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Pharmacology in the News

Geriatric Times

May/June 2001

Vol. II

Issue 3

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Risedronate Prevents Hip Fractures, Increases Bone Mineral Density

Each year more than 1.5 million fractures, including 300,000 hip fractures, are attributed to osteoporosis. Risedronate sodium (Actonel) has been shown to increase bone mineral density (BMD) and decrease the risk of fractures, and it is one of two bisphosphonates approved by the U.S. Food and Drug Administration for both the prevention and treatment of postmenopausal osteoporosis.

Bisphosphonates work by inhibiting the resorption of bone and promoting new bone formation. They are also approved for the prevention and treatment of osteoporosis caused by chronic use of corticosteroids. Other treatment options for bone loss include hormone replacement therapy, calcitonin (Miacalcin, another hormone) and selective estrogen receptor modulators (such as raloxifene [Evista]), but only the bisphosphonates are FDA-approved to treat osteoporosis in men, who comprise 20% of patients, as well.

One of the challenges of osteoporosis treatment has been identifying which drugs are most appropriate for each patient. Risk factors for hip fracture are commonly divided into two categories: skeletal (e.g., low BMD or a previous fracture) and nonskeletal (e.g., age, difficulty standing from a sitting position, poor hand-eye coordination, poor gait, or a history of fall-related injuries).

In a manufacturer-supported study published in the Feb. 1 issue of The New England Journal of Medicine, researchers confirmed earlier findings that risedronate is more effective in preventing hip fractures in women with confirmed osteoporosis than in those with other risk factors. Michael R. McClung, M.D., and colleagues with the Hip Intervention Program Study Group randomized 9,331 women -- 5,445 aged 70 to 79 years old with confirmed osteoporosis and 3,886 aged 80 years or older with nonskeletal risk factors -- to three years of risedronate (2.5 mg/day or 5 mg/day) or placebo; all participants were also given calcium supplementation at 1000 mg/day.

The overall incidence of hip fracture was 2.8% among the women assigned to risedronate, compared with 3.9% among those assigned to placebo. Among women 70 to 79 years old, the incidence of hip fracture was 1.9% in those on risedronate, compared to 3.2% in those taking placebo.

Risedronate had a slight but not significant effect on the incidence of hip fracture in women in the 80 years or older group, the majority of whom had been recruited based on nonskeletal risk factors. Results from this study suggest that women with a history of fractures are more likely to benefit from bisphosphonate drug therapy and that elderly women should be selected for this treatment based on bone density measurements, as opposed to their risk of falling.

Risedronate has been shown safe to take for up to four years. The most common side effects include abdominal pain, skin rash, arthralgia, diarrhea and headache. While bisphosphonates have been reported to have an upper gastrointestinal safety profile similar to placebo, in preclinical studies both risedronate and alendronate (Fosamax) had the potential to irritate gastric mucosa at high doses. Results of two recent trials involving 581 healthy postmenopausal women showed that risedronate was associated with a significantly lower incidence of upper gastrointestinal side effects than alendronate. Researchers suggested that bisphosphonates may differ in their potential to cause gastrointestinal damage and that if a patient does not tolerate one, try another -- JH

Daffodils Offer New Treatment Option for Alzheimer's Disease

The 4 million people across the United States who suffer from Alzheimer's disease (AD) will soon have another treatment option available. As reported in the March 5 Pink Sheet, Feb. 28 marked the U.S. Food and Drug Administration's approval of Janssen Pharmaceutica's new AD treatment, Reminyl (galantamine hydrobromide). Galantamine, extracted from the bulbs of the Narcissus pseudonarcissus -- more commonly known as the daffodil -- is expected to become available in the United States in May. Results of a study published in the June 27, 2000, issue of Neurology showed that galantamine was effective in four AD measures of improvement: cognitive, global, daily function and behavior scores. According to Janssen, improvement in each of these areas in the same patient group is what sets galantamine apart from its competitors, rivastigmine tartrate (Exelon) and donepezil (Aricept). They added that while these other treatments have demonstrated improvement in these areas, neither has shown improvement in all four categories in one population group.

Galantamine has a dual mechanism of action. It combines allosteric modulation of nicotinic acetylcholine receptors with reversible, competitive inhibition of acetylcholinesterase. Its benefits over placebo include sustained cognitive function, better outcomes on activities of daily living and better outcomes on behavioral symptoms (these results were sustained throughout studies of 12-month duration).

The studies on which the approval of galantamine were based were 13 to 26 weeks in duration and evaluated total daily doses, given in divided doses, of 8 mg, 16 mg, 24 mg and 32 mg. Improvements over placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) were 1.7 units for 8 mg, 3.3 units for 16 mg, 3.1 units to 3.9 units for 24 mg, and 3.8 units to 4.1 units for 32 mg. Comparatively, in labeling reports, rivastigmine showed improvements on the ADAS-cog between 1.9 units (low dose) and 4.9 units (high dose) over placebo, and donepezil showed 2.8 units to 3.1 units (5 mg/day to 10 mg/day doses) of improvement over placebo.

The most common side effects reported by patients completing trials with galantamine were gastrointestinal, with nausea, vomiting, anorexia, diarrhea and weight loss occurring in 5% or more of patients.

Galantamine is currently approved in tablet form, with an oral solution pending FDA approval. The recommended dose range is between 16 mg/day and 24 mg/day, to be given bid. Initial dosage should be 8 mg/day bid for four weeks; if the dose is well tolerated, it should be increased to 16 mg/day. Galantamine should be taken with meals to decrease adverse gastrointestinal reactions.

Janssen is also conducting trials to assess the safety and efficacy of concomitant use of galantamine and risperidone (Risperdal) for the treatment of AD. Although risperidone is not yet approved for treatment of psychoses in AD, Janssen sees potential synergies between the two drugs. They indicated that, together, galantamine and risperidone could provide a treatment package for both cognitive decline and symptoms of AD. Janssen plans to present two-year data from open-label extension studies of galantamine at this year's American Academy of Neurology meeting in May -- RR