1. New Developments in Osteoporosis
Douglas C. Bauer, MD
University of California, San Francisco
Research funding from NIH, Amgen, SKB, P and G, and Merck

2. What’s New in Osteoporosis
Absolute risk
Under recognition
Poor compliance
When to stop bisphosphonates
New treatments

3. 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…

4. What Would You Do? Start calcium 1000 mg + vitamin D 800 iu per day
Start alendronate 70 mg or risedronate 35 mg per week
Start raloxifene 60 mg/d
Both 1) and 2)
Both 1) and 3)

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. Cummings et al., NEJM 332(12):767-773, 1995
BMD and Risk Factors
Cummings et al., NEJM 332(12): , 1995

7. 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”

8. Hip BMD and Fracture Risk at Age 70
Hip fracture risk
T-score 5 year Lifetime
> % 4%
-1 to % 8%
-2 to % %
< % %

9. Hip BMD and Fracture Risk at Age 50
Hip fracture risk
T-score 5 year Lifetime
> -1 <1% 10%
-1 to % %
-2 to % %
< % %

10. Treatment Threshold Concept
AGE
Current treatment threshold based on T-score 80 70
Treatment threshold concept based on WHO Absolute Fracture Risk
10-Year Fracture Probability (%) 60 50
Adapted from JA Kanis et al, Osteoporos Int. 2001;12:

11. Calculating Absolute Fracture Risk: FRAX

12. 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

13. 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

14. 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

15. What Else Can Be Done To Prevent Osteoporosis?

16. 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)

17. Calcium and Vitamin D Elderly women in long-term care
Chapuy, 1992
Elderly women in long-term care
30% decrease in hip fracture
Porthouse, 2005:
Women >70 with 1+ risk factor
No benefit on hip, nonspine (RR=1.01, CI: 0.71, 1,43)
Chapuy, NEJM, 1992

18. 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?

19. 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 1 10
Relative Hazard (± 95% CI)
Cummings, Jama, 1998

20. Risedronate HIP Study: Two Groups
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

21. 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…

22. Bisphosponates Once-a-week
Alendronate: Daily vs. Weekly
Identical effects on BMD
Possibly fewer effects on esophagus
No fracture trials
Schnitzer, Aging, 2000

23. 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

24. Horizon: Percentage Change in Total Hip BMD
–2.0
–1.0
0.0
1.0
2.0
3.0
4.0
–3.0
5.0
[6.00*]
[4.70*]
[2.83*]
[1.93*]
ZOL 5 mg
% Change From Baseline
Placebo 6 12 18 24 30 36
Months
ZOL n =
PBO n =
3516
3224
2350
3544
3543
3241
2408
Bracketed values are least square mean difference
*P < .0001
Black et al, NEJM, 2007

25. Horizon: Risk of New Vertebral Fracture
RRR 70% (CI: 62, 76)
Placebo
ZOL 5 mg 15
12.8%
RRR 71% (CI: 61, 78) 10
% Patients With New
Vertebral Fracture
7.7%
RRR 60% (CI: 43, 72) 5
3.8%
3.7%
2.2%
1.5%
0–1
0–2
0–3
Years
RRR = relative risk reduction;
95% confidence interval
Black et al, NEJM, 2007

26. Horizon: Risk of Clinical Fractures (Hip, Vert, Non-Vert)
Placebo (n = 3861)
ZOL 5 mg (n = 3875) 15
RRR 25% (CI: 13, 36)
10.6% 10
% Patients With New Fracture
7.9%
RRR 40% (CI: 15, 57)
RRR 75% (CI: 60, 85) 5
2.5%
2.6%
1.5%
0.6%
Hip Fracture
Clinical Vertebral Fracture
Clinical Non- vertebral Fracture
RRR = relative risk reduction;
95% confidence interval
Black et al, NEJM, 2007

27. A New Side Effect of Potent Bisphosphonates?

28. 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

29. 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)

30. Another Worry with Bisphosphonates?

31. 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?

32. What Would You Do?
Assess compliance and continue current an oral bisphosphonate
Switch to IV bisphosphonate
Switch to raloxifene 60 mg/day
Stop bisphosphonate, continue calcium/D, repeat BMD in 3-5 years

33. 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 Jama, 2006

34. FLEX Change in Femoral Neck BMD: % Change from FIT Baseline
Start of FLEX 1 2 3 4 5 6
F 0
F 1
F 2
F 3
F 4
FL 0
FL 1
FL 2
FL 3
FL 4
FL 5
Mean Percent Change
Year 2%
FLEX
FIT
= Placebo
= ALN (Pooled 5 mg and 10 mg groups)
P<0.001 ALN vs PBO

35. Cumulative Incidence of Fractures During FLEX
ALN
(N = 662)
PBO
(N = 437)
RR (95% CI)
Vertebral
Morphometric
11%
10%
0.9 (0.6, 1.2) 2%
0.5 (0.2, 0.8) 5%
Clinical
Other fractures
Non-vertebral
20%
1.0 (0.8, 1.4)
19%
Hip 3% 3%
1.1 (0.5, 2.3)

36. Implications of Bisphosphonate Trials
Bisphosphonates reduce risk of spine, hip and non-spine 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

37. The NOF Guidelines Revisited in 2008: Who Should Be Treated?
Treatment thresholds:
Existing hip or vertebral fracture. Yes
T-score < Yes
“Osteopenia” with risk factors. Probably not

38. Other Anti-resorptive Agents
Less effective than bisphosphonates
Calcitonin
Raloxifene
Hormone replacement

39. Multiple Outcomes of Raloxifene Evaluation (MORE)
Design:
7705 women >55 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)

40. Women’s 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
WHI Writing Group, Jama, 2004

41. 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

42. 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

43. 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
To answer these questions, we conducted a randomized, double blind trial , the Path Study. Dr. Dennis Black presented overall 1 yr results on Sat. during the plenary session, but I will summarize the key design features here.
Path is a two year study of 238 postmenopausal women
Black, NEJM 2005

44. One Year Change in BMD with PTH alone, ALN alone, or PTH + ALN10 8 6 *
*** 4
Mean Change (%) 2 -2 -4 -6
Total Spine
Total Hip
Radius 1/3
* p<.05
*** p<.0001
PTH
PTH/ALN
ALN
Black, NEJM 2003

45. Change in DXA Spine BMD Over 24 Months of Treatment20
24 month change 15
PTH Discontinued
+12%
ALN 10
Mean change (%)
PTH 5
+ 4%
PLB 12 24
Month
Black, NEJM, 2005

46. 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?

47. 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

48. 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...

49. What Would You Do? Mrs. P…
68 WF 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…

50. What Would You Do?
Mrs. P. has now been on an oral bisphosphonate for 5 years
No new fractures
Repeat BMD: T-score –2.3
How would you advise her?

51. Thanks For Listening. Questions Welcome!