Osteoporosis and Bisphosphonate Treatment

1
Osteoporosis and Bisphosphonate Treatment

• Kate Bottomley
• ST2

2
Outline

• Osteoporosis
• Making the Diagnosis
• Bisphosphonates
• Primary Prevention
• Secondary Prevention
• Compliance
• Safety issues
• References

3
Osteoporosis

• World Health Organization (WHO)
• Osteoporosis defined in women as a bone mineral
  density 2.5 standard deviations below peak bone
  mass (20-year-old healthy female average) as
  measured by DEXA (T score)
• Decreased bone density and degeneration/distortion
  of microarchitecture
• Increased fragility and risk of
• 200,000 fractures/ yr in UK
• gt13 women and 112 men suffer OP
• What about men??

4
Osteoporosis

• Osteoporosis costs the NHS and government 2.3
  billion a year thats 6 million a day
• Morbidity and Mortality following
• Mortality rates increased in year following hip
  fracture by 15-25
• How many return to same level of functioning?
• 17 of remaining life was spent in a nursing
  facility.
• Reduced life expectancy by 1.8 years

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Risk Factors for sustaining an osteoporotic
fracture

• Age
• Body mass index
• Smoking status
• Use of HRT
• Alcohol use
• Parental Hx of OP
• Rheumatoid Arthritis
• Cardiovascular disease
• Type 2 diabetes

• Asthma
• TCAs
• Corticosteriods
• Hx of falls
• Menopausal Sxs
• Chronic liver disease
• GI malabsorption
• Other endocrine disorders

6
Bisphosphonates

• Adsorbed onto hydroxyapatite crystals in bone
• Slows rate of growth and dissolution (turnover
  rate)
• Inhibit recruitment and promote apoptosis of
  osteoclasts
• Indirectly stimulate osteoblast activity
• First approved mid 1990s
• PO preparation
• Poorly absorbed
• Impaired by food esp milk
• Calcium and Vit D too

7
Bisphosphonates

• Licensed for use in
• Postmenopausal OP (prevention/ treatment)
• Corticosteroid induced OP (prevention/ treatment)
• Pagets disease
• Hypercalcaemia of malignancy
• Osteolytic lesions and bone pain (mets) in breast
  cancer (?)
• Mulitple myeloma
• Etidronate can increase the risk of fractures,
  less likely if given cyclically

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Do bisphosphonates work?

• Primary prevention of a (4 yrs)
• 4272 women alendronate or placebo, low BMD but no
  
• vertebral fractures on XR
• RR 0.56 95 CI, 0.39-0.80
• NNT 60 - over 4 years to prevent 1st
• Secondary Prevention of a (3 yrs)
• 1946 women alendronate or placebo
• Lat spine XR 0, 24, 36/12
• on XR RR 0.53 95 CI, 0.41-0.68
• NNT 9 over 3 years to prevent 2nd
• Cummings et al. Effect of alendronate on risk of
  fracture in women with low bone density but
  without vertebral fractures results from the
  Fracture Intervention Trial. JAMA Dec 1998. 280
  (24)2077-82
• Black et al. Randomised trial of effect of
  alendronate on risk of fracture in women with
  existing vertebral fractures. Lancet Dec 1996.
  348 (9041) 1535-1541

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Do bisphosphonates work?

• Meta-analysis of risk reduction for fracture with
  alendronate
• Statistically significant risk reduction for
  secondary prevention of fracture at all sites
• For primary prevention only statistically
  significant for vertebral fractures
• Holder et al. Alendronate for fracture
  prevention postmenopause. Am Fam Physician, Sept
  2008. Vol./is. 78/5 (579-81), 0002-838X

10
Do bisphosphonates work?

• RCT to test efficacy and safety of OD risedronate
• 5mg vs placebo, Secondary prevention only
• New vertebral
• NNT 20 (to prevent a second fracture)
• New non vertebral
• NNT 43 (to prevent a second fracture)
• Harris et al, Effects of risedronate treatment
  on vertebral and nonvertebral fractures in women
  with postmenopausal osteoporosisa randomised
  controlled trial. JAMA. Oct 1999. Vol 282, Iss
  14 (1344-52)

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Primary Prevention - NICE

• Postmenopausal with osteoporosis
• Not normal BMD or osteopenia
• Alendronate if
• gt70 with with confirmed OP (T score) AND
  independent clinical risk factor for fracture OR
  an indicator of low BMD
• 65-69 y.o. with confirmed OP (T score) AND
  independent clinical risk factor for fracture
• Postmenopausal women lt65 y.o. with confirmed OP
  (T score) AND independent clinical risk factor
  for fracture AND an indicator of low BMD
• If gt75 y.o. doesnt need DEXA

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Primary Prevention - NICE

• If Alendronate CI Risedronate/ etidronate
• Interestingly
• gt70 with OP AND risk factor OR low BMD
• 65-69 with OP AND risk factor
• Postmenopausal lt65 with OP AND risk factor AND
  low BMD

Age Independent clinical risks for () Independent clinical risks for () Independent clinical risks for ()
Age 0 1 2
65-69 N/A -3.5 -3.0
70-74 -3.5 -3.0 -2.5
75 -3.0 -3.0 -2.5
Parental Hx of hip Alcohol intake 4
units/day RA
13
Secondary Prevention - NICE

• NICE likes alendronate
• Postmenopausal and osteoporosis (T -2.5)
• If gt75 clinician decide if DEXA appropriate
• Higher threshold for other bisphosphonates
• Risedronate and etidronate (alendronate CI) and
  fulfil table

Age Independent clinical risks for () Independent clinical risks for () Independent clinical risks for ()
Age 0 1 2
50-54 N/A -3.0 -2.5
55-59 -3.0 -3.0 -2.5
60-64 -3.0 -3.0 -2.5
65-69 -3.0 -2.5 -2.5
70 -2.5 -2.5 -2.5
Parental Hx of hip Alcohol intake 4
units/day RA
14
SIGN Simpler!

• Postmenopausal w OP on DEXA of spine/hip.
  With/out (1/2)
• PO alendronate or risedronate PLUS Calcium Vit
  D
• Frail elderly woman (gt80 years)
• 1000mg Calcium and 800iu Vit D OD
• Frail elderly woman (gt80 years) OP on DEXA (1)
  or multiple vertebral s (2)
• PO alendronate or risedronate PLUS Calcium Vit
  D
• Men Dx of OP with/out fragility (1/2)
• PO alendronate or risedronate PLUS Calcium Vit
  D
• Proven Hypogonadism may benefit from
  testosterone

15
Compliance

• Difficult to take
• Study in US 35,537 women w bisphosphonate Px
• 20 persisted with Rx during 24/12
• Another study - adherence/persistence over 12/12
• Adherence/persistence rates
• Alendronate 61/21
• Risedronate 58/19
• Weekly preparation 63/22
• Siris et al. Adherence to bisphosphonate
  therapy and fracture rates in osteoporotic
  womenrelationship to vertebral and non-vertebral
  fractures from 2 US claim databases. Mayo Clinic
  Proceedings, Aug 2006. Vol 81, iss 8 (1013-22)
• Downey et al. Adherence and persistence
  associated with the pharmacological treatment of
  osteoporosis in a managed care setting. Southern
  Medical Journal. June 2006. Vol 99, Iss 6
  (570-5)

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Safety concerns

• Skeletal safety
• atypical fractures and delayed healing
• GI intolerance
• Hypocalcaemia
• Acute phase reactions
• Chronic musculoskeletal pain
• Renal safety
• Cardiovascular safety inc AF
• Osteonecrosis of the jaw

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Summary

• More evidence for secondary prevention than
  primary
• Site dependant
• NICE guidance very confusing!
• SIGN easier
• Poor compliance
• Rare but significant side effects

18
References

• Pharmacology. 4th Ed. Rang, Dale and Ritter.
  Churchill Livingstone, Edinburgh, 2001.
• NICE aldendronate, etidronate, risedronate,
  raloxifene and strontium ranelate for the primary
  prevention of osteoporotic fragility fractures in
  postmenopausal women. Oct 2008
• NICE aldendronate, etidronate, risedronate,
  raloxifene, strontium ranelateand teriparatide
  for the secondary prevention of osteoporotic
  fragility fractures in postmenopausal women. Oct
  2008
• Zoledronic Acid and Clinical Fractures and
  Mortality after Hip Fracture. Lyles et al. NEJM.
  Sept 17, 2007. 10.1056/NEJMoa074941
• Estimating Hip Fracture Morbidity, Mortality and
  Costs. Braithwaite et al. Journal of the
  American Geriatrics Society. Vol 51, Iss 3,
  p364-370.
• http//bisphosphonates.legalview.info/
• BNF 55, March 2008. p406-410
• SIGN guidance. Management of Osteoporosis.
  Guideline 71. June 2003.
• Schneider. Bisphosphonates and low-impact
  femoral fracturescurrent evidence on
  alendronate-fracture risk. Geriatrics, Jan 2009.
  vol/is 64/1 (18-23), 1936-5764
• Holder et al. Alendronate for fracture prevention
  postmenopause. Am Fam Physician, Sept 2008.
  Vol./is. 78/5 (579-81), 0002-838X
• Harris et al, Effects of risedronate treatment on
  vertebral and nonvertebral fractures in women
  with postmenopausal osteoporosisa randomised
  controlled trial. JAMA. Oct 1999. Vol 282, Iss
  14 (1344-52)
• Feldstein et al. Bone mineral density
  measurement and treatment for osteoporosis in
  older individuals with fractures a gap in
  evidence based practice guideline implementation.
  Archives of Internal Medicine. Oct 2003. Vol
  163, Iss 18 (2165-72)
• Majumdar et al. Multifaceted intervention to
  improve diagnosis and treatment of osteoporosis
  in patients with recent wrist fracturea
  randomised controlled trial. CMAJ. Feb 2008.
  Vol 178, Iss 5 (1488-2329)
• Siris et al. Adherence to bisphosphonate therapy
  and fracture rates in osteoporotic
  womenrelationship to vertebral and non-vertebral
  fractures from 2 US claim databases. Mayo Clinic
  Proceedings, Aug 2006. Vol 81, iss 8 (1013-22)
• Downey et al. Adherence and persistence
  associated with the pharmacological treatment of
  osteoporosis in a managed care setting. Southern
  Medical Journal. June 2006. Vol 99, Iss 6
  (570-5)
• Cummings et al. Effect of alendronate on risk of
  fracture in women with low bone density but
  without vertebral fractures results from the
  Fracture Intervention Trial. JAMA Dec 1998. 280
  (24)2077-82
• Black et al. Randomised trial of effect of
  alendronate on risk of fracture in women with
  existing vertebral fractures. Lancet Dec 1996.
  348 (9041) 1535-1541
• Hodsman et al. Do Bisphosphonates reduce the
  risk of osteoporotic fractuers? An evaluation of
  the evidence to date. JAMC. May 2002. 166
  (11)1426-30.