their role in bone remodeling
a. Osteoclasts are multinucleated giant cells that attach to bone surfaces where they secrete acid and proteolytic enzymes that dissolve underlying bone, leaving a resorption pit.
b. Osteoblasts then receive a signal to move in and secrete osteoid, a bone specific collagen, which is subsequently mineralized with calcium and phosphate crystals (hydroxyapatite), refilling the resorption pit with new bone.
c. Osteocytes are cells that reside in the bone matrix and function as mechanoreceptors, sensing areas of mechanical stress in bone and orchestrating the rate and sites of bone remodeling by sending signals to osteoclasts and osteoblasts.
d. A key regulator of bone remodeling is the receptor activator of nuclear factor K-Beta (RANK) and RANK ligand (RANK-L) system.
i. RANK-L is an endogenous ligand that binds to and activates RANK to initiate/ promote bone resorption.
Important proteins in Bone Remodeling
- A key regulator of bone remodeling is the receptor activator of nuclear factor K-Beta (RANK) and RANK ligand (RANK-L) system.
i. RANK-L is an endogenous ligand that binds to and activates RANK to initiate/ promote bone resorption. - Osteoprotegerin is a decoy receptor that binds to RANK-L and prevents it from attaching to RANK; it is therefore a major endogenous inhibitor of bone remodeling.
- Another more recently identified regulator is the Wnt- Frizzled / LRP 5-βCatenin system, which activates osteoblasts, and this activation is blocked by another compound called sclerostin.
Osteoporosis Large Summary
a. Osteoporosis is defined as impaired bone strength that predisposes to the development of fragility fractures.
b. Fragility fractures are bone fractures that occur with low trauma (a fall from a standing height or less).
i. The most common fragility fractures are vertebral fractures, hip fractures and wrist fractures.
c. The most important risk factors for the development of fragility fractures are previous fragility fractures, low bone mass, age and frequent falls.
d. Low bone mass can be identified by bone mineral density (BMD) testing.
i. Using bone densitometry criteria, osteoporosis is diagnosed when the lowest T-score (number of standard deviations the patient is below the average BMD for young normal adults) is < -2.5 and osteopenia is diagnosed when the lowest T-score is -1.0 to
- 2.4, whereas BMD is normal when T-scores at all sites are > -1.0.
e. Osteoporosis is the most common cause but other conditions may contribute to or be the sole cause of low bone mass and fragility fractures, so an assessment for other bone disorders and secondary bone loss should be undertaken.
Low bone mass can be identified by bone mineral density (BMD) testing.
Using bone densitometry criteria, osteoporosis is diagnosed when the lowest T-score (number of standard deviations the patient is below the average BMD for young normal adults) is < -2.5 and osteopenia is diagnosed when the lowest T-score is -1.0 to -2.4, whereas BMD is normal when T-scores at all sites are > -1.0.
Determining which patients should receive active osteoporosis therapy
a. Treatment should be initiated for anyone who has sustained a vertebral or hip fragility fracture and for any patient who has a T-score < -2.5. For patients with osteopenia (T-score: -1.0 to -2.4) and no previous fragility fractures
b. The FRAX tool (URL: www.shef.ac.uk./FRAX; or Google: FRAX) is a valuable adjunct to assist in making treatment decisions. Developed by the World Health Organization (WHO) and easily accessed online, this tool utilizes a weighted risk factor equation to estimate the 10 year probability of a fragility fracture, and treatment is generally recommended if the fracture risk is > 3% for hip fracture or > 20% for a major osteoporosis fracture.
Non-Pharmacologic Treatment of Osteoporosis
a. Non-pharmacologic interventions consist of adequate calcium intake (1000-1500 mg daily) and vitamin D intake (1000 units daily), regular exercise, and fall prevention.
b. Dairy products are the best calcium source (~ 300 mg per serving: cup of milk, ounce of cheese, 6 ounces of yogurt) because dairy products contain both calcium and phosphorus, the two major mineral components of bone.
c. When adequate calcium intake cannot be achieved by dairy products, calcium supplements should be added in amounts sufficient to achieve the goal calcium intake (diet plus supplements = 1000-1500 mg/day).
d. Calcium carbonate and calcium citrate are equally well absorbed with meals if gastric acid is present.
i. However, calcium carbonate absorption is significantly reduced in patients who have deficient gastric acid production (atrophic gastritis and proton pump inhibitors).
e. Exercise should consist of both aerobic and resistance work. This improves both bone and muscle strength and can reduce the risk of falling.
f. Fall frequency and risks should be assessed at each visit and measures instituted to correct or mitigate any identified fall risk factors, such the use of sedatives, visual impairment, musculoskeletal impairment and obstacles to ambulation in the home environment.
Pharmacologic agents for Osteoperosis
a. Pharmacologic agents are classified into two main categories: anti-resorptive medications and anabolic medications.
b. Anti-resorptive medications inhibit osteoclastic bone resorption and allow natural bone formation to continue for a variable period of time, resulting in a net gain of bone mass.
c. Anabolic agents stimulate osteoblastic new bone formation, increasing bone mass by progressive bone accrual.
d. Anti-Resorptive Agents:
1. Bisphosphonates
Alendronate
Risedronate
Ibandronate
Zoledronic Acid
Non-Bisphosphonates
2. Denosumab 3. Raloxifene (Evista) 4. Estrogen Therapy 5. Calcitonin
e. Anabolic Agents
Teriparatide
Osteomalacia and Rickets
a. Osteomalacia is defined as impaired bone mineralization resulting in soft, weak bones.
b. Osteomalacia is caused by any condition that results in a low extracellular fluid calcium x phosphate product that is insufficient to mineralize bone osteoid.
i. When this occurs in adults, it is referred to as Osteomalacia
ii. When it occurs in children, because of its distinctive effects on the growing skeleton, it is referred to as Rickets.
c. The best recognized causes are acquired and congenital disorders of vitamin D intake, absorption or metabolism or phosphorus intake or metabolism
i. Vitamin D disorders result in poor intestinal absorption of both calcium and phosphorus resulting in low serum calcium and phosphorus levels.
e. Phosphorus disorders often produce profoundly low serum phosphorus levels. In either case the result is an inadequate calcium x phosphate product in the extracellular fluid resulting in deficient bone mineralization.
i. This leads to Osteomalacia in adults and Rickets in children.
Osteomalacia Clinical and Lab Presentation
a. Osteomalacia presents clinically with bone pain, bone deformities and fractures, whereas Rickets is manifested by bone pain, bone deformities, muscle weakness and short stature.
b. Laboratory evaluation of these conditions often shows hypocalcemia and or hypophosphatemia, elevated serum alkaline phosphatase, elevated serum PTH (secondary hyperparathyroidism) and very low urinary calcium excretion.
c. Radiologically, osteomalacia may show true fractures as well as pseudofractures, also known as Milkman’s fractures or Looser’s lines; pseudofractures are felt to represent linear areas of bone demineralization at sites where arteries come into contact with bone surfaces.
d. By X-ray, Rickets show long bone bowing, flaring of the ends of long bones and delayed epiphyseal calcification.
Difference between Rickets and Osteomalacia
a. Osteomalacia presents clinically with bone pain, bone deformities and fractures
b. Rickets is manifested by bone pain, bone deformities, muscle weakness and short stature.
i. Also bowed-legs
