Prevention of osteoporotic fractures
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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….

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Prevention of Osteoporotic Fractures

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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 1994The 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-score5 yearLifetime

> -1 1% 4%

-1 to -2 1% 8%

-2to -3 4% 16%

< -3 9% 29%


Hip BMD and Fracture Risk at Age 50

Hip fracture risk

T-score5 yearLifetime

> -1 <1% 10%

-1 to -2 1% 16%

-2to -3 1% 27%

< -3 2% 41%


100

T-score

-4

-3

-2

-1

0

1

T-score

-4

-3

-2

-1

0

1

10

WHO 10-Yr. Hip Fracture Risk in Women

1

0.1

Prior fracture

No prior fracture

0.01

50

55

60

65

70

75

80

50

55

60

65

70

75

80

Age (years)

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

  • Chapuy, 1992

    • Elderly women in long-term care

    • 30% decrease in hip fracture

  • Porthouse, 2005:

    • >70 with 1+ risk factor

    • No benefit on hip, nonspine (RR=1.01, CI: 0.71, 1,43)

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)

0.97 (0.72, 1.29)

T -2.0 – -2.5

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


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

  • Possibly fewer effects on esophagus

  • No fracture trials

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

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


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 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


6

5

4

Mean Percent Change

3

2

1

0

F 0

F 1

F 2

F 3

F 4

FL 0

FL 1

FL 2

FL 3

FL 4

FL 5

Year

= Placebo

= ALN (Pooled 5 mg and 10 mg groups)

FLEX Change in Femoral Neck BMD: % Change from FIT Baseline

Start of FLEX

2%

FLEX

FIT

P<0.001 ALN vs PBO


Cumulative Incidence of Fractures During FLEX

ALN

(N = 662)

PBO

(N = 437)

RR (95% CI)

Vertebral

11%

10%

0.9 (0.6, 1.2)

Morphometric

Other fractures

Non-vertebral

20%

19%

1.0 (0.8, 1.4)

Hip

3%

3%

1.1 (0.5, 2.3)


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 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

24 month change

15

PTH Discontinued

+12%

ALN

10

Mean change (%)

PTH

5

+ 4%

PLB

0

0

12

24

Month

Black, NEJM, 2005


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?


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!


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