Osteoporosis Treatment - A Practical Guideline

Skeletal disorder characterised by compromised bone strength predisposing to an increased risk of fracture

WHO estimates 70 million people suffering from osteoporosis

Hip Fractures

• most severe complication
• worldwide incidence of 1.5 million annually
• 20% end up in nursing homes
• 20% mortality within 1 year of fracture
• 2/3 never return to pre-fracture functional level
  

Fragility Fractures (USA, Northern Europe and S.E. Asia data)

• Hips 20% age at 70s
• Spine 50% age at 60s
• Wrist 30% age at 50s
  

Children

• Overlooked at-risk group
• Strategy - achieve maximal bone mass during bone development period
• Decrease risk of osteoporosis at later life
• Primary health - stress diet & physical activity
• Osteoporosis is a paediatric disease with a geriatric outcome (Kitchin & Morgan 2003)‏

Lifestyle Factors

• Physical activity increases bone mass by increasing muscle mass - thus increasing stress on bone
• Obese individuals or high muscle mass individuals tend to have higher bone mass
• Smoking & alcohol decreases bone mass

Calcium & Vit D

• Recommended daily dosage:
• 800mg
  children ages 1-10
• 1000mg
  male
  pre-menopausal women,
  post-menopausal women on HT
• 1200mg
  teenages & young adults 11-24
• 1500mg
  post-menopausal women not on estrogen
• 1200mg to 1500mg
  Pregnant & nursing mothers
  

• Post-menopausal women desiring to reduce risk of osteoporosis should consume 1000 to 1500mg of elemental calcium with 400-800 IU of vitamin D (NIH Consensus Development Panel on Optimal Calcium Intake, 1994)

Calcium Intake

• Should not exceed 2500mg a day
• Offers no health benefit
• May cause hypocalcaemia & hypercalciuria
  
• Calcium carbonate or Caltrate
  600mg of calcium with 200 IU vit D per tab
  Taken as 1 tablet bd with food
• Calcium citrate or Citracal
  315mg of calcium with 200 IU vit D per tab
  Taken as 2 tablets bd with food

Diagnosis of Osteoporosis

BMD - Who Needs It

• All women > 65 years
• Post-menopausal woman with major risk factors
• All individuals > 50 years with history of osteoporotic fracture
• All individuals on long term steroids
• Men with hypogonadal conditions
• Men > 70 years
• Patients with diseases a/w bone loss and fracture

Treatment Guidelines

• T-score is < -2.5
• T-score is < -1.5 with a major risk factor
• Major risk factor:-
  Personal history of fracture
  Family history of fracture
  Current cigarette smoker
  Weight < 127 lbs
  

Pharmacotherapy

• “Hormones”
  Oestrogens
  SERMS
  rPTH
  Calcitonins
• Strontium ranelate
• Biphosphonates
  Alendronate
  Risedronate
  Ibandronate
  Zoledronic acid
  

Secondary Causes

• Pharmcotherapy eg steroids, phenytoin
• Endocrine disorders eg Cushing’s
• GI disorders eg eating disorders
• Genetic disorders eg OI
• Miscellaneous eg organ transplant, RA
  

Evaluation for 2o causes

• History & Physical Examination
  25-OH Vit D
  Serum Calcium
  Serum phosphorus, Alk phosphatase, Cre
  Parathyroid hormone
  Thyroid function test
  Serum protein electrophoresis
  Serum testosterone in men
  

Estrogen Therapy or HT

• Inhibits bone resorption and increases BMD
  Binds to estrogen receptors on bone
  Blocks production of cytokines that increases osteoclasts
  Many different formulations and applications
  Reduced vertebral (33%) and non-vertebral (27%) fractures
  Torgerson 2001
  

Current Indications for HT

• 2nd line treatment due to risk for breast and endometrial cancers
  Only for post-menopausal women who cannot tolerate non-estrogen medications
  To be used with the lowest dose possible and for the shortest period of time to achieve treatment goals
  

SERMs Raloxifene

• Selective estrogen receptor modulators
  Binds to estrogen receptors
  Estrogen agonist activity on bone and circulating lipoproteins
  Estrogen antagonist activity on breast and endometrial tissues
  Increased risk for DVT
  Does not block vasomotor symptoms of menopause
  

Raloxifene

• Increased spine BMD by 2.3% and hip BMD by 2.5% after 3 years
  50% reduction in spine fractures
  No effect on hip or other non-vertebral fractures
  Cranney 2002, Black 1999

• 60mg coated tablets taken once daily
  Must be stopped 72 hours prior to and during prolonged immobilisation
  Decreased absorption with ampicillin
  

Calcitonin

• Using salmon’s calcitonin due to prolonged action and greater potency compared to mammalian source
  Intra-nasal spray
  Analgesic effect
  Not appropriate as 1st line treatment
  Only used as 2nd or 3rd line treatment in patients who cannot tolerate bisphosphonates
  Inhibits osteoclast activity and osteoclast lifespan
  

Calcitonin 200 IU

• 33% reduction in new vertebral fractures
  36% reduction in those with history of previous fractures
  PROOF study
  Chesnut 2000
  No effect on non-vertebral fractures

Parathyroid Hormone

• Stimulates osteoblast activity
  Recombinant PTH - teriparatide or Forteo
  Once-daily subcutaneous injection in a 28-day kit
  Can be used up to 24 months
  Indicated in:
  Patients with very high risk of future vertebral fractures
  Those who failed to respond to bisphosphonate
  

Recombinant PTH

• 83% reduction in moderate to severe vertebral fracture risk in men on 20mcg daily
  Kaufman 2005
  65% reduction in new vertebral fractures in women on 20mcg daily
  Neer 2001
  53% reduction in non-vertebral fracture risk
  Gallagher, Vargas 2005, Neer 2001

• May cause orthostatic hypotension - 1st dose given supine
  Very expensive - 10x cost of bisphosphonate treatment
  Can be used sequentially or together with bisphosphonates
  

Strontium Ranelate “Protos”

• Act on osteoblasts to increase bone formation
  Increases osteoprotegerin which reduces the number and activity of osteoclasts to decrease bone resorption
  Less problem with suppression of remodeling and over-mineralisation
  

Strontium Ranelate

• 41% reduction in vertebral fractures over 3 years
  Seeman 2008 (Pooled data from SOTI & TROPOS Trials)‏
  43% reduction in hip fractures over 5 years
  Reginster 2007 (TROPOS Trial)‏
  

Strontium Ranelate Vertebral Fractures

• 41-59% fracture risk reduction in patients with osteopaenia with or without a prevalent fracture
  Seeman 2008
  

Strontium Ranelate

• Taken 1 satchet daily at bed-time
  Reported to have DRESS syndrome
  rare occurrence, only in Europe
  

Biphosphonates

• Biphosphonates
  Inhibits osteoclasts to decrease bone resorption and allows osteoblasts to slightly increase BMD
  1st line therapy for osteoporosis
  Examples
  Alendronate (Fosamax) - has 10-year f/up studies
  Risedronate (Actonel)‏
  Ibandronate (Bonviva)‏
  

Bisphosphonates

• Poor bioavailability - < 1% absorbed on oral intake
  Drastically reduced if taken with or around meal times
  Not to be taken together with calcium supplements
  

Alendronate 10mg Daily - Vertebral Fractures

• 48% relative risk reduction in 994 post-menopausal patients with T < -2.5 regardless of history of fractures
  Lieberman 1995Fracture Intervention Trial I & II
  FIT I (with h/o fractures) RRR - 47%
  Black 1996
  FIT II (without h/o fractures) RRR - 45%
  Cummings 1998
  

Alendronate 70mg Once A Week “Fosamax”

• Comparable efficacy to 10mg daily dosing
  Schnitzer 2000
  

Risedronate 5mg Daily “Actonel”

• Vertebral Efficacy with Risedronate Therapy or VERT trials
  65% RRR at 1 year
  41% RRR at 3 year
  Harris 1999
  61% RRR at 1 year
  49% RRR at 3 year
  Reginster 2000
  

Risedronate 5mg Daily

• Hip Intervention Programme
  9000 patients
  Reduction in Hip fractures
  60% at 3 years
  Harris NEJM 2001
  

Risedronate 35mg Once A Week

• Comparable efficacy to 5mg daily dosing
  Brown 2002

Ibandronate “Bonviva”

• Newest oral bisphophonate
  2.5mg daily dosing and 150mg once a month dosing
  Vertebral fracture prevention data only for 2.5mg daily dosing
  Chestnut 2004, Felsenberg 2005, Miller 2005
  

Zoledronic Acid “Aclasta”

• A single annual 5mg IV infusion has been shown to decrease morphometric vertebral fractures by 70% over a 36 month period
• Hip fracture relative risk reduction of 41%
• Non-vertebral relative risk reduction of 25%

Zoledronic Acid Demonstrated Broad Efficacy in Women With Postmenopausal Osteoporosis

• In women with postmenopausal osteoporosis, once yearly infusion of ZOL 5 mg over 3 years significantly reduces
  Vertebral fractures (morphometric 70%, clinical 77%)(1)
  Hip fractures (41%)(1)
  Non-vertebral fractures (25%)(1)
  Days of disability due to fracture or back pain(2)
  Height loss(1)
  Significantly superior to placebo in increasing or preserving BMD(1)
  Markers of bone formation and resorption were reduced and maintained within premenopausal reference range over 36 months(1)
  Generally well tolerated(1)
  Fracture efficacy coupled with high adherence suggests potential role for ZOL 5 mg as treatment for osteoporosis(1)
  
• 1. Black DM, et al. N Engl J Med. 2007;356:1809-1822.
• 2. Black DM, et al. Presented at: ASBMR 28th Annual Meeting; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.
  

Practical Points

• Patient compliance
  Avoids heart-burn, oesophagitis
  Proven to work

Zoledronic Acid

• Side effects include:
  Pyrexia, myalgia, influenza-like symptoms
  Headache, arthralgia
  Usually lasts 2 – 3 days
• Serious AF in 2.4% of study population

• 

AF in Zoledronic Acid

• HORIZON PFT trial – 2.4% increased incidence of AF seen in ZA group
• But this was not found in the 2nd large trial HORIZON RFT
  Nor in the clinical trials with Zometa in over 20,000 patients
  
  

Non-Vertebral Fractures

• Alendronate & risedronate effective in preventing non-vertebral fractures
• Fosamax International Study Trial Group FOSIT- 51% reduction in hip fractures
  Pols 1999
• Meta-analysis of Fosamax for prevention of hip fractures in post-menopausal women showed 55% overall risk reduction
• Hip Intervention Program HIP study - RRR 36% with Alendronate 5mg om vs placebo
  McClung 2001
• Ibandronate - evidence still lacking

Subtrochanteric Insufficiency Fractures

• Associated with patients on long-term (>2.5 years) alendronate therapy
• Tend to be “younger” (age 60s) and socially active
• Fractures at the metaphyseal-diaphyseal junctions
• Prodromal symptoms
• Due to prolonged suppression of bone remodeling
  Goh 2007
  

You should speak with your Orthopaedic doctor regarding the best treatment for you.

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