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Osteoporosis

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					     Osteoporosis

Clinical cases and literature review
      Catherine Bakewell, MD
Quick overview
   Definition—(per WHO) normal bone density is a
    value within one standard deviation of the mean
    value in young adults of the same sex and race.
   BMD btw 1 and 2.5 standard deviations below the
    mean is defined as osteopenia,
   BMD > or = 2.5 standard deviations below the
    mean is defined as osteoporosis (and is associated
    with skeletal fragility)
Risk Factors
   History of fragility fracture in a first-degree relative
   Low body weight (less than 58 kg [127 lb])
   Current cigarette smoking
   Female sex
   Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy,
    prolonged premenopausal amenorrhea [greater than one year])
   White race
   Advanced age
   Lifelong low calcium intake
   Alcoholism
   Inadequate physical activity
   Recurrent falls
   Dementia
   Impaired eyesight despite adequate correction
   Poor health/frailty
   Medical conditions: chronic obstructive pulmonary disease, gastrectomy, hyperparathyroidism,
    hypogonadism, multiple myeloma, celiac disease
   Glucocorticoid therapy for more than three months
   Other drugs: anticonvulsants, GnRH agonists, lithium, excessive doses of thyroid hormone
Screening
 BMD should be measured in all
  postmenopausal women < 65 y.o. who have
  one or more risk factors for osteoporosis.
 Measurement of BMD is also recommended
  for all women 65 years and older.
Mrs. T
 A 53 year old woman presents to your clinic
  with concerns about osteoporosis, and she is
  requesting screening.
 What do you want to know?
Mrs T. (cont)
 You decide to get a DXA scan, which
  shows:
 A total T score of –2.0 at the hip, and –1.7
  at the spine.
 She complains of some height loss, but a
  chest X-ray is negative for compression
  fractures.
Treatment of Osteopenia
 You tell her she should take calcium and
  vitamin D supplementation.
 She asks ―didn’t they just do a study that
  showed that that didn’t work? I thought I
  read something about that in the paper.‖
EBM
   Jackson et al, N Engl J Med. 2006.
    ―Calcium plus Vitamin D supplementation
    and the risk of fractures.‖
   Design: Randomized, placebo-controlled trial, 36K women at 40 different sites, healthy, postmenopausal aged 50 – 70
    years (of note, corticosteriod use was an exclusion criteria). Mean follow up period: 7 years.
   Intervention: CaCO3 1000mg plus Vitamin D 400 IU daily. Personal use of calcium, vitamin D, bisphosphonates,
    and calcitonin was allowed. 52% of women were taking HT at baseline.
   Outcomes: no difference in number of hip, wrist, vertebral, or total fractures. At year 6, Calcium plus vitamin D did
    increase BMD by 0.9% at the hip but not at the spine.
   Conclusions: No significant benefit, slight increase in risk of kidney stones
Problems? Flaws?
Study limitations
   Although not statistically significant, treated women did have 12% fewer hip fractures,
    the type of fracture associated with the largest morbidity and mortality. Plus bone
    density at the hip increased slightly.

   Women in this trial were also at low risk; many had already had the benefits of taking
    large amounts of calcium and vitamin D, and more than half were taking hormone
    therapy.

   Vitamin D dosing was potentially inadequate (further discussion to follow)

   40% of women in the intervention group did not take the supplements
What doses do you recommend?
Vitamin D
 Bishoff-Ferrari et al. performed meta-
  analysis (JAMA 2005)
 12 studies included: examined efficacy of
  different doses of Vitamin D
 Conlusion: oral Vit D btw 700-800 IU/d
  reduces risk of non-vertebral fractures; 400
  IU/d is not sufficient.
Calcium
 To maintain neutral calcium balance:
 1,000mg/d for premenopausal women
 1,500 mg/d for postmenopausal women
Counselling
   Mrs. T needs to be counselled re:

Bisphosphonates for Osteopenia

   Should Mrs. T be started on Fosamax?
Physiologic effects
   * Decreased bone resorption

    * Decreased bone formation by 70-95%

    * Increased mineralization density

    * Slight increase in bone volume

    * Increase bone strength first 5 years

    * Decreased fracture rate first 5 years,
    compared to placebo

    * Half-life in bone greater than 10 years

    * Long-term effects on bone unknown

Guidelines


   National Osteoporosis Foundation
    recommends tx for women with T < -2.0 or
    < -1.5 with risk factors.
Schousboe et al, 2005
 Modeled cost-effectiveness of treating
  osteopenic women with alendronate for 5
  years.
 Compared cost per quality-adjusted life-
  year (QALY) of tx vs not tx women aged 55
  - 75, femoral neck scores of – 1.5 to – 2.4.
 Costs ranged from 74 K to 322K per QALY
  gained.
Conclusions
 Therapy only deemed cost effective in
  women who had risk factors unrelated to
  BMD, such as dementia, visual impairment,
  or frequent falls.
 Current recommendation is to reserve
  bisphosphonates for women with T scores
  of –2.5, or those with osteopenia and
  pathologic fracture.
Mrs T. Goes Home

   So you decide that Mrs. T should start with
    supplementation and lifestyle modification,
    and undergo repeat DEXA scan in 2 years
    time.
What about other therapies?
 Calcitonin
 SERMs
 Estrogen
 Intermittant PTH
Calcitonin
 produced by cells in the thyroid gland
 acts directly on osteoclasts to stop bone
  resorption
 Taken as a nasal spray (Miacalcin), dose
  200 units per spray (per day)
 More expensive than bisphosphonate
 Very safe, moderately effective
Estrogen
 Reasonable to start under age 60 (or for first
  ten post-menopausal years).
 Most physicians only recommend for
  treatment of post menopausal symptoms.
 Excellent at maintaining bone mineral
  density.
 Consider switching to SERM after 5 – 10
  years.
Selective Estrogen Receptor
Modulators (ex:Raloxifene)
 Prevents vertebral osteoporotic fractures in
  women with osteoporosis, and stabilizes
  bone density.
 Physiological substitute for estrogen at the
  bone.
 Increased risk of thrombosis.
 Can worsen menopausal symptoms.
Ms. B
 Ms B is a 67 yr old woman with a T-score
  of –3. You have had her on Ca, Vit D, and
  Boniva (due to her awful GERD) for 2
  years now. She develops the acute onset of
  thoracic back pain, and CXR reveals a new
  compression fracture.
 What are you going to do?!
Intermittent PTH
   Recombinant (1-34) variant FDA approved in 2002,
    stimulates both osteoclasts and osteoblasts.
   Intermittent spikes of PTH stimulate more bone formation
    than resorption.
   Administered at a dose of 20 mcg/day SC for 18 to 24
    months.
   After discontinuation, patients should be treated for the
    next two years with an anti-resorping medication;
    otherwise the bone density will decrease.
   Other doses, durations are being experimented with, but
    not officially approved.
Mrs. S
 Mrs. S is a 78 year old woman with
  osteoporosis (T score –2.6 at the hip by
  DEXA 2 years ago) on Fosamax 70 mg
  weekly.
 She is concerned because she has heard
  about reports of dead jaw bone in people on
  this medication.
 What do you say to her?
Woo et al, Annals, 2006
   Systematic review– Bisphosphonates and
    Osteonecrosis of the Jaws
   368 patient cases
   Strongly assoc with use of aminobisphosphonates
    (IV preparation), for people with malignancy,
    related to severe suppression of bone turnover
   94% of pts tx with pamidronate or zoledronic acid
    or both
Osteonecrosis, cont
   85% of affected patients have metatstatic breast
    cancer or multiple myeloma. Only 4% have
    osteoporosis.
   For pts with cancer receiving IV bisphosphonate,
    prevalence 6 – 10%.
   In pts on alendronate for osteoporosis, prevalence
    unknown.
   60% of all cases occur after dental surgery (such
    as tooth extraction), the remaining 40% are assoc
    with denture or physical trauma.
Osteonecrosis, cont
Osteonecrosis, cont

Osteonecrosis, cont
Mrs S.
You can reassure Mrs. S that her chances of
 osteonecrosis are very, very low.
 However, (for other patients) it is
 reasonable to hold off on initation of
 bisphosphonate until after necessary dental
 procedures.
Ms. W
   Ms W is a charming 45 year old woman
    with rheumatoid arthritis, who has been on
    low dose prednisone (5mg/day) for 10 years
    now.

   What is her risk of osteoporosis?
Glucocorticoid induced bone loss
   Unlike other agents that increase bone loss
    (thyroxine, sustained PTH), glucocorticoids
    accelerate resorption while inhibiting bone
    formation.
   Patients beginning on high dose prednisone (mean
    21mg/day) lost a mean of 27% of their L-spine in
    one year        .
            (Reid et al, 1990)



   Luckily, the decline in BMD slows thereafter.
Mechanisms for glucocorticoid
induced osteoporosis
General guidelines
 Keep duration of therapy as short as
  possible
 Consider high dose pulse therapy rather
  than tx for weeks or months
 Don’t forget the basics (weight bearing
  exercise, smoking cessation, minimize
  alcohol)
Screening
 Measure baseline BMD if it is anticipated
  that a patient will be on glucocorticoids for
  > 3 mo.
 DEXA repeated yearly if on preventative
  therapy.
Supplementation

   Adequate Calcium and vitamin D supplementation
    appear to largely negate the effects of low dose
    (up to 10mg/day) steroid administration. (Buckley et al, 1996;
    Saag et al, 1998).


   Recommended supplemenation doses that for
    postmenopausal women: 1500mg Calcium plus
    800IU of Vitamin D.
HRT
 For premenopausal women with oligo or
  amenorrhea on steroids, the ACR
  recommends addition of oral contraceptive.
 For men with testosterone deficiency
  (decreased libido, fatigue) consider
  testosterone supplementation.
Bisphosphonates
 Should be initiated on essentially everyone
  initiating long-term glucocorticoid therapy
  (>5mg/day for >3 months) except those on
  HRT (unless pt has fxr on HRT) or
  premenopausal women who may become
  pregnant.
 ACR Recommendations (2001 Update)
What would Schousboe say?
 Given the high costs of bisphosphonate for
  prevention, perhaps a better strategy would
  be:
 DEXA at baseline and yearly
 Start bisphosphonate tx only if BMD is
  abnormal (T score < -1.0).
 Alendronate 35mg weekly for prevention,
  and 70mg weekly for treatment.
Calcitonin
 Consider calcitonin if bisphosphonate
  contraindicated or not tolerated.
 May also reduce pain from prior fractures.
Thiazides
 Measure urinary calcium excretion.
 Thiazide diuretics (and salt restriction)
  shown to decrease calcium excretion.
 Enthusiasm tempered by lack of evidence
  that thiazides increase BMD in pts on
  corticosteriods.
Ms W.
 Should have a DEXA scan at the hip and
  lumbar spine.
 Should be on Calcium and Vit D.
 Add bisphosphonate if T score < -1.0.
 Consider addition of thiazide, especially if
  hypertensive or she has elevated urinary
  calcium excretion.
 Evaluate for estrogen deficiency.
References
   Bischoff-Ferrari HA, Wellet WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-
    analysis of randonized controlled trials. JAMA 2005; 293:2257-64.
   Buckley LM, Leib ES, Cartularo KS, et al. Calcium and Vitamin D3 supplementation prevents loss in the spine
    secondary to low-dose corticosteroids in patients with rheumatoid arthritis. Ann Intern Med. 1996; 125: 961.
   Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J
    Med. 2006;354:669-83.
   Laan, RF, Van Riel, PL, Van de Putte, LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in
    patients with rheumatoid arthritis. Ann Intern Med 1993; 119:963
   Ott S. Osteoporosis and bone physiology: description, diagnosis, treatment, and explanation of underlying physiology.
    Retrieved on September 26th, 2006 from University of Washington Web Site:
    http://courses.washington.edu/bonephys/
   Primer on the Rheumatic Diseases. 12th Ed. Atlanta, GA: Arthritis Foundation; 2001: 511-27; 596.
   Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American
    College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001;
    44:1496.
   Reid, IR, Heap, SW. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy.
    Arch Intern Med 1990; 150:2545.
   Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced
    osteoporosis. N Engl J Med. 1998; 339: 292.
   Schousboe JT, Nyman JA, Kane RL, et al. Cost-effectiveness of aldenronate therapy for osteopenic postmenopausal
    women. Ann Intern Med. 2005;142: 734 – 41.
   Woo SB, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and Osteonecrosis of the Jaws. Ann Intern
    Med. 2006;144:753-761.

				
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