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Lasofoxifene reduced risk of osteoporotic fractures.

Lasofoxifene reduced risk of osteoporotic fractures.

Critique date: Tue, 09/07/2010 - 7:53pm
Institution: 
Mount Sinai School of Medicine
   
Article Citation
Citation: 
Cummings, S. R., Ensrud, K., Delmas, P. D., LaCroix, A. Z., Vukicevic, S., Reid, D. M., et al. (2010). Lasofoxifene in postmenopausal women with osteoporosis. The New England Journal of Medicine, 362(8), 686-696.
   
Clinical Bottom Lines

1. At 0.5 mg per day vs. placebo lasofoxifene is associated with reduced risk in the following: vertebral fracture, hazard ratio (HR) 0.58 with 95% confidence interval (CI) of 0.47 to 0.70;  non-vertebral fracture, HR 0.76; 95% CI, 0.64 to 0.91;  ER-positive breast cancer  HR 0.19; 95% CI 0.07 to 0.56; coronary heart disease events HR 0.68; 95% CI, 0.50 to 0.93, and stroke HR 0.64; 95% CI, 0.41 to 0.99.

2 Lasofoxifene is associated with an increase in venous thromboembolic events at  both 0.25 mg and 0.5 mg daily; hazard ratios, 2.67 (95% CI, 1.55 to 4.58) and 2.06 (95% CI, 1.17 to 3.60), respectively.

   
Methods
Type of Study: 
Therapy / Prevention
Study Design: 
Randomized, controlled clinical trial
Follow-up Period: 
5 years
Setting: 
community-based, 113 sites in 32 countries
Patient Population: 

Participants:

Number of participants: 8556 women in 113 sites in 32 countries

Mean age and range: 67 +/- 5.2

Participants were recruited in each of the Pfizer investigational sites located in multiple US states and worldwide; it is unclear how the participants were recruited.

Inclusions:

Women between the ages of 59 and 80

Bone mineral density T score of –2.5 or less at the lumbar spine or femoral neck,

Self-reported good or excellent health

Had undergone mammography within the previous 6 months, with no findings that were suggestive of breast cancer

Significant Exclusions: 

Diseases affecting bone metabolism

History of breast cancer, venous thromboembolic disease, or superficial thrombophlebitis within the previous 5 years

Stroke or myocardial infarction in the previous 6 months

Treatment with estrogen, raloxifene, or tibolone within the previous 3 months

Treatment with bisphosphonates, sodium fluoride, or parathyroid hormone for more than 1 month within the previous 2 years

Treatment with oral corticosteroids for 3 months or more within the previous year

History of endometrial hyperplasia or cancer

Unexplained vaginal bleeding or spotting in the previous year

Clinical diagnosis of vertebral fracture within the previous 12 months,

More than three fractures detected on radiographs of the spine, or a T score of –4.5 or less at the femoral neck or lumbar spine

Intervention/Exposure: 
  1. Run-in period: 1 g of calcium and 400 to 800 IU of vitamin D and placebo during a 6- to 8-week run-in period.
  2. Intervention:Women who received 75% or more of above pills during the run in period were randomly assigned to receive lasofoxifene, at a dose of either 0.25 mg per day (the lower dose lasofoxifene group) or 0.5 mg per day (the higher-dose lasofoxifene group), or placebo. The trial was planned to continue for 5 years. All women continued to receive 1 gram of calcium and 400 to 800 IU of vitamin D regardless of whether they were taking higher-dose lasofoxifene, lower-dose lasofoxifene, or placebo.

Duration– planned for 5 years

Outcome Measures: 

Primary Outcome:Trial was planned to continue for 5 years. Vertebral fracture was the primary end point for the first 3 years of the trial, and nonvertebral fracture and ER-positive breast cancer were co-primary end points through 5 years.

Vertebral fractures were detected by lateral spine radiographs obtained at 12, 24, 36, and 60 months, and vertebral fractures were diagnosed if two of three criteria were met: an increase of one grade in a 4-point rating of vertebral deformity from normal (0 points) to severe (3 points), a decrease of 20% or more and 4 mm or more in vertebral height, or a qualitative diagnosis of a vertebral fracture.

Nonvertebral fractures, regardless of the degree of trauma but excluding fractures of the skull, face, fingers, and toes, were confirmed by means of radiographic studies.

Secondary Outcomes: Major coronary heart disease and stroke

Other Covariates: Baseline characteristics were similar for all 3 groups, characteristics identified were age, race, radiographic evidence of vertebral facture, family history of breast CA, current smoking status, diabetes, hypertension, hysterectomy, BMI, bone mineral density T score at the lumbar spine and femoral neck. 

Participant Follow-up: 
Assessment of outcomes at 5 years was completed for 6614 randomly assigned patients (77.3%). A total of 1820 patients in the placebo group (63.8%), 1753 patients in the lower-dose lasofoxifene group (61.5%), and 1777 patients in the higher-dose lasofoxifene group (62.3%) received the assigned study drug for 5 years.
   
Conclusion
Results: 

At the 5 year follow-up period, 0.5 mg lasofoxifene (the clinically intended dose) compared to placebo demonstrated statistically significant risk reductions in non-vertebral fractures, vertebral fractures, ER-positive breast cancer, invasive breast cancer, major coronary disease events and stroke; and statistically significant risk increases in venous thromboembolic events.

Major Outcomes in 5 Years, Lasofoxifene 0.5 mg

 Outcome

Placebo Event Rate

Treatment Group Event Rate

Hazard Ratio (95% CI), P Value

Differences in Rates in no/1000 person-yr

Nonvertebral  Fracture

10.38%

8.06%

0.78

(0.64 to 0.91)

0.002

–5.9

Vertebral fracture

9.55%

5.68%

0.59

(0.47 to 0.70)

<0.001

–9.3

Hip fracture

1.23%

0.95%

0.77

(0.46 to 1.27)

0.3

–0.6

ER-positive breast  cancer

0.77%

0.15%

0.19

(0.07 to 0.56)

<0.001

–1.4

Invasive breast cancer

0.73%

0.11%

0.15

(0.04 to 0.50)

<0.001

–1.4

Major coronary heart disease event

3.33%

2.28%

0.68

(0.50 to 0.93)

0.02

–2.4

Stroke

1.75%

1.12%

0.64

(0.41 to 0.99)

0.04

–1.4

Venous thromboembolic event

0.63%

1.30%

2.06

(1.17 to 3.61)

0.01

1.5

Pulmonary embolism

0.07%

0.32%

4.50

(0.97 to 20.8)

0.03

0.54

All-cause mortality *

2.28%

2.56%

1.12

(0.80 to 1.56)

0.51

0.6

Fatal stroke *

0.18%

0.25%

1.40

(0.44 to 4.40)

0.57

0.15

 

Major Outcomes 5 Years, Lasofoxifene 0.5 mg

Outcomes with Risk Reductions

Number Needed to Treat

Nonvertebral  Fracture

43

Vertebral fracture

26

Hip fracture

357

ER-positive breast  cancer

161

Invasive breast cancer

161

Major coronary heart disease event

95

Stroke

158

 

Major Outcomes 5 Years, Lasofoxifene 0.5 mg

Outcomes with Risk Increases

Number Needed to Harm

Venous thromboembolic event

150

Pulmonary embolism

407

All-cause mortality

357

Fatal stroke

1426
Concerns Regarding Methodology, Applicability to Older Adults, etc.: 

1. Lasofoxifene offers an alternative to raloxifene for patients who may benefit from an estrogen receptor modulator for osteoporosis or those who may not tolerate bisphosphonates.

2. Compared to raloxifene which has not been shown to reduce rates of nonvertebral fractures; this study indicates that lasofoxifene offers a reduction in nonvertebral fractures.

3. The reductions in vertebral fractures are based on radiograph examinations, it is unclear whether lasofoxifene would also reduce the risk for clinically significant symptomatic vertebral fractures.

4. Under methods, investigators state that during annual follow-up patients who were found to have any of the following were referred to her physician to consider alternative treatment for osteoporosis:

- BMD reduced by 7% or more at the hip or 5% or more at the lumbar spine in any year, or by 10% or more at either site during the during the study

-T score at either site less than -4.5

- an osteoporotic fracture

Investigators also state that patients were encouraged to continue taking the study drug if they received a non-hormonal agent such as a bisphosphonate. It is unclear how many patients were in this subset; and how they were treated in the study. This is a potential confounding factor that may have influenced treatment effect favoring lasofoxifene.

5. The benefits of using lasofoxifene must be balanced against the increase risk of thromboembolic events. Patients on lasofoxifene were around twice as likely to have a thromboembolic event vs. placebo and this may not be approptiate for a patient with increased risk of thromboembolic events. 

Funding Source and Role: 
Industry Sponsored - Pfizer
Created By: 
Maria Kristina Gestuvo, Geriatrics Fellow, Brookdale Department of Geriatrics, Mount Sinai Medical Center
This is a review of the validity of a single study; the ‘bottom lines’ do not reflect comparison with the rest of the literature on this subject.