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					     Osteoporosis

         Dr Janet Horner
Leeds Teaching Hospitals NHS Trust
                Overview
• What is osteoporosis?
• Fracture risk?
• Who should we target for DXA?
  – Secondary prevention
  – Primary prevention
• What treatments are available and who do
  we treat?
WHAT IS OSTEOPOROSIS?
                    Healthy vertebrae                                                           Osteoporotic vertebrae
Rizzoli R, ed. In: Atlas of Postmenopausal Osteoporosis (First Edition). Science Press, 2004.
                 Osteoporosis
Qualitative Definition   Common sites of fracture

‘…a systemic skeletal                  Spine
disease characterised
by low bone mass and
microarchitectural
deterioration of bone                  Neck of femur
tissue, with
consequent increase in
bone fragility and
                                       Wrist
susceptibility to
fracture’
 WHO definition of osteoporosis
• Based on the measurement of BMD
• The number of SDs from the average BMD in a
  group of 25-year-old women (T-score)
• Normal: T-score of -1 SD or more
• Osteopenia: T-score between -1 and -2.5 SD
• Osteoporosis: T-score below -2.5 SD
• Established osteoporosis: T-score below -2.5 SD,
  with one or more associated fragility fractures.
                 Z scores
• The number of SDs from the average BMD
  in an group of age-matched women

• Gives indication of severity – ie much
  worse than would be expected from age
  related bone loss
• Z score < -2.0, consider secondary causes
                Age-related changes in BMD
                 Attainment of peak bone mass        Consolidation
                                                                           Age-related bone loss


                                                                          Menopause
Bone mass




                Men


                Women

            0                 10                20    30             40          50            60
                                                       Age (years)

  Compston JE. Clin Endocrinol 1990; 33: 653–
  682.
  Consequences of osteoporosis
•Asymptomatic in absence of #
•Substantial pain, disability and reduced quality of
life.
•Women >50y
          – 1 in 3 risk of vertebral #
          – 1 in 6 risk of hip #.
•After a hip fracture - some patients die within a
year; 50% of survivors are incapacitated and 20%
require long-term residential care
•Lifetime risk for woman of dying from hip # same
as risk of dying from breast cancer
            Scale of the problem
• Prevalence
   – ~1.2M women in England and Wales


• Osteoporosis causes over 180,000 fractures per year in
  men and women in the UK. Cost £1.8B/y in UK.


• Total number of fractures is increasing


• 10-20% of women with osteoporosis receive Rx
      FRACTURE RISK?

Age and BMD are key risk factors
and currently the only quantifiable
 risk factors for fragility fracture
         BMD – estimating # risk
             10 year probability of #, aged 70

           50
           40
    #       30
Probability
    %       20
            10
            0
                 1     0     -1     -2      -3   -4
                                  T score
                      Age - estimating # risk

                           Fracture risk in women
                     20
5y fracture risk %




                     15                                                   Hip
                     10                                               Vertebrae
                     5
                                                                       Wrist
                     0
                          35 40   45 50    55 60 65       70 75   80 85
                                          Age group, yr



                                              Adapted from Rosen at al JBMR 2004
                         # risk and BMD and age
                                      Hip # risk in women
                              Age, yrs
Fracture probability %


                         20
                              80
                         15 70

                         10
                              60
                         5
                              50
                         0
                               -3   -2.5   -2   -1.5     -1      -0.5   0   0.5   1
                                                       T score

                                           Kanis, Osteoporosis International 2001
                Fracture History

• Women with vertebral # have
   – 3-5 times greater risk of further # in next 12 months
   – increased risk of hip #
• Women with wrist # >45y after fall from standing
  ht or less associated with doubling of risk of
  further osteoporotic fracture
• 30% of women >50y with wrist # have
  osteoporosis
    % absolute annual risk of osteoporotic
                  fracture
•   Age
•   T-score
•   Fragility # >50y
•   Number of additional risk factors
       •   FH hip #
       •   Current smoker
       •   Steroid use ever
       •   Alcohol >2u/day
       •   RA
WHO SHOULD WE TARGET
      FOR DXA?
NICE Technology Appraisal TA087
     Osteoporosis Jan 2005

• Secondary prevention of osteoporotic
  fragility fracture (# after fall from standing
  height)
• Postmenopausal women
  – not men, not CSO
• Recommendations based on cost and
  clinical effectiveness
WHO SHOULD WE TARGET
      FOR DXA?

 Postmenopausal women who
 sustain a fragility fracture and
       who are < 75years
     WHO SHOULD WE TARGET FOR
        DXA?– primary prevention

Currently RCP case finding strategy

Untreated hypogonadism (ie HRT refused or inappropriate)
• perimenopausal with other risk factors
• premature natural/surgical menopause (<45y)
• 2y amenorrhoea >6m and not pregnancy related

Glucocorticoid use : >3months, patient <65y (M or F)

Risk of secondary osteoporosis (M or F)
• Malabsorption, Inflammatory bowel disease, Chronic liver disease,
   Hyperparathyroidism, Thyrotoxicosis
     WHO SHOULD WE TARGET FOR
        DXA?– primary prevention
Radiological osteopenia or vertebral deformity (M or F)


Other risk factors
• Family history of osteoporosis / maternal hip fracture<80y
• Smoker
• Alcohol intake >35u/w (F) , >50u/w (M)
• Low BMI <19
• Height loss >2cm in 1 y
  NICE: Osteoporosis - primary prevention



• Cost effectiveness

• No opportunistic screening <70y
 WHAT TREATMENTS ARE
AVAILABLE AND WHO DO WE
        TREAT?
NICE guidelines – secondary prevention

• Selection of patients for Rx based on
  – inter-related factors, age and BMD
  – other age-independent risk factors



• Adequate calcium and vitamin D provided
  NICE guidelines – secondary prevention:
             Bisphosphonate
• >75years, without need for DEXA scanning

• 65-75years, if osteoporosis confirmed by DEXA
  (T score < -2.5)

• <65years
  – T score  - 3.0
  – T score -2.5 to -3.0 and age-independent risk factor
     • FH hip #
     • medical conditions associated with bone loss - IBD, RA,
        coeliac disease, hyperthyroidism
  NICE guidelines – secondary prevention:
           Strontium ranelate
• Bisphosphonates contraindicated
     • renal impairment, oesophageal stricture
• Unable to comply with dosing instructions
  for bisphosphonates
• Unsatisfactory response to bisphosphonates
     • 1year of Rx and further fragility fracture or
       loss in BMD
• Intolerant of bisphosphonates
  NICE guidelines – secondary prevention:
               Raloxifene

• Strontium ranelate contraindicated

                            OR

• Unsatisfactory response to strontium ranelate

                            OR

• Intolerant of strontium ranelate
   – Nausea and diarrhoea
  NICE guidelines – secondary prevention:
               Teriparatide
• Women >65y
  – unsatisfactory response to bisphosphonates
     • 1year of Rx and further fragility fracture or loss in
       BMD
                            AND
  – T score -4.0
                         OR
  – T score -3.0 and >2 fractures and additional
    age-independent risk factor
  NICE guidelines – secondary prevention:
                summary

• Secondary prevention of osteoporotic
  fractures in postmenopausal women
  –   Bisphosphonate first line Rx
  –   Strontium ranelate as second line Rx
  –   Raloxifene as third line Rx
  –   Teriparatide in very severe osteoporosis
  NICE: Osteoporosis - primary prevention



• Number of additional risk factors and T-
  score determine Rx decisions in women
  >70years
                  Vertebral #
    Endo Rev 2002: Meta - analysis of therapies for
            postmenopausal osteoporosis


AGENT              No of trials         RR
                   (patients)           (95%CI)

Vitamin D          8 (1130)         0.63 (0.45, 0.88)
Alendronate        8 (9360)         0.52 (0.43, 0.65)
Risedronate        5 (2604)         0.64 (0.54, 0.77)
Raloxifene         1(6828)          0.60 (0.5, 0.7)
              Non-vertebral #
    Endo Rev 2002: Meta - analysis of therapies for
            postmenopausal osteoporosis


AGENT              No of Trials RR (95%CI)
                   (Patients)

Alendronate        6 (3723)         0.51(0.38,0.69)
Risedronate        7 (12,958)       0.73(0.61,0.87)
       Teriparatide (NEJM 2001 )
                n=1637
• Daily injections
• Median Rx period 21 months

• Raised spinal BMD by 9 and 13%
                      (dose dependent)
• Reduced new vertebral fractures by 65%
• Reduced non-vertebral fracture risk by 35-
  40%
   Strontium Ranelate (NEJM 2004)

• RCT 1649 PMF with osteoporosis and at
  least 1 vertebral #

• 2g oral strontium ranelate or placebo for 3y
• Reduced vertebral # by 49% at 1yr and 41%
  over 3y
   Strontium Ranelate (JCEM 2005)

• RCT 5091 PMF with osteoporosis >74y

• 2g oral strontium ranelate or placebo for 3y
• Reduced non-vertebral # by 16% at 3y

• Inadequately powered to look at hip # alone
• Post hoc subgroup analysis of elderly high risk
  group did show reduction
                    Ibandronate
BONE study (Chesnut CH, et al. J Bone Miner Res
  2004;19:1241–9)
• After 3 years treatment with daily ibandronate - 62%
  reduction in new vertebral fractures


MOBILE study(Miller PD, et al. J Bone Miner Res 2005;20,
  8: 1315-1322)
• Once-monthly oral ibandronate (150mg) is at least as
  effective as daily ibandronate at 1 and 2 years with
  comparable safety to daily ibandronate
                   Ca/vitamin D
• No indication for using Ca and vitD ALONE for
  prevention of further # in previously mobile elderly

Record study (Lancet 2005)

• 5292 people >70y (85% F) who were mobile prior to
  sustaining low trauma #
• 800iu vitD or 1000mg Ca or 800iu vitD and 1000mg Ca
  or placebo
• End point – fragility # - 13% of 5292 had new fragility #
• No difference in incidence between groups
      Other Ca/vitamin D studies
• BMJ 2005
  – 3314 PMF >70y with 1 risk factor for hip#
  – 1000mg Ca and 800iu D3
  – No effect on hip #
• NEJM 2006
  –   WHI – 36, 292 PMF 50-79y
  –   1000mg Ca and 400iu D3
  –   Small significant  BMD
  –   No effect on hip #
       Calcium and vitamin D
• Requirements – calcium:
  – Postmenopausal women 1000mg/day
  – Dietary or supplements
• Requirements – vitamin D:
  – Postmenopausal women 800iu or 20ug/day
• Vitamin D concentrations
  – Population reference range vs. target range
                   Conclusions
• Osteoporosis still unrecognised and under-treated
• Treatment target – fracture risk
• Guidance on secondary prevention available
• Guidance on primary prevention awaited
• New agents – ibandronate, strontium ranelate, teriparatide
• Recent trials of calcium/vitamin D – not effective Rx
• Risk factor algorithm - aggregating other risk factors -
  predict individual fragility fracture risk - awaited
• Optimum age to start Rx ??
• Optimum duration of Rx ??
  10year probability of fracture: age and BMD
      Age (yrs)                                          T-score

                                  +1              0     -1         -2     -3     -4


     50                             2.4           3.8    5.9        9.2   14.1   21.3

     60                             3.2           5.1    8.2       13.0   20.2   30.6

     70                             4.3           7.1   11.5       18.3   28.4   42.3

     80                             4.6           7.7   12.7       20.5   31.8   46.4

Kanis et al. Osteoporosis Int 2001; 12: 989-95.

				
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