Transcript The Effect of 3 Years of Raloxifene on Vertebral and Non

Prevention of Osteoporotic Fractures
Douglas C. Bauer, MD
University of California, San Francisco
Research funding from NIH, Amgen, SKB, P and G, and Merck
What’s New in Osteoporosis
• Under recognition
• Absolute risk
• Poor compliance
• Anabolic agents
Don’t Miss the Obvious…
Under Recognition of Osteoporosis
• Among women with fracture, <20% 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
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)
The W.H.O. Guidelines 1994
The measurement defines a disease
• Densitometry became widespread
• How to apply the BMD numbers to the concept of
“diagnosis” of osteoporosis?
• T < -2.5 = “osteoporosis”
• T between -1.0 and -2.5 = “osteopenia”
Hip BMD and Fracture Risk at Age 70
Hip fracture risk
T-score
5 year
Lifetime
> -1
1%
4%
-1 to -2
1%
8%
-2 to -3
4%
16%
< -3
9%
29%
Hip BMD and Fracture Risk at Age 50
Hip fracture risk
T-score
5 year
Lifetime
> -1
<1%
10%
-1 to -2
1%
16%
-2 to -3
1%
27%
< -3
2%
41%
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
Age (years)
50 55 60 65 70 75 80
Age (years)
Who Should Be Tested and Treated*?
• Hip BMD if >65, or >50 with risk factors
• Treatment thresholds:
- T-score < -2.0 without risk factors
- T-score < -1.5 with risk factors
• Treatment without BMD indicated:
- Previous vertebral or hip fracture
- Removed: >70 with multiple risk factors
*Revised 2003 NOF Guidelines, Caucasian women not on therapy
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
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)
Calcium and Vitamin D
– Elderly women in longterm care
– 30% decrease in hip
fracture
Incidence (%)
• Chapuy, 1992
• Porthouse, 2005:
– >70 with 1+ risk factor
– No benefit on hip, nonspine
(RR=1.01, CI: 0.71, 1,43)
9
Placebo
Calcium + D
6
3
0
0
6
12
Months
18
Chapuy, NEJM, 1992
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 < -2.5)
…but no head-to-head fracture studies
• What about those with higher BMD (“osteopenia”)?
Multiple risk factors?
Effect of Alendronate
Depends on Baseline BMD
Baseline hip BMD
T -1.5 – -2.0
1.06 (0.77, 1.46)
T -2.0 – -2.5
0.97 (0.72, 1.29)
T < -2.5
0.69 (0.53, 0.88)
Overall
0.86 (0.73, 1.01)
0.1
Cummings, Jama, 1998
1
Relative Hazard (± 95% CI)
10
Risedronate HIP Study: Two Groups
Group 1
• 5445 age <80; hip BMD T-score < -3.0
• 39% decreased hip fracture risk
Group 2
• 3886 age >80; risk factors for hip fx
• No significant effect on hip fracture risk
McClung, NEJM, 2001
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…
Bisphosponates Once-a-week
Alendronate: Daily vs. Weekly
• Identical effects on BMD
• No fracture trials
5
BMD (%)
• Possibly fewer effects
on esophagus
6
10 mg / d
70 mg / wk
4
3
2
1
0
6
12
Months
Schnitzer, Aging, 2000
Zolendronate Once-a-year
• Extremely potent bisphosphonate
• One year, multicenter controlled trial
• 360 women 45-80, T-score < -2.0
• IV zolendronate (4 mg once or 1 mg
every 3 mo) vs. placebo
• Outcome: bone turnover and BMD
Reid, NEJM, 2002
Yearly Zolendronate and Hip BMD
4
3.5
BMD (% change)
3
Placebo
4 mg x1
1 mg x4
2.5
2
1.5
1
0.5
0
0
-0.5
3
6
-1
-1.5
Time (months)
9
12
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
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
How Long to Use Bisphosphonates?
• Long half-life also suggests that lifelong 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
FLEX Change in Femoral Neck BMD:
% Change from FIT Baseline
Mean Percent Change
Start of FLEX
6
5
4
2%
3
2
1
0
F0
F1
F2
F3
F4
FL 0
FL 1
FL 2
FL 3
FL 4
Year
FIT
= Placebo
= ALN (Pooled 5 mg and 10 mg groups)
FLEX
P<0.001 ALN vs PBO
FL 5
Cumulative Incidence of Fractures
During FLEX
PBO
(N = 437)
ALN
(N = 662)
RR (95% CI)
11%
10%
0.9 (0.6, 1.2)
Non-vertebral
20%
19%
1.0 (0.8, 1.4)
Hip
3%
3%
1.1 (0.5, 2.3)
Vertebral
Morphometric
Other fractures
Implications of Bisphosphonate Trials
• Bisphosphonates reduce risk of spine, hip and nonspine fracture in women with spine fracture or low BMD
(T-score < -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
The NOF Guidelines Revisited in 2005:
Who Should Be Treated?
• Hip BMD treatment thresholds:
- T-score < -2.0 without risk factors. Use -2.5
- T-score < -1.5 with risk factors. Probably not
• Treatment without BMD indicated:
- Existing vertebral or hip fracture. Yes!
- >70 with multiple risk factors. No!
Other Anti-resorptive Agents
• Less effective than bisphosphonates
–Calcitonin
–Raloxifene
• Hormone replacement
The Future: Anabolic Agents
• Most treatments for osteoporosis inhibit bone
resorption (and formation)
• Anabolic agents stimulate formation > 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
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
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 (N=118)
– Alendronate alone, 10 mg/d (N=60)
– PTH + Alendronate (N=59)
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
Change in DXA Spine BMD Over 24
Months of Treatment
20
Mean change (%)
24 month change
15
PTH Discontinued
+12%
ALN
10
PTH
5
+ 4%
PLB
0
0
12
Month
24
Black, NEJM, 2005
Summary: PTH
• Substantial BMD increase. Reduction in spine and nonspine 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?
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
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...
Thanks For Listening. Questions Welcome!