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

New Developments in Osteoporosis
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
• Absolute risk
• Under recognition
• Poor compliance
• When to stop bisphosphonates
• New treatments
What Would You Do? Mrs. P…
• 66 grandmother and prominent politician
without previous fracture or other risk
factors. Sister with breast cancer,
otherwise healthy. No meds
• Hip BMD T-score –2.2
• No contraindication to treatment
• Will follow your advice…
What Would You Do?
1) Start calcium 1000 mg + vitamin D 800 iu per
day
2) Start alendronate 70 mg or risedronate 35
mg per week
3) Start raloxifene 60 mg/d
4) Both 1) and 2)
5) Both 1) and 3)
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%
Treatment Threshold Concept
10-Year Fracture
Probability (%)
40
AGE
30
80
70
20
60
Current treatment threshold
based on T-score
Treatment threshold concept based
on WHO Absolute Fracture Risk
50
10
0
-3 -2.5 -2 -1.5 -1 -0.5
BMD T-score
Adapted from JA Kanis et al, Osteoporos Int. 2001;12:989-995
0
0.5
1
Calculating Absolute Fracture Risk: FRAX
http://www.shef.ac.uk/FRAX/tool.jsp
Who Should Be Tested and Treated*?
• Preventive measures for everyone: calcium, vitamin D,
exercise, clean living
• Hip BMD: women >65, men >70, and after fracture
• Treatment thresholds:
– Anyone with hip or spine fracture
– T-score < -2.5
– “Osteopenia” and 10 year hip fracture risk >3% or
OP-related fracture risk >20%
*Revised 2008 NOF Guidelines
Under Recognition of Osteoporosis
• Among women with fracture or BMD<2.5 , only 20-30% are evaluated and
treated!
• Ask about fracture history, note
vertebral fractures, use chart reminders.
• Be aggressive about screening and,
when indicated, appropriate treatment
Soloman, Mayo Clin Proc, 2005
Medical Work-up
• Very little data, lots of opinions
• A reasonable start:
– Vitamin D (25-OH, not 1,25-OH)
– serum calcium, Cr, TSH
• Additional tests that may be helpful:
– Sprue serology, SPEP, UEP
• Unlikely to be helpful:
– PTH, urine calcium
Jamal et al, Osteo Inter, 2005
What Else Can Be Done To Prevent
Osteoporosis?
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:
– Women >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
• Four approved agents: alendronate, risedronate,
ibandronate, and zolendronic acid (recently)
– No head-to-head fracture studies
• What we know: fracture risk reduced 30-50% if
– Existing vertebral fracture OR
– Low BMD (T-score < -2.5)
• What about those with higher BMD (“osteopenia”)?
Multiple risk factors?
Effect of Alendronate on Non-spine
Fracture 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). Weekly dosing
• 50-60% persistence after one year (ask!)
–Similar to other preventative tx
–Multiple practice settings
• Less frequent administration improves
compliance…
Zolendronate Once-a-year: Horizon
• Extremely potent bisphosphonate
• 3 year, multicenter controlled trial
• 7741 women 55-89, T-score < -2.5 or
< -1 + vertebral fracture
• IV zolendronate (5mg IV once/yr) vs.
placebo
• Outcome: BMD, turnover, fracture
Black et al, NEJM, 2007
% Change From Baseline
Horizon: Percentage Change in Total Hip BMD
ZOL n =
PBO n =
5.0
[6.00*]
[4.70*]
4.0
[2.83*]
3.0
[1.93*]
ZOL 5 mg
2.0
1.0
Placebo
0.0
–1.0
–2.0
–3.0
0
6
12
18
Months
24
30
36
3516
3516
3224
2350
3544
3543
3241
2408
Bracketed values are least square mean difference
*P < .0001
Black et al, NEJM, 2007
Horizon: Risk of Clinical Fractures
(Hip, Vert, Non-Vert)
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
% Patients With
New Fracture
15
RRR 25%
(CI: 13, 36)
10.6%
10
7.9%
RRR 40%
5
(CI: 15, 57)
2.5%
RRR 75%
(CI: 60, 85)
2.6%
1.5%
0.6%
0
Hip
Fracture
RRR = relative risk reduction;
95% confidence interval
Clinical Vertebral
Fracture
Clinical Non- vertebral
Fracture
Black et al, NEJM, 2007
A New Side Effect of Potent
Bisphosphonates?
Osteonecrosis of the Jaw
• Associated with potent bisphos use:
– 94% treated with IV bisphosphonates
– 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 identification, 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
• Dental exam before initiating bisphosphonates
recommended but unlikely to help
• Utility of stopping bisphosphonates before
dental procedures unknown (not advised)
Another Worry with Bisphosphonates?
What Would You Do?
• Mrs. P has now been on an oral
bisphosphonate for 5 years
• No new fractures
• Repeat hip BMD: T-score –2.3
• How would you advise her?
What Would You Do?
1) Assess compliance and continue
current an oral bisphosphonate
2) Switch to IV bisphosphonate
3) Switch to raloxifene 60 mg/day
4) Stop bisphosphonate, continue
calcium/D, repeat BMD in 3-5 years
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 Jama, 2006
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)
Morphometric
11%
10%
0.9 (0.6, 1.2)
Clinical
5%
2%
0.5 (0.2, 0.8)
Non-vertebral
20%
Hip
3%
19%
3%
1.0 (0.8, 1.4)
1.1 (0.5, 2.3)
Vertebral
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, even yearly, effective
• After 5 years of treatment, some may stop.
– Who? For how long? How to monitor?
• Best data of any approved treatment
The NOF Guidelines Revisited in 2008:
Who Should Be Treated?
• Treatment thresholds:
–Existing hip or vertebral fracture. Yes
–T-score < -2.5. Yes
–“Osteopenia” with risk factors. Probably not
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?
• Data for other anti-resorptive agents (SERMs, calcitonin)
less compelling
Conclusions 2
• PTH: impressive effects on BMD and fracture
– Indications not established: severe cases?
– Long-term safety? Convenience?
– Sequential treatment?
• Many other potential treatments (tibolone,
strontium, statins, RANKL AB). Stay tuned...
Thanks For Listening. Questions Welcome!