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Vitamin and Osteoporosis Definitions Prevalence Prevalence

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Vitamin and Osteoporosis Definitions Prevalence Prevalence Powered By Docstoc
					                                           Definitions
                    Vitamin D and
                     Osteoporosis           No consensus       Ca absorption
                                            Deficiency < 20    increases 45-65%
                                              Severe < 10      when from 20 to
                                              10 < Mod < 16    32
                    Tom Morrione                               Intoxication > 150
                                              16 < Mild < 20
                                            20-29 = relative
                                            insufficiency
                                            > 30 = adequate




Prevalence                                 Prevalence
 1 billion < 30      48% white              30-50% UAE,
 40 – 100% CD        preadolescent girls    Turkey, Saudi
 elders < 30         in Maine < 20          Arabia, India,
 > 50% PMP           42% 15-49 AA           Lebanon and
 women on OP         women < 20             Australia < 20
 meds < 30                                  73% pregnant
                     32% med
 52% Hispanic and                           women < 20
                     students, residents
 AA children in
 Boston < 20         and MD < 20




                                           Physiology
Physiology




                                                                                    1
Without Vitamin D                            Vitamin D
 10-15% of dietary Ca                         Osteoporosis & Fracture
 60% dietary phosphorus                       Falls
 D < 30                                       Cardiovascular
  Decrease in intestinal Ca absorption        Depression
  Associated with increased PTH               Cancer
                                              Total Mortality
                                              Treatment/Dosing




Osteoporosis and Fracture                    Osteoporosis and Fracture
 33% women 60-70                              Chapuy: 1992 (NEJM)
 66% women > 80                                3270 women 1200mg Ca/800IU D3 for
 Underdx’d in men                              3 years
  7% white                                     RR reduction
  5% black                                      • Hip fracture: 43%
  3% hispanic                                   • Nonvertebral fracture: 32%
 Fracture: 47%                                Dawson-Hughes: 1997 (NEJM)
 women and 22%
                                               389 age > 65 500mg Ca/700IU D3
 men > 50
                                               Nonvertebral fracture RR red by 58%




Osteoporosis and Fracture                    Osteoporosis and Fracture
 Jackson et al: 2006 (NEJM)
  WHI
  36,282 postmenopausal, 50-79
  1000mg Ca / 400IU D3
  Mean 25(OH)D level 18
  No significant reduction (avg f/u 7 yrs)
  Adherence rate 59%!
   • Adjusted   RR red hip fx by 29%
   • 4 per 10,000
   • NNT 5045 or 1914




                                                                                     2
Osteoporosis and Fracture                   Osteoporosis and Fracture
 Bischoff-Ferrari, et al: 2005 (JAMA)        Hip Fractures
   Meta-analysis of RCTs                       400IU pooled RR 1.15 (CI 0.88-1.5)
   D2 or D3 with minimum 1 yr f/u              700-800IU pooled RR 0.74
   • Only found valid ones with D3             NNT = 45, treatment duration of 24-60
                                               mos
   RR of 1st fx with or w/o Ca supp
                                             Nonvertebral Fracture
   7 studies
                                               400IU pooled RR 1.03 (CI 0.86-1.24)
   Results?
                                               700-800IU pooled RR 0.77
                                               NNT = 27, treatment duration 12-60
                                               mos




Osteoporosis and Fracture                   Falls
 Optimal fracture prevention?                Theory
   Mean 25(OH)D of about 40                    Vitamin D receptor on
                                               muscle cells
 Primarily white population
                                             Bischoff-Ferrari et al,
 Could not find association with Ca          2006 (Am J Clin
 RECORD Trial (Lancet 2005)                  Nutr)
   Baseline Vit D increased from 15 to 25      Performance speed
   ? Enough for fracture prevention            and proximal muscle
                                               strength improved
   Only had 48% compliance rate
                                               with D




Falls                                       Falls
 Bischoff-Ferrari, et al: 2004 (JAMA)        Prince et al: 2008 (Arch Int Med)
   Meta-analysis RCTs                          ? Efficacy of ergocalciferol (in setting
   Age > 60, any type of D                     of calcium supp)
   5 Studies (400IU to 800IU)                  302 comm. dwelling women (70-90)
   Pooled OR 0.78                              Starting with D < 24 and with h/o
   NNT = 15                                    falls in past year
                                               RR reduction of 19%
                                                • RR 23% in winter/spring




                                                                                          3
Cardiovascular                                                                  Cardiovascular
 CVD Deaths                                                                      Giovannucci, et al: 2008 (Arch Int
   Latitude
                                                                                 Med)
   Winter months
   Higher altitudes                                                                Prospective study of 40-75 yo
 Vitamin D                                                                         Followed for 10 years
   Smooth muscle                                                                   25(OH)D < 15
   Inflammation                                                                     • Risk for MI RR 2.42
   Vascular
   Calcification                                                                   22.6 < D < 29.9 = RR 1.6
   RAS                                                                             15 < D < 22.5 = RR 1.43
   Blood Pressure
               http://www.abcnews.go.com/Health/SkinCare/wireStory?id=5032187




Cardiovascular                                                                  Depression
 Krause et al: 1998 (Lancet)                                                     Historical
   RCT with UVA and UVB                                                          association
    • UVB increased 25(OH)D 162%                                                 ? Chicken and Egg
    • Reduced ambulatory BP (-6/-6)                                                reduced sun
 Pfiefer et al: 2001 (J Clin End Met)                                              exposure
   Group with mean D of 10                                                         reduced vitamin
                                                                                   intake
    • Given 800IU D3
    • Increase 25(OH)D 72%                                                         different housing or
    • Reduced BP 9.3%/8.5%                                                         clothing habits




Depression                                                                      Cancer
 Hoogendijk et al: 2008 (Arch Gen                                                D < 20 associated with 30-50%
 Psych)                                                                          increased risk of:
                                                                                   Colon cancer;
   Population-based cohort study
                                                                                   Breast cancer;
   1,282 community dwelling (65-95)
                                                                                   Prostate cancer; and
    • 169 minor depression
                                                                                   Higher mortality rates from them
    • 26 major depression
                                                                                 WHI
    • Both groups with 14% lower levels D
      (P<.001)                                                                     253% increase risk of colorectal CA with
                                                                                   D < 12 over f/u 8 years
    • PTH 5% and 33% higher respectively
      (P<.08)




                                                                                                                              4
Cancer                                      Total Mortality
 Nurses’ Health Study cohort                 Autier et al: 2007
                                             (Arch Int Med)
  OR Colorectal CA
                                               Meta-analysis RCTs
   • Vit D 16.2   OR 1.0                       Impact of D supp
   • Vit D 39.9   OR 0.53                      on death from any
                                               cause
 Prospective Study 1954 men for                 •   CHF
 colorectal CA                                  •   CHD
                                                •   CVD
   • Vit D intake 6–94 IU day; OR 1.0
                                                •   Fracture
   • Vit D intake 233–652 IU day; OR 0.53
                                               18 studies




Total Mortality                             Intoxication
 Compliance ranged 48% to 95%                NEJM Case Report
 Summary RR (SRR) = 0.93 (0.87-              58 yo female
                                               RA and DM
 0.99)
                                               Presented with:
 ? Dose                                         •   Fatigue

 ? Duration                                     •   Constipation
                                                •   Back pain
 Timing of deaths not reported                  •   Nausea/vomitting
                                                •   Forgetfulness
 Long-term dosing




Intoxication                                                           Sources
 Dietary supplement                                                    0.5 minimal
  Dose = 400 IU D3                                                     erythemal dose:
                                                                       UVB 5-10
  Actually contained 188,640 IU D3                                     minutes
  25(OH)D = 470                                                        exposure of
                                                                       arms and legs
 Dose of D3 needed to cause                                            to direct
 hypercalcemia in a healthy person?                                    sunlight
                                                                       (depends on
  40,000 IU daily
                                                                       time, season,
                                                                       latitude and
                                                                       pigmentation)




                                                                                         5
                                                                               Sources




                                 lpi.oregonstate.edu/ss05/osteoporosis.html




FDA Recommendations                                                            Dosing
Table 2: Adequate Intakes (AIs) for Vitamin D [5]
                                                                                To increase 12 to 36 requires
                                                                                3000IU daily dosing!
Age                 Children    Men         Women      Pregnancy   Lactation

                    5 mcg
Birth to 13 years
                    (200 IU)                                                    Dark skin may require 6x UVB to
14-18 years
                                5 mcg
                                (200 IU)
                                            5 mcg
                                            (200 IU)
                                                       5 mcg
                                                       (200 IU)
                                                                   5 mcg
                                                                   (200 IU)
                                                                                stimulate D production
                                5 mcg       5 mcg      5 mcg       5 mcg
                                                                                US Pharmaceutical Version = D2
19-50 years
                                (200 IU)    (200 IU)   (200 IU)    (200 IU)
                                                                                 50,000 IU cap or 8,000 IU/cc
                                                                                D3 400, 1000, 2000, 4000, 5000
                                10 mcg      10 mcg
51-70 years
                                (400 IU)    (400 IU)


71+ years
                                15 mcg      15 mcg                              and 50,000 IU
                                (600 IU)    (600 IU)



http://ods.od.nih.gov/factsheets/vitamind.asp




Dosing                                                                         Chronic Disease of Aging
      Rough Rule
        100IU = 1ng/mL increase                                                   1200000
                                                                                  1000000
      50,000 IU qwk x 8 wks
                                                                                   800000
        Repeat labs
                                                                                   600000                  Annual
        If D < 30 repeat 50,000 IU weekly                                          400000
                                                                                                           Incidence

      Keep checking!                                Deficient for a                200000
      reason…                                                                           0
                                                                                            Fx   Stroke




                                                                                                                       6
Incidence and Cost
 $17 billion/yr
 Lifetime risk
   53% for Caucasian females
   21% for Caucasian males
   • More likely to have a fracture than have
     prostate cancer
 Expected to triple over next 5
 decades

                                                    http://www.iofbonehealth.org/health-professionals/about-osteoporosis/epidemiology.html




Outcomes                                             Bone Densitometry
 24% mortality rate within first year
   Higher for males and AA females                                                           Each SD Decrease in
 40% regain pre-fracture function                                                            BMD = 2x increase in
                                                                                             fracture risk
   50% post-hip fracture require                                                             (RR = 1.5 – 2.6)
   assistance
   33% totally dependent




WHO Criteria                                         Screening
Why –2.5?                           Classificatio
  Proportion of         T-Score                                                          USPSTF                 NOF/AACE
                                         n
  women age > 50
  who have OP by                                               Females
  BMD of hip,             > -1        Normal                                                Yes                      Yes
  spine, and                                                    >=65
  forearm (30%) is                  Osteopenia                                                                    Weight <
  about same % of      -1 > T > -                                                  Age 60-64 if                   127lbs
                                    (Low Bone
  Caucasian               2.5                             Postmenopau                    Weight <                 Early
                                     Denisty)
  women over 50                                           sal women                      154lbs                   menopause
  who have                          Osteoporosi           with RF                        Estrogen                 FH fracture
                         > -2.5
  fractures                              s                                               deficient                Medical
                                                                                                                  causes




                                                                                                                                             7
Screening                                      Screening
 Men age > 70                                  1.    Endocrine with           1.   RA, COPD
 Signs of OP                                         hormonal excess          2.   Medications
                                                    1. hyperPTH
   Radiographic evidence                                                           1.   Oral glucocorticoids
   Low-trauma fracture                              2. Cushings                         (5mg, 3 months)
 Diseases or conditions                             3. Hyperthyroidism             2.   GnRH agonists
                                                     GI disease                         (lupron)
 known to cause OP                             2.
                                                                                   3.   Antiepileptics
 Follow patients (on                                1. Malabsorbtion
                                                                                        (phenobarb, dilantin,
 and off treatment)                                    (celiac, Crohn,                  tegretol)
                                                       bariatric surgery,
                                                                                   4.   Excessive thyroid
                                                       gastrectromy)
                                                    2. Cirrhosis




Medicare Coverage                              FRAX
 Estrogen deficient
 women at risk for OP
 Individuals with
 vertebral
 abnormalities
 (osteopenia or fx)
 Chronic steroid tx
 Primary hyperPTH
 Q2yr monitoring on
 Rx




Case Study #1                                  Case Study #2
 60 yo caucasian           Takes Ca 500mg           ICD9
 female, nonsmoker         bid and Vit D bid          Wrist Fracture
 Menopause 49, no          Exercises 3x/week          733.12                        Would you
 estrogen therapy          Height 64”, wt             Menopause V49.81              recommend
                           120lbs                   Results                         phramacologic
 HCTZ for htn
                                                      Spine T-score -1.6            therapy to this
 Fx right wrist last                                                                patient?
 year playing tennis       Would you                  Hip T-score -1.8

 No family history
                           order a bone
                           density test?              Treat all postmenopausal women with
                                                      fragility fractures and low bone density




                                                                                                                8
                           Case Study #2
                            65 yo woman
                                                               Would you
                            No estrogen since
                            menopause                          order a bone
                            No fx history
                                                               density test?
                            Ca 600mg bid                     Spine T-score -1.6
                            Walks daily                      Hip T-score -1.8
                            Weight 160lbs
                                                           Would you recommend
                            No family hx fx               phramacologic therapy to
                                                               this patient?




Case Study #2              Case Study #2
 > 1.5 inch loss from      140
 young adult height
                           120
 > 0.75 inch short
                           100
 term loss
                            80
 Most common fx type                                                         # Subjects
                            60
 Most unrecognized!
                            40
 3-5x increased risk
 for future spine/hip fx    20
                             0
                             Fracture Mentioned Mentioned OP in Treatment
                             Present   in report in summary record for OP
                            130 of 934 (53%) 69 (23%) 30 (17%) 22 (7%) 9




Case Study #2              Post-Fracture Treatment
 If she had the CXR
 first would you still            40
 need the DXA for dx?             35
                                  30
 Clinical diagnosis of            25
 OP may be made with              20
 fragility fracture of            15                                        % of
 spine or hip (733.01)            10                                        Subjects
                                   5
 Still need DXA for
                                   0
 severity and baseline                 DXA     Ca    Vit D   OP
                                       post-                 Rx
                                        Fx

                                                          Hajcar EE, et al. CMAJ. 2000; 163:819




                                                                                                  9
The Grey Zone                                                        Risk Factors

                                                                    Risk Factor                RR                95% CI
        Assess RF and Measure BMD if Patient Has RF
                                                                    Prior Fracture            1.62              1.3-2.01
                                                                    Parental                  2.28             1.48-2.51
                          -1.0 < T-score < -2.5
                                                                    History
                                                                    Smoking                   1.60             1.27-2.02
Hip or           Other            10-yr             Secondary
Vertebral        Fractures >      probability of    Causes with
                                                                    Steroids                  2.25              1.6-3.15
Fractures OR     Age 50 (not      Hip fx > 3%       High Fracture   ETOH > 3/day              1.70              1.2-2.42
T-score < -2.5   fingers, toes,   or all major >    Risk
                 face)            20%                               RA                        1.74              0.94-3.2




Secondary Causes                                                     Secondary Causes
                                                                         How often are these present?
    Diseases              Conditions                 Drugs                  664 postmenopausal women with T-
                                                                            score –2.5 or below
Hypogonadism Vitamin D                        Steroids                       • 54% (358) excluded for known secondary
Malabsorption deficiency                      Antiepileptics                   cause
COPD          Hypercalciuria                  GnRH                           • 173 women (46-87)
                                              agaonists                         • CBC, chem, 24-hour urine, PTH, vit D, TSH,
RA                                                                                SPEP
Myeloma                                       Depo-Provera
                                              Excess
                                              thyroxine                      44% had a secondary cause!




Secondary Causes                                                     Lab Testing

 Vitamin D deficiency                              20%                   CMP
                                                                         CBC
 Hypercalciuria                                    10%
                                                                         24-hour urine
 Malabsorption                                     7%                    calcium and creatine
     Celiac                                                              25-OH Vitamin D
 Hyperparathyroidism                           3%                        TFTs (if symptomatic)
 Too much thyroxine                            2%                        92% of new
                                                                         diagnosis at cost of
 Cushing’s                                     <1%                       $56-$79 per patient
 Other                                         1%                        (medicare rates)




                                                                                                                               10
Treatment                                                           Treatment
                                                                     Anti-resorptive
                                                                     therapy
                                                                       Estrogen
                                                                       Raloxifene
                                                                       Calcitonin
                                                                       Risedronate
                                                                       Alendronate
                                                                       Ibandronate
                                                                       Zoledronic Acid


        http://www.wikinvest.com/concept/Osteoporosis_drug_market




Raloxifene                                                          Calcitonin
 Evista – 60mg                     No effect on hip or               Miacalcin – 200U           No effect on hip or
 daily                             non-vert fracture                 daily                      non-vert fracture
 BMD increase 2-                   Reduces incidence                 BMD increase 1-
 3% at hip and                     of invasive BCA                   2% spine
 spine 2-3 years
 30-50% decreased                                                    36% decreased
 vertebral fracture                                                  vertebral fracture
 osteopenia or                                                       osteopenia or
 previous vertebral                                                  previous vertebral
 fracture                                                            fracture




Bisphosphonates                                                     Giant Osteoclast Formation
 BMD increase 5-                   Fosamax, Actonel                  Weinstein, et al
                                                                     (1/09)
 8% at spine and                   and Reclast                         Long-term aledronate
 3-6% at hip                           reduction in non-                 increase in OC
 after 3 years                         vertebral fx 25-              5 groups, 51 bone
                                       40%                           biopsies
 40-70%                                Reduction in hip fx 40-          Placebo x 3 years
 decreased                             60%                              1/5/10mg/day x 3
                                                                        years
 incidence of                      Boniva – no effect                   20mg/day x 2yrs then
 vertebral                         on NVFx or Hip Fx                    1 off
 fractures                                                           Distinct, giant,
                                                                     hypernucleated, detached
                                                                     undergoing protracted
                                                                     apoptosis




                                                                                                                      11
                                                         Osteonecrosis of the Jaw
Bisphosphonates                                          (ONJ)
 Side effects:                                            ONJ rarely reported in        Invasive procedure
   RCTs: no increase in UGI complaints                    patients taking oral          completed prior to
                                                          bisphosphonates               initiation
   “Class warning” re: UGI symptoms
                                                          No reports of ONJ in          Routine dental
   “Class warning” re: infrequent bone, joint
                                                          controlled trials             care
   and/or muscle pain
                                                          involving 60,000
   “Class warning” re: jaw osteonecrosis                  patient years
   Flu-like symptoms may occur with first                 2 cases in reclast trial
   monthly dose or IV injection




Bisphosphonates Causing                                  Bisphosphonates Causing
Fractures?                                               Fractures?
 Odvina et al, 2005: Journal of Endo &                    9 patients – spontaneous nonspinal
 Metab                                                    fractures
   Severely Suppressed Bone Turnover (SSBT)                 Group 1 – fosamax alone (1-4)
   Aledronate     inhibits normal repair of                 Group 2 – fosamax with estrogen (5-7)
   microdamage (MD)        accumulation of MD               Group 3 – fosamax with steroids (8-9)
   2 – 7 fold increase in MD    20% reduction in          3 of group 1 and 2 had femoral shaft
   “bone toughness”                                       fractures
   ? Secondary mineralization                             Bone bx – 100x decrease BFR (worse with
                                                          steroids and estrogen)
                                                          Therapy stopped after bx
                                                            4 patients with delayed healing




Bisphosphonates Causing                                  Bisphosphonates Causing
Fractures?                                               Fractures?
 Goh et al, 2006             5/9 reported                 NEJM Editorial Debate
 Subtroch insufficiency      prodromal pain
                             between 2-6 months             Lenart, 3/20/8
 fractures on fosamax
   Retrospective review      Groups differed with             • 15 postmenopausal, aledronate 5.4+-2.7
   13 women                  radiologic findings                presenting with atypical low-energy
    • 9 on aledronate          Aledronate – thickening          fractures
    • 8/9 AO class A           of femoral cortex and          • 10/15 unique radiographic pattern (class A)
    • 4 others class B & C     3/6 bilateral cortical           “simple with thick cortices pattern”
                               thickening
                                                                 • Aledronate 7.3 +- 1.8 vs 5/10 without   2.8+-
                                                                   1.3




                                                                                                                   12
Bisphosphonates Causing                                      Bisphosphonates Causing
Fractures?                                                   Fractures?
 NEJM Editorial Debate Continues!                             NEJM Editorial Debate – More!
  Kwek, 7/17/08                                                 Lee, 7/17/08 (voice of reason?)
   • 64% involvement of contralateral femur                      • Femoral insufficiency fractures not limited
   • 76% prodromal symptoms                                        to patients on bisphosphonates
      • Treated as spinal stenosis or dismissed                  • Nonadherance to bisphosphonates        15 –
   • ? Completion of a stress fracture                             20% increased risk of subsequent fracture
   • Recommending that with thigh pain
     imaging
      • If documented fx    image contralateral femur




Non-FDA-Approved Drugs                                       Forteo
 Calcitriol                                                   Spinal Fractures          Approved 2002
 Other                                                          Fracture ARR of            Can not market
                                                                9.3% at 19 months          directly to public
 Bisphosphonates
                                                              Nonvertebral              $600-700 month
 Sodium Floride                                               Fractures
 Strontium                                                      Fracture ARR of         Daily shot
 Renelate                                                       2.9% at 19 months       Bisphosphonates
 Tibolone                                                     BMD                       after completion to
                                                                Spine 9.7%              maintain gains
 Denosumab                                                      Hip 2.6%




Manufacturer Statement                                       Monoclonal Anitbodies
  “The safety and efficacy of FORTEO                          RANKL Ab
 have not been evaluated beyond 2                               Inhibits
                                                                development and
 years of treatment. (median 19                                 activity of
 months in women and 10 months in                               osteoclasts
 men) Consequently, use of the drug                             Decreases bone
 for more than 2 years during a                                 resorption
                                                                Increases bone
 patient’s lifetime is not                                      density
 recommended.”
                      http://pi.lilly.com/us/forteo-pi.pdf




                                                                                                                 13
                                                   Monoclonal Anitbodies
                                                    Cummings, et al NEJM
                                                    8/2009 (FREEDOM)        Vertebral fracture red
                                                      7868 women 60-90        2.3% vs 7.2%
                                                      -4.0 < BMD –2.5          • Risk ratio 0.32     68%
                                                      60mg Denosumab        Hip fracture
                                                      subcut q6 months vs     0.7% vs 1.2%
                                                      placebo                  • Hazard ratio 0.60
                                                      Primary – vert fx          40%
                                                      Secondary –           Nonvert Fx
                                                      nonvert/hip fx          6.5% vs 8%
                                                                               • HR 0.8    20%




Monoclonal Anitbodies                              Monoclonal Anitbodies
 Increased BMD            RANKL and RANK            Same issue NEJM          Nonrenal vs
   3 year eval            – TNF family              Smith et al              bisphos clearance
   • 9% at spine
                           ? Inhibition of            Denosumab in           Cost?
   • 6% at hip                                        elderly men with
                           RANKL      increase
   ? Increased                                        androgen
                           in cancer or
   adherence                                          deprivation for PCA
   • 50% stop oral
                           infection
                            • Longer f/u current      1468 men MAB vs
     bisphosphonates in
     one year                                         placebo
   No femoral shaft                                   1.5% vs 3.9% RR
   fractures                                          0.38    62%
                                                      decrease




Treatment: Point #1                                Treatment: Point #2
 Reduction in factures occurs early in              Hip fractures are reduced by
 course of therapy                                  aledronate, risedronate and
  Reduction of Clinical Vertebral                   zoledronic acid
  Fractures        at 1 year:
    • Evista: 68%
                                                      Reduction in hip fracture at 3 years
    • Fosamax: 59%                                     • Reclast: 41%
    • Actonel: 69%                                     • Fosamax: 51%
  Pooled non-vert: 66% at 6 mos, 59%                   • Actonel: 40%
  at 36 mos




                                                                                                           14
Treatment: Point #2                      Treatment: Males
 Treatment length?                        Testosterone
   Resumption of bone loss stopping        Effective only in hypogonadal males
   estrogen, raloxifene and calcitonin     Aledronate
   After 5 years of aledronate    some      • Approved for steroid-induced OP
   decrease in BMD over next 5 years       Risedronate: currently under study
       • Jury is still out
                                           Forteo: approved for men at high risk
 1stDXA after treatment?                   MAB?
 ? Combination therapy




Antiepileptic Drugs (AED)

15 million AED prescriptions 2000
Decreased BMD in up to 60% on AEDs
Fracture risk 2-6x
Higher risk with older AEDs
In US 83% treated with older AEDs
Altered vitamin D metabolism
Measure BMD 5 years after starting Rx
or postmenopausal




                                                                                   15

				
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