Postmenopausal Osteoporosis PMO

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

• ? ? ? ? ?
• Clifford J. Rosen, M.D.
• NEJM, Volume 353595-603 August 11, 2005 Number 6

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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

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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?

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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.

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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.).

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Normal bone trabeculae
Bone trabeculae with osteoporosis
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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.
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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).

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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.

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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.

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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.
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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.

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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.

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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.

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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.
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• 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.
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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.

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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.

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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.

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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).

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 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
  .

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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.

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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.
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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.

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Raloxifene (Evista)

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  ???,???????,??????????
• ???????????(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

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  ?????60mg??95??????????,?????????????,?clofibrate
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  diazoxide?????????????????????????,????????2,????
  ??????????????????
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  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???
  ?????????????????????????????????

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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.

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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. ?????????????

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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.

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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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