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Evidence-Based Management of Osteoporosis. A Systematic Review of Agents Currently Available for Osteoporosis and their Use in Clinical Practice. Benefits of Therapy: Summary. Contemporary pharmacologic treatments significantly decrease fracture risk:

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evidence based management of osteoporosis

Evidence-Based Managementof Osteoporosis

A Systematic Review of Agents Currently Available for Osteoporosis and their Use in Clinical Practice

benefits of therapy summary
Benefits of Therapy: Summary

Contemporary pharmacologic treatments significantly decrease fracture risk:

  • “Antiresorptive” therapy produces a modest increase in bone mineral density (BMD)
  • However, decreases in fracture risk—especially in the spine—occur much faster and to a larger extent than predicted by the relatively small change in BMD. This implies an important improvement in bone “quality”
  • Anabolic therapy with teriparatide increases BMD more than antiresorptive treatment, but it is not yet obvious that fracture protection is greater
objective of intervention
Objective of Intervention

The most important clinical objective is the prevention of fractures—both vertebral and non-vertebral fractures

Changes in surrogate markers--bone mineral density (BMD) and biochemical markers of bone turnover--are “necessary” but are not “sufficient”

non pharmacological options
Non-Pharmacological Options
  • Nutrition: Wide range of nutrients studied
    • Calcium supplementation as needed (1500 mg total intake)
    • Vitamin D as needed (400 IU to 800 IU daily)
  • Exercise: Multiple health benefits
  • Fall prevention and/or hip protectors in the frail elderly
  • Other lifestyle modifications
    • Avoiding alcohol and tobacco abuse
non pharmacological options5
Non-Pharmacological Options
  • Taken as a whole, non-pharmacological options seem to be relatively inexpensive and modestly effective
  • Exercise, in particular, has other health benefits, although the same is likely to be true for diet optimization
  • Optimization of diet, exercise, and fall prevention should be viewed as an important adjunct to the pharmacologic treatment of osteoporotic patients
fda approved therapeutic options
FDA-Approved Therapeutic Options

Treatment

Reduces vertebral fractures

Prevention

Stops bone loss

Estrogen

Calcitonin(Miacalcin, Fortical)

Alendronate(Fosamax)

Risedronate(Actonel)

Ibandronate(Boniva: oral, injection)

Raloxifene (Evista)

PTH(Forteo)

resorption formation

Normal Coupling of Bone Remodeling

Treatment Agents: Mechanism of Action

Resorption = Formation

  • Most treatment agents (bisphosphonates, SERMs, calcitonin, estrogen) act primarily on the left side of the equation—to decrease bone resorption
  • A decrease in resorption is followed by a decrease in formation
  • Only teriparatide acts on the right side of the equation—to stimulate formation
antiresorptive treatment summary
Antiresorptive Treatment: Summary
  • Antiresorptive treatment produces a decrease in the biochemical markers of bone turnover and a modest increase in BMD
  • Because a decrease in resorption is followed by a decrease in formation, BMD improvement tends to “plateau” after several years
antiresorptive treatment summary9
Antiresorptive Treatment: Summary
  • Antiresorptive treatment decreases fracture risk much more rapidly and to a larger extent than one would predict from the relatively small changes in BMD

Note: Fracture protection can be observed in the absence of a significant change in BMD

  • Fracture protection persists even when the BMD reaches a plateau
  • Fracture reduction is most conspicuous in older patients with prevalent vertebral fractures
antiresorptive agents clinical efficacy trials of different agents cannot be compared directly
Antiresorptive Agents: Clinical EfficacyTrials of Different Agents Cannot Be Compared Directly
  • For the prevention of osteoporosis, agents must demonstrate protection against bone loss—typically in a population of early postmenopausal women
  • For the treatment of osteoporosis, agents must demonstrate protection against fracture—typically, against vertebral fracture in a population of older postmenopausal women with low BMD, with or without prevalent vertebral fractures
  • Not every treatment agent has been evaluated in a clinical trial with sufficient statistical power to examine protection against nonvertebral fracture. in general—or hip fracture, in particular
calcium and vitamin d reduce nonvertebral fracture incidence
Calcium and Vitamin D Reduce Nonvertebral Fracture Incidence

15

Placebo

Calcium-vitamin D

P = 0.02

Cumulative incidence (%)

10

0

0

6

12

18

24

30

36

Month

Dawson-Hughes B, et al. N Engl J Med1997;337:670-6

vitamin d insufficiency 30 ng ml prevalence by latitude
Vitamin D Insufficiency (<30 ng/mL): Prevalence by Latitude

n=259/532

(48.7%)

42 N

n=342/642

(53.3%)

35 N

n=198/362

(54.7%)

P = NS for Test of Trend

Holick MF, et al. J Clin Endocrinol Metab 2005;90:3215-24

slide13

Estrogen Treatment (ET)

  • Several approved oral and transdermal preparations available
  • Approved for prevention (not treatment) of osteoporosis
  • Treats symptoms of low estrogen levels
  • Skeletal effects
    • Decrease in biochemical markers of 50-60%
    • 2-year BMD increase of 4-6% at hip and spine
    • Decreased incidence of vertebral and hip fractures (34%) after 5 years in the WHI
    • Effects in women with osteoporosis have not been evaluated in randomized controlled trials

Writing Group for the WHI. JAMA 2002;288:321

slide14

Estrogen Treatment (ET)

Current Status of Estrogen for Osteoporosis

  • Long-term use not recommended
  • Adverse effects may outweigh benefits

Writing Group for the WHI. JAMA 2002;288:321

calcitonin
Calcitonin
  • Calcitonin: 200 units daily by nasal spray
  • Approved for treatment (not prevention)
  • Skeletal effects:
    • Decrease in biochemical markers of 20%
    • Small effect (1-2%) on bone density in spine
    • Reduced incidence of vertebral fractures (36%) in women with pre-existing vertebral fractures
    • No effect on non-vertebral or hip fractures has been observed
  • Adverse effects: nasal stuffiness

Chesnut CH, et al. Am J Med 2000;109:267-276

slide16

Raloxifene

  • Raloxifene 60 mg daily
  • Approved for both prevention and treatment
  • Skeletal effects:
    • Decrease in biochemical markers of 30%
    • 3-year BMD increases of 2-3% at hip and spine
    • Decreased incidence of vertebral fractures (30-50%) in women with pre-existing vertebral fractures or low bone density. No effect on non-vertebral or hip fractures has been observed.
  • Adverse effects: hot flashes, venous thrombosis, leg cramps
  • Extra-skeletal effects: Reduction in breast cancer

Ettinger B, et al. JAMA 1999;282:637-645

slide17

BisphosphonatesRisedronate, Alendronate and Ibandronate

Three bisphosphonates are available for prevention and treatment of osteoporosis—in daily oral, intermittent oral, and intermittent parenteral formulations:

  • Risedronate (Actonel®): 5 mg daily or 35 mg weekly
  • Alendronate (Fosamax®): 10 mg daily or 70 mg weekly for treatment, 5 mg daily or 35 mg weekly for prevention; available as oral suspension
  • Ibandronate (Boniva® ): 2.5 mg daily or 150 mg monthly by mouth; 3 mg iv over 15-30 seconds every 3 months
slide18

BisphosphonatesRisedronate, Alendronate and Ibandronate

  • Approved Indications
    • Treatment and prevention of postmenopausal osteoporosis (ibandronate, risedronate, alendronate)
    • Treatment and prevention of glucocorticoid-induced osteoporosis (risedronate)
    • Treatment of glucocorticoid-induced osteoporosis (alendronate)
    • Treatment of men with low bone density (alendronate)
slide19

BisphosphonatesRisedronate, Alendronate and Ibandronate

  • Approval for these diverse indications was based on studies performed with daily oral bisphosphonate administration
  • No studies of approved intermittent dosing (weekly, quarterly, monthly) were designed with a primary fracture endpoint; all examined the surrogates BMD and biochemical markers
  • Intermittent ibandronate dosing regimen with extended dose-free intervals demonstrated 50% fracture reduction at 3 years as primary end point
bmd changes with bisphosphonates
BMD Changes with Bisphosphonates
  • There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of BMD changes or fracture reduction
  • In the absence of head-to-head clinical studies, comparisons of efficacy such as BMD changes and fracture reduction between bisphosphonates should not be made
extended dosing
Extended Dosing
  • Extended dosing is based on the hypothesis that the intermittent administration of a medication will have a durable clinical benefit
  • That durable benefit would ideally be assessed by a “hard” clinical endpoint such as fracture protection
  • Absent that clinical endpoint, the benefit could be assessed indirectly by pharmacokinetics and the effects of treatment on surrogate endpoints such as BMD and biochemical markers of turnover
extended dosing22
Extended Dosing
  • A successful extended dosing regimen would presumably show an effect on biochemical markers of bone turnover—but it’s not obvious a priori what the ideal marker profile might be
  • A successful dosing regimen would also presumably show an effect on BMD at diverse sites—but it’s again not obvious what the ideal BMD response might be
extended dosing23
Extended Dosing
  • The “bridging” approach has been based on the assumption that extended dosing will reduce fracture risk if the extended dosing affects the surrogates—markers and BMD—in a fashion that is “non-inferior” to standard, daily dosing that has been proven to reduce fracture risk
bridging from daily to less frequent dosing regimens
Bridging From Daily to LessFrequent Dosing Regimens

On this basis, weekly alendronate1 and risedronate2 and monthly ibandronate are assumed to be able to produce similar antifracture efficacy to their respective daily regimens

Daily

bisphosphonate

regimen

(with proven

antifracture

efficacy)

Regimens shown to be equivalent in terms of lumbar spine BMD at 1 year, using non-inferiority or equivalence tests

Less frequent bisphosphonate dosing regimen

  • Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.
  • Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.
  • Miller P et al, J BoneMin Res, 2005, 20, 8, 1315-1322
precedent for applying the bridging concept alendronate
Precedent for Applying the Bridging Concept: Alendronate
  • Equivalence study comparing 35 mg twice weekly and 70 mg once weekly to 10 mg daily alendronate
  • Inclusion criteria
    • Females 40-90 years old
    • ≥ 2 years since menopause
    • Lumbar spine or femoral neck T-score ≤ -2.5, or prior vertebral or hip fracture
  • Daily supplementation with 500 mg calcium and 250 IU vitamin D
  • 30-minute post-dose fast

Alendronate

10 mg daily

oral

Primary endpoint = equivalence of lumbar spine BMD at Year 1

Alendronate

70 mg

weekly oral

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.

alendronate bmd results daily vs weekly year 1
Alendronate: BMD Results (Daily vs Weekly) Year 1

8.0

7.0

10 mg Daily at Year 1

70 mg Once Weekly at Year 1

6.0

5.0

Mean % Changein BMD From Baseline

4.0

3.0

5.4

5.1

4.4

2.0

3.9

3.1

2.9

2.9

2.3

1.0

0.0

Lumbar Spine

Total Hip

Femoral Neck

Trochanter

  • Equivalence demonstrated between weekly and daily dosing regimens.

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.

alendronate bmd results daily vs weekly year 1 2
Alendronate: BMD Results (Daily vs Weekly) Year 1&2

10 mg Daily at Year 11

10 mg Daily at Year 22

70 mg Once Weekly at Year 11

70 mg Once Weekly at Year 22

8.0

7.4

6.8

7.0

6.1

5.9

6.0

5.0

4.3

4.1

Mean % Changein BMD From Baseline

3.5

4.0

3.3

3.0

5.4

5.1

4.4

2.0

3.9

3.1

2.9

2.9

2.3

1.0

0.0

Lumbar Spine

Total Hip

Femoral Neck

Trochanter

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

1. Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.

2. Rizzoli R, et al. J Bone Miner Res. 2002;17:1988-1996.

precedent for applying the bridging concept risedronate
Precedent for Applying the Bridging Concept: Risedronate

Risedronate

5 mg daily

oral

  • Non-inferiority study comparing 35 mg and 50 mg once-weekly to 5 mg daily risedronate
  • Inclusion criteria
    • Females ≥ 50 years of age
    • Postmenopausal ≥ 5 years
    • Lumbar spine or femoral neckT-score ≤ -2.5; or lumbar spineT-score ≤ -2.0 and at least one prevalent vertebral fracture
  • Daily supplementation with 1000 mg calcium and 500 IU vitamin D*
  • 30-minute post-dose fast

Primary endpoint = non-inferiority of lumbar spine BMD at Year 1

Risedronate

35 mg

weekly oral

* For patients with low serum levels of vitamin D at baseline.

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.

risedronate bmd results daily vs weekly year 1
Risedronate: BMD Results (Daily vs Weekly) Year 1

5 mg Daily at Year 1

35 mg Once Weekly at Year 1

8.0

7.0

6.0

5.0

Mean % Changein BMD From Baseline

4.0

3.0

4.0

3.9

3.3

2.0

3.0

2.5

2.4

2.1

1.9

1.0

0.0

Lumbar Spine

Total Hip

Femoral Neck

Trochanter

  • Equivalence demonstrated between weekly and daily dosing regimens.

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.

risedronate bmd results daily vs weekly year 1 2
Risedronate: BMD Results (Daily vs Weekly) Year 1&2

5 mg Daily at Year 11

5 mg Daily at Year 22

35 mg Once Weekly at Year 11

35 mg Once Weekly at Year 22

8.0

7.0

5.2

6.0

4.7

4.7

5.0

4.2

Mean % Changein BMD From Baseline

3.4

4.0

3.0

2.5

3.0

1.9

4.0

3.9

3.3

2.0

3.0

2.5

2.4

2.1

1.9

1.0

0.0

Lumbar Spine

Total Hip

Femoral Neck

Trochanter

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

1. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.

2. Harris ST, et al. Curr Med Res Opin. 2004;20:757-764.

applying the bridging concept ibandronate
Applying the Bridging Concept: Ibandronate
  • Non-inferiority study comparing 100 mg and 150 mg once-monthly to 2.5 mg daily ibandronate
    • If non-inferiority was demonstrated, a pre-planned statistical superiority test was conducted
  • Inclusion criteria
    • Females 55-80 years old
    • ≥5 years since menopause
    • Mean lumbar spine (L2–L4) BMD T-score <–2.5 and ≥–5.0
  • Daily supplementation with 500 mg calcium and 400 IU vitamin D
  • 60-minute post-dose fast

Ibandronate

2.5 mg oral

daily

Primary endpoint = non-inferiority of lumbar spine BMD at Year 1

Ibandronate

150 mg

once-monthly

oral

Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.

ibandronate bmd results daily vs monthly year 1
Ibandronate : BMD Results (Daily vs Monthly) Year 1

Ibandronate 2.5 mg Daily at Year 1

Ibandronate 150 mg Monthly at Year 1

8.0

7.0

6.0

Mean % Changein BMD From Baseline

5.0

4.0

3.0

4.8

4.6

3.7

2.0

3.2

3.0

2.2

1.7

2.0

1.0

(316)

(314)

(314)

(315)

(316)

(316)

(315)

(315)

0.0

Lumbar Spine

Total Hip

Femoral Neck

Trochanter

Year 1 P=0.001 P<0.0001 P=0.09 P<0.0001

vs 2.5 mg daily

  • Non-inferiority was demonstrated between monthly and daily dosing regimens.
  • The monthly dosing regimen was statistically superior at lumbar spine, total hip, and trochanter.

Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.

Per-protocol population (n).

ibandronate bmd results daily vs monthly year 1 2
Ibandronate: BMD Results (Daily vs Monthly) Year 1&2

2.5 mg Daily at Year 1

150 mg Monthly at Year 1

150 mg Monthly at Year 2

2.5 mg Daily at Year 2

8.0

6.6

7.0

6.2

6.0

5.0

(291)

(289)

Mean % Changein BMD From Baseline

5.0

4.2

4.0

(294)

4.0

(292)

3.1

(289)

3.0

2.5

(292)

(289)

4.8

4.6

1.9

(292)

3.7

2.0

3.2

3.0

2.2

1.7

2.0

1.0

(316)

(314)

(314)

(315)

(316)

(316)

(315)

(315)

0.0

Lumbar Spine

Total Hip

Femoral Neck

Trochanter

Year 1 P=0.001 P<0.0001 P=0.09 P<0.0001

Year 2 P<0.0001 P<0.0001 P=0.0002 P<0.0001

vs 2.5 mg daily

Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.

Per-protocol population (n).

ibandronate summary of daily vs monthly bmd results
Ibandronate: Summary of Daily vs Monthly BMD Results
  • Non-inferiority demonstrated between monthly and daily dosing regimens
  • The monthly dosing regimen was statistically superior to the daily dosing regimen in terms of BMD elevations across all sites at Year 2, per pre-planned analysis
  • The increase in BMD between years 1 and 2 was statistically significant across all sites

Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.

observations bmd changes
Observations: BMD Changes

There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of BMD changes or fracture reduction In the absence of head-to-head clinical studies, comparisons of efficacy such as BMD changes and fracture reduction between bisphosphonates should not be made

Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.

Harris ST, et al. Curr Med Res Opin. 2004;20:757-764.Rizzoli R, et al. J Bone Miner Res. 2002;17:1988-1996.Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12. Data on file (Reference # 161-094, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.

responders analysis40
Responders Analysis
  • Categorization of responders is an attempt at differentiating success at increasing or maintaining BMD (responders) from those with decreasing BMD
  • MOBILE and FACT studies looked at responders
    • % patients with lumbar spine or hip trochanter BMD changes at baseline1-3
  • There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of BMD changes or fracture reduction
  • In the absence of head-to-head clinical studies, comparisons of efficacy such as BMD changes and fracture reduction between bisphosphonates should not be made

MOBILE – Monthly Oral iBandronate In LadiEs; FACT – Fosamax Actonel Comparison Trial.

Fosamax is a registered trademark of Merck & Co., Inc.

Actonel is a registered trademark of Procter & Gamble Pharmaceuticals Inc.

1. Rosen CJ, et al. J Bone Miner Res. 2005;20:141-151.

2. Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.

3. Data on file (Reference # 161-092) Hoffmann-La Roche Inc., Nutley, NJ 07110.

patients with lumbar spine and trochanter bmd values baseline

FACT: Results Year 1

% Patients With Lumbar Spine and Trochanter BMD Values ≥ Baseline

87.3%*

84.5%*

75.6%

67.8%

Risedronate35 mg/week

Risedronate35 mg/week

Alendronate70 mg/week

Alendronate70 mg/week

100

80

60

Patients (%)

40

20

Lumbar Spine

Trochanter

0

In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared.

* P<0.001 vs risedronate. Modified intent-to-treat population.

Rosen CJ, et al. J Bone Miner Res. 2005;20:141-151.

patients with lumbar spine and trochanter bmd values baseline42

MOBILE: Results Year 1

% Patients With Lumbar Spine and Trochanter BMD Values ≥ Baseline

92.4%**

90.8%*

83.8%

80.0%

n=314

n=314

n=315

n=316

150 mg

Monthly

2.5 mg

Daily

150 mg

Monthly

2.5 mg

Daily

100

80

60

Patients (%)

40

Lumbar Spine

Trochanter

20

0

* P= 0.008vs 2.5 mg; **P<0.001 vs 2.5 mg.

Per-protocol population.

Data from one or both sources.

Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.

Data on file (Reference # 161-094) Hoffmann-La Roche Inc., Nutley, NJ 07110.

daily and monthly oral ibandronate
Daily and Monthly Oral Ibandronate
  • The MOBILE study examined BMD and biochemical marker changes with daily (2.5 mg) and monthly (150 mg) ibandronate therapy over 1 and 2 years
  • The changes in BMD with monthly therapy were superior to those seen with daily treatment

Miller PD, et al. J Bone Miner Res 2005;20:1315-22

Reginster JY, et al. Ann Rheum Dis 2006;65:654-61

relationship between change in bmd and risk of vertebral fracture the bone study
Relationship between change in BMD and risk of vertebral fracture: the BONE study

17

16

15

14

13

12

11

10

9

8

7

6

5

4

3

Placebo

Oral daily and intermittentibandronate

Fracture rate/per 100 patients

–4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9

BMD change (%)

Wasnich R, et al. Osteoporos Int 2003;14 (Suppl. 7):S76(Abstract P272)

slide45

BisphosphonatesRisedronate, Alendronate and Ibandronate

  • None of the approved intermittent bisphosphonate regimens (weekly, monthly or quarterly) has demonstrated protection against vertebral or nonvertebral fractures
  • Each intermittent regimen was approved on the basis of changes in BMD and biochemical markers over 1-2 years that were non-inferior (alendronate, risedronate) or superior (ibandronate) to those observed with standard daily therapy with the same agent over that same study period
slide46

BisphosphonatesRisedronate, Alendronate and Ibandronate

Rationale for Approval of Intermittent Regimens

  • In each case, daily oral bisphosphonate therapy had already demonstrated fracture protection in other trials
  • It was assumed that, if changes in the surrogates were comparable to daily therapy in a head-to-head trial, intermittent therapy would also be effective for fracture protection
slide47

BisphosphonatesRisedronate and Alendronate

Effects on Markers and Fracture Prevention

  • Increases of 5-8% in bone density in the spine, and 3-5% in the hip after 3 years
  • Reduced incidence of vertebral fractures by 40-65%
  • Reduced nonvertebral fractures (30-40%), including hip fractures (40-60%; alendronate), in women with osteoporosis
slide48

Control

Alendronate 10 mg

10

8

6

Mean % Change from Baseline

4

2

0

-2

6

12

18

24

30

36

Month

Osteoporosis Therapy: Bisphosphonates

Spinal BMD Change with Daily Alendronate

Liberman UA, et al. N Engl J Med 1995;333:1437-43

slide49

Control

Risedronate 5 mg

10

8

6

Mean % Change from Baseline

4

2

0

6

12

18

24

30

36

Month

Osteoporosis Therapy: Bisphosphonates

Spinal BMD Change with Daily Risedronate

Harris ST, et al. JAMA 1999; 282:1344-52

slide50

BisphosphonatesIbandronate

Effects on Bone Markers and Fractures

  • Increases of 6% in bone density in the spine and increases of 3-5% in the hip after 3 years of daily treatment
  • Reduced incidence of vertebral fractures by 50%; reduction in non-vertebral fractures in post-hoc analysis only in patients with

BMD < -3.0

slide51

Control

Ibandronate 2.5 mg

10

8

6

Mean % Change from Baseline

4

2

0

6

12

18

24

30

36

Month

Osteoporosis Therapy: Bisphosphonates

Spinal BMD Change with Daily Ibandronate

Delmas PD, et al. Osteoporos Int 2004;15:792-8

bisphosphonates
Bisphosphonates

Side effects

  • Randomized controlled trials: No increase in UGI complaints
  • “Class warning” regarding UGI symptoms for bisphosphonates administered orally
    • Clinical reports of UGI symptoms: abdominal pain, esophagitis or dysphagia, with esophageal ulcers in some patients
    • GI effects minimized by proper dosing, and possibly, with intermittent dosing

1 Boniva PI March 2005, Boniva Injection PI January 2006

bisphosphonates53
Bisphosphonates
  • “Class precautions” regarding infrequent bone, joint and/or muscle pain
  • “Class precautions” regarding jaw osteonecrosis
  • “Influenza-like illness” in 4.9% of patients in the first year of quarterly IV ibandronate administration vs 3.3% with monthly oral ibandronate and 0.8-1.1% with daily oral ibandronate 1

1 Boniva1, Fosomax, Actonel PIs

slide54

Bisphosphonates

  • Contraindications
    • Esophageal stricture or impaired esophageal motility (alendronate); inability to stand or sit for at least 30 minutes (alendronate and risedronate) or 60 minutes (ibandronate)
    • Hypocalcemia

Note: UGI symptoms are not an absolute contraindication

Use in pregnancy: Class C

slide55

Bisphosphonates

Dosing requirements

  • Tablets should be taken on an empty stomach after an overnight fast with 6-8 oz of plain water while patient is in upright position
  • Patients should not eat or lie down for at least 30 minutes (alendronate and risedronate) or 60 minutes (ibandronate)
  • Calcium and vitamin D supplements, if needed, should be taken at a different time of day than the bisphosphonate
  • Alendronate is available as an oral solution (70 mg weekly)
slide56

Bisphosphonates

Unsettled Issues: Are There Differences

Among Bisphosphonates

  • Effects on BMD and biochemical markers?
  • Magnitude of fracture protection—vertebral, non-vertebral, hip? No head to head trials.
  • Onset of fracture protection?
  • Short-term and long-term tolerability/safety?
  • Adherence to treatment (compliance, persistence)?
  • Effects after discontinuation of therapy—possible “drug holiday”?
  • Annualized costs of the medication?
bisphosphonates fda approved indications
Bisphosphonates: FDA-Approved Indications
  • “For the treatment of osteoporosis, Fosamax increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures)” 1
  • “In postmenopausal women with osteoporosis, Actonel increases BMD and reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures” 2
  • “In postmenopausal women with osteoporosis, Boniva increases BMD and reduces the incidence of vertebral fractures” 3

1 Fosamax PI July 2005 2 Actonel PI January 2006 3 Boniva PI March 2005

summary fracture protection
Summary: Fracture Protection
  • It is not possible to compare the pivotal trials of different treatment agents vis-à-vis fracture endpoints, making it difficult and problematic to draw firm clinical conclusions from attempts at such comparisons
  • Although pivotal trials studied similar populations of postmenopausal women, there were important differences in demographics, inclusion criteria, and fracture endpoints
  • “The absence of evidence is not evidence of absence”
non vertebral fractures a summary
Non-Vertebral Fractures: A Summary

Demonstrating Fracture Reduction in Multiple Trials Appears To Be Related to Assessing Agent Efficacy in High Risk Stratified Subgroups with low BMD:

• In FIT study, subgroups with lower baseline hip BMD showed greatest effect: reductions for overall and hip fracture greatest in those with BMD T-scores < -2.5

• Alendronate meta-analysis of 4 studies: In overall group non-vertebral fracture reduction was about 25%, whereas it was 59% in women with T-scores < -2.5

• In risedronate HIP study, women 70-79 years of age with a BMD < -3.0 plus risk factor or < -4.0 without risk factor showed significant hip fracture reduction (40%, p=.009), but another group without pre-specified low BMDs did not show significant reductions in hip fracture.

non vertebral fractures a summary60
Non-Vertebral Fractures: A Summary

• In BONE study (ibandronate) post-hoc analysis showed reduced non-vertebral fractures (30%) only in patients with baseline femoral neck T-score < -3.0; no hip fracture effect demonstrated

“Because the the incidence of fracture increases as BMD decreases, it is possible that trials with very low BMD patients could observe a higher incidence of hip fractures and thus increase the chance to detect a therapeutic effect.”

Nguyen, Eisman, Nguyen. Anti-Hip Fracture Efficacy of Bisphosphonates: A Bayesian Analysis of Clinical Trials (JBMR, Vol 21, No. 1 2006)

slide61

Summary: Vertebral Fracture ReductionTrials of Different Agents Cannot Be Compared DirectlyFracture Rates over 3-5 Years; % Reduction

Raloxifene

Alendronate

Risedronate

Calcium

Calcitonin

Ibandronate

30

25

36%

% of Patients

with New Vertebral Fracture

20

49%

30%

15

41%

10

47%

52%

5

50%

50%

0

PROOF1 MORE2 FIT VFA3 VERT NA4 VERT MN5 BONE6 MORE2 FIT CFA7OP with Prevalent Vertebral Fractures * OP without Vert Fx *

1Chesnut CH, et al. Am J Med. 2000;109:267-76 2Ettinger B, et al. JAMA. 1999;282:637-45

3Black DM, et al. Lancet 1996;348:1535-41 4Harris ST, et al. JAMA. 1999;282:1344-52

5Reginster J, et al. Osteoporos Int. 2000;11:83-91 6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-9

7Cummings SR, et al. JAMA. 1998;280:2077-82 * All reductions are statistically significant

slide62

Summary: Nonvertebral Fracture ReductionTrials of Different Agents Cannot Be Compared DirectlyFracture Rates over 3-5 Years; % ReductionIncluded Fractures Varied From Study to Study

Raloxifene

Alendronate

Risedronate

Ibandronate

Calcium

Calcitonin

30

NS NS p = .063 p = .02 p = .063 NS NS

25

% of Patients with New Non-vertebral Fracture

20

15

33%

20%

10

39%

5

N/A

0

PROOF1 MORE2 FIT VFA3 VERT NA4 VERT MN5 BONE6 MORE2 FIT CFA7OP with Prevalent Vertebral Fractures OP without Vert Fx

1Chesnut CH, et al. Am J Med. 2000;109:267-76 2Ettinger B, et al. JAMA. 1999;282:637-45 (pooled groups)

3Black DM, et al. Lancet 1996;348:1535-41 4Harris ST, et al. JAMA. 1999;282:1344-52

5Reginster J, et al. Osteoporos Int. 2000;11:83-91 6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-9

7Cummings SR, et al. JAMA. 1998;280:2077-82 N/A = not available; NS = not statistically significant

slide63

Summary: Hip Fracture ReductionTrials of Different Agents Cannot Be Compared DirectlyFracture Rates over 3-5 Years; % ReductionNot All Studies Had Sufficient Statistical Power

Raloxifene

Alendronate

Risedronate

Ibandronate

Calcium

Calcitonin

6

NS NS p = .047 NS p = .02 NS

5

4

% of Patients with Hip Fracture

3

30%

2

51%

1

N/A

N/A

0

PROOF1 MORE2 FIT VFA3 VERT NA4 VERT MN5 HIP8 BONE6 FIT CFA7

1Chesnut CH, et al. Am J Med. 2000;109:267-76 2Ettinger B, et al. JAMA. 1999;282:637-45 (pooled groups)

3Black DM, et al. Lancet 1996;348:1535-41 4Harris ST, et al. JAMA. 1999;282:1344-52

5Reginster J, et al. Osteoporos Int. 2000;11:83-91 6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-9

7Cummings SR, et al. JAMA. 1998;280:2077-82 8McClung MR, et al. N Engl J Med. 2001;344:333-40

N/A = not available; NS = not statistically significant

assessment of fracture risk reduction
Assessment of Fracture Risk Reduction
  • In general, there is a weak relationship between BMD changes after therapy and fracture risk reduction
  • Changes in BMD after therapy explain an estimated 4% to 28% of the reduction in fracture risk observed with antiresorptive agents; in fact, some degree of fracture protection occurs in the absence of a measured change in BMD in individual patients
  • A change in bone turnover is at least as good a surrogate for fracture risk reduction as change in BMD
  • For these reasons, therapeutic efficacy of antiresorptive agents should be based on fracture risk reduction outcomes

Eastell R, et al. J Bone Miner Res. 2003;18:1051-56

summary assessment of fracture risk reduction
Summary: Assessment ofFracture Risk Reduction
  • In trials of different antiresorptive agents, there is an imperfect relationship between changes in BMD (or changes in biochemical markers) and the observed reductions in fracture risk
    • Although the trials with different agents are difficult to compare, the agents associated with smaller changes in BMD and smaller changes in biochemical markers—nasal spray calcitonin and raloxifene—have mustered evidence for vertebral fracture protection only
  • It is not clear that changes in BMD or biochemical markers can be used to assess fracture risk reduction in individual patients in clinical practice
slide66

Practical Questions and Reasonable Answers About Antiresorptive Agents

  • Use in combination?
    • Limited benefit
    • Increased cost and side effects
    • Theoretical concern about over-suppression of turnover
    • Rarely justified
  • What happens with continued therapy?
    • Continued anti-fracture effect of risedronate on vertebral (50%) and non-vertebral (37%) fractures through at least 5 years 1
    • Persistent reduction in vertebral fractures (38-50%) over 4 years with raloxifene 2
    • No abnormalities on bone biopsies after 10 years of alendronate therapy 3

1 Sorensen OH, et al. Bone 2003;32:120

2 Delmas PD, et al. J Clin Endocrinol Metab 2002;87:3609

3 Recker R, et al. J Bone Miner Res 2004:19(Suppl 1):S45 (abstract)

slide67

Practical Questions and Reasonable Answers About Antiresorptive Agents

  • What happens when treatment is stopped?
    • Resumption of bone loss after stopping estrogen and raloxifene--and probably calcitonin
    • After 5 years of alendronate, there is some increase in bone turnover and a decrease in hip BMD over the next 5 years 1
  • How long should therapy be continued?
    • Estrogen no longer recommended as the primary treatment for osteoporosis
    • Raloxifene or calcitonin: no limit
    • Bisphosphonates
      • Long-term in high-risk patients
      • The effect of stopping therapy on fracture rate is unclear

1 Bone HG, et al. N Engl J Med 2004;350:1189

anabolic agents to treat osteoporosis
Anabolic Agents to Treat Osteoporosis
  • Anabolic agents increase bone mass to a greater degree than can be achieved with antiresorptive therapies
  • Anabolic Agents
    • Fluoride, GH, IGF-I, strontium ranelate
    • Parathyroid hormone and related peptides (PTH 1-34, PTH 1-84, PTHrP)
slide69

Mode of Administration and Dose Determine the Effect of PTH on Bone

Effect

Mode

Continuous

high dose

Catabolic

Intermittent

low dose

Anabolic

  • Recruitment of new osteoblasts
  • Osteoblast life span
  • Osteoblast activity

Other cellular and regulatory effects

Dobnig H, Turner RT. Endocrinology 1997;138:4607

osteoporosis therapy rhpth 1 34
Osteoporosis Therapy: rhPTH [1-34]

Teriparatide

rhPTH [1-34] (Forteo®) 20 mcg daily subcutaneously

Indication: treatment of men and postmenopausal women with osteoporosis who are at high risk for fractures

Effects 1

  • Increased bone density in spine by 9% and hip by 3% vs placebo over 18 months
  • Reduced incidence of vertebral fractures (65%) and non-vertebral fragility fractures (53%) in women with pre-existing vertebral fractures
  • Studies too small to evaluate effect on hip fractures

1 Neer RM, et al. N Engl J Med 2001;344:1434-41

slide71

Osteoporosis Therapy: rhPTH [1-34]

Teriparatide

  • In human subjects:
    • Mild, transient elevation in serum calcium
    • Mean increase in urine calcium of 30 mg/24 hours. No statistically significant increase in hypercalciuria
    • Leg cramps (2.6% vs. 1.3% in controls)
    • Dizziness (8.0% vs. 5.4% in controls)
  • In rats:
    • Increased incidence of osteosarcoma with high-dose, long-term exposure (“Black Box Warning”)

Neer RM, et al. N Engl J Med 2001;344:1434

slide72

Practical Questions and Reasonable Answers About rhPTH [1-34]

  • In which patients?
    • Postmenopausal females and males with established osteoporosis at “high risk” for fractures
  • What pretreatment workup?
    • Serum calcium, alkaline phosphatase, PTH
    • 25-OH vitamin D, 24-hour urine calcium
  • For how long?
    • ≤ 24 months
    • No longer-term data on safety or efficacy
  • How much does treatment cost?
    • Approximately $800/year for antiresorptives
    • $7000/year for teriparatide
slide73

Practical Questions and Reasonable Answers About rhPTH [1-34]

  • Given after an antiresorptive?
    • Gains in BMD may be delayed by prior use of alendronate, but if so, gains are eventually seen
  • Given simultaneously with an antiresorptive?
    • No apparent benefit to simultaneous PTH and alendronate
    • Early gains appear robust with raloxifene and estrogen, but no comparison with PTH alone
  • Followed by an antiresorptive?
    • Yes, on the basis of current data
  • Is retreatment an option?
    • Perhaps, if clinically indicated (but no studies available)
treatment summary monotherapy
Treatment Summary: “Monotherapy”
  • Contemporary single agents significantly decrease fracture risk:
    • “Antiresorptive” therapy produces a modest BMD increase, yet decreases fracture risk—especially in the spine—much faster and to a larger extent than predicted by the relatively small change in BMD. This implies an important improvement in bone “quality”
    • Anabolic therapy is also now available. Teriparatide treatment increases BMD more than antiresorptive treatment, but it is not yet obvious that fracture protection is greater.
summary predicting fracture risk
Summary: Predicting Fracture Risk
  • Along with BMD, bone turnover is an important and independent determinant of fracture risk
  • Among women treated with antiresorptive therapies, reduction in bone turnover is associated with reduced fracture risk
  • Change in bone turnover is a rapid predictor of treatment-related anti-fracture response in individuals
  • Reduction in bone turnover and increases in BMD are important indicators of antifracture efficacy of anticatabolic drugs
    • Both for vertebral and nonvertebral fracture
  • Results cannot be directly extrapolated to anabolic agents such as fluoride, PTH or strontium ranelate
treatment summary implications
Treatment Summary: Implications

• Fracture risk protection is conferred by a number of mechanisms: BMD stabilization and/or bone quality improvement; effects on bone resorption, all of which should be considered when selecting therapy

• Fracture protection parameters (i.e.) are important determinants for reducing fracture risk

• Adherence to drug regimens and ensuring persistence are important determinants of patient outcomes

• Patient preferences should be considered