Skeletal and Muscle Systems Part 2 Flashcards
Congenital Diseases of Bone
- Osteogenesis Imperfecta
- Achrondoplasia
- Osteopetrosis
General Terms
see below
Dysostoses
- congential malformations of bone
-Aplasia- absence of bone
-Supernumerary- extra bones
Abnormal fusion of bones
Dysplasias:
- abnormalities of bone osteogenesis
- —-mutations affecting bone or cartilage growth
Examples of dysplasias:
- Osteogenesis imperfect
- Achrondoplasia
- Osteopetrosis
Osteogenesis Imperfecta (OI) Brittle bone disease
● Cellular pathophysiology -Etiology is Genetic mutation -Defective synthesis of Collagen type 1 -----Extracellular bone matrix -----Skin, joints, eyes -Phenotype has broad range -Inadequate supply of bone- fragile skeleton
4 Clinical Classifications
See below
Type 1 OI:
Normal lifespan
Modest increase fracture rate in childhood that decreases in puberty
Blue Sclerae so that underlying choroid visible
Hearing loss
Small misshapen teeth
Type II OI:
- Fatal pre or immediately post-partum due to in utero fractures
Achrondroplasia
● Cellular pathophysiology
- Etiology is genetic mutation
- Fibroblast growth factor receptor 3 (FGFR3) is activated
- Activated FGFR3 inhibits chondrocyte proliferation
- Suppression of epiphyseal growth plate expansion long bones
- Long bone growth stunted
- All bones that develop from cartilaginous framework
Achrondoplasia: Clinical
-Clinical Major Cause of Dwarfism: - Disproportionate shortening of proximal extremities -Bowed legs -Lordosis
Severe cases can lead to perinatal death from respiratory failure
Osteopetrosis (Stone Bone)
● Cellular pathophysiology
-Etiology is genetic mutations
-Rare
-Exact molecular cause of osteoclast dysfunction not certain.
-Defective Osteoclast-mediated bone resorption
(Normally, the cells decalcify the matrix prior to matrix digestion.)
-Bone abnormally hard and structurally unsound with tendency to break.
Osteopetrosis : Clinical
- Fractures
- Compression of cranial nerve that leads to related problems
- Recurrent infections due to reduced marrow space affecting hematopoiesis
- Hepatosplenomegaly due to extramedullary (outside the marrow) hematopoiesis
Osteopenia
• Not a disease
• Condition of Low Bone Mass
– T score between -1 and -2.5
• Diagnosed by Bone Density test
• 34 mil women and 12 mil men
• Could develop Osteoporosis if prevention strategies not taken.
– Especially if person has Osteoporosis risk factors
Osteoporosis
• Disease • Porous bones that are fragile • Can be prevented and treated • 44 million Americans, 17 billion dollars – 80% are women • 1 of 2 women • 1 of 8 men lose trabecular bone volume (spongy interior matrix) (up to 20%) excess resorption
Types of Osteoporosis
See below
Type 1: Postmenopausal Osteoporosis
- women 51-75 yr, accelerated bone loss, especially trabecular
- common fractures of vertebrae and distal femur
Type II: Senile Osteoporosis
- Men and women greater than 71
- Proportional loss corticol and trabecular
- Common fx’s of vertebrae and distal femur
Type III: Secondary Osteoporosis
- Men and women any age
- Secondary to other such as drug therapy and diseases
Table 21: Broken into Categories of Generalized Osteoporosis
See Below
Primary
- Post menopause: MOST COMMON
- Senile - also most common
Secondary
- Endocrine
- Neoplasia
- GI disorders
- Disease Drugs
- Miscellaneous
Endocrine Disorders
- Hyperparathyroidism
- Hypogonadism
- Pituiatry tumors
- Diabetes type 1
- Addison Disease
Neoplasia
- Multiple myeloma
- Carcinomatosis
GI Disorders
- Malnutrition
- Malabsorption
- Hepatic insufficiency
- Vitamin C and D deficiencies
- Idiopathic
Disease Drugs
- Anticoagulants
- Chemotherapy
- Corticosteroids
- Anticonvulsants
- Alcohol
Miscellaneous
- Osteogenesis Imperfecta
- Immobilization
- Pulmonary Disease
- Homocystinuria
- Anemia
Osteoporosis Risk Factors
Risk Factors that can not be Changed • Female more than male • Age • Body size (Small, thin) (< 21 kg/m2) • Ethnicity (White and Asian women) • Family history
Osteoporosis Risk factors
Changeable Risk Factors
• Sex hormones. Low estrogen levels due to missing menstrual periods or to menopause can cause osteoporosis in women. Low testosterone levels can bring on osteoporosis in men.
• Calcium and vitamin D intake
• Low Exercise Activity level
• Smoking
• Drinking alcohol in excess
• Some Medications
• Glucocorticoid, steroid, antiepileptics, excess TH, chemotherapy, GRH antags.
• Chronic diseases
• Hyperthyroid, hyperparathyroidism, RA, SLE, chronic lung, malasorptive GI, eating disorders, MS, Parkinson’s, Spinal injury, hematologic/oncologic
Osteoporosis Male Risk factors
Male risk factors • Small stature • Prostate cancer • Sedentary lifestyle • Alcohol • smoking
Male Prevention
Prevention • Calcium and Vitamin D • Weight bearing exercise • No smoke • Reduce alcohol intake • Monitor with bone mass density • Medications • Fall prevention strategies Male prevention Same as women
HRT or ERT menopausal women (Not recommended as of 7/2002)
Treatment • Balanced diet: – rich in calcium and vitamin D • An exercise plan • A healthy lifestyle • Medications, if needed
Osteopenia V Osteoporosis
- if osteopenia, initiate lifestyle prevention strategies
- If osteoporosis, then continue lifestyle prevention/treatment and perhaps medications
Outcomes of Osteoporosis
• Common fractures are vertebrae, forearm, hip and ribs
• Vertebrate fractures
– Height loss, spinal deformity, chronic back pain, difficult breathing
• Most common cause of hip fractures
– Disability, mortality
Let us delve into a cellular molecular pathway
See Below
Normal paracrine (localized secretion to affect activity) regulation of osteoclast and osteoblast
●Osteoclasts are originally macrophage precursor cells
●Receptor activator for nuclear factor ΚB (RANK)
●RANK receptors are on the Osteoclast precursor
●Stromal or osteoblasts release RANK ligand
●Stromal or osteoblasts release macrophage cell stimulating factor (M-CSF)
The key event that leads to bone resorption
● The key event that leads to bone resorption
RANK ligand + RANK receptor on osteoclast precursor
+
M-CSF ligand + M-CSF receptor on osteoclast precursor
↓
activate to differentiate to osteoclast mature cell
● COUNTER BALANCE by the Stromal or osteoblasts release osteoprotegerin (OPG)which blocks the RANK ligand + RANK receptor interaction on osteoclast precursor
View image in textbook if more description needed
What changes to lead to postmenopausal pathophysiology of osteoporosis?
decrease estrogen postmenopause leads to increased osteoclast activity
and a period of accelerated loss
● increased osteoclast activity
● LOW estrogen leads to increase IL-1, IL-6, and TNF which in turn leads to increase in RANK and RANK ligand and less OPG. Ultimately, will lead to more osteoclast activity
Acquired Diseases of Bone development
See below
Paget’s Disease (Osteitis Deformans):
- chronic bone inflammation
-repetitive episodic regional resorption of bone followed by rapid bone formation
-the result is disorganized and not as strong as normal
-cuase could be a paramyxovirus infection-not conclusive yet
-Which bones affected?
can be a variety of bones- see text for examples
-numerous skeletal, neuromuscular, cardiovascular complications possible- symptoms related to bone deformations or nerve impingement
-many cases are mild
-sometimes during episodes, the overlying skin in warm
-if skull proliferating, can have headache, auditory, and visual problems
-Low back ache - bowing of lone bones
Metabolic and Nutritional Bone Alterations
Rickets/Osteomalacia
Rickets
- Infant or growing child
- Lack of Vitamin D
- bowed legs and other deformities
Osteomalacia
- adults
- calcium and or phosphorus deficiency
- disease or nutritional
Osteonecrosis (Avascular necrosis):
Ischemic necrosis followed by bone infarction
Causes:
Vascular compression or disruption such as following a fracture
steroids
thromboembolic disease
primary vessel disease
Clinical course of osteonecrosis
- depends on size and location
- range from pain to osteoarthritis
Osteomyelitis
inflammation of bone and marrow cavity
usually due to an infection
-most common are pyogenic bacteria and mycobacterium tuberculosis
Joints
see diseases below
Osteoarthritis
-degenerative joint disease
joint damage and inflammation caused by biochemical alteration of articular cartilage in one or a few joints
inflammation part is secondary and not always present
etiology unknown for primary osteoarthritis
associated with age
secondary osteoarthritis is due to trauma or infection or gender predisposition (hips in men, hands/knees in women)
Pathophysiology of Osteoarthritis:
- proliferation chondrocytes(cartilage cells) of articular cartilage
- matrix integrity cracks
- cartilage degraded
- expose bone
- stress on bone stimulates disordered growth
- maybe synovial inflammation
Symptoms of Osteoarthritis
joint pain, a.m. stiff, limit of movement
inflammatory component has been controversial:
- whether it is primary or secondary, it occurs
- anti-inflammatory drugs have not been able to reverse or necessarily slow disease progression
Rheumatoid Arthritis (RA):
-autoimmune humoral and cellular - inflammatory joint - etiology unknown genetic and environment likely - Under investigation: viruses human T-cell lymphotropic virus type I retroviruses Epstein-Barr virus Herpes virus Rubella virus - bacteria under investigation mycoplasma mycobacteria enteric bacteria -antibodies- rheumatoid factors to synovial lymphocyte generated IgG which is considered foreign T lymphocytes migrate to area CD4+ (recruit other inflammatory WBCs) synovial membranes joints and other tissue joint destruction, neuropathies, skeletal muscle inflammation, vasculitis, other
Rheumatoid Arthritis: Active Disease
ongoing joint pain significant morning stiffness significant fatigue active synovitis persistant increase in erythrocyte sedimentation rate (ESR) or C-reactive protein
Hyperuricemia and Gout
- increase serum uric acid
- purine breakdown –> uric acid
- recurrent attacks with urate crystals in synovial fluid
- aggregated deposits of urate in joints -cripple and deformity
- renal disease
Primary Gout: (90% of cases)
enzyme defects unknown
- overproduction of uric acid
- normal excretion (majority)
- increased excretion (minority)
- under excretion of uric acid with normal production
Secondary Gout: (10% of the cases)
associated with increased nucleic acid turnover - e.g. leukemia’s, chronic renal disease, inborn errors of metabolism
- Overproduction of uric acid with increased urinary excretion
- Reduced excretion of uric acid with normal production -Overproduction of uric acid with increased urinary excretion e.g.,
- complete HGPRT deficiency (Lesch-Nyhan syndrome)
Clinical features of Gout
● pain that can be severe, warmth, erythema
● 50% in big toe, 90% in instep, ankle, heal, wrist
● Systemic symptoms rare
● Acute recurring episodes of various frequencies (months to few years)
● Untreated can resolve
● over time the symptoms fail to resolve completely and develop chronic tophaceous gout
Pseduogout (Chondrocalcinosis):
- calcium pyrophosphate crystal deposits various joints
