Osteoporosis

    Info from Dr. Heather Blumer Lecture - 2011

    Dempster D. J. Bone Miner Res

    http://www.cmaj.ca/content/182/17/1864.full

    http://www.osteoporosis.ca/multimedi...tober_2010.pdf

     

    Definition

    NIH definition:

    "A skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.  Bone strength reflects the integration of 2 main features: bone density and bone quality."

     

    Bone Quantity (Bone Density Measurement)

    • Acquisition (to peak bone mass - if diseases, peak not acquired)
    • Loss (age related)
      • Genetics
      • Diet & Lifestyle
      • Disease
      • Drugs

    Bone Quality

    • Architecture (Varies by bone)
    • Bone Turnover (osteoclasts vs. osteoblasts)
    • Accumulated Damage (microfractures)
    • Mineralization (Diseases change bone mineral)

    osteoporosisBone.jpg

    boneGraph.jpg

     

     

    Etiology

    Primary Osteoporosis

    • Due to post-menopausal decline in estrogen, worsens with age

    Secondary Osteoporosis

    Diseases

    • GI disorders: malabsorption (gastrectomy, IBD, chronic liver disease), poor nutrition
    • Endocrine: Hypogonadism (early menopause, anorexia, drugs), Cushing's syndrome, hyperparathyroidism, hyperthyroid
    • Malignancy: breast Ca, Prostate ca, Multiple Myeloma, lymphoma, Leukemia
    • Physical: Propensity to falling, immobilization
    • Others: Rheumatologic (SLE, AnkSpond, RA -->all TNF driven), Kidney Disease

    Drugs

    • Glucocorticoids (>3mo = significant duration)
    • Anti-convulsants
    • Heparin
    • Anti-estrogens, anti-androgens (hypogonadal drugs)
    • SSRIs
    • PPIs

    Fragility Fracture

    • Fracture sustained
      • A.) Minimal Trauma
      • B.) Fall from standing height
    • Includes:
      • Wrist (Colles fracture)
      • Vertebra
      • Hip
      • Humerus, Pelvis, Rib
    • NOTE: skull, metatarsal/metacarpal, ankle are not fragility fractures

     

    Screening

    • See Osteoporosis Canada Guideline
    • All below groups must get DEXA q1-3 yrs (usually 3y)

    Assessment

    History

    • Risk Factors for low BMD, fractures, falls.
      • The theme of this history is to determine if need to be screened (50-65yo) or if moderate risk if need treatment:
        • Prior fragility fracture
        • Parental hip fracture
        • Glucocorticoid use
        • Current smoking
        • High Alcohol intake (>3 units/day)
        • Rheumatoid arthritis
        • Falls in past 12mo
        • Gait and balance

    Physical

    • Risk Factors:
      • Weight (wt loss >10% since age 25 is significant)
      • Get-Up-and-Go test (get up out of a chair without using arms, walk several steps and return)
    • Screen for vertebral fractures
      • Height (>2cm loss or historical >6cm is significant)
      • Rib-to-pelvis distance (<= 2 fingter breadths significant)
      • Measure occiput-to-wall distance (kyphosis) (>5cm is significant)

    Labs

    • Lytes, esp Calcium (corrected for albumin - for every 10g/L decrease in albumin, up calcium by 0.2mmol/L)
    • CBC
    • Creatinine
    • Alk Phos
    • TSH
    • Serum protein electrophoresis if vertebral fractures (?? not sure why)
    • 25-hydroxy Vitamin D (25-OH-D) (not done, not covered anymore)

     

    DEXA Scan

    • Dual Energy Xray Absorptiometry
    • Gives T-scores standardized to peak bone mass: healthy person at 25yo.
    • Take the lowest T-score of all measurements (Lumbar spine, Femoral neck, Total hip)
      • T-Score Result
        0 to -1.0 Normal
        -1.0 to -2.5 Osteopenia
        -2.5 + Osteoporosis

    10 Year Fracture Risk

    • CAROC Basal Risk
    • 10 Year Fracture Risk is calculated using: (See graph)
      • Gender
      • Age
      • Bone Density Value 
      • -----------------------------Move Up One Category if:
      • Previous Fragility Fracture
      • Prednisone
    • T-Score Result
      <10% Low Risk
      10-20% Medium Risk
      > 20% High Risk
    • Can use FRAX tool

     

     

    - NOTE: Fragility fracture or recent prolonged systemic steroid use increases basal risk by one category (i.e. low to moderate)

    - Take the lowest T-score of all measurements (Lumbar spine, Femoral neck, Total Hip)

     

    TscoreCurves.jpg

    Guidelines

    • >65yo screen everyone q3y
    • if 50-65 screen if 1major RF or if 2 minor RFs
    Major Risk Factors Minor Risk Factors
    • Fragility Fracture >40
    • Vertebral Comression Fracture
    • Low BMD
    • FHx of osteoporotic fracture
    • Systemic Steroid Tx >3mo

    --------------------

    Other: Malabsorption syndromes, 

    primary hyperPTH, propensity to fall, 

    osteopepnia on XRay, hypogonadism, 

    early menopause.

    • RA
    • Past Hx of hyperthyroidism
    • Chronic anticonvulsant therapy
    • Low dietary Ca
    • Smoker
    • Excessive alcohol/caffeine
    • Weight ≤57kg or loss ≥10% of wt age age 25
    • Chronic heparin therapy

     

    Another way to think about it....

     

    Note: I don't like this table.  Should be 

    DEXA for:

    • women and men >65 yr
    • postmenopausal women <65 with risk factors
    • premenopausal women or men with fragility fractures of seconary causes

     

    guidelines.jpg

    Treatment

    Indications

    • Difrent guidelines exist.
    • #1 - see flow chart above
    • #2 -  this one is from Toronto Notes 2011:

     

    • Women:
      • T-score < -2.5 with no RF's
      • T-score < -1.5 with ≥1 RF's
      • Any spine or hip #
    • Men
      • >65yo with T-score < -2.5
      • >50yo with with fragility/vertebral compression #
      •  Any age T-score < -1.5 AND steroid therapy ≥3mo OR any age with hypogonadism

     

    Lifestyle

    • Everyone should be on
      • Vitamin D 800-2000 IU (pick your favourite, Osteoporosis Canada recommends 800, and Cancer society recommends 1000)
      • Calcium 1200 (potentially risk of artery calcification if taking too much)
      • Lifestyle
    • Pharmacologic intervention if:
      • High Risk
      • Moderate Risk (Maybe, depends on the individual + other risk factors (such as frequent >2/yr falls, see chart above)

    Drugs

     

    treatmentGuidelines.jpg

     

    Bisphosphonates

    • First line for osteoporosis
    • Mechanism: works by getting integrated into bone (similar to pyrophosphate).  However when osteoclasts start to break it down, they absorb it, and cannot break the P-C bond (normally P-O), and eventually die.
    • Etidronate (400mg x2weeks every 3mo)
    • Alendronate (10 mg/day if vitamin D or 70 mg/week w/o vitamin D)
    • Risedronate (5mg/day, 35mg/week, 150 mg/mo)
    • S/E:
      • Oral preparations have GI symptoms (gastric inflammation and esophageal erosion). esp Alendronate and Risedronate.
        • Can be prevented by sitting up for 30-60min after intake.
      • Injections can give flu-like symptoms for several days (first injection only), improve for subsequent.
      • Osteonecrosis of the jaw

     

    • Osteonecrosis of the Jaw
      • Typically seen after dental procedures as a non-healing ulcer that erodes to bone.  Characterized by pain.  On exam, see exposed bone.  Risk Factors: Dental extraction, poor dentition, periodontal disease.  Dental evaluation recommended prior to bisphosphonate therapy.

     

     

    Teriparatide

    • PTH analogue - peptide (injection)
    • Chronically elevated PTH causes increase in serum Ca++ mostly through bone resorption.  However research shows that periodic spikes of PTH actually activate osteoblasts more than osteoclasts, thereby increasing bone mass.  Hence this is the only FDA approved agent that increases bone mass.
    • S/E: Nausea, leg cramps, dizziness.  However MAIN side effect is potential of osteosarcoma (shown in rats, but rats bones grow over lifetime unlike humans).
    • BLACK BOX WARNING: increases risk of osteosarcoma (contraindicated with previous radiation therapy)
    • Contraindicated in pts with malignancy involving bone, Paget's disease, or existing hyperPTH or hypercalcemia.

     

    SERM

    • US Preventative Task Force advises against hormal therapy for chronic diseases, including osteoporosis after menopause
      • Trend toward increased risk of breast cancer, coronary heart disease, stroke, venous thromboembolism, and urinary incontinence.
    • Raloxifene
    • Raises estrogen, but not really. E2 only effect.
    • +'ve: prevents osteoporotic #, improves lipid profile, decreased breast ca risk.
    • -'ve: increased risk of DVT/PE, stroke, hot flashes, leg cramps, and endometrial ca.

     

    HRT

    • Not indicated for osteoporosis.  Only indicated for hot flashes.

     

    Calcitonin

    • Off market due to bone cancer risk.

     

    Denosumab (Prolia (R))

    • Monoclonal antibody inhibits osteoclast formation.
    • Reserved for patients with high rik fracture (including multiple RF's, hx of fractures). 
    • Abstract Summarizing Research as of July 2012 (see attached powerpoint)
    • Osteoporosis affects one in four women and one in eight men over the age of 50.  A variety of treatment options exist for osteoporosis, however bisphosphonates remain first line therapy due to their efficacy and side-effect profile, but there are patients who are unable to tolerate bisphosphonates.  In 2010 Health Canada approved a new therapy for osteoporosis in postmenopausal women - Denosumab (Prolia ®).  Based on the Health Canada publication, the main phase III clinical trial that encouraged its approval was the FREEDOM trial by Cummings et al, 2009.  In this study, 7868 women aged 60-90 with bone mineral density of -2.5 to -4.0 were treated for 3 years with denosumab.  At a 3 year follow-up the investigators found that denosumab decreased vertebral fractures by 68% and hip fractures by 40%.   This was a large multicenter study that used vertebral fractures as a primary end point.  However, to this day there have been no studies directly comparing denosumab to current first-line therapy.  The two studies by Brown et al and Kendler et al show that denosumab increases bone mineral density, and is non-inferior to alendronate, however their primary outcome was bone mineral density as opposed to the fracture risk, which is a more clinically relevant variable.  At present, denosumab may be a good alternative to bisphosphonates in patients that are unable to tolerate bisphosphonates and are able to cover its high cost.   However, further studies are needed to show whether denosumab can replace the bisphosphonates as first-line therapy for osteoporosis in postmenopausal women.
    • Bottom line:

      • Reduces vertebral fractures (68%) and Hip Fractures (40%)

      • Good for patients who cannot tolerate bisphosphonates.

      • Potentially better than bisphosphonates at increasing bone mineral density, but no head-to-head trials yet.

     

    Corticosteroid Use

    • Large risk factor for osteoporosis
    • Patients ≥ 50yo taking ≥7.5mg/day of prednisone for >3mo require:
      • Bisphosphonate, calcium, vitamin D (D3 may cause better bone density, but no effect on fractures shown)
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