# Presentation: 321576

## Relationship of Drug Associated Change in Bone Mineral Density to Fracture Risk  

- Marc C. Hochberg, MD, MPH
- FDA Endocrinologic and Metabolic Drugs    Advisory Committee
- 25 September 2002

## Osteoporosis:  Definition(NIH Consensus Conference, 2000)

- [A] skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture
- Bone strength reflects bone mass and bone quality
- Bone mass is estimated by bone mineral density
- Bone quality refers to microarchitecture, turnover, damage accumulation (eg, microfractures), and degree of mineralization

- NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. * *
*JAMA.  *2001;285:785–795.

## Bone Mineral Density and Bone Turnover

- Components of the “new” definition of osteoporosis
- Are changes in bone mineral density and bone turnover with antiresorptive therapy important in explaining the antifracture efficacy of these agents?
- Vertebral fractures
- Nonvertebral fractures

## Pharmacologic Treatment of Osteoporosis

- Antiresorptive agents
- Bisphosphonates
- Alendronate, Risedronate
- Calcitonin
- Estrogen (not FDA approved for treatment)
- Selective estrogen receptor modulators
- Anabolic agents
- Fluoride (not FDA approved)
- Parathyroid hormone (not FDA approved)

## Antiresorptive Agents

**Antiresorptive Agents**

- Inhibit bone resorption
- Fewer resorption sites; improves bone microarchitecture (fewer cavities)
- Shallower resorption sites; improves bone balance (amount of formation greater than resorption)
- Slower turnover rate; allows better mineralization of bone
- Result:
- Increased bone mass
- Improved bone strength and bone quality
- Out of proportion to increase in bone mass

## Vertebral Fractures

## Changes in Bone Density and Antifracture Efficacy of Antiresorptive Agents

**Methods**
- Identified 13 randomized placebo-controlled trials of antiresorptive agents that reported both vertebral fracture incidence and changes in BMD
- Used Poisson regression
- Related BMD and fracture risk reduction
- Pooled data to obtain “best fit”
- Sensitivity analysis performed

- Wasnich RD, Miller PD.  *J Clin Endocrinol Metab. * 2000;85:231–236.

## Greater Increase in Bone Mineral Density (BMD) and Larger Reduction in Fracture Risk

- Percent Change in Spine BMD (vs Placebo)

- Relative Risk Reduction (%)

**A** = alendronate

**C** = calcitonin

**E **= etidronate

**H** = hormone replacement

**R** = raloxifene

**T **= tiludronate

**C**

- 54% risk
- reduction

- 22%

- 0.0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 1.2

- 1.4

- 1.6

- Relative Risk of Vertebral Fracture

**A**

**A**

**A**

**A**

**C**

**E**

**H**

**R**

**R**

**R**

**A**

**C**

**T**

**T**

**T**

**C**

**T**

**E**

**A**

- Wasnich RD, Miller PD.  *J Clin Endocrinol Metab.*  2000;85:231–236.

## Predicting the Effect of Antiresorptive Treatments on Vertebral Fractures

**Predicting the Effect of Antiresorptive ****Treatments on Vertebral Fractures**

- BMD = Bone mineral density.
- Cummings SR et al. *Am J Med 2002*;112:281-9.

**Results (Method 1)**
- Identified 12 randomized, placebo-controlled trials of antiresorptive agents that lasted 2 years and reported both vertebral fracture incidence (5 fractures per treatment group) and changes in spine BMD
- Used weighted regression models to estimate the association of change in spine BMD and reduction in vertebral fracture risk
- Expected RR = 0.75 - 0.03 X % increase in LSBMD

## Reduction in Fracture Risk Predicted From  Lumbar Spine Bone Mineral Density (BMD)

- *Wasnich RD, Miller PD.  *J Clin Endocrinol Metab. * 2000;85:231–236.
- †Cummings SR et al. *Am J Med*.  2002;112:281-9.

## Predicting the Effect of Antiresorptive Treatments on Vertebral Fractures

**Predicting the Effect of Antiresorptive ****Treatments on Vertebral Fractures**

- BMD = Bone mineral density.
- Cummings SR et al. *Am J Med 2002*;112:281-9.

**Results (Method 2)**
- Relative risk reduction in vertebral fractures exceeded that estimated from the regression model using change in lumbar spine BMD.
- Observed RR = 0.83 X Expected RR - 0.11
- Concluded that observed changes in lumbar spine BMD explain only a small proportion of the actual reduction in risk of vertebral fractures.

## Extended “New” Analysis

- Repeated “Wasnich & Miller” analysis excluding trials of non-approved medications and adding risedronate VERT studies; total of 13 trials.
- Results largely unchanged
- Change in LSBMD remains significantly associated with reduction in risk of VFx
- RR = 0.90 (95% CI: 0.83, 0.97) per 1%  in BMD
- Independent effect of treatment even without any increase in LSBMD
- RR = 0.81 (95% CI: 0.66, 1.00)

## Summary:  Change in BMD and Reduction in Risk of Vertebral Fractures

- Greater increase in BMD is associated with greater reduction in fracture risk
- Models predict that an 8% increase in BMD at the  spine (or 5% increase in BMD at the hip) would decrease risk by ~50%
- Significant treatment effect independent of BMD
- Models predict that an antiresorptive agent that does not increase BMD would decrease risk by ~25%
- Probably due to  bone turnover (resorption)

- BMD=Bone mineral density.

## Different Effects of Antiresorptive Therapies on Vertebral and Nonvertebral Fractures

**Different Effects of Antiresorptive Therapies ****on Vertebral and Nonvertebral Fractures**

- Some agents (eg, calcitonin, raloxifene) decrease vertebral fracture risk, but have not been shown to reduce risk of nonvertebral fractures
- Smaller changes in BMD and bone turnover were also observed for these agents compared to aminobisphosphonates

## Nonvertebral Fractures

## Changes in Bone Density and Turnover:  Reductions in Incidence of Nonvertebral Fractures

**Methods**
- Pooled all randomized, double-blind, placebo-controlled clinical trials with data on changes in BMD and/or BCM of bone turnover and incidence of nonvertebral fractures
- Larger studies given greater weight
- Related BMD and BCM over 1 year to reduction in fracture risk over duration of trial

- BMD = Bone mineral density.
- BCM = Biochemical markers.
- Hochberg MC et al. *J Clin Endocrinol Metab*. 2002;87:1586-92.

## Changes in Bone Density and Turnover:Reductions in Incidence of Nonvertebral Fractures

**Results**
- 18 trials identified
- 30 active antiresorptive treatment groups
- 69,369 woman-years of follow-up
- 92% in the 8 largest studies
- 2,415 women with new nonvertebral fractures
- 90% in the 8 largest studies

- Hochberg MC et al. *J Clin Endocrinol Metab*. 2002;87:1586-92.

## Relative Risk (RR) of Nonvertebral Fracture

- BMD = Bone mineral density.
- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Relative Risk (RR) of Nonvertebral Fracture

- BMD = Bone mineral density.
- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Relative Risk (RR) of Nonvertebral Fracture

- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Relative Risk (RR) of Nonvertebral Fracture

- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Correlation of BMD or BCM With Reduction in Nonvertebral Fracture Risk

- Increases in BMD and decreases in BCM at 1 year were both significantly associated with reduction in risk of new nonvertebral fractures
- Spine BMD		0.08 per 1%  (*P* = 0.02)
- Hip BMD		0.27 per 1%  (*P* = 0.006)
- Resorption BCM	0.07 per 10%  (*P* < 0.05)
- Formation BCM	0.14 per 10%  (*P* = 0.01)

- BMD = Bone mineral density.
- BCM = Biochemical markers.
- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Sensitivity Analyses

- Results generally robust to removal of both individual trials as well as all trials of individual agents

## Extended “New” Analysis

- Repeated analysis excluding trials of non-approved medications; total of 15 trials.
- Results largely unchanged
- Change in BMD at 1 year remains significantly associated with reduction in risk of non-VFx
- RR = 0.92 (95% CI: 0.86, 0.99) per 1%  in LSBMD
- RR = 0.78 (95% CI: 0.64, 0.95) per 1%  in HBMD
- No significant independent effect of treatment without any increase in LSBMD

## Summary:  Nonvertebral Fractures

- Greater increase in BMD or decline in BCM at 1 year is associated with greater reduction in fracture risk
- Models predict that a 6%  in BMD at spine or 3%  BMD at the hip, or 70%  in BCM of resorption or 50%  in BCM of bone formation would decrease risk of nonvertebral fractures by ~40% to 45%
- No significant treatment effect independent of BMD or BCM

- BMD = Bone mineral density.
- BCM = Biochemical markers.
- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Conclusions

-  BMD and  BCM are important indicators of antifracture efficacy of antiresorptive drugs
- Both for vertebral and nonvertebral fracture
-  BMD (and large  BCM) appear to be necessary to  risk of nonvertebral fractures
- Is there a threshold effect for vertebral fractures?
- Consistent with hypothesis of Riggs & Melton (2002)
- Further analyses of existing data needed
- Results cannot be extrapolated to anabolic agents such as fluoride or PTH

- BMD = Bone mineral density, BCM = Biochemical markers, PTH = Parathyroid hormone.
- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Extended “New” Analysis

- Repeated both analyses including data from pivotal phase III trial of teripartide (Neer et al, 2001)
- Results largely unchanged for both VFx and non-VFx
- Change in BMD remains significantly associated with reduction in risk of VFx
- Change in BMD at 1 year remains significantly associated with reduction in risk of non-VFx
- Significant independent effect of treatment without any increase in BMD for VFx but not for non-VFx

## Revised Extended Conclusions

-  BMD is an important indicator of antifracture efficacy for both antiresorptive and anabolic drugs (eg., PTH)
- Both for vertebral and nonvertebral fracture
- Larger s in BMD appear to be necessary to  risk of nonvertebral fractures
- Reductions in BCM of bone turnover are independent predictors of reductions in risk of vertebral but not for nonvertebral fractures

- BMD = Bone mineral density, BCM = Biochemical markers, PTH = Parathyroid hormone.
- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

## Back-ups

## Osteoporosis: Definition(Consensus Conference, 1993)

- [A] systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bony tissue, with a consequent increase in bone fragility and susceptibility to fractures.

## Osteoporosis: Definition(World Health Organization, 1994)

- Bone mineral density that is more than 2.5 standard deviations below the young average value (T-score > -2.5)

## Low Bone Mineral Density:Risk Factor for Fracture

- 2. Cummings SR et al. *Lancet*. 1993;341:72–75.
- 3. Ettinger B et al. *JAMA*. 1999;282:637–645.
- 4. Hochberg MC et al. *J Clin Endocrinol Metab*. 2002;87:1586-92.

**Low Bone Mineral Density:****Risk Factor for Fracture**

- 60% to 80% of bone strength is related to bone mineral density1
- Low bone mineral density predicts increased fracture risk2,3
- Increases in bone mineral density are associated with a reduction in fracture risk4

## Fracture Rates and Relative Risk by BMD Category*

- 0

- 0.5

- 1

- 1.5

- 2

- 2.5

- 3

- 3.5

**Rate per 100 Person-Years**

- BMD Category

**Normal**

**Osteopenia**

**Osteoporosis**

- *Data From National Osteoporosis Risk Assessment (NORA)
- Siris ES et al:  *JAMA.*  2001;286:2815–2822.

- Adjusted relative risk:
- Normal	1.0
- Osteopenia	1.7 (1.6, 1.9)
- Osteoporosis	2.7 (2.4, 3.1)

## High Bone Turnover:  Risk Factor for Fracture

- Higher levels of bone turnover are associated with increased rates of bone loss in untreated postmenopausal women
- Higher levels of bone turnover are associated with increased risk of hip fracture in postmenopausal women

## Bone Mineral Density and Bone Turnover:  Risk Factors for Hip Fracture

**Bone Mineral Density and Bone Turnover: **** Risk Factors for Hip Fracture**

- BMD = Bone mineral density.
- CTX = C–Telopeptide.
- D-Pyr = Deoxypyridinoline
- Garnero P et al.  *J Bone Miner Res.  *1996;11:1531–1538.

## Bone Mineral Density, Quality and Turnover: 

**Bone Mineral Density, Quality and Turnover: **
**Independent Risk Factors for Fracture **

- 3

- 2

- 1

- 0

- BMD

- Heel BUA

- 2.9

- Risk of Hip Fracture

- (Odds Ratio)

- Urinary CTX

- 2.5

- 2.6

- BMD = Bone mineral density.
- BUA = Broadband Ultrasonographic Attenuation.
- CTX = C–Telopeptide.
- Garnero P et al.  *Osteoporos Int*.  1998;8:563–569.

## Antiresorptive Agents Should Prevent Fractures Through Effects on Bone Strength

- Reduce biochemical markers ofbone turnover to premenopausal levels
-    Increase both cortical and trabecular bone mass (bone mineral density) and improve bone quality
- Decrease fracture risk

## Reduction in Biochemical MarkersPredicts Increase in Bone Mineral Density (BMD) 

- Changes in markers occur before changes in BMD
- Percent changes in bone turnover markers are much greater than the percent change in BMD
- Significant, albeit modest, correlations exist between changes in bone turnover markers and changes in BMD within individual studies
- Significant strong correlations exist between changes in bone turnover markers and changes in BMD across studies

## Change in Resorption Markers and BMD

- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:1586-92.

**Change in Resorption Markers and BMD**

## Change in Formation Markers and BMD

- Hochberg MC et al.  *J Clin Endocrinol Metab*.  2002;87:In press.

**Change in Formation Markers and BMD**

## Assessing the Effects of Antiresorptive Therapies in Reducing Osteoporotic Fracture

- “At present ...BMD measurement is the best surrogate clinical marker of therapeutic efficacy.”

- BMD = Bone mineral density.
- Chesnut CH, Rosen CJ, et al.  *J Bone Miner Res.*  2001;16:2163–72.

## Relationship of Change in Bone Turnover to Reduction in Risk of Vertebral Fractures

- Secondary analysis of data from a subset of 2,622 participants in MORE trial who had measurement of bone markers
- 2-part analysis
- Association of tertiles of change in bone markers with risk of vertebral fracture
- Multivariate analysis of change in bone markers as continuous variables adjusting for confounders

- MORE = Multiple Outcomes of Raloxifene Evaluation.
- Bjarnason NH et al. *Osteoporos Int.  *2001;12:922–930.

## Changes in Biochemical Markers Predict Vertebral Fracture Risk Reduction During Raloxifene Therapy

- 1

- 0

- 0.97

- 0.35*

- 0.89

- Osteocalcin (μg/L)

- 1

- 0

- 0.38*

- 0.74

- 1.05

- Relative Risk of Spine Fracture

- Relative Risk of Spine Fracture

- Bone Alkaline Phosphatase (μg/L)

- **P*<0.05.
- Bjarnason et al. *Osteoporos Int.  *2001;12:922–930.

- _>_–8.7

- –8.7–3.1

- >–3.1

- _>_–5.7

- –5.7–1.9

- >–1.9

## Relationship of Change in Bone Turnover to Reduction in Risk of Vertebral Fractures

- In patients treated with raloxifene, reduction in bone formation at 6 months was significantly related to reduction in vertebral fracture risk after adjustment for age, baseline BMD, BMI, smoking status, and prevalent vertebral fracture
- OR 0.76 (0.61, 0.96) for 8.9 μg/L  in serum OC
- OR 0.63 (0.50, 0.80) for 5.5 μg/L  in serum BAP

- BMD = Bone mineral density.
- BMI = Body mass index.
- Bjarnason NH et al. *Osteoporos Int.  *2001;12:922–930.

## Relationship of Change in Bone Turnover to Reduction in Risk of Vertebral Fractures

- Secondary analysis of data from a subset of 2,442 participants in VERT study who had measurement of bone markers.
- In patients treated with risedronate, reduction in bone resorption at 3 months was significantly related to reduction in vertebral fracture risk
- 30%  in urinary NTX/Cr ~ 17%  in VFx risk

- VERT = Vertebral Efficacy and Risedronate Therapy.
- NTX/Cr = N-telopeptide/creatinine.
- Eastell R et al.  *J Bone Miner Res. * 2001;Abstract 1107.

## Reduction in Bone Turnover Predicts Fracture in Alendronate Treated Women: The FIT Study

- DC Bauer et al, for the FIT Research Group
- Presented at IOF WCO, 14 May 2002

## Research Question

- Among alendronate and placebo treated women, are baseline values and changes in biochemical markers of bone turnover associated with:
- Vertebral fracture?
- If so, are effects of bone turnover independent of BMD?

## Methods: Design and Subjects

- Prospective cohort study
- Fracture Intervention Trial (FIT)
-  6459 postmenopausal women
-  FNBMD < 0.68 gm/cm2
- Randomized to ALN (5 mg/d) or placebo
- ALN increased after 2 years to 10 mg/d
- Calcium/vit D supplements if needed (>80%)

## Methods: Measurements

- Bone turnover at baseline and 1 year (non-fasting archived serum)
-  BAP (Hybritech)
-  sCTX (Crosslaps)
-  P1NP (Orion)
- BMD at baseline and 1 year (Hologic QDR-2000)
- Fracture outcomes (3.6 yr follow-up)
-  Central review of paired lateral spine radiographs

## Results: Placebo Group

- Markers fell 8-31% over 1 year
- Neither baseline marker level nor change over 1 year were associated with vertebral fracture

## Results: Alendronate Group

- Baseline marker not associated with fracture
- Greater reductions in one or more markers were associated with fewer vertebral fractures

## Alendronate Group: Change in BAP and Risk of Spine Fracture

**Change in BAP (mg/dl)**

**29**

**28**

**22**

**20**

**19**

**RR per SD:**
**0.74 (0.63, 0.87)**

**Alendronate Group: Change in BAP ****and Risk of Spine Fracture**

## Alendronate Group: Change in Spine BMD and Risk of Spine Fracture

**Change in BMD (%)**

**RR per SD:**
**0.92 (0.76, 1.11)**

**Alendronate Group: Change in Spine BMD and Risk of Spine Fracture**

## Additional Analyses

- Change in marker results similar after:
- Adjustment for baseline BMD or vertebral fx
- Limiting analysis to women with osteoporosis
- low BMD and/or existing VFx
- Further adjustment for change in spine BMD did not alter results

## Conclusions

- In the Fracture Intervention Trial:
- Baseline markers not associated with fracture
- Change in one or more marker was associated with subsequent vertebral fracture in alendronate treated women.
- Effect independent of BMD
- Reduction in bone turnover clearly plays an important role in the efficacy of alendronate treatment

## Antiresorptive Agents:Mechanisms of Fracture Risk Reduction

**Antiresorptive Agents:****Mechanisms of Fracture Risk Reduction**

**?**