Call for greater use of comparative effectiveness studies to help advance disease management

April 03, 2007

Porto [March, 31st 2007]. The largest retrospective, observational study comparing two osteoporosis therapies on the basis of fracture reduction was presented today at the Seventh European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ECCEO) in Porto, Portugal.1 Patients taking the osteoporosis treatment risedronate (Actonel®, risedronate sodium) were almost half as likely to sustain a hip fracture as those taking alendronate in the first year of treatment, according to the REAL (RisedronatE, ALendronate) study.

Only a few "head-to-head" observational studies, or comparative effectiveness studies, have been conducted in the field of osteoporosis. Beyond the safety and efficacy data provided by placebo-controlled randomized trials, healthcare professionals have increasingly expressed interest in more head-to-head data comparing therapies on the relevant clinical endpoint, fracture.

Comparative effectiveness filling the knowledge gap

Today experts are highlighting that well-designed comparative effectiveness studies can help advance our clinical knowledge where little data exists. Dr. Olaf Klungel, Associate Professor, Division of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, Netherlands, is a leading expert in the field of comparative effectiveness study design.

"There is a wealth of data available from large healthcare databases that enable us to research important clinical questions," said Dr. Klungel, "Robust methodology exists for comparing different therapies through observational database analysis. We must advance physicians' understanding and evaluation of these studies so that they can confidently integrate the information into their clinical decisions, when appropriate."

Physicians want to know the impact of their clinical decisions on the disease outcomes that matter most to patients. In the cardiovascular area, observational methods have been applied to compare antihypertensive therapies on the relevant outcomes of heart attack and stroke.2,3 In osteoporosis, similar methods are now being applied to compare therapies on the basis of fracture.

REAL life results in osteoporosis

REAL, a retrospective cohort study, included 33,830 women newly treated with once-weekly doses of either Actonel or alendronate in 'real-life' clinical practice. Results showed that at 12 months patients on Actonel had a 43% (p=0.01) lower incidence of hip fractures compared to patients on alendronate. At 6 months similar results were seen, with Actonel resulting in a 46% (p=0.02) greater reduction in risk of hip fracture versus alendronate. The two treatments were not compared on the basis of side effects in this study.

"In osteoporosis, it is unlikely that prospective, head-to-head clinical fracture trials will be conducted due to the large number of patients required to show a difference between two effective therapies," said Professor Delmas, REAL study author, Université Claude Bernard, Lyon. "Large, comparative, retrospective analyses, like the REAL study, are one way to fill the knowledge gap and should be considered in the total body of evidence for a drug to optimise treatment decisions and enhance patient care."

About the REAL study

The RisedronatE, ALendronate (REAL) cohort study was a retrospective analysis of a health service utilization database. These databases are generated by medical insurers for the payment or reimbursement of health services. They include longitudinal, patient specific information such as diagnosis codes for reimbursable expenses (e.g. fractures) and pharmacy dispensations. The REAL study utilized a U.S database of 12 million insured participants. It was a pooled dataset of one health plan within Ingenix Lab/Rx, and the 100 employer health plans within Medstat Marketscan.

From the dataset, women aged 65 years and older were identified who were new users of weekly bisphosphonate therapy, either risedronate 35 mg (N=12,215) or alendronate 35 mg or 70 mg (N=21,615). Patients had to have at least six months medical history prior to treatment initiation and were followed for 12 months after bisphosphonate initiation to assess 6 and 12 month fracture incidence at both the hip and at a composite group of non-vertebral sites (hip, wrist, clavicle, humerus, pelvis and leg). Standard statistical methods were used to compare the incidence of fracture between the risedronate and alendronate groups (Cox proportional hazard modeling). As with all retrospective cohort studies, an important concern is that in real world clinical practice patients are not randomly assigned to treatment groups, potentially introducing "selection bias" into the results. The risedronate and alendronate groups were compared for risk factors for fracture at baseline, and all results were risk-adjusted for potential differences in baseline fracture risk.

In the study, patients on risedronate had 46% (p=0.02) and 43% (p=0.01) lower incidence of hip fracture than patients taking alendronate at 6 and 12 months, respectively. Prior to risk adjustment for baseline differences in fracture risk, the crude incidence of fracture in each population was as follows: At six months, 0.29% of alendronate patients had sustained a hip fracture, compared to 0.17% of risedronate patients. At 12 months, 0.58% of alendronate patients had suffered a hip fracture, compared to 0.37% of risedronate patients.

With respect to nonvertebral fracture, patients on risedronate had 19% (p=0.05) and 18% (p=0.03) lower incidence of nonvertebral fracture than patients on alendronate at 6 and 12 months, respectively. Prior to risk adjustment for baseline differences in fracture risk, the crude incidence of fracture in each population was as follows: At six months, 1.31% of alendronate patients had experienced nonvertebral fracture, compared to 1.14% of risedronate patients. At 12 months, 2.30% of alendronate patients had sustained nonvertebral fracture, compared to 1.99% of risedronate patients.

Please see the full prescribing information for each treatment to obtain more information on the adverse events associated with each therapy.

All study investigators had full access to the complete dataset, and each of them independently verified the results of the analyses at their respective institutions. The study was sponsored by The Alliance for Better Bone Health.

About osteoporosis

Osteoporosis is a skeletal disease that increases bone fragility and susceptibility to fracture. Fracture is a devastating consequence of osteoporosis and can occur at any site of the body. A 50-year-old woman has around a 40% lifetime risk of suffering a fracture from osteoporosis4 - equivalent to the women's lifetime risk for cardiovascular disease.5

About The Alliance for Better Bone Health

The Alliance for Better Bone Health was formed by Procter & Gamble Pharmaceuticals and Aventis part of the sanofi-aventis Group, in May 1997 to promote bone health and disease awareness through numerous activities to support physicians and patients around the globe.

About Procter & Gamble [NYSE:PG]

Three billion times a day, P&G brands touch the lives of people around the world. The company has one of the strongest portfolios of trusted, quality, leadership brands, including Pampers®, Tide®, Ariel®, Always®, Whisper®, Pantene®, Mach3®, Bounty®, Dawn®, Pringles®, Folgers®, Charmin®, Downy®, Lenor®, Iams®, Crest®, Oral-B®, Actonel®, Duracell®, Olay®, Head & Shoulders®, Wella, Gillette®, and Braun. The P&G community consists of over 135,000 employees working in over 80 countries worldwide. Please visit for the latest news and in-depth information about P&G and its brands.

About sanofi-aventis

Sanofi-aventis is one of the world leaders in the pharmaceutical industry, ranking number one in Europe. Backed by a world-class R&D organisation, sanofi-aventis is developing leading positions in seven major therapeutic areas: cardiovascular, thrombosis, oncology, metabolic diseases, central nervous system, internal medicine and vaccines. Sanofi-aventis is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).

Forward Looking Statements

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For P&G: All statements, other than statements of historical fact included in this release, are forward-looking statements, as that term is defined in the Private Securities Litigation Reform Act of 1995. Such statements are based on financial data, market assumptions and business plans available only as of the time the statements are made, which may become out of date or incomplete. We assume no obligation to update any forward-looking statement as a result of new information, future events or other factors. Forward-looking statements are inherently uncertain, and investors must recognize that events could differ significantly from our expectations. In addition to the risks and uncertainties noted in this release, there are certain factors that could cause actual results to differ materially from those anticipated by some of the statements made. These include: (1) the ability to achieve business plans, including with respect to lower income consumers and growing existing sales and volume profitably despite high levels of competitive activity, especially with respect to the product categories and geographical markets (including developing markets) in which the Company has chosen to focus; (2) the ability to successfully execute, manage and integrate key acquisitions and mergers, including (i) the Domination and Profit Transfer Agreement with Wella, and (ii) the Company's merger with The Gillette Company, and to achieve the cost and growth synergies in accordance with the stated goals of these transactions; (3) the ability to manage and maintain key customer relationships; (4) the ability to maintain key manufacturing and supply sources (including sole supplier and plant manufacturing sources); (5) the ability to successfully manage regulatory, tax and legal matters (including product liability, patent, and intellectual property matters as well as those related to the integration of Gillette and its subsidiaries), and to resolve pending matters within current estimates; (6) the ability to successfully implement, achieve and sustain cost improvement plans in manufacturing and overhead areas, including the Company's outsourcing projects; (7) the ability to successfully manage currency (including currency issues in volatile countries), debt, interest rate and commodity cost exposures; (8) the ability to manage continued global political and/or economic uncertainty and disruptions, especially in the Company's significant geographical markets, as well as any political and/or economic uncertainty and disruptions due to terrorist activities; (9) the ability to successfully manage competitive factors, including prices, promotional incentives and trade terms for products; (10) the ability to obtain patents and respond to technological advances attained by competitors and patents granted to competitors; (11) the ability to successfully manage increases in the prices of raw materials used to make the Company's products; (12) the ability to stay close to consumers in an era of increased media fragmentation; and (13) the ability to stay on the leading edge of innovation. For additional information concerning factors that could cause actual results to materially differ from those projected herein, please refer to our most recent 10-K, 10-Q and 8-K reports.


1. Silverman S, et al. Effectiveness of bisphosphonates on non-vertebral and hip fractures in the first year of therapy, the risedronate and alendronate cohort study. Osteoporosis Int. 2007 Jan; 18(1): 25-34

2. Psaty BM, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995 Aug; 274(8): 620-625

3. Klungel OH, et al. Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med 2001 Jan; 161: 37-43

4. Melton LJ et al. Perspective. How many women have osteoporosis? J Bone Miner Res 1992; 7: 1005-1010

5. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002; 359: 1929-36

Ketchum UK

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