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Relative Effectiveness of Osteoporosis Drugs for Preventing Nonvertebral Fracture

Suzanne M. Cadarette, PhD; Jeffrey N. Katz, MD, MS; M. Alan Brookhart, PhD; Til Stürmer, MD, MPH; Margaret R. Stedman, MPH; and Daniel H. Solomon, MD, MPH
[+] Article and Author Information

From Brigham and Women's Hospital, Harvard Medical School, and Boston University, Boston, Massachusetts.


Acknowledgment: The authors thank Raisa Levin, MS, for preparing the study data for analysis.

Grant Support: By grant K25 AG027400 from the National Institute on Aging (Dr. Brookhart), a Canadian Institutes of Health Research Post-Doctoral Fellowship (Dr. Cadarette), grants K24 AR02123 and P60 AR47782 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Dr. Katz), grants from the Arthritis Foundation and grants R21 AG027066 and P60 AR47782 from the National Institutes of Health (Dr. Solomon), and grant RO1 AG023178 from the National Institute on Aging (Dr. Stürmer).

Potential Financial Conflicts of Interest:Grants received: M.A. Brookhart (Amgen), D.H. Solomon (Merck). Grants pending: M.A. Brookhart (Amgen).

Reproducible Research Statement:Study protocol, statistical code, and data set: Not available.

Requests for Single Reprints: Suzanne M. Cadarette, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120.

Current Author Addresses: Drs. Cadarette, Brookhart, and Stürmer and Ms. Stedman: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120.

Dr. Katz: Department of Orthopaedic Surgery and Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115.

Dr. Solomon: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115.

Author Contributions: Conception and design: S.M. Cadarette, M.A. Brookhart, T. Stürmer, D.H. Solomon.

Analysis and interpretation of the data: S.M. Cadarette, J.N. Katz, M.A. Brookhart, T. Stürmer, M.R. Stedman, D.H. Solomon.

Drafting of the article: S.M. Cadarette, T. Stürmer, D.H. Solomon.

Critical revision of the article for important intellectual content: S.M. Cadarette, J.N. Katz, M.A. Brookhart, T. Stürmer, M.R. Stedman, D.H. Solomon.

Final approval of the article: S.M. Cadarette, J.N. Katz, M.A. Brookhart, T. Stürmer, M.R. Stedman, D.H. Solomon.

Provision of study materials or patients: D.H. Solomon.

Statistical expertise: M.A. Brookhart, T. Stürmer, M.R. Stedman.


Ann Intern Med. 2008;148(9):637-646. doi:10.7326/0003-4819-148-9-200805060-00003
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We found little difference in nonvertebral fracture rates among new recipients of alendronate and risedronate, regardless of the duration of observation (6, 12, or 24 months since treatment initiation), assumptions underlying the analysis (on-treatment or intent-to-treat), or subgroup considered. Our results contrast with findings from other observational studies that document risedronate as more effective than alendronate in preventing nonvertebral fractures (1213). Our findings are also somewhat surprising because randomized, controlled trials (RCTs) show that alendronate improves bone mineral density and reduces bone turnover markers better than risedronate (34). Previous observational studies comparing bisphosphonates included preventive doses of alendronate that are less effective than treatment doses (26). We restricted our study to new recipients of pharmacotherapies approved for osteoporosis treatment. We also studied nonvertebral fracture sites most commonly associated with osteoporosis: hip, humerus, and radius or ulna (rather than also including clavicle, leg, and pelvis) (1213). These methodological differences in study design may partially explain the differences between our findings of equivalent fracture prevention between bisphosphonates, compared with previous observational studies suggesting that risedronate is more effective than alendronate in preventing nonvertebral fractures.

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Figures

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Figure 1.
Study flow diagram.

Osteoporosis drugs were oral bisphosphonates (alendronate, 10 mg or 70 mg; risedronate, 5 mg or 35 mg), nasal calcitonin, or raloxifene. *May meet >1 exclusion criterion.

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Figure 2.
Cumulative incidence of nonvertebral fractures within 12 months of treatment initiation, by drug.
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Figure 3.
Nonvertebral fracture risk within 12 months of treatment initiation compared with alendronate.

Hazard ratios and 95% CIs (error bars) were calculated by using Cox proportional hazard models stratified by state and adjusted for propensity score quintiles, age, race, diagnosis of osteoporosis, and fracture history (previous nonvertebral and vertebral fracture). The intent-to-treat analysis (Primary) was censored on the date of death or end of follow-up (12 months after treatment initiation, 31 December 2003 [New Jersey], or 31 December 2005 [Pennsylvania]). OT 15 = patients receiving treatment who were censored on the first day of switching agents, losing drug plan eligibility, entering a nursing home, or discontinuing use of the drug (last date covered by drug plan plus 15 days, allowing for 30-day gaps between prescriptions) on the date of death or end of follow-up; OT 90 = patients receiving treatment who were censored as for OT 15, except that follow-up was extended to 90 d after drug discontinuation; Fx Hx = patients with a history of any fracture within 12 mo before treatment initiation; No Fx Hx = patients with no known history of fracture within 12 mo before treatment initiation; ≥2 Script = patients who filled ≥2 consecutive prescriptions of their index drug, excluding those who lost drug plan eligibility, entered a nursing home, died, had a nonvertebral fracture, or switched agents within the first 30 d; No Cancer = patients with no diagnosis of malignant neoplasm within 12 months before drug initiation; OP = patients with a medical claim for osteoporosis diagnosis within 12 mo before drug initiation; No OP = patients with no medical claim for osteoporosis diagnosis within 12 mo before treatment initiation; No HT = women with no history of hormone therapy within 12 mo before treatment initiation.

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Figure 4.
Nonvertebral fracture rates within 12 months, by fracture risk group and drug.

Age cut-off was determined by the median cohort age (79 y). Fracture history was identified by Medicare claims within 12 months before treatment initiation. 65–79 y, No Fx = patients age 65 to 79 years without fracture history (lowest risk); ≥80 y, No Fx = patients age ≥80 years without fracture history; 65–79 y, Fx = patients age 65 to 79 years with fracture history; ≥80 y, Fx = patients age ≥80 years with fracture history (highest risk).

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Comments

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Relative Effectiveness of Osteoporosis Drugs for Preventing Nonvertebral Fracture
Posted on May 6, 2008
Abhimanyu Beri
Michigan State University
Conflict of Interest: None Declared

We read with great interest the article by Cadarette et al (1). Osteoporosis and fracture risk in the elderly, especially post-menopausal women is a growing problem in the population. A few things came to our mind while reading this article. First, the authors do not mention or control regarding patients' dietary calcium intake and physical activity, two factors that are the first recommendations for prevention of osteoporosis. Secondly, there is also no estimation of prescription and over the counter calcium and vitamin D supplementation in the patients (2,3). This may be lower in poorer patients who might have been preferentially included in this study. Thirdly, the subset that was prescribed calcitonin was a less healthy group, as evident by their age, higher co-morbidity score the fact that they had more prescription drugs per patient and had a much higher incidence of co-morbidities. We would specifically like to point out a history of falls, vertebral fractures, Parkinson's and dementia that was almost 50% more than the other drug groups. A basic requirement for prescription of bisphosphonates is the ability to sit upright or stand for 30 minutess after swallowing these drugs orally (4). As patients with the above co-morbidities are less likely to have this ability, we feel that a bias during prescription may have been present and that the less healthy patients were prescribed calcitonin. And as we do not know the T-scores for these patients, we cannot estimate the true degree of osteoporosis in them.

References:

1.Cadarette SM, Katz JN, Brookhart MA, Stürmer T, Stedman MR, Solomon DH. Relative Effectiveness of Osteoporosis Drugs for Preventing Nonvertebral Fracture. Ann Intern Med 2008; 148: 637-646

2.Papadimitropoulos E, Wells G, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficiency of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocrin Rev. 2002; 23: 560-569.

3.Positive effects of exercise on falls and fracture risk in osteopenic women. Hourigan SR, Nitz JC, Brauer SG, O'Neill S, Wong J, Richardson CA. Osteoporos Int. 2008 Jan 11 [Epub ahead of print]

4.http://www.merck.com/product/usa/pi_circulars/f/fosamax/fosamax_pi.pdf (Accessed on May 6, 2008)

Conflict of Interest:

None declared

In response
Posted on June 25, 2008
Suzanne M. Cadarette
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
Conflict of Interest: None Declared

We agree with and appreciate the comments raised by Drs. Beri and Khattri. In their letter, Drs. Beri and Khattri highlight our finding that calcitonin recipients under study were sicker than alendronate recipients based on measured variables (1). They also point out that bisphosphonate dosing instructions are complex, and thus frail patients may have been preferentially treated with calcitonin, administered by daily nasal spray. We agree that residual confounding could explain part of our findings, and discussed limitations of administrative claims data in our manuscript. Results from our theoretical sensitivity analysis identified that it is unlikely that the higher fracture risk observed among calcitonin recipients compared with alendronate recipients is due to unmeasured confounding. However as this analysis was based on the assumption of a single unmeasured confounder (2), it is possible that multiple unmeasured confounding factors collectively introduced bias into the results. Nonetheless, we did adjust for many factors associated with frailty, such as age, history of falls, vertebral fractures, Parkinson's disease, dementia, comorbidity score and medication use. We also completed seven different subgroup analyses, all with results similar to our main findings: no large difference in nonvertebral fracture rates between risedronate or raloxifene and alendronate, and higher nonvertebral fracture risk among calcitonin recipients compared with alendronate recipients. Of interest, however, we did document more fractures among raloxifene recipients compared with alendronate recipients in the subgroup with previous fracture. We therefore emphasize caution in interpreting findings comparing calcitonin and alendronate, as well as results comparing raloxifene and alendronate, as raloxifene recipients were apparently healthier based on measured variables. Our results comparing bisphophonates are more compelling because risedronate and alendronate recipients were similar based on measured risk factors for fracture, however, we cannot rule out potential differences in unmeasured factors.

1. Cadarette SM, Katz JN, Brookhart MA, Stürmer T, Stedman MR, Solomon DH. Relative effectiveness of osteoporosis drugs for preventing nonvertebral fracture. Ann Intern Med. 2008;148:637-46.

2. Schneeweiss S. Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics. Pharmacoepidemiol Drug Saf. 2006;15:291-303.

Conflict of Interest:

Dr. Solomon has received salary support from Merck through a research grant to the Brigham and Women's Hospital for unrelated work. There was no pharmaceutical industry support for this study.

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Summary for Patients

Drug Therapy for Osteoporosis

The summary below is from the full report titled “Relative Effectiveness of Osteoporosis Drugs for Preventing Nonvertebral Fracture.” It is in the 6 May 2008 issue of Annals of Internal Medicine (volume 148, pages 637-646). The authors are S.M. Cadarette, J.N. Katz, M.A. Brookhart, T. Stürmer, M.R. Stedman, and D.H. Solomon.

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