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Postmenopausal Osteoporosis (PMO) (????????)

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Title: Postmenopausal Osteoporosis (PMO) (????????)


1
Postmenopausal Osteoporosis (PMO) (????????)
  • ? ? ? ? ?
  • Clifford J. Rosen, M.D.
  • NEJM, Volume 353595-603 August 11, 2005 Number 6

2
Outline
  • Case Presentation
  • The Clinical Problem
  • Strategies and Evidence
  • Overview
  • Planning an Intervention Strategy
  • Nonpharmacologic Options
  •          Physical Activity
  • Pharmacologic Options
  •          Antiresorptive Agents
  •          Postmenopausal Hormone-Replacement
    Therapy
  •          Selective Estrogen-Receptor Modulators
  •          Bisphosphonates
  •          Calcitonin
  •          Strontium Ranelate
  •          Anabolic Agents
  •          Combination Therapy
  • Areas of Uncertainty
  • Guidelines
  • Summary and Recommendations

3
Case Presentation
  • A 63-year-old woman presents with a history of
    acute low back pain. She had menopause at 44
    years of age but never received postmenopausal
    hormone-replacement therapy.
  • She reports a history of a Colles' fracture at
    the age of 60 years. Her mother sustained a hip
    fracture at 70 years of age.
  • Lumbar-spine films reveal a new vertebral
    fracture. Dual-energy x-ray absorptiometry (DEXA)
    of the hip shows a BMD T score of 1.3.
  • How should her case be managed?

4
The Clinical Problem (1)
  • PMO is a common disease with a spectrum ranging
    from asymptomatic bone loss to disabling hip
    fracture.
  • The National Institutes of Health consensus
    conference defined osteoporosis as a disease of
    increased skeletal fragility accompanied by low
    BMD (a T score for BMD below 2.5) and
    microarchitectural deterioration.
  • In the United States, there are 1.5 million
    osteoporotic fractures per year, with an annual
    direct cost of nearly 18 billion.
  • It is predicted that the prevalence of fracture
    will increase by the year 2025, yet less than a
    quarter of all women who sustain an osteoporotic
    fracture currently receive appropriate Tx for
    osteoporosis.

5
The Clinical Problem (2)
  • Fractures occur because of qualitative and
    quantitative deterioration in the trabecular and
    cortical skeleton. Bone quality cannot be
    measured clinically, but BMD can be measured
    painlessly, quickly, safely, accurately,
    precisely, and relatively inexpensively several
    methods are available, DEXA is currently the most
    validated. Low bone mass at any skeletal site is
    associated with a substantially increased risk of
    fracture.
  • Other risk factors include advancing age, low BW,
    maternal history of osteoporosis, the direction
    of a fall (a fall backward and to one side is
    most likely to result in a fracture), and most
    important, the presence of a previous fracture.
  • These and other risk factors for osteoporosis
    were reviewed in a recent Clinical Practice
    article in the Journal (Screening for
    osteoporosis. N Engl J Med 2005353164-171.).

6
??????(WHO)????????????
Definition Category QUI/Stiffness T-score
Within 1SD of the young adult reference mean Normal T gt -1.0
More than 1SD below young adult mean, but less than 2.5 SD below this value Low Bone Mass (Osteopenia) -1.0 gt T gt -2.5
2.5 SD or more below the young adult Osteoporosis T lt -2.5
More than 2.5 SD below young adult mean in the presence of one or more fragility fractures Severe Osteoporosis (established osteoporosis) T lt -2.5
7
??????????????
QUI/Stiffness T-score Category
T gt -1.0 Normal
-1.0 gt T gt -2.0 Grade 1 Osteoporosis
-2.0 gt T gt -3.0 Grade 2 Osteoporosis
-3.0 gt T gt -4.0 Grade 3 Osteoporosis
-4.0 gt T Grade 4 Osteoporosis
8
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9
Normal bone trabeculae
Bone trabeculae with osteoporosis
10
Figure 1. DEXA of the Spine and Hip of a
66-Year-Old Postmenopausal Woman.
  • Dx of osteoporosis can be made on the basis of
    BMD of the hip (Panel A) and the spine (Panel B).
    The density of lumbar vertebrae 1 through 4 (L1
    through L4), both as a percentage of the mean
    value for a young adult and as a T score, does
    not indicate osteoporosis, because of the high
    values for L3 and L4. Since the latter probably
    reflect OA changes in the spine, the use of the
    two lowest values is recommended for diagnosis.
  • Note that in this p't the T scores at the hip are
    relatively high, as compared with the spine. The
    density of the total hip includes the lesser
    trochanter and adjacent cortical bone and thus
    has a higher value. The red lines on the left
    side of each panel indicate the specific area
    being measured, and the blue areas on the right
    side indicate the expected age-related means (1
    SD) for white women.
  • BMD measurement results in less than 10 mrem of
    radiation exposure, as compared with 30 to 60
    mrem for a CXR. The color stripes in each panel
    indicate the degree of concern related to bone
    density red denotes high concern and green low
    concern.

Screening for osteoporosis. N Engl J Med
2005353164-171.
11
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12
Figure 2. Flow Chart for Recommendations
Regarding Selection of p'ts for DEXA.
  • For peripheral densitometry, each system will
    have different levels of T-score cutoff. In most
    cases, DEXA will be recommended for p'ts with T
    scores of 1.0 or lower. It is important to
    identify diseases or drugs that are likely to
    cause skeletal fragility or to increase the risk
    of falls.
  • Risk factors that warrant BMD testing include an
    age of more than 65 years, a personal history of
    fracture (particularly fragility fracture) or
    height loss of more than 2 cm, a family history
    of fracture in a first-degree relative, low BW
    (less than 126 lb), and recent weight loss (more
    than 5 ). Other risk factors include female sex,
    late menarche, early menopause, low Ca intake,
    vit D insufficiency, smoking, excess alcohol
    intake, physical inactivity and muscle weakness,
    and impaired vision or balance.
  • Secondary causes include hyperparathyroidism,
    hyperthyroidism, Cushing's syndrome,
    glucocorticoid therapy, inflammatory disorders
    (including arthritis, bowel disease, and
    pulmonary disease), hypogonadism (including Tx
    with LHRH agonists and aromatase inhibitors),
    cancer (especially hematologic conditions),
    congenital disorders (including osteogenesis
    imperfecta and homocystinuria), and neurologic
    disorders (including immobilization and Tx with
    antiepileptic drugs).

13
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14
Strategies and Evidence Overview (1)
  • A comprehensive management plan includes
    evaluation of those at highest risk, exclusion of
    secondary causes of low BMD, and selection of the
    appropriate Tx. A history of fragility fractures
    (unrelated to substantial trauma) in a
    postmenopausal woman strongly supports a
    diagnosis of osteoporosis, regardless of BMD.
  • Secondary causes such as primary
    hyperparathyroidism, Vit D deficiency due to low
    intake, lack of exposure to sunlight, or
    malabsorption, and multiple myeloma should be
    excluded, particularly if the z score (the number
    of standard deviations from the mean for an age-
    and sex-specific reference group) for BMD is
    depressed (i.e., below 2.00).
  • Biochemical markers of bone turnover such as
    N-telopeptide or osteocalcin rarely help in
    establishing a diagnosis or selecting Tx,
    although they may be useful in determining
    whether there is accelerated bone loss,
    particularly during the first few years of
    menopause.

15
Overview (2)
  • Decision making should also take into account
    several caveats. Osteoporosis therapy can reduce
    the risk of fracture by as much as 50 , but some
    women have fractures despite Tx. Also, changes in
    lifestyle and the use of pharmacologic
    interventions are lifetime commitments, and
    therefore cost, compliance with a medication
    regimen, and safety must be considered in
    decisions on therapy.
  • Moreover, a substantial percentage of
    osteoporotic fractures occur in women who have T
    scores above 2.5. (A T score is the number of
    standard deviations the BMD measurement is above
    or below the young-normal mean bone density.)
  • In some cases, there is a substantial discrepancy
    between the spine and hip T scores. Thus,
    decisions with regard to Tx should not be based
    solely on BMD.

16
Self-assessment of Osteoporosis 1.Height
loss of more than 2.5 cm 2.Occiput fails to touch
the wall when standing next to the wall 3.A
bend back These are clues that you may already
have osteoporosis. Please consult your doctor if
you have these problems.
17
Planning an Intervention Strategy
  • Therapy for PMO is considered to be primary
    prevention when it is prescribed for those at
    risk without a T score below 2.5 or a history of
    fragility fracture and is considered to be Tx for
    those with established disease, including
    previous osteoporotic fracture, markedly reduced
    BMD, or both.
  • The choice of an appropriate regimen will depend
    on whether the therapy is designed principally to
    prevent bone loss in p'ts with osteopenia (a T
    score between 1 and 2.5) or to reduce the
    likelihood of a first or subsequent fracture in
    osteoporosis.

18
Nonpharmacologic Options (1)
  • Ca supplementation should be adjunctive Tx for
    all women with established osteoporosis and must
    be part of any preventive strategy to ameliorate
    bone loss.
  • Increased Ca intake reduces the
    hyperparathyroidism associated with advancing age
    and can enhance mineralization of newly formed
    bone.
  • A recent meta-analysis of 15 Ca intervention
    trials involving healthy women and PMO
    demonstrated an increase of nearly 2 in spine
    BMD after two years, although the risk of
    vertebral and nonvertebral fracture was not
    reduced to a statistically significant level.
  • A total Ca intake of 1200 to 1500 mg/d (through
    diet, supplements, or both) is recommended for
    all postmenopausal women.

19
Nonpharmacologic Options (2)
  • Vit D is essential for skeletal maintenance and
    enhancement of Ca absorption. Dietary
    insufficiency of this Vit is a growing problem,
    with as many as two thirds of p'ts with hip
    fracture classified as having a deficiency of Vit
    D (defined as a serum 25-hydroxyVit D 25(OH) Vit
    D level below 15 ng/ml 37.4 nmol/l).
  • Elderly persons with chronic conditions that
    require assisted-living situations are
    particularly vulnerable to Vit D deficiency
    because of lack of adequate exposure to sunlight.
  • One large trial showed a reduction of 33 in hip
    fracture among nursing home residents who were
    randomly assigned to receive Ca and Vit D, as
    compared with those given placebo.

20
Vit D3 and Ca to prevent hip fractures in the
elderly women
  • BACKGROUND. Hypovitosis D and a low Ca intake
    contribute to increased parathyroid function in
    elderly persons. Ca and vit D supplements reduce
    this 2nd hyperparathyroidism, but whether such
    supplements reduce the risk of hip fractures
    among elderly people is not known.
  • METHODS. We studied the effects of
    supplementation with vit D3 (cholecalciferol) and
    Ca on the frequency of hip fractures and other
    nonvertebral fractures, identified
    radiologically, in 3270 healthy ambulatory women
    (mean /- SD age, 84 /- 6 years). Each day for
    18 months, 1634 women received triCa phosphate
    (containing 1.2 g of elemental Ca) and 20
    micrograms (800 IU) of vit D3, and 1636 women
    received a double placebo. We measured serial
    serum PTH and 25-hydroxyvit D (25(OH)D) in 142
    women and determined the femoral BMD at base line
    and after 18 months in 56 women.

N Engl J Med 19923271637-1642.
21
  • RESULTS. Among the women who completed the
    18-month study, the number of hip fractures was
    43 lower (P 0.043) and the total number of
    nonvertebral fractures was 32 lower (P 0.015)
    among the women treated with vit D3 and Ca than
    among those who received placebo. The results of
    analyses according to active Tx and according to
    intention to treat were similar. In the vit D3-Ca
    group, the mean serum PTH had decreased by 44
    from the base-line value at 18 months (P lt 0.001)
    and the serum 25(OH)D had increased by 162 over
    the base-line value (P lt 0.001). The BMD of the
    proximal femur increased 2.7 in the vit D3-Ca
    group and decreased 4.6 in the placebo group (P
    lt 0.001).
  • CONCLUSIONS. Vit D3 and Ca reduces the risk of
    hip fractures and other nonvertebral fractures
    among elderly women.

N Engl J Med 19923271637-1642.
22
Nonpharmacologic Options (3)
  • In another trial, Tx with a single oral dose of
    100,000 IU of Vit D3 every four months reduced
    nonvertebral fractures by nearly a third among
    elderly people who are able to walk.
  • Similarly, among older men and women in New
    England, Ca citrate (500 mg/d) and Vit D3 (700
    IU/d) reduced the risk of nonvertebral fracture.
  • There is strong evidence that Vit D enhances
    muscle strength and reduces the risk of falling.
  • Table 1 lists the various forms of Ca and Vit D
    supplements.
  • Counseling with regard to avoidance of smoking
    and excessive alcohol intake is routinely
    warranted, particularly since smoking and alcohol
    intake have been linked in some studies to
    greater fracture risk.

23
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24
Physical Activity
  • Bed rest or immobility due to other causes can
    result in rapid bone loss. Moreover, the number
    of falls and the percentage of falls that result
    in fracture increase with age.
  • A recent Cochrane meta-analysis found that muscle
    strengthening, balance training, assessment of
    the home for hazards, withdrawal of psychotropic
    medications, and the use of a multidisciplinary
    program to assess risk factors all protect
    against falls.
  • Another approach is to pad the hip with a hip
    protector to reduce trauma during a fall
    although p't compliance with this strategy is
    generally poor, when used properly, the strategy
    has been reported to reduce the risk of hip
    fracture.
  • Regular physical activity, including aerobic,
    weight-bearing, and resistance exercise, is
    effective in increasing BMD of the spine and
    strengthening muscle mass in postmenopausal
    women, but there are no large trials establishing
    whether these interventions reduce the fracture
    risk.

25
Pharmacologic Options
  • An aggressive intervention program can reduce the
    risk of fracture and improve the quality of life
    among PMO.
  • Several pharmacologic options are available, and
    these can be classified according to their
    mechanism of action.
  • Two main classes of drugs
  • Antiresorptive agents (agents that block bone
    resorption by inhibiting the activity of
    osteoclasts).
  • Anabolic agents (agents that stimulate bone
    formation by acting primarily on osteoblasts).
  • Table 2 is a review of agents that have been
    approved by FDA.

26
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27
Antiresorptive Agents
  • By suppressing osteoclast activity,
    antiresorptive agents slow the remodeling cycle,
    thereby enhancing mineralization of the bone
    matrix and potentially stabilizing the trabecular
    microarchitecture.
  • These agents increase BMD in women with
    osteopenia or osteoporosis and reduce the risk of
    fracture in women with osteoporosis, although
    efficacy varies among the agents (Table 2).

28
 Postmenopausal Hormone-Replacement Therapy(1)
  • HRT was once considered the primary therapy for
    PMO. Estrogen slows bone resorption by blocking
    cytokine signaling to the osteoclast, increases
    BMD, and reduces incidence of new vertebral
    fractures by nearly 50 .
  • Low-dose conjugated estrogens (0.3 or 0.45 mg/d)
    or ultra-low-dose estradiol (0.014 mg/d) also
    increases BMD, but the antifracture efficacy of
    these therapies has not been established.
  • Among women in the Women's Health Initiative
    trial, in those randomly assigned to receive
    conjugated estrogens, with or without a
    progestin, the reduction in hip fracture was 33
    .

29
Postmenopausal Hormone-Replacement Therapy(2)
  • Discontinuation of estrogen results in measurable
    bone loss, although it is not certain whether
    discontinuation results in a greater fracture
    risk than continuation.
  • Recent concern about the nonskeletal risks
    associated with long-term use of estrogen
    (including the risk of breast cancer and the risk
    of CV disease), coupled with the availability of
    other drugs to treat osteoporosis has markedly
    lessened enthusiasm for HRT in the Tx and
    prevention of osteoporosis.

30
Risks and Benefits of Estrogen Plus Progestin in
Healthy Postmenopausal Women Principal Results
From the Women's Health Initiative Randomized
Controlled Trial
  • Context  Despite decades of accumulated
    observational evidence, the balance of risks and
    benefits for hormone use in healthy
    postmenopausal women remains uncertain.
  • Objective  To assess the major health benefits
    and risks of the most commonly used combined
    hormone preparation in the United States.
  • Design  Estrogen plus progestin component of the
    Women's Health Initiative, a randomized
    controlled primary prevention trial (planned
    duration, 8.5 years) in which 16608
    postmenopausal women aged 50-79 years with an
    intact uterus at baseline were recruited by 40 US
    clinical centers in 1993-1998.

JAMA. 2002288321-333.
31
  • Interventions  Participants received conjugated
    equine estrogens, 0.625 mg/d, plus
    medroxyprogesterone acetate, 2.5 mg/d, in 1
    tablet (n 8506) or placebo (n 8102).
  • Main Outcomes Measures  The primary outcome was
    coronary heart disease (CHD) (nonfatal MI and CHD
    death), with invasive breast cancer as the
    primary adverse outcome. A global index
    summarizing the balance of risks and benefits
    included the 2 primary outcomes plus stroke,
    pulmonary embolism (PE), endometrial cancer,
    colorectal cancer, hip fracture, and death due to
    other causes.

JAMA. 2002288321-333.
32
  • Results 
  • On May 31, 2002, after a mean of 5.2 years of
    follow-up, the data and safety monitoring board
    recommended stopping the trial of estrogen plus
    progestin vs placebo because the test statistic
    for invasive breast cancer exceeded the stopping
    boundary for this adverse effect and the global
    index statistic supported risks exceeding
    benefits.
  • This report includes data on the major clinical
    outcomes through April 30, 2002. Estimated hazard
    ratios (HRs) (nominal 95 confidence intervals
    CIs) were as follows CHD, 1.29 (1.02-1.63)
    with 286 cases breast cancer, 1.26 (1.00-1.59)
    with 290 cases stroke, 1.41 (1.07-1.85) with 212
    cases PE, 2.13 (1.39-3.25) with 101 cases
    colorectal cancer, 0.63 (0.43-0.92) with 112
    cases endometrial cancer, 0.83 (0.47-1.47) with
    47 cases hip fracture, 0.66 (0.45-0.98) with 106
    cases and death due to other causes, 0.92
    (0.74-1.14) with 331 cases. Corresponding HRs
    (nominal 95 CIs) for composite outcomes were
    1.22 (1.09-1.36) for total CV disease (arterial
    and venous disease), 1.03 (0.90-1.17) for total
    cancer, 0.76 (0.69-0.85) for combined fractures,
    0.98 (0.82-1.18) for total mortality, and 1.15
    (1.03-1.28) for the global index.
  • Absolute excess risks per 10 000 person-years
    attributable to estrogen plus progestin were 7
    more CHD events, 8 more strokes, 8 more PEs, and
    8 more invasive breast cancers, while absolute
    risk reductions per 10 000 person-years were 6
    fewer colorectal cancers and 5 fewer hip
    fractures.
  • The absolute excess risk of events included in
    the global index was 19 per 10 000 person-years.

JAMA. 2002288321-333.
33
  • Conclusions 
  • Overall health risks exceeded benefits from use
    of combined estrogen plus progestin for an
    average 5.2-year follow-up among healthy
    postmenopausal US women.
  • All-cause mortality was not affected during the
    trial.
  • The risk-benefit profile found in this trial is
    not consistent with the requirements for a viable
    intervention for primary prevention of chronic
    diseases, and the results indicate that this
    regimen should not be initiated or continued for
    primary prevention of CHD.

JAMA. 2002288321-333.
34
Selective Estrogen-Receptor Modulators
  • Raloxifene inhibits bone resorption through the
    same mechanism as do estrogens.
  • Raloxifene increases spine BMD slightly and
    decreases the risk of vertebral fracture by 40
    in women with osteoporosis, but it has no effect
    on the risk of nonvertebral fracture.
  • The risk of breast cancer is reduced with
    long-term use of raloxifene, although the drug is
    not approved for this indication.
  • New selective estrogen-receptor modulators are
    currently in phase 2 and 3 clinical trials.

35
Raloxifene (Evista)
  • ????????????,????????????,??????????????,?????????
    ?????????????????,????????????,???????????????,???
    ??????????????????????????,???????,???????????????
    ???????,????????????????????????,?????????????????
    ???,???????,??????????
  • ???????????(Selective Estrogen Receptor
    Modulators , SERMs)??????,??????????(estrogen
    receptor),???????,??????????????????????
  • Tamoxifene???????SERMs,???????????????,???????????
    ?????????,????tamoxifene????????????????

36
  • ????Raloxifene?1997?12?????FDA??,?????????????????
    ?????????????????,??????????????????
  • Raloxifene???????????????,?????????????????,??????
    ????(bone turnover),??????????Raloxifene??????????
    ????????,??,???????raloxifene?????????????,???????
    ????????,???????????????,raloxifene????????
  • Raloxifene?????????????????????(LDL)?????(?6-11),
    ????????????(HDL)??????(triglycerides)??,?????????
    ???????,????????

37
  • Raloxifene????????60,????????,???????????,???????
    ?????60mg??95??????????,?????????????,?clofibrate
    , indomethacin, naproxen, ibuprofen, diazepam,
    diazoxide?????????????????????????,????????2,????
    ??????????????????
  • ??raloxifene????cytochrom p450????,????????????,??
    ampicillin?cholestyramine???,raloxifene????????wa
    rfarin???,???prothrombin time??,????????
  • Raloxifene????????,???glucuronide????,????????,???
    ?1 ???????????????????27.7???

38
  • Raloxifene??????????????????(25)??????(leg
    cramps, 6),???????????(early stage)????,?????????
    ????,???????????(HRT)??,?????raloxifene???,???????
    ????????,??????????????????,???raloxifene?????????
    ????,??raloxifene????????????(thromboembolism)????
    ????,?????????????,?????????(???????????)??,????72
    ????????,?????????????????????,?????????
  • ??,?????????????? (1) ???????????(2)
    ????????(thromboembolism),????????????????????(ret
    inal vein thrombosis)??????(3)
    ??raloxifene?????????(4) ??????????????(5)
    ??????????????????raloxifene???????????????,????
    ????????????????????????????????biphosphonates???
    ?????????????????????????????????

39
Bisphosphonates (1)
  • The most widely prescribed antiresorptive agents
    and are often considered first-line therapy for
    PMO. These agents suppress resorption by
    inhibiting the attachment of osteoclasts to bone
    matrix and enhancing programmed cell death.
  • First-generation bisphosphonates include
    etidronate and clodronate neither drug is
    approved for osteoporosis.
  • Alendronate and risedronate, two
    second-generation nitrogen-containing
    bisphosphonates, have been shown in randomized
    trials to increase BMD in postmenopausal
    osteopenia or osteoporosis in women with
    osteoporosis, they have been shown to reduce the
    incidence of hip, vertebral, and nonvertebral
    fracture by nearly 50 , particularly during the
    first year.

40
Bisphosphonates (2)
  • As is the case with other antiresorptive drugs,
    increases in BMD with alendronate or risedronate
    account for a small fraction of their
    antifracture efficacy.
  • Hence, follow-up DEXA may substantially
    underestimate the reduction in fracture risk.
  • Alendronate can be safely administered for at
    least seven years without adversely affecting
    bone strength. Moreover, discontinuation of
    long-term (five years or more) alendronate
    therapy results in minimal bone loss over the
    ensuing three to five years.
  • Alendronate or risedronate once weekly has been
    shown to reduce the rate of drug-induced
    esophagitis, as compared with daily doses.
  • In a recent one-year head-to-head study,
    alendronate increased spine and hip BMD slightly
    more than risedronate, although the clinical
    significance of this finding is uncertain.

41
  • Alendronate (Fosamax)?FDA???????1.
    ?????????????????(1995?)2. ??????????????????????
    ??(1996?)
  • ?????????????????????????????????,???????(Clcr)?
    ????35????
  • Alendronate????????????????????,??????????????????
    ??????????????????????????????????????????????????
    ????????????,?????alendronate??????,??????????????
    ?????????????????????????????????,??????30????????
    ????,??????????????????????
  • ?????alendronate????????????????,?????????????????
    ?????,?????????,???alendronate??????alendronate???
    ????,??????????????,???????????????

42
  • Alendronate?????????????0.78,?????0.59,?????????
    ??????????????10mg???????????,??????,?????????????
    ????????????????78??????????????????????,????????
    ,??????????????????????????????????,??????????????
    Clcr??35ml/min????
  • ????????????1. ???????????????,???????????2.
    ?????????30????3. ??alendronate?????????4.
    ??????5. ?????????????

43
Bisphosphonates (3)
  • IV pamidronate has been used to treat women who
    cannot tolerate oral bisphosphonates however,
    its efficacy in reducing fracture has not been
    established. Acute and delayed hypersensitivity
    reactions can occur and its use is
    contraindicated in Vit D deficiency, since the
    drug can cause a precipitous drop in serum Ca
    levels.
  • In 2005, ibandronate, at a dose of 2.5 mg/d or
    150 mg monthly, was approved by FDA for both
    prevention and Tx of PMO. Daily ibandronate has
    been shown to reduce significantly the incidence
    of vertebral fracture in women with osteoporosis
    and to reduce incidence of nonvertebral fracture
    in women with severe osteoporosis (T score, below
    3.0).
  • IV zoledronate, which is approved for Tx of
    malignant hypercalcemia, multiple myeloma, and
    skeletal metastases, can suppress bone resorption
    and increase BMD in postmenopausal women for as
    long as one year after a single 4-mg dose. Phase
    3 trials are under way to evaluate the safety and
    efficacy of this drug in reducing osteoporotic
    fracture.

44
Calcitonin
  • Calcitonin is an endogenous peptide that
    partially inhibits osteoclast activity.
  • Nasal calcitonin and subcutaneous calcitonin are
    approved for PMO. Although Tx of women with
    osteoporosis with nasal calcitonin at a dose of
    200 IU/d has been shown to reduce the incidence
    of vertebral (but not nonvertebral) fracture in a
    single randomized trial, methodologic flaws in
    the study have limited enthusiasm for this agent.
  • In placebo-controlled studies, nasal calcitonin
    has reduced the pain associated with new spine
    fractures, although it is now considered
    preferable to treat osteoporosis with more potent
    agents and to manage pain separately.

45
A randomized trial of nasal spray salmon
calcitonin in postmenopausal women with
established osteoporosis the prevent recurrence
of osteoporotic fractures study. PROOF Study
Group.
  • PURPOSE We conducted a 5-year, double-blind,
    randomized, placebo-controlled study to determine
    whether salmon calcitonin nasal spray reduced the
    risk of new vertebral fractures in postmenopausal
    women with osteoporosis.
  • SUBJECTS AND METHODS A total of 1,255
    postmenopausal women with established
    osteoporosis were randomly assigned to receive
    salmon calcitonin nasal spray (100, 200, or 400
    IU) or placebo daily. All participants received
    elemental Ca (1,000 mg) and vit D (400 IU) daily.
    Vertebral fractures were assessed with lateral
    radiographs of the spine. The primary efficacy
    endpoint was the risk of new vertebral fractures
    in the salmon calcitonin nasal spray 200-IU group
    compared with the placebo group.

Am J Med. 2000 Sep109(4)267-76.
46
  • RESULTS During 5 years, 1,108 participants had
    at least one follow-up radiograph. A total of 783
    women completed 3 years of Tx, and 511 completed
    5 years. The 200-IU dose of salmon calcitonin
    nasal spray significantly reduced the risk of new
    vertebral fractures by 33 compared with placebo
    200 IU 51 of 287, placebo 70 of 270, relative
    risk (RR) 0.67, 95 confidence interval (CI)
    0.47- to 0.97, P 0.03. In the 817 women with
    one to five prevalent vertebral fractures at
    enrollment, the risk was reduced by 36 (RR
    0.64, 95 CI 0.43- to 0.96, P 0.03). The
    reductions in vertebral fractures in the 100-IU
    (RR 0.85, 95 CI 0.60- to 1.21) and the 400-IU
    (RR 0.84, 95 CI 0.59- to 1.18) groups were
    not significantly different from placebo. Lumbar
    spine BMD increased significantly from baseline
    (1 to 1. 5, Plt0.01) in all active Tx groups.
    Bone turnover was inhibited, as shown by
    suppression of serum type-I collagen cross-linked
    telopeptide (C-telopeptide) by 12 in the 200-IU
    group (P lt0.01) and by 14 in the 400-IU group
    (Plt0.01) as compared with placebo.
  • CONCLUSION Salmon calcitonin nasal spray at a
    dose of 200 IU daily significantly reduces the
    risk of new vertebral fractures in PMO.

Am J Med. 2000 Sep109(4)267-76.
47
 Strontium Ranelate
  • Strontium ranelate is orally administered and
    stimulates Ca uptake in bone while inhibiting
    bone resorption.
  • In a randomized trial in PMO, daily strontium
    ranelate reduced the risk of vertebral fracture
    by 40 . However, a significant reduction in
    nonvertebral fracture was observed only in a post
    hoc analysis of a small subgroup of women.
  • This drug was recently approved by European
    regulatory agencies, but it is not currently
    approved by FDA.

48
Anabolic Agents (1)
  • The prototypical anabolic drug is sodium
    fluoride, which was widely used in the 1970s and
    1980s because of its ability to stimulate the
    formation of new bone. However, a randomized
    trial in 1990 established that despite dramatic
    increases in BMD, the risk of nonvertebral
    fracture actually increased with the use of
    fluoride.
  • In 2002, synthetic PTH (134) (teriparatide) was
    the first anabolic agent approved by FDA for PMO.
    Unlike antiresorptive agents, PTH stimulates bone
    remodeling by increasing bone formation. In a
    large randomized trial involving postmenopausal
    severe osteoporosis, 20 µg of PTH per day
    administered S.C. markedly increased BMD and
    reduced vertebral and nonvertebral fractures by
    more than 50 .
  • However, the trial was stopped after 20 months
    because of concern about the development of
    osteosarcoma in rats treated with high doses of
    PTH (134).

49
Effect of PTH (1-34) on Fractures and BMD in PMO
  • Background Once-daily injections of PTH or its
    amino-terminal fragments increase bone formation
    and bone mass without causing hypercalcemia, but
    their effects on fractures are unknown.
  • Methods We randomly assigned 1637 postmenopausal
    women with prior vertebral fractures to receive
    20 or 40 µg of PTH (1-34) or placebo,
    administered subcutaneously by the women daily.
    We obtained vertebral radiographs at base line
    and at the end of the study (median duration of
    observation, 21 months) and performed serial
    measurements of bone mass by DEXA.

N Engl J Med 20013441434-1441.
50
  • Results New vertebral fractures occurred in 14
    women in the placebo group and in 5 and 4 ,
    respectively, of the women in the 20-µg and 40-µg
    PTH groups the respective relative risks of
    fracture in the 20-µg and 40-µg groups, as
    compared with the placebo group, were 0.35 and
    0.31 (95 confidence intervals, 0.22 to 0.55 and
    0.19 to 0.50). New nonvertebral fragility
    fractures occurred in 6 women in the placebo
    group and in 3 of those in each PTH group
    (relative risk, 0.47 and 0.46, respectively 95
    confidence intervals, 0.25 to 0.88 and 0.25 to
    0.86). As compared with placebo, the 20-µg and
    40-µg doses of PTH increased BMD by 9 and 13 more
    percentage points in the lumbar spine and by 3
    and 6 more percentage points in the femoral neck
    the 40-µg dose decreased BMD at the shaft of the
    radius by 2 more percentage points. Both doses
    increased total-body BMD by 2 to 4 more
    percentage points than did placebo. PTH had only
    minor side effects (occasional nausea and
    headache).
  • Conclusions Tx of PMO with PTH (1-34) decreases
    the risk of vertebral and nonvertebral fractures
    increases vertebral, femoral, and total-body BMD
    and is well tolerated. The 40-µg dose increased
    BMD more than the 20-µg dose but had similar
    effects on the risk of fracture and was more
    likely to have side effects.

N Engl J Med 20013441434-1441.
51
Anabolic Agents ( 2)
  • As a result, a "black-box" warning was added to
    the teriparatide label. However, retrospective
    studies have found no association between
    osteosarcoma and primary or secondary
    hyperparathyroidism in humans, and no cases of
    osteosarcoma have been reported in the more than
    200,000 p'ts treated with PTH.
  • The current recommendation is that PTH therapy
    should be limited to persons with
    moderate-to-severe osteoporosis and that the
    duration of therapy should not exceed two years.
  • PTH (134) is well tolerated, although mild but
    asymptomatic hypercalcemia (i.e., a serum Ca
    level between 10.5 and 11.0 mg/dl 2.6 and 2.8
    mmol/l) can occur rarely.
  • Cost and the requirement of subcutaneous
    administration are major limiting factors.

52
Combination Therapy
  • Although studies have suggested that combining
    antiresorptive agents may slightly increase BMD
    as compared with monotherapy, there are no data
    to indicate that combination therapies are
    superior for reducing the risk of fracture.
  • There is also no evidence that combining PTH with
    an antiresorptive drug results in additive or
    synergistic effects, but concurrent use of cyclic
    PTH (i.e., daily parathyroid for 3 months
    followed by no Tx for 3 months for a period of 15
    months) with alendronate may be just as effective
    as daily PTH with alendronate.
  • Nevertheless, bone loss will occur after the
    discontinuation of PTH, but it can be prevented
    if this therapy is followed by Tx with an
    antiresorptive drug such as alendronate.

53
Areas of Uncertainty (1)
  • The optimal timing and type of preventive therapy
    are still not clearly defined. Many
    postmenopausal women have T scores between 1.0
    and 2.5 but no other risk factors.
  • Postmenopausal hormone-replacement therapy, once
    considered the best preventive approach for these
    women, is no longer recommended in light of the
    associated risks reported in the Women's Health
    Initiative trial.
  • Bisphosphonates prevent bone loss in women with
    osteopenia and can be used as prophylaxis, but
    cost-effectiveness and concerns about the effects
    on skeletal mineralization over decades may be
    limiting factors.
  • Studies such as the extension of the Fracture
    Intervention Trial (evaluating alendronate) have
    provided some reassurance with regard to
    long-term use.

54
Areas of Uncertainty (2)
  • Also uncertain is the appropriate care for p'ts
    who continue to have fractures despite aggressive
    pharmacologic intervention. Whether new agents
    such as the synthetic Ab to the receptor
    activator of nuclear factor- B ligand (AMG 162)
    or strontium ranelate will be effective in
    preventing new fractures in such p'ts needs to be
    tested.
  • Finally, controversy persists about the use of
    vertebroplasty or kyphoplasty, procedures that
    introduce material to expand compressed vertebrae
    and reduce the pain associated with new
    fractures. Both the absence of randomized,
    placebo-controlled trials and concerns about the
    mechanical strength of adjacent vertebrae after
    these procedures preclude making recommendations
    for their use.

55
(Guidelines)
56
Summary and Recommendations (1)
  • A careful Hx taking and P.E. that address risk
    factors for or signs of osteoporosis
    (particularly previous fragility fractures,
    height loss, or both, as well as possible
    secondary causes of bone loss) combined with
    measurement of BMD should guide therapeutic
    decisions.
  • Given the high prevalence of low levels of 25(OH)
    Vit D in women with osteoporosis, measurement of
    a serum 25(OH) Vit D level by a reliable
    laboratory is reasonable.

57
Summary and Recommendations (2)
  • Tx plans for the woman in the vignette should
    include Ca supplementation to a level of at least
    1200 mg/d and 800 IU of Vit D, as well as
    pharmacologic therapy. I would start with an oral
    bisphosphonate (alendronate or risedronate) once
    weekly or ibandronate once monthly, given the
    documented reductions in the incidence of hip and
    vertebral fracture with these agents.
  • Alternatively, one could consider PTH (134) for
    two years if a p't cannot tolerate a
    bisphosphonate or has had multiple fractures,
    although with this regimen, cost and compliance
    need to be taken into consideration.
  • Irrespective of the choice of therapy, careful
    follow-up, with attention to pain, lifestyle, and
    risk factors for future fracture, is necessary.

58
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