Update on Osteoporosis

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Update on Osteoporosis

• New Data and New Drugs
• Linkage to Falls Services

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NICE GUIDELINES FOR SECONDARY PREVENTION OF
FRACTURES, 2005

• BISPHOSPHONATES are recommended as treatment for
  secondary prevention after osteoporosis fractures
• In women aged 75 and older, without the need for
  DEXA
• In women aged between 65 and 75 if the presence
  of osteoporosis is confirmed by DEXA
• In women younger than 65 years of age, if they
  have a very low BMD (t lt -3.0), or confirmed
  osteoporosis with added risk factors

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A Model Osteoporosis Service

• Fracture Liaison service (FLS)
• Osteoporosis nurses see fracture patients as
  in-patient or out-patient discuss situation,
  offer DEXA, etc
• Direct access DEXA Service (DADS) for GPs
• GPs get back computer-generated treatment
  suggestions. Complex cases referred to Osteo
  Clinic
• Waiting list for Scanning FLS 8 weeks, DADS 10
  weeks

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RECENT BISPHOSPHONATE EVIDENCE

• TEN YEAR DATA ON THERAPY
• DIRECT COMPARISON OF DIFFERENT BISPHOSPHONATES
• IV BISPHOSPHONATES

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alendronate 10 mg over 10 years
Continual increases in total hip BMD with
Alendronate 5 mg
Discontinuation
Alendronate 10 mg
(6.7) plt0.001
Mean change (SE)
(3.4) plt0.001
(2.9) plt0.05
Year
Adapted from Bone et al 20047
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Superior Total Hip BMD with FOSAMAX in FACT
5.0
FOSAMAX Once Weekly 70 mg (n464) Risedronate 35
mg once weekly (n481)
Mean change (SE)
4.5
4.0
3.5
3.0
plt0.001
2.5
2.2
plt0.001
2.0
92
1.5
1.2
1.0
0.5
0.0
0
6
12
Month
FACTFOSAMAX ACTONEL Comparison Trial Treatment
difference1.1, plt0.001 Adapted from Rosen CJ et
al J Bone Miner Res 200520141151. FOSAMAX Once
Weekly (alendronate) is a trademark of Merck
Co., Inc., Whitehouse Station, NJ, USA.ACTONEL
(risedronate) is a registered trademark of
Procter Gamble Pharmaceuticals, Mason, OH, USA.
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Alendronic Acid and Risedronate which to use
and when?

• Alendronic Acid is first line in all areas of
  Scotland. It is generic and price is now
  6/month.
• It causes higher BMD gains than risedronate
  (24/month)
• Alendronate trials excluded all patients with GI
  history or aspirin/NSAID use.
• ?Give all patients Alendronic Acid and only
  consider Risedronate if intolerant?
• OR Give Risedronate in defined patient groups as
  first line therapy? Fracture efficacy well
  proven in elderly and those on aspirin/NSAID

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Intravenous Bisphosphonates

• Palmidronate, Ibandronate and Zoledronate

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Ibandronate

• DIVA study Daily Oral v 2 or 3 Monthly IV
  Ibandronate - (3 min injection)
• 1395 patient RCT all osteoporotic
• BMD improved significantly better with IV
  Therapy. ?Dose Effect or Adherence effect
• No fracture data available
• Similar side-effects, except 5 acute phase
  response with IV preparation

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Zolendronate

• Annual IV preparation SMC approval 2008
• For use in patients intolerant or unable to
  comply with usual oral bisphosphonates
• Used extensively in malignant disease and Pagets
  Disease.
• HORIZON (Primary Fracture Trial)
• HORIZON (Recurrent Fracture Trial, RFT)

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Zoledronic Acid Reduced Cumulative 3-Year Risk of
Clinical Fractures (Hip, Clinical Vertebral,
Non-vertebral)
25(13, 36)
15
10.7(388/3861)
77(63, 86)
10
41(17, 58)
8.0(292/3875)
Cumulative Incidence () of New Clinical
Fractures Over 3 Years
5
2.6(84/3861)
2.5(88/3861)
1.4(52/3875)
0.5(19/3875)
0
Clinical Vertebral Fracture
HipFracture
Non-vertebral Fracture
Values above bars are 3-year cumulative event
rates based on Kaplan-Meier estimates. P
.0024 P lt .0001 P .0002 Hazard ration
risk reduction vs placebo Hip fracture was not
excluded from analysis of non-vertebral
fracture. Adapted from Black DM, et al. N Engl J
Med. 20073561809-1822.
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Zoledronic Acid Reduced Cumulative 3-Year Risk of
Clinical Vertebral Fractures (Strata I II) by
77
3
77(63, 86)
P lt .0001
2
Cumulative Incidence ()
1
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Time to First Clinical Vertebral Fracture (months)
Hazard ratio risk reduction vs placebo (95
confidence interval) Adapted from Black DM, et
al. N Engl J Med. 20073561809-1822.
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Zoledronic Acid 5 mg Reduced Cumulative 3-Year
Risk of Clinical Fractures by 35 Over Time
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Hazard Ratio, 0.65 (95 CI, 0.500.84) P .0012
Absolute Risk Reduction, 5.3
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1065 1013 950 895 762 628 473 316 212 12
9 Placebo 1062 1010 947 884 742 611 443 305 190 11
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Lyles KW, et al. N Engl J Med. Volume 357,
Issue Nov, Date 2007 11 05, Pages 1799-809
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Zoledronic Acid 5 mg Reduced Cumulative 3-Year
Risk of Non-vertebral Fractures by 27 Over Time
27
Hazard Ratio, 0.73 (95 CI, 0.550.98) P .0338
Absolute Risk Reduction, 3.1
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1065 1015 957 903 770 636 478 321 217 13
0 Placebo 1062 1014 961 902 758 626 458 320 201 12
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Lyles KW, et al. N Engl J Med. Volume 357,
Issue Nov, Date 2007 11 05, Pages 1799-809
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Zoledronic Acid 5 mg Reduced Subsequent Fracture
Risk Over Time
35 (16, 50)
27 (2, 45)
46 (8, 68)
30NS (-2, 59)
20
18
16
13.9(139/1062)
14
10.7(107/1062)
12
Event Rate ()
8.6(92/1065)
10
7.6(79/1065)
8
6
3.8(39/1062)
3.5(33/1062)
4
2.0(23/1065)
1.7(21/1065)
2
0
ClinicalFractures
Non-VertebralFractures
ClinicalVertebralFractures
HipFractures
P .0012 P .0338 P .0210, relative risk
reduction vs placebo NS not significant.
Values above bars are cumulative event rates
based on Kaplan-Meier estimates at Month 24.
Lyles KW, et al. N Engl J Med. Volume 357,
Issue Nov, Date 2007 11 05, Pages 1799-809
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Zoledronic Acid 5 mg Reduced Risk of All-Cause
Mortality by 28 Over Time
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Hazard Ratio, 0.72 (95 CI, 0.560.93) P .0117
Absolute Risk Reduction, 3.7
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1054 1029 987 943 806 674 507 348 237 14
4 Placebo 1057 1028 993 945 804 681 511 364 236 14
9
Lyles KW, et al. N Engl J Med. Volume 357,
Issue Nov, Date 2007 11 05, Pages 1799-809
18
Most Frequent AEs by Preferred Term With 5
Incidence for Any Group
Lyles KW, et al. N Engl J Med. Volume 357,
Issue Nov, Date 2007 11 05, Pages 1799-809
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Zoledronate Hip Fracture Trial - continued

• First RCT of secondary prevention after Hip
  fracture
• Only followed up for 1.9 years stopped due to
  very positive results.
• Study population had very high absolute fracture
  risk
• Zoledronate clearly showed fracture reduction
  effect
• Safety data showed no major problems no
  increased risk of AF /CVA. No case of ONJ
• Reduction in Death unexpected and needs more
  work
• Timing of Zoledronate may be crucial - ?after 6
  weeks. Sub-analysis underway

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Osteonecrosis of the Jaw
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OJN some facts and figures

• Incidence about 0.7 per 100000 patient years
• Over 90 of cases in patients with malignant
  disease
• Over 90 of cases occur in patients given IV
  bisphosphonates
• 60 of patients have had recent trauma/dental
  work.
• Only 3 of reported cases of OJN have occurred in
  patients being treated for osteoporosis

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DRUG THERAPY FOR OSTEOPOROSIS

• Alternate OPTIONS
• PTH
• Strontium Ranelate
• Calcitonin
• RANK Ligand antibodies?
• Lasofoxifene

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Effects of rhPTH - nonvertebral fractures
Neer et al (2001), NEJM, 344
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Lothian Formulary Guidelines for PTH

• Restricted use (2nd line after bisphosphonate)
• For woman aged over 65 who
• Have severe osteoporosis, T lt-2.5 with 2
  fractures.
• Inadequate clinical response to bisphosphonate
• Occurrence of further fractures after 1 year
• Intolerant to therapy
• Are willing to administer daily SC injections.
• Patients should be off bisphosphonate but be on
  Ca/VitD
• Named Consultant use only

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Strontium Ranelate

• SMC approval 2005
• Aged over 75
• Previous fracture or high risk
• Bisphosphonate intolerant
• 2G satchet dissolved in water once daily
• Poor absorbtion similar to bisphosphonates
• Main side-effect diarrhoea, minor GI symptoms

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Protelos reduces vertebral fracture risk in
patients with prevalent vertebral fracture(s)
SOTI
N1442
Patients ()
placebo
? RR - 49Over 1 year
Strontium ranelate2g/d


? RR - 41 Over 3 years
NNT9

P lt0.001

Over 3 years RR 0.59 95 CI 0.480.73
Plt0.001 No. risk of patients with vertebral
fracture(s) Strontium ranelate N139 (20.9)
placebo N222 (32.8)

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TROPOS reduction of non-vertebral fracture risk
with Protelos
Reginster JY et al. http//jcem.endojournals.org
Kaplan-Meier, adjusted Cox Model
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Strontium Ranelate in Patients over 80

• Subanalysis of SOTI and TROPOS
• 1488 patients over the age of 80 (80-100). 3 year
  follow-up.
• Intention to treat analysis fracture risk
  reduction was
• Vertebral 32 and non-vertebral 31
• Only drug with 5 year fracture data. Proven AAA
  evidence in over 80s
• Side-effect profile similar to placebo main
  issue is GI symptoms

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Salmon Calcitonin Nasal Spray

• Calcitonin previously available as injection
  only, but now has a nasal spray.
• Once daily 200mcg. Easy to use.
• Evidence of efficacy in vertebral fracture, but
  not in non-vertebral fracture
• Potential role in bisphosphonate-intolerant
  patients and those with painful vertebral fracture

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RANK L / OPG SYSTEM - Denosumab

• A new target in bone metabolism. RANKL stimulates
  osteoclast activity. OPG inhibits osteoclasts and
  causes apoptosis
• Denosumab is a monoclonal antibody which blocks
  activity of RANKL. Given as SC injection twice
  per year
• FREEDOM Trial 68 reduction in Vertebral, 20
  reduction in non-vertebral and 40 reduction in
  Hip fractures (Sept 2008)
• Some safety concerns around infections. Likely to
  get Licence soon. ?Price.

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LASOFOXIPHENE a new SERM

• New SERM to follow Raloxiphene.
• PEARL study RCT of 8556 subjects. Mean age 67.
  Reported Sept 2008
• 42 reduction in vertebral fractures at 3 years
• 24 reduction in non-vert at 5 years. No
  significant hip data.
• Reduction in incidence of breast cancer and CVS
  events. VTE risk doubled
• No licence yet.

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Refracture rates - Glasgow

• Fracture Liaison Service 6137 patients with
  6755 fractures over first 5 years
• Observational data - mean FU - 28 months
• 8.8 sustained refracture. Background hip
  fracture rate is 2
• Refractures happen quickly - 43 of refractures
  after hip fracture occur within 6 months
• Drug therapies are unlikely to influence this
  reinforcing the need for falls risk reduction

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Secondary Prevention after Hip Fracture

• Observational cohort study USA databases.
• 20644 patients over 65 with first Hip Fracture.
• Mean Age 80
• Primary outcome measure recurrent hip fracture
• 6779 were dispensed anti-resorptive therapy.
• Those dispensed active therapy shown a RR
  reduction of 25 (CI 0.66-0.87)
• ASBMR (2006)

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Mrs MD Age 79

• ACUTE ADMISSION TO HOSPITAL
• PC Off Legs Acopia
• History Recurrent falls for several months
• Reducing mobility/lost confidence
• PMH Hypertension
• Colles fracture age 65
• CVA good recovery age 75
• Fractured NOF age 77
• FH Angina and Stroke disease
• Mother had Hip fracture aged 70s

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Mrs MD - continued

• SH Lives alone Ex-smoker
• Package of Care once daily.
• Drugs Aspirin / Bisoprolol / Simvastatin
• Bendroflumethazide / Lisinopril
• This Case History demonstrates a catalogue of
  MISSED Opportunities
• 2 previous fragility fractures / history of
  maternal hip fracture
• Never had DEXA scan
• On good cardiovascular therapy, but no bone
  protection
• Should have had osteoporosis assessment after
  both fractures

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Mrs MD - continued

• Previous fractures were both the result of Falls
  and had history of multiple falls prior to
  hospital admission
• No apparent Falls assessments done
• No referral for Falls work-up in Geriatric Day
  Hospital
• No documented assessment of visual acuity
• No apparent review of medications
• Environmental assessment completed by OTs at
  time of CVA

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The Future - Risk Scores for Osteoporosis?

• Increasing efforts to calculate risk similar to
  cardiovascular risk scoring.
• FRAX score WHO and IOF approved tool,
• Launched February 2008 www.shef.ac.uk
• Calculates 10 year risk of a major osteoporotic
  fracture or of hip fracture
• BMD is not essential to generate a risk score

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www.shef.ac.uk/FRAX
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www.shef.ac.uk/FRAX
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www.shef.ac.uk/FRAX
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National Clinical Audit of Falls and Bone Health
in Older People Healthcare Commission (Nov 2007)

• 91 of PCOs in England and Wales took part
• Each provided data from 40 non-hip and 20 hip
  fracture patients
• Audit comprised 5642 non-hip and 3184 hip
  fractures.
• Non-hip mean age 79, and 86 women
• Hip mean age 83, and 80 women

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National Audit Nov 2007 Key Points

• 31 of operations for Hip fracture were delayed
  beyond the 48 hour target.
• Most patients returning home from AE after a
  fragility fracture were not offered falls risk
  assessment and only 22 were referred for
  exercise to reduce falls risk.
• After 3 months, only 20 were on appropriate
  treatment for osteoporosis
• Less than 50 of hip fracture patients were on
  appropriate bone therapy at 3 months
• The 5 who attended Falls Clinics received
  better falls and bone assessments and treatments

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Scottish Government - NHS HDL (2007) 13
Delivery Framework for Adult Rehabilitation and
Prevention of Falls in Older People

• Health Boards are asked to take the lead in
  developing with all relevant partners, a combined
  falls prevention and bone health strategy, by the
  
• end of 2007-8

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Falls Prevention and Risk Minimisation a
Mapping ExerciseScott Porter Research
commissioned by NHS QIS, June 2007

• Definition for a Progressive service
• Designated Falls Lead
• Established and integrated strategy across Health
  and social services
• Combined Falls and Bone Health service in place.
• A Multi-disciplinary Falls assessment facility is
  available using standardised tools and
  interventions

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Results of Mapping Exercise, 2007

• Only 2 of 14 Scottish Health Boards met the
  criteria for a progressive service
• Another 4 were defined as Focused or Evolving
  services
• Five Health Boards were exploring options with
  patchy services but with obvious gaps
• Three were felt to have no significant service

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Falls and Bone Health the Vision - Part 1

• Each CHP will have a Falls Coordinator with links
  to community rehab / rapid response teams.
  Primary care and AE refer fallers to a central
  contact point.
• Elderly fallers will be assessed by a member of
  this team and appropriate action taken. If
  required refer for full work-up
• Falls work-up will include
• Strength and balance training
• Home hazard assessment and intervention
• Visual assessment and referral
• Medication review and modification
• Basic Osteoporosis assessment will be done by
  Falls team looking for risk factors. ?Use of
  FRAX risk tool. Onward referral if necessary

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Falls and Bone Health the Vision Part 2

• Direct access DEXA scanning available for at
  risk patients referral could come from falls
  service
• Fracture Liaison Service sees patients with
  fragility fractures provides information and
  organises DEXA scans.
• DEXA scans advise Primary Care on therapy
  taking local Drug formulary into account.
• Fracture Liaison assesses patient for falls risk
  and refers to Falls Coordinator in CHP if
  required
• Osteoporosis Clinics are available in secondary
  care to see more complex patients.

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Mrs JM Age 72

• History Fall at home
• Colles Fracture treated in AE
• FU at Fracture Clinic
• At Clinic - Reviewed by Orthopods satisfactory
  reduction. Seen by Fracture Liaison Nurse who
  sees patient and -
• Information sheet on Osteoporosis
• Offered DEXA scan and agrees
• Slow Timed get up and go test
• Mrs JM agrees to referral to Falls Coordinator of
  local CHP
• DEXA Score shows Hip and Spine t-score of -3.1
  and -2.7 respectively.
• Commenced on Bisphosphonate and Ca/VitD

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Mrs JM - continued

• Falls Coordinator
• Organises Home Assessment by member of team
• Visit leads to provision of new safety equipment
  in house and removal of falls hazards
• Mrs JM referred to local geriatric Day Hospital
• No need for package of care identified
• Day Hospital
• 8 week individualised balance and exercise
  programme
• Visual acuity satisfactory
• Postural Hypotension identified medication
  review leads to withdrawal of diuretic
• Mrs JM discharged after 10 weeks
• Advised to contact Health Centre if further falls