Orthopedics Hyperguide Review | Dr Hutaif General Ortho -...

Fluoroquinolones may cause side effects to the musculoskeletal system that include arthralgias, chondrotoxicity, and tendinopathy. Cartilage damage was found in animal studies at therapeutiCdoses. The cartilage cells of the physeal plate were damaged.
Cartilage blistering, erosions, matrix degeneration, and chondrocyte loss were also present. The fluoroquinolones are not to be used in children, pregnant women, and nursing mothers unless under special circumstances (such as drug resistance in children with cystiCfibrosis).
The fluoroquinolones are safe in the other groups of patients. One should remember the following: Light-headedness and dizziness may occur in young women.
Nausea, vomiting, and diarrhea are the most common complications.
Nonsteroidal anti-inflammatory drugs taken in combination will worsen side effects. Photosensitivity may occur.
Achilles tendonitis and rupture may occur.

Fluoroquinolones may cause side effects to the musculoskeletal system that include arthralgias, chondrotoxicity, and tendinopathy. Achilles tendonitis and rupture is the most common tendinopathy associated with fluoroquinolone use (usually ciprofloxacin). Fifty
percent of cases are bilateral. The interval to rupture is between 2 and 60 days.
Patients at increased risk include:
Patients older than 60 years of age
Patients with diabetes
Patients with impaired renal function
Patients who partake in strenuous sports activities

Four proteins that regulate osteoclast activation have been discovered:
1/. Receptor activator of nuclear factor-kappa B (RANK) binds to a receptor on osteoclast precursor cells and positively effects their final differentiation into osteoclasts.
2/. Osteoprotegerin is a soluble decoy receptor that resembles RANK and inhibits osteoclasts.
3/. Tumor necrosis factor-related activation induced cytokine (TRANCE)
4/. Osteoclast differentiation factor
Note:
Core binding factor alpha 1 (Cbfa1) is a transcription factor (coded by the Cbfa1 gene) that is necessary and sufficient for differentiation of cells into osteoblasts and facilitates chondrocyte differentiation during enchondral bone formation

Four proteins that regulate osteoclast activation have been discovered:
1/. Receptor activator of nuclear factor-kappa B (RANK) binds to a receptor on osteoclast precursor cells and positively effects their final differentiation into osteoclast activation.
2/. Osteoprotegerin is a soluble decoy receptor that resembles RANK and inhibits osteoclasts.
3/. Tumor necrosis factor-related activation induced cytokine (TRANCE)
4/. Osteoclast differentiation factor
Note:
Core binding factor alpha 1 (Cbfa1) is a transcription factor (coded by the Cbfa1 gene) that is necessary and sufficient for differentiation of cells into osteoblasts and facilitates chondrocyte differentiation during enchondral bone formation

Core binding factor alpha 1 (Cbfa1) and its gene (Cbfa1) have been described as anaboliCregulators of bone. Cbfa1 is a transcription factor and is responsible for the differentiation of precursor cells into osteoblasts. It also enhances differentiation of chondrocytes during enchondral bone formation. When there is deficiency of Cbfa1 there can be abnormal bone development, as in clediocranial dysplasia

The human genome is composed of approximately 30,000 unique genes. Each gene is composed of a promotor or regulator region and a transcriptional or coding region. Regulatory proteins or transcription factors bind to the promoter region of the gene
to signal the beginning of transcription of the DNA into RNA or repress the expression of the gene. The coding region contains both introns and exons. Exon sequences of the gene directly code for the proteins, and the introns are spacers. The intron sequences are enzymatically removed from the newly transcribed messenger RNA by a splicing mechanism

The human genome is composed of approximately 30,000 unique genes. Each gene is composed of a promotor or regulator region and a transcriptional or coding region. Regulatory proteins or transcription factors bind to the promoter region of the gene
to signal the beginning of transcription of the DNA into RNA or repress the expression of the gene. The coding region contains both introns and exons. Exon sequences of the gene directly code for the proteins, and the introns are spacers. The intron sequences are enzymatically removed from the newly transcribed messenger RNA by a splicing mechanism

Pagetâs disease is a remodeling disease in which there is marked bone resorption by the osteoclast. The osteoblasts repair the bone in a mosaiCpattern with thickened trabeculae and cement or remodeling lines. There is both increased osteoclastiCactivity and increased bone formation by the osteoblast.
Inadequate mineralization of newly formed bone is called osteomalacia. In children, there is decreased mineralization at the growth plate.
Osteoporosis refers to low bone mass and microarchitectural deterioration of bone. There are two types of osteoporosis:
High turnover osteoporosis is increased osteoclastiCactivity and normal osteoblastiCactivity. In high turnover, the osteoclasts resorb large amounts of bone and the osteoblasts are unable to replace the bone. One finds markers for high levels of bone resorption and bone formation in the serum and the urine.
Low turnover osteoporosis is normal osteoclastiCactivity with decreased osteoblastiCactivity. In low turnover, the osteoclastiCactivity is at the normal rate; however, there is insufficient osteoblastiCactivity to fill in the osteoclastiCresorption cavities. The markers for osteoclastiCresorption are normal and the markers for bone formation are decreased.

Bone resorption is assessed by measuring the products of bone remodeling. N-telopeptide, pyridinoline, and deoxypyridinoline are collagen cross-link products that are released during bone turnover. These collagen cross-links can be measured in the urine. A new marker can be measured in the serum and is called carboxy terminal collagen cross-links (CrossLaps).
Bone formation is assessed with serum alkaline phosphastase and osteocalcin.
Liver function tests include aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase.Correct
Answer: Urine N-telopeptide, pyridinoline, and deoxypyridinoline

Key features of Pagetâs disease:
Remodeling disease caused by excessive osteoclastiCactivity
Rarely diagnosed in patients younger than 40 years of age; most patients diagnosed after age 50
Most common sites include pelvis, femur, spine, skull, and tibia
Less common sites include clavicles, scapulae, ribs, and facial bones
Rarely found in the hands and feet
PagetiCbone
is more susceptible to fracture is less compact
is more vascular
tends to bow in weight bearing areas
GeographiCclustering (up to 4% in patients older than 55 years of age) England
Northern Europe North America Australia, New Zealand
Rare in Asia, China, Indonesia, Malaysia, and sub-Saharan Africa
Possibly a slow viral disease
RNA paramyxovirus (e.g., respiratory syncytial virus and measles) Correct Answer: Hands and feet

Key features of Pagetâs disease
Remodeling disease caused by excessive osteoclastiCactivity
Rarely diagnosed in patients younger than 40 years of age; most patients diagnosed after age 50
Most common sites include pelvis, femur, spine, skull, and tibia
Less common sites include clavicles, scapulae, ribs, and facial bones
Rarely found in the hands and feet
PagetiCbone
is more susceptible to fracture is less compact
is more vascular
tends to bow in weight bearing areas
GeographiCclustering (up to 4% in patients older than 55 years of age) England
Northern Europe North America Australia, New Zealand
Rare in Asia, China, Indonesia, Malaysia, and sub-Saharan Africa
Possibly a slow viral disease
RNA paramyxovirus (e.g., respiratory syncytial virus and measles) Correct Answer: Sub-Saharan Africa

Marked bone resorption by the osteoclast and marked bone formation by the osteoblast occurs in active Pagetâs disease. The activities of the osteoclast and osteoblast are linked together

Osteocytes do not directly resorb bone. Osteocytes have receptors for parathyroid hormone, and they mobilize poorly crystallized calcium salts that surround them without resorbing the bone matrix. The osteocytes connect with each other through long, thin cytoplasmiCprocesses

Osteocytes respond to mechanical signals and transmit messages to other cells to increase bone remodeling

The activation of osteoclasts is a complex process. Surface receptors on the osteoclast precursor cells are called RANK. Receptor activator of nuclear factor âkB ligand (RANKL) is expressed on the surface of osteoblasts/stromal cells. The RANKL proteins leave the osteoblast and attach to the RANK receptor on the osteoclast precursor. Macrophage colony stimulating factor then facilitates the production of active osteoclasts from the osteoclast precursor.
Osteoprotegerin (OPG) is an inhibitor that is produced on the cell surface of hematopoietiCprecursor cells and mature osteoclasts. OPG binds to RANK receptor to inhibit the activation of osteoclasts
RANKL
Stimulates osteoclast differentiation and osteoclast activity
Inhibits osteoclast apoptosis
Induces hypercalcemia when injected
Loss of expression induces: Osteopetrosis
Tooth eruption defects
T and B cell differentiation defects
OPG
Soluble decoy receptor for RANKL Blocks osteoclast formation Reduces hypercalcemia
Overexpression induces osteopetrosis Loss of expression induces osteoporosis Prevents calcification of large arteries

The activation of osteoclasts is a complex process. Surface receptors on the osteoclast precursor cells are called RANK. Receptor activator of nuclear factor âkB ligand (RANKL) is expressed on the surface of osteoblasts/stromal cells. The RANKL proteins leave the osteoblast and attach to the RANK receptor on the osteoclast precursor. Macrophage colony stimulating factor then facilitates the production of active osteoclasts from the osteoclast precursor.
Osteoprotegerin (OPG) is an inhibitor that is produced on the cell surface of hematopoietiCprecursor cells and mature osteoclasts. OPG binds to RANK receptor to inhibit the activation of osteoclasts.
OPG
Soluble decoy receptor for RANKL Blocks osteoclast formation Reduces hypercalcemia
Overexpression induces osteopetrosis Loss of expression induces osteoporosis Prevents calcification of large arteries

Calbindin, a vitamin D dependent and calcium binding protein, assists in the transport of calcium against chemical and electrical gradients. Most regulation calcium resorption in the kidney occurs in the distal convoluted segment

The addition of a second hydroxyl group at the 1 position to 25 hydroxy vitamin D3 is the rate-limiting step in the formation of the active from of vitamin D3. Impaired renal function is common in older individuals

The active from of vitamin D (1,25 dihydroxyvitamin D3) regulates the control of RANKL production by the osteoblast.
The activation of osteoclasts is a complex process. Surface receptors on the osteoclast precursor cells are called RANK. Receptor activator of nuclear factor âkB ligand (RANKL) is expressed on the surface of osteoblasts/stromal cells. The RANKL proteins leave the osteoblast and attach to the RANK receptor on the osteoclast precursor. Macrophage colony stimulating factor then facilitates the production of active osteoclasts from the osteoclast precursor

Traditionally, 24,25 dihydroxyvitamin D3 was considered an inactive form of vitamin D. Recent studies suggest that 24,25 dihydroxyvitamin D3 influences growth plate chondrocyte maturation as a potent mitogen in the proliferative zone and may also contribute to bone formation and fracture repair

Osteoblasts have receptors for parathyroid hormone. Once stimulated, the cells release interleukin-6 (IL-6). IL-6 signals osteoclasts to resorb bone. The osteoblasts secrete neutral proteases that degrade the osteoid surface. Osteoclasts then attach to the bone surface and secrete acid proteases that degrade the bone matrix. Parathyroid hormone related protein increases osteoblast expression of receptor activator of nuclear factor âkB ligand (RANKL). RANKL binds to osteoclast precursor cells for the formation of active osteoclasts

Osteoblasts have receptors for parathyroid hormone. Osteoblasts have neutral proteases that begin the degradation of the osteoid matrix. Once stimulated, the cells release interleukin-6 (IL-6). IL-6 signals osteoclasts to resorb bone. The osteoblasts secrete neutral proteases that degrade the osteoid surface. Osteoclasts then attach to the bone surface and secrete acid proteases that degrade the bone matrix. Parathyroid hormone related protein increases osteoblast expression of receptor activator of nuclear factor âkB ligand (RANKL). RANKL binds to osteoclast precursor cells for the formation of active osteoclasts

Parathyroid hormone inhibits the production of osteoprotegerin. Osteoprotegerin is a decoy inhibitor of the receptor activator of nuclear factor âkB. Osteoprotegerin inhibits osteoclast activation