Week 4: Metabolic Bone Disease, Osteoporosis Flashcards
Define osteoporosis
systemic skeletal disease characterized by
- low bone mass
- microarchitectural deterioration of bone tissue
- increased bone fragility and susceptibility to fracture
- bone mineral density (BMD) below 2.5 SD below mean peak value in young adults
Normal bone turnover
each cycle consists of resting bone surface, resorption, reversal, bone formation, mineralization (3 weeks of breakdown, 3 months of formation and mineralization)
- osteoblasts activate osteoclasts through RANKL
- bone resorption for about 4 weeks in a bone remodeling unit
- Reversal: Apoptosis of osteoclasts, release TGF-b and IGF-1 that signal osteoblasts to lay down bone
- Mineralization, osteoblasts become osteocyte
- osteocytes release sclerostin, which inhibits osteoblasts
- when osteocytes recognize abnormal bone, it removes sclerotin signaling
Concepts behind pathogenesis of osteoporosis
- bone resorption is greater than bone formation
- through each cycle of bone remodeling, there is net bone loss
Non modifiable risk factors for osteoporosis
- gender: females have less bone mass and smaller skeletal dimensions than men.
- Race: caucasians/asians have less bone mass than Hispanics who have less than Blacks
- Bone geometry
- age: decrease of bone mass ~1%/year after 35-40yo
- prior history of fragility fracture: vertebral fracture increases risk 5x for another
- Hereditary
- Body weight/small stature: less than 127 lbs
Modifiable risk factors for osteoporosis
- Diet: low calcium diet
- Estrogen: following menopause, rapid loss of bone (perhaps due to increased RANKL, IL-1, IL-6, decreased OPG)
- physical activity
- extreme exercise: fall of estrogen production if exercise induces amenorrhea
- cigarette smoking
- alcohol abuse
- nuliiparity
Secondary causes of osteoporosis
- failure to develop normal skeletal mass during growth due to poor nutrition or inadequate exercise
- endocrine deficiency or excess
- estrogen or testosterone deficiency
- cushing’s: excessive glucocorticoids impairs osteoblasts
- hyperthyroidism: high thyroid hormone causes increased bone turnover and loss. more clast less blast
- hyperPTH - immobilization or weightlessness
- hematologic malignancies, e.g. MM, Il1 increases clast, MP-6 inhibits blasts
- Glitazones for DM: fibroblasts diverted from blasts to fat
- inherited defects on collagen synthesis
- systemic mastocytosis
- heparin therapy: activates osteoclasts
- idiopathic juvenile osteoporosis
- bariatric surgery: malabsorption, Mg and VitD deficiency
- solid organ transportation: chronic illness, GCs, drugs
Clinical features of osteoporosis
- thoracic and lumbar vertebral fractures. Most common, many asymptomatic
- Femur fracture
- distal radius fracture
Complications of fractures
-acute pain, chronic back pain, loss of height, kyphosis, disability, depression, mortality following hip fracture
Assessment of osteoporosis
- Radiology
- spine x-ray most useful
- doesn’t distinguish osteoporosis from osteomalacia - Measurement of bone mineral density
- gold standard: dual energy x-ray absorptiometry - Serum chemistry testing
- Ca, phosphate, alkaline phosphatase, VitD, TSH, PTH
Radiological features of osteoporosis
Vertebral fractures
- early: decreased BMD
- advanced: compression of vertebral disk, fish mouthing look
- severe: smaller vertebral bodies
- Schmorel’s node: protrusion of disk into vertebral body
Diagnosis of osteoporosis
- T score less than -2.5 in any region.
- osteopenia: T score between -1 and -2.5
- for every Std Dev decline, fracture risk increases 2-3x
- z scores are matched for age and gender and based on ethnicity, but not used for dx. T scores are of interest.
Fracture risk reduction in osteoporosis
- preserve/increase BMD: Ca/VitD supplements, drug therapy (HRT, anti bone resorption)
- Fall prevention: exercises, VitD, balance exercises
Guidelines for osteoporosis therapy
- all women with T score less than -2.5
- all women with T score less than -1.5 with risk factors other than menopause
- all postmenopausal women who have had a fragility fracture
Drug therapies for osteoporosis
- Antiresorptives
- bisphosphates: prevents release of acid for bone resorption by osteoclasts. induces apoptosis of osteoclasts
- SERMs
- estrogen: alter ratio of RANKL and OPG. concern for increase of Coronary heart disease and breast cancer
- calcitonin: antiosteoclastic - Anabolic agents
- (Teraperidtide) PTH 1-34: low dose PTH stimulates osteoblasts. Requires daily subQ injections. Expensive. May case hypercalcemia
Side effects of oral bisphosphonates
- upper GI distress
- flu-like syndrome
- osteonecrosis of jaw: super rare
- no increase in A fib
- frozen bone/atypical fractures: can’t repair minor bone injury due to inhibited osteoclast activity -consider a drug holiday
Zolendronic acid
- once a year IV infusion
- side effects: severe flu like symptoms, increase in Cr
- no increase in A fib, and no osteonecrosis of jaw
Define osteomalacia and rickets
- usually due to Vit D deficiency or phosphorus deficiency
- characterized by inadequate mineralization of bone collagen
- radiology: decreased density of bone-looks like osteoporosis
- Rickets: in children, growth retardation and widening of epiphyses
Causes of Vitamin D deficiency
- inadequate sunlight exposure or impaired cutaneous production
- extensive use of sunscreen
- poor dietary intake
- malabsorption: gastrectomy, sprue, small intestinal disease, pancreatic insufficiency
Disorders of Vitamin D metabolism
- Accelerated loss of Vitamin D
- increased metabolism
- impaired enterohepatic recirculation
- nephrotic syndrome - Impaired 25 hydroxylation
- liver disease, isoniazid - Impaired 1a-hydroxylase
- renal failure, ketoconazole - target organ resistance
Causes of phosphate deficiency
- decreased intestinal absorption
- decreased intake
- Al2(OH)2 excess (antacid)
- X linked hypophosphatemia rickets
- autosomonal dominant hypophosphatemic rickets
- hereditary hypophosphatemic rickets with hypercalcuria
- Fanconi
- autosomonal dominant hypophosphatemic rickets
- Tumor induced osteomalacia
X linked hypophosphatemia rickets
Normal
-Phosphatonin (FGF-23) is released from bone and inhibits Na/Phosphate transporter in kidney. It is excreted instead of reabsorbed.
Disease
-PHEX gene is mutated. Lack of ability to degrade phosphatonin
-renal phosphate wasting
-most common cause of rickets in US
Autosomonal dominant hypophosphatemic rickets
- activating mutation of FGF23. PHEX is unable to break down this mutated FGF23.
- incomplete penetrance
- may have delayed onset of disease
Tumor induced osteomalacia
- mesenchymal tumors
- usually in adults
- sporatic, acquired
- tumor produced FGF23 acts on proximal tubule to decrease phosphate transport and decrease active Vit D synthesis
Clinical features of osteomalacia
- may have no symptoms in mild cases
- bone pain
- muscle weakness and pain
- reduced BMD
- fractures, pseudofractures (stress fractures)
- symptoms of hypocalcemia in severe Vitamin D deficiency
Clinical features of rickets
Short stature
Deformities of lower extremities (also upper extremities but less so): bow leg
Swelling of wrists (epiphysis)
Rachitic rosary (swelling of cartilage-bone junction)-costochondral junction
Skull deformities: frontal bossing, flattening of skull
Bone pain
Cupping and fraying (inadequate mineralization of bone) of diaphysis and epiphysis
Symptoms of hypocalcemia if due to severe vitamin D deficiency
Radiographic features of osteomalacia
- osteopenia
- pseudofractures
- biconcave vertebrae
- deformed pelvis
- protrusio acetabuli
Evaluation of osteomalacia
- Labs
- serum Ca: normal to low in Vit D def. (VDD), normal in XLH, TIO
- phosphate: normal to low in VDD, low in XLH and TIO
- alk phos: high in all (released by osteoclast)
- PTH: high in VDD, normal in XLH, TIO
- 25(OH)D: low in VDD< normal XLH, TIO
- 1,25(OH)2D: normal to low in VDD, normal in XLH, low in TIO
- TmPO4 (tubular maximum for phosphate): low in all
- FGF23: normal in VDD, high XLH, TIO
- xrays
