Risedronate

Risedronate is a type of drug called a bisphosphonate and is used to treat adults who are at risk of developing osteoporosis, such as women in menopause, to maintain and strengthen their bones. Risedronate is also used to treat a bone condition called Paget disease. Some precautions need to be taken to prevent gastrointestinal side effects. Side effects during treatment with risedronate are generally mild, but some cases of dangerous bone deterioration in the jaw have been reported.

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Uses

Risedronate is used in the prevention and treatment of osteoporosis during menopause and in men and women undergoing treatment with drugs called glucocorticoids. Women with breast cancer may receive risedronate to reduce the risk of developing osteoporosis during treatment. Risedronate is also approved for the treatment of Paget disease, which is characterized by soft bones and pain.

Normal bone versus bone affected with osteoporosis.

How Risedronate Works

Making new bone involves the coordinated actions of cells called osteoclasts and osteoblasts. Osteoclasts remove bone in a process called resorption. Osteoclasts eventually die and are replaced by osteoblasts. Osteoblasts lay down new bone, osteocytes, in the bone cavity left behind by the osteoclasts. Risedronate first binds to the hydroxyapatite crystals of bone, then enters the osteoclast cell. Once inside the cell, risedronate prevents the formation of proteins that are necessary for the osteoclast to function. The impaired osteoclast is unable to resorb bone.

History and Development

Bisphosphonates were first synthesized in 1897, but their therapeutic potential was not thoroughly investigated until the 1990s. The first-generation bisphosphonates had unwanted side effects. Second- and third-generation bisphosphonates were developed by making small modifications to the first-generation. Like all third-generation bisphosphonates, risedronate is more effective and safe than its predecessors. Risedronate was approved for use in the United States in April 2000. Canada approved risedronate in August of the same year.

Administration

Risedronate is available in tablets of 5 mg, 30 mg, 35 mg, and 75 mg. Dosage regiments for postmenopausal women consist of either daily doses of 5 mg, weekly doses of 35 mg, or two consecutive daily doses of 75 mg taken once a month. Similar regiments are used in other individuals at risk for osteoporosis. For Paget disease, 35 mg of risedronate is given daily for two months with re-treatment if necessary.

How The Body Affects Risedronate

Risedronate reaches a steady level in plasma within 60 days of beginning treatment. Very little risedronate is absorbed by the body, and absorption is hindered by food. Taking risedronate 30 minutes before breakfast can reduce absorption by 55%, whereas extending the interval to one hour can reduce absorption over 30%. Animal studies have suggested that 60% of a dose is absorbed into bone and the remainder excreted in the urine.

Risedronate is not metabolized (broken down), and is therefore excreted unchanged in the urine. Approximately half the dose is excreted in the urine within 24 hours. Shortly after ingestion, the time required to reduce risedronate concentrations in the blood by half, the half-life, is only 1.5 hours. The half-life slows to 480 hours after the blood is cleared, and risedronate slowly leaves the bone. Weekly and monthly dosing is possible because of this long half-life.

Effectiveness in Clinical Trials

Risedronate strengthens and preserves bone in individuals at risk of developing osteoporosis and bone fractures. Bone turnover, the process of bone resorption and formation, causes the release of distinctive markers into the blood. Risedronate reduces the concentration of these markers, which suggests that the rate of bone resorption and formation has decreased. This reduction in bone turnover reaches a maximum within six months of treatment. Risedronate can reduce bone turnover in postmenopausal women to levels seen in premenopause.

Physicians use bone mineral density (BMD) to measure the strength of bone; the higher the BMD, the stronger the bone. Risedronate increases BMD in postmenopausal women. In one clinical trial of postmenopausal women who had low bone mass, treatment with risedronate (5 mg daily) for 24 months improved BMD in the spine by 4%.^[1] Women who were treated with placebo had no improvement. The beneficial effect of risedronate on BMD occurred in women who had recently entered menopause as well as those who had been in menopause for several years. Along with improvements in BMD, risedronate reduces the risk of developing bone fractures. An analysis of the risk of fractures was performed on five placebo-controlled studies of women with osteoporosis.^[2] Treatment with 5 mg risedronate daily reduced the risk of fractures in the vertebrae by 45% in the first three years of treatment. Men with osteoporosis benefit similarly from treatment with Actonel.

Risedronate also improves BMD and risk of fracture in patients undergoing treatment with glucocorticoids. A clinical trial of 518 men and women found that treatment with risedronate (5 mg daily) for one year increased BMD by 2%.^[3] The risk of fracture had decreased by 70%.

One of the largest studies to examine the effectiveness of risedronate in the treatment of Paget disease enrolled 162 men and women with moderate to severe disease.^[4] The patients received 30 mg risedronate daily for 84 days. They were followed without treatment for an additional 112 days without treatment. Risedronate alleviated the pain in over 40% of patients. X-rays revealed improvements in bone structure as well.

Side Effects

The use of bisphosphonates has been associated with gastrointestinal complications. These include inflammation in the esophagus (esophagitis) and ulcers in the esophagus and stomach. Risedronate is thought to be less harmful on the gastrointestinal tract than are other bisphosphonates. If proper precautions are taken, see “Risks and Precautions”, the risk of developing these complications is extremely low.

Reports of bone deterioration in the jaw surfaced during widespread bisphosphonate use several years after the drugs entered the market. This painful softening of the bone, called osteonecrosis or osteomalacia, occurred primarily in individuals with cancer who underwent dental surgery. The bisphosphonates may have hindered recovery from the surgery by preventing the formation of blood vessels in the jaw. Osteonecrosis in the jaw has been reported in a few patients using risedronate. Most often osteonecrosis occurred in individuals being treated for diseases such as cancer, and therefore they may have been at a higher risk of developing complications. More research is needed to determine the risk of jaw damage.

Clinical trials have shown that risedronate reduces levels of calcium and phosphate in the blood. These low levels return to normal after several months.

The most common side effects of risedronate are the following:

• joint pain
• chest pain
• muscle pain
• bone pain
• constipation
• diarrhea
• upset stomach
• flu syndrome
• abdominal pain
• nausea
• swelling
• headache
• dizziness
• rash
• sinusitis

Many side effects are mild and transient. If muscle, bone, or joint pain become severe, a physician should be consulted. In preparations of risedronate with calcium, side effects such as flatulence, nausea, and abdominal pain may occur.

Risks and Precautions

Risedronate should be taken in the fasting state, at least 30 minutes before breakfast or two hours after. Risedronate may irritate the esophagus and cause a burning sensation or difficulty in swallowing. This esophageal irritation may be avoided by taking risedronate with water and standing or sitting upright for at least 30 minutes after swallowing the dose. A physician should be consulted if swallowing becomes painful or difficult, or severe chest pain or heartburn develops.

Abnormal bone and mineral metabolism, such as low blood calcium levels, should be effectively treated before starting risedronate therapy. Often calcium and vitamin D supplements are taken with risedronate, especially if dietary intake is inadequate.

Individuals with kidney dysfunction should not receive the drug because risedronate is largely eliminated in the urine.

Drug Interactions

Risedronate is unlikely to affect the metabolism of other drugs because it is not metabolized. However, both non-steroidal antiinflammatory drugs (NSAIDs) and risedronate may increase the risk of gastrointestinal irritation or ulcers. Clinical trials of risedronate showed no increased risk of gastrointestinal complications in patients who received both risedronate and NSAIDs. Regardless, caution and vigilance are needed if NSAIDs and risedronate are to be given together.

Calcium, magnesium, and aluminum interfere with the absorption of risedronate, so risedronate and these supplements should be taken at different times of the day.

Controversy

In January 2006, Proctor and Gamble and Sanofi-Aventis Pharmaceuticals filed a false claims lawsuit against Roche and GlaxoSmithKline. They claimed that advertising for GlaxoSmithKline’s Boniva (a rival bisphosphonate) made claims about Boniva’s effectiveness that were not supported by data from clinical trials. In September of the same year, the injunction was rejected.

Law firms are actively seeking patients who have developed jaw osteonecrosis as a result of treatment with bisphosphonates. They argue that the patients should be compensated because bisphosphonate manufacturers were aware of the problem but downplayed its significance.

References

1. ↑ Fogelman I, Ribot C, Smith R, et al. Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group. J Clin Endocrinol Metab 2000;85:1895-900.
2. ↑ Adachi JD, Rizzoli R, Boonen S, et al. Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a meta-analysis of individual patient data. Abstract. Aging Clin Exp Res 2005;17:150-6.
3. ↑ Wallach S, Cohen S, Reid DM, et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Abstract. Calcif Tissue Int 2000;67:277-85.
4. ↑ Siris ES, Chines AA, Altman RD, et al. Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study. Abstract. J Bone Miner Res. 1998;13:1032-38.

External Links

• Proctor and Gamble: Actonel Main Page
• Medline Plus: Drug Information: Risedronate
• Cochrane Reviews: Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women
• Healthline: Risedronate: Information on Uses, Dosage, Side Effects
• Medwatch: Medwatch 2007 Safety Alerts