Prevention of Osteoporotic Fractures

1
Prevention of Osteoporotic Fractures

• Douglas C. Bauer, MD
• University of California, San Francisco
• Research funding from NIH, Amgen, SKB, P and G,
  and Merck

2
Whats New in Osteoporosis

• Under recognition
• Absolute risk
• Poor compliance
• Anabolic agents

3
Dont Miss the Obvious
4
Under Recognition of Osteoporosis

• Among women with fracture, lt20 are evaluated and
  treated for osteoporosis!
• Ask about fracture history, note vertebral
  fractures, use chart reminders.
• Be aggressive about screening and treatment

Soloman, Mayo Clin Proc, 2005
5
Key Risk Factors

• In addition to age, gender and race- Previous
  fracture (especially spine) - Family history of
  fracture- Low body weight - Current cigarette
  smoking
• Independent of BMD (additive)

6
BMD and Risk Factors
Cummings et al., NEJM 332(12)767-773, 1995
7
The W.H.O. Guidelines 1994The measurement
defines a disease

• Densitometry became widespread
• How to apply the BMD numbers to the concept of
  diagnosis of osteoporosis?
• T lt -2.5 osteoporosis
• T between -1.0 and -2.5 osteopenia

8
Hip BMD and Fracture Risk at Age 70

• Hip fracture risk
• T-score 5 year Lifetime
• gt -1 1 4
• -1 to -2 1 8
• -2 to -3 4 16
• lt -3 9 29

9
Hip BMD and Fracture Risk at Age 50

• Hip fracture risk
• T-score 5 year Lifetime
• gt -1 lt1 10
• -1 to -2 1 16
• -2 to -3 1 27
• lt -3 2 41

10

• WHO 10-Yr. Hip Fracture Risk in Women

100
T-score -4 -3 -2 -1 0 1
T-score -4 -3 -2 -1 0 1
10
1
0.1
No prior fracture
Prior fracture
0.01
50
55
60
65
70
75
80
50
55
60
65
70
75
80
Age (years)
Age (years)
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Who Should Be Tested and Treated?

• Hip BMD if gt65, or gt50 with risk factors
• Treatment thresholds- T-score lt -2.0 without
  risk factors- T-score lt -1.5 with risk factors
• Treatment without BMD indicated- Previous
  vertebral or hip fracture- Removed gt70 with
  multiple risk factors

Revised 2003 NOF Guidelines, Caucasian women not
on therapy
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Medical Work-up

• Very little data, lots of opinions
• A reasonable start
• Vitamin D (25-OH, not 1,25-OH)
• Calcium, Cr, TSH
• Additional tests
• Sprue serology
• SPEP, UEP

13
Non-pharmacologic Interventions

• Little new data
• Smoking cessation, avoid alcohol abuse
• Physical activity modest transient effect on
  BMD may reduce fracture risk
• Conflicting data on hip protector pads
  (compliance is big issue)

14
Calcium and Vitamin D

• Chapuy, 1992
• Elderly women in long-term care
• 30 decrease in hip fracture

• Porthouse, 2005
• gt70 with 1 risk factor
• No benefit on hip, nonspine (RR1.01, CI 0.71,
  1,43)

Chapuy, NEJM, 1992
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Bisphosphonates

• Three approved agents alendronate, risedronate,
  ibandronate (recently)
• What we know fracture risk reduced 30-50 if
• Existing vertebral fracture OR
• Low BMD (T-score lt -2.5)
• but no head-to-head fracture studies
• What about those with higher BMD (osteopenia)?
  Multiple risk factors?

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Effect of Alendronate on Non-spine Fractures
In women without vertebral fractures (FIT)
Overall
0.86 (0.73, 1.01)
0.1
1
10
Relative Hazard ( 95 CI)
Cummings, Jama, 1998
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Effect of Alendronate Depends on Baseline BMD
Baseline hip BMD
T -1.5 -2.0
1.06 (0.77, 1.46)
0.97 (0.72, 1.29)
T -2.0 -2.5
T lt -2.5
0.69 (0.53, 0.88)
Overall
0.86 (0.73, 1.01)
0.1
1
10
Relative Hazard ( 95 CI)
Cummings, Jama, 1998
18
Risedronate HIP Study Two Groups

• Group 1
• 5445 age lt80 hip BMD T-score lt -3.0
• 39 decreased hip fracture risk
• Group 2
• 3886 age gt80 risk factors for hip fx
• No significant effect on hip fracture risk

McClung, NEJM, 2001
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Do Bisphosphonates Differ? Maybe

• FACT

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Risedronate
Only US study results shown here (all treated
patients) similar
results were observed in the international study.
The displayed values are geometric means, which
are back
-
transformed from
In(Fraction
of Baseline)

1 x 100.
Data available on request from Merck Co., Inc.
Please specify
20451160(1)
-
FOS.
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Compliance with Bisphosphonates is Poor

• Burdensome oral administration (fasting, remain
  upright for 30 minutes)
• 50-60 persistence after one year (ask!)
• Similar to other preventitive tx
• Multiple practice settings
• Less frequent administration improves compliance

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Bisphosponates Once-a-week
Alendronate Daily vs. Weekly

• Identical effects on BMD
• Possibly fewer effects on esophagus
• No fracture trials

Schnitzer, Aging, 2000
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Zolendronate Once-a-year

• Extremely potent bisphosphonate
• One year, multicenter controlled trial
• 360 women 45-80, T-score lt -2.0
• IV zolendronate (4 mg once or 1 mg every 3 mo)
  vs. placebo
• Outcome bone turnover and BMD

Reid, NEJM, 2002
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Yearly Zolendronate and Hip BMD
4
Placebo
3.5
4 mg x1
3
1 mg x4
2.5
2
1.5
BMD ( change)
1
0.5
0
9
0
3
6
12
-0.5
-1
Time (months)
-1.5
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Osteonecrosis of the Jaw

• Associated with potent bisphos use
• 94 treated with IV
• 4 of cases have OP, most have cancer
• 60 caused by tooth extraction
• Risk factors unknown. Duration of tx? Over
  suppression of turnover?
• Key early identifcation, conservative tx

Woo et al Ann Intern Med, April 2006
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ONJ and Osteoporosis

• How big a concern with oral treatments?
• 30,000-40,000 subjects in RCTs
• Duration of treatment 3-10 years
• No confirmed cases of ONJ
• Utilily of stopping bisphosphonates after
  prolonged use or before dental procedures unknown

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How Long to Use Bisphosphonates?

• Long half-life also suggests that life-long
  treatment may not be necessary
• Concerns about excessive suppression of bone
  resorption
• FIT Long-term Extension (FLEX) study
• 1099 ALN-treated FIT subjects
• Randomized to ALN or PBO for 5 yr.

Black, NEJM, 2004
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FLEX Change in Femoral Neck BMD Change from
FIT Baseline
Start of FLEX
2
FLEX
FIT
Plt0.001 ALN vs PBO
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Cumulative Incidence of Fractures During FLEX
ALN (N 662)
PBO (N 437)
RR (95 CI)
Vertebral

10
0.9 (0.6, 1.2)
11
Morphometric
Other fractures
Non-vertebral
19
1.0 (0.8, 1.4)
20
3
1.1 (0.5, 2.3)
3
Hip
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Implications of Bisphosphonate Trials

• Bisphosphonates reduce risk of spine, hip and
  non-spine fracture in women with spine fracture
  or low BMD (T-score lt -2.5)
• May not reduce risk of hip or non-spine fracture
  in women without osteoporosis
• Intermittent dosing just as effective
• After 4-5 years of treatment, some may stop.
  Duration?
• Best data of any approved treatment

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The NOF Guidelines Revisited in 2005 Who Should
Be Treated?

• Hip BMD treatment thresholds- T-score lt -2.0
  without risk factors. Use -2.5- T-score lt -1.5
  with risk factors. Probably not
• Treatment without BMD indicated- Existing
  vertebral or hip fracture. Yes!- gt70 with
  multiple risk factors. No!

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Other Anti-resorptive Agents

• Less effective than bisphosphonates
• Calcitonin
• Raloxifene
• Hormone replacement

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Multiple Outcomes of Raloxifene Evaluation (MORE)
Design 7705 women gt55 with low BMD or
fracture Raloxifene (60 or 120 mg) vs. placebo
for 3 yr. Primary Endpoints New spine fracture
RR 0.65 (0.53, 0.79) Non-spine fracture RR
0.94 (0.79, 1.12) Other Endpoints Breast cancer
RR 0.24 (0.13, 0.44)
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Womens Health Initiative

• RCT of ERT, PERT or PBO among women age 50-79,
  10,739 with hysterectomy. Primary prevention
• PERT, ERT arms stopped after 5-7 years
• Follow-up 93 complete
• Endpoints ERT vs. PBO
• Hip RR 0.61 (0.41, 0.91)
• Non-spine RR 0.70 (0.63, 0.79)
• CVD RR 1.12 (1.01, 1.24)
• Never say never

WHI Writing Group, Jama, 2004
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ULTRA Trial

• 417 women 60-80 y.o. with low BMD
• Intact uterus
• 0.014 mg/day transdermal E2 vs. placebo
• No progestin
• Annual endometrial biopsies

Ettinger, Obstet Gynecol, 2004
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Effects of Ultralow E2 on BMD
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Pooling both Ultralow E2 trials

• Clinical fractures (N) Placebo
  Ultra E2
• ULTRA 10 4
• Prestwood 6 2
• Total 16 6
• RR 0.4 P 0.04

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The Future Anabolic Agents

• Most treatments for osteoporosis inhibit bone
  resorption (and formation)
• Anabolic agents stimulate formation gt resorption
• Example anabolic steroids, fluoride
• Surprise finding PTH is anabolic when
  administered intermittently in animals and humans
• RCT of PTH (20 or 40 mcg) among 1637 older women
  with vertebral fracture

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Daily SQ PTH (1-34) for 18 months

• Big effects on BMD
• Spine increased 9-13
• Hip increased 3-6
• Wrist decreased 1-3
• Big effects on fracture
• Vertebral decreased 65
• Non-spine decreased 54
• Well tolerated

Neer, NEJM, 2001
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Anabolic Anti-resorptive? Sequential Treatment?

• PTH and Alendronate (PaTH) Study
• 238 postmenopausal osteoporotic women
• 1st year randomize to
• PTH (1-84) alone, 100 ug/d (N118)
• Alendronate alone, 10 mg/d (N60)
• PTH Alendronate (N59)
• Change in spine BMD similar in all three groups
• 2nd year re-randomize the PTH groups to
• ALN (10mg/d) or Placebo

Black, NEJM 2005
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One Year Change in BMD with PTH alone, ALN alone,
or PTH ALN
10
8
6


4
Mean Change ()
2
0
-2
-4
-6
Total Spine
Total Hip
Radius 1/3
PTH
PTH/ALN
ALN
plt.05 plt.0001
Black, NEJM 2003
43
Change in DXA Spine BMD Over 24 Months of
Treatment
20
24 month change
15
PTH Discontinued
12
ALN
10
Mean change ()
PTH
5
4
PLB
0
0
12
24
Month
Black, NEJM, 2005
44
Summary PTH

• Substantial BMD increase. Reduction in spine and
  non-spine fractures. Hip fracture?
• Use with antiresorptive agents? Not during,
  after.
• Lingering PTH safety issues
• Cortical bone BMD decreases during therapy?
• Carcinogenesis?
• Very expensive, daily self-administered
  injections...
• Use with severe OP, when other agents have
  failed?

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Conclusions 1

• Aggressive screening and treatment fewer
  fractures
• Identify those who have already have the
  disease!
• Bisphosphonates treatment of choice
• Use for spine fracture or low BMD. Intermittent
  dosing.
• Duration of therapy? 5 years then off?
• ERT WHI confirms effectiveness but unacceptable
  side effects. Ultra low dose?
• Data for other anti-resorptive agents (SERMs,
  calcitonin) less compelling

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Conclusions 2

• PTH impressive effects on BMD and fracture
• Indications not established
• Long-term safety? Convenience?
• Sequential treatment?
• Many other potential treatments (tibolone,
  strontium, statins, RANKL AB). Stay tuned...

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Thanks For Listening. Questions Welcome!