Treatment of Osteoporosis

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					            Treatment of Osteoporosis
                   Drugs available today


                        Estrogen       Mechanism of Action
                      replacement
                     therapy (ERT)      They simply slow down
                                           bone resorption




             Selective

               EVISTA
             Estrogen
             Receptor                … as a result,
             Modulators
               Raloxifene HCI        Maintain or increase bone mass
                                     Reduce fracture risk
8/19/2010                       OSTEOPOROSIS                          1
   Long-term prevention of bone loss by Estrogen


                                Treatment with Estrogen




                               Treatment with Estrogen




8/19/2010               OSTEOPOROSIS                           2
                     Lindsay et al 1976 – Lancet I:1038-1040
   Estrogen Replacement Therapy
           in Osteoporosis

                           PROS
    • Decreases rate of bone loss after menopause

    • Maintains/increases BMD

    • Relieves postmenopausal symptoms

    • May prevent Alzheimer’s disease


8/19/2010                     OSTEOPOROSIS          3
   Estrogen Replacement Therapy
           in Osteoporosis

                                      CONS
     • Troublesome side effects, e.g., irregular bleeding, fluid
        retention, mastalgia, headache, mood swings (some from
        concomitant progestin)

     • Fracture risk data largely based on observational evidence

     •   Possible   increased risk of breast cancer with long-term use

     • Must be taken with progestin to avoid risk of endometrial
       hyperplasia/cancer
8/19/2010                               OSTEOPOROSIS                     4
Hormone Replacement Therapy
                (HRT)

             … also a cure for
             heart disease ?

            … NOT as we thought
8/19/2010       OSTEOPOROSIS     5
            … the warning came




8/19/2010
                      from the HERStudy
                       OSTEOPOROSIS       6
Estrogen’s effect on heart questioned
               A randomized Trial of
                  E2 + Progestin
                      on the
              20 Prevention of C H D
                        in
             Postmenopausal Women


            showed no overall effects after 4.1 years of Rx


                                            The Heart and
                                          Estrogen/progestin
                                          Replacement Study
                                               (HERS)
                                       JAMA Vol. 280 No. 7,
8/19/2010              OSTEOPOROSIS      August 19, 1998    7
            New guidelines for hormone
            replacement therapy (HRT)


                   The American Heart Association
                   is advising physicians to steer
  New data         clear of prescribing HRT for the
 contribute        sole purpose of preventing heart
to hormone         attack and stroke in women who
   therapy         already have cardiovascular
  confusion        disease.                    July 23, 2001

                                           CNN Medical Unit
ASSOCIATED PRESS
                                         By Rhonda Rowland
8/19/2010                 OSTEOPOROSIS                        8
                             Estrogen & Strokes


                                   Oct. 24, 2001 — Estrogen
                                   pills fail to ward off new
                                   strokes in older women
                                   who have already suffered
                                   them, a study finds.
            The latest study, conducted by Catherine M. Viscoli and others
            from Yale University, was published in Thursday’s New England
            Journal of Medicine.
                                                             MSNBC NEWS SERVICES

8/19/2010                       OSTEOPOROSIS                                   9
            Hormone therapy benefits questioned
            No proof of protection against some menopause illnesses




                          April 18, 2002 — A new report from
                          an international panel of experts,
                          sponsored by the National Institutes
                          of Health, raises serious questions
                          about many of the supposed benefits
                          of hormone replacement therapy.


8/19/2010                         OSTEOPOROSIS                        10
            Estrogen Plus Progestin Study
                       Stopped
                   Due to Increased
                  Breast Cancer Risk,
                Lack of Overall Benefit
                NIH, Press Release, July 9, 2002


8/19/2010   OSTEOPOROSIS                           11
    Women’s Health Initiative (WHI)
       Clinical Study Centers
               Seattle, WA
                               Minneapolis, MN
             Portland, OR
                                        Milwaukee, WI Detroit, MIBuffalo, NY
                                        Madison, WI                       Worcester, MA
                                     Iowa City, IA             Bronx, NY      Boston, MA
                                          Chicago, IL    Pittsburgh, PA       Pawtucket, RI
              Sacramento, CA                  Columbus, OH                  Stony Brook, NY
                  Reno, NV                   Cincinnati, OH              Newark, NJ
               Oakland, CA                                             Washington, DC
               Stanford, CA
                                            Memphis, TN             Winston-Salem, NC
                 Los Angeles, CA                                     Chapel Hill, NC
   Torrance, CA Orange, CA
                                                             Atlanta, GA
                     San Diego, CA
                            Tucson, AZ                 Birmingham, AL
             Honolulu, HI              San Antonio, TX
                                              Houston, TX       Gainesville, FL


                                                                  Miami, FL
8/19/2010                                 OSTEOPOROSIS                                    12
                        WHI HRT Study
                    Baseline Hypotheses

                                                                          Benefit
                Risk
                                                                             Stroke
             Breast Cancer                                           Coronary Artery Disease



      Threshold Level                                         Threshold Level
  Early STOP=Clear Harm                                  Early STOP=Clear Benefit
                                                                            Additional Benefits:
 Additional Risks:                                                          • Osteoporosis Treatment
 • VTE                                 Plan to Study                        • Colon Cancer
                                                                            • Overall Mortality
                                         Until 2005
8/19/2010                                      OSTEOPOROSIS                                    13
  Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.
             Women’s Health Initiative
               Findings at Early Interruption
                                                                                    Benefit
            Risk
        29% Increase
    Coronary Artery Disease
     41% Increase
             Stroke
     26% Increase
        Breast Cancer

                                                                  Threshold Level
    Early STOP=Clear Harm
  VTE                                                                      Fracture Reduction
                                                                           Colon Cancer

8/19/2010                                     OSTEOPOROSIS                                  14
  Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.
                                         WHI HRT Study
                                  Effect of HRT on Event Rates
                                           Risks                      Benefits              Neutral
  in 10,000 Women Per Year



                             60
                                                                                                     ---
                             50    Additional Events                                                                Estrogen
       Number of Cases




                                                                                                                    +Progestin
                                  7       8        8         18
                             40
                                                                                                                    Placebo
                                                                      Reduced
                             30                                        Events
                             20                                         6         5

                             10                                                            ---

                             0
                                   CHD   Stroke   Breast      VTE Colorectal Hip EndometrialDeaths
                                                  Cancer           Cancer Fracture Cancer

                                                       Adapted from: Women's Health Initiative. WHI HRT Update.
                                                       Available at: http://www.nhlbi.nih.gov/whi/hrtupd/upd2002.htm. 2002.
8/19/2010                                                       OSTEOPOROSIS                                                  15
            … reactions from the
               other side of the Atlantic

                        The WISDOM trial is a major research
                     project, which will eventually involve over
                     16,000 post-menopausal women, aged 50-
                        69, in the UK and a further 6,000 from
                     Australia and New Zealand. To date, 5,000
                       women have been recruited in the UK.

                        The study is funded by the Medical
                       Research Council, the Department of
                      Health, the British Heart Foundation and
                                   other funders.


                       … WISDOM Study
8/19/2010              OSTEOPOROSIS to proceed                     16
       … the Americans got the
  statistics wrong   ―… they had not conclusively
                                    demonstrated
                         the increased risk of heart disease‖.




8/19/2010                OSTEOPOROSIS                            17
            … but    U.K. Hormone Trial
                    to Pause for Review

                           For at least 3 months,
                     no new patients will be enrolled …

                              … an international
                      panel to recommend whether to
                       continue the trial in the face of
                                 evidence
                       that prompted termination of a
                              similar U.S. study

                                     Science 2 AUGUST 2002

8/19/2010             OSTEOPOROSIS                           18
            … more news




            … the bad news
                 first


8/19/2010       OSTEOPOROSIS   19
            … more news



              Estrogen raises ovarian
                    cancer risk
             July 16, 2002 — In another piece of the
                 increasingly complex hormone-
               replacement health puzzle, women
                given estrogen-only therapy after
            menopause ran a significantly higher risk
            of ovarian cancer, researchers reported
                            Tuesday.

8/19/2010           OSTEOPOROSIS                        20
               HRT
                 Linked to

                 Increased Risk of
                        Asthma
                     Exacerbations
                               American College
             PHILADELPHIA,     of Chest Physicians
            November 8, 2001
                                   Annual Meeting
8/19/2010           OSTEOPOROSIS                    21
            … more - this time good - news




                   … HRT reduces the risk
                            of




8/19/2010              OSTEOPOROSIS          22
                 Hormone
            Replacement Therapy




8/19/2010
                 Which system is next?
                    OSTEOPOROSIS         23
            Life without
                 HRT

              … what did Patti has to
                      say?




8/19/2010            OSTEOPOROSIS       24
            … the Vanishing Promises
                    of HRT




8/19/2010         OSTEOPOROSIS         25
                                         By Jill Nelson
            Life without HRT             MSNBC CONTRIBUTOR




                          Yesterday I threw out my hormones.
                             I’d only been on them a year.
News on line             Unlike chocolate or sale catalogues,
                      I didn’t even have to run water over them
                                 to insure that I wouldn’t,
                              in a moment of desperation,
                           rescue them from the garbage bin
                             and promise to quit tomorrow.
                     I’m too concerned with my health for that.
8/19/2010                 OSTEOPOROSIS                            26
                                                July 12, 2002—
            EVISTA           Small increase in Bone Mineral
                                            Density
            Raloxifene HCI
                             Risk of spinal fractures
                              could be reduced by up to
                                            50 %.


                         Selective
                         Estrogen
                         Receptor
8/19/2010
                         Modulators
                             OSTEOPOROSIS                 27
            … small increase in
                          Bone Mineral Density …




?
8/19/2010
                           … and reduced risk of
                                Fractures?
                             OSTEOPOROSIS          28
            Y
                E
                               S
            … we now know that it is true
8/19/2010       OSTEOPOROSIS                29
                                  JAMA 2002           288:321-333

                                             Cardiovascular and Coronary events
                                                after treatment with Raloxifene




            EVISTA
            Raloxifene HCI    Raloxifene Therapy for 4 years


                                did not significantly affect


                             the risk of Cardiovascular Events

8/19/2010                     OSTEOPOROSIS                                   30
?           … still confused?




8/19/2010          OSTEOPOROSIS   31
?
            … then, what about the
                 H.R.T Bar ...?




                     Where The Problems
                     Associated With The
                    Menopause Are Only A
                        Snack Away"
8/19/2010          OSTEOPOROSIS            32
            The active ingredients in the
              HRT Bar are high in plant
            Oestrogens (phytoestrogen)
               The various seed and fruit
               in the bars can help in Controlling:
                    Hot flushes
                    Mental agility
                    Delaying possible onset of Alzheimer's
                    Protecting breast tissue
                    Acting as antioxidants
                    Controlling cholesterol levels
                    Reducing loss of bone density

                               … according to the

8/19/2010                          OSTEOPOROSIS               33
            … Increasingly, new research is
              questioning the purported
            health benefits of soy in adults,
              as well as raising concerns
               about adverse effects in
                       children.

             JR Barrett
                  Soy and Children's Health: A Formula for Trouble?--
                  NIEHS Puts A New Face on Public Service.

             Environ Health Perspect 1 Jun 2002;110: A294-6




8/19/2010             OSTEOPOROSIS                                34
  Combination Therapy
            Bisphosphonates + Estrogens
              Currently,
               there is no
                evidence that
                 Combination
                  Treatments
                   give better
                   protection
                   against fractures
8/19/2010                OSTEOPOROSIS     35
            News on line    Wednesday, July 25, 2001

                   Head-to-Head
                Osteoporosis Fracture Study
                       to Compare
                    Evista® & Fosamax®
                     The EVista Alendronate
                     Comparison (EVA) trial is the
                     first large-scale, head-to-head
                     study comparing a SERM and a
                     bisphosphonate.
                     It's also the first head-to-head
                     fracture trial comparing
                     approved osteoporosis
8/19/2010            therapies.
                        OSTEOPOROSIS                    36