Bisphosphonates are approved to treat osteoporosis in both men and postmenopausal women, in osteoporosis caused by corticosteroids (but they should not be used for this purpose; see boxes above), and Paget’s disease. For women at risk of developing osteoporosis, Fosamax and Actonel are also approved to prevent osteoporosis.

Fosamax and Actonel belong to a class of drugs called bisphosphonates, which act on bone. They inhibit activity of the bone cells that resorb bone, and because resorption and synthesis are linked, they decrease bone turnover (synthesis and breakdown). Osteoporosis can develop in the elderly as well as in people who take corticosteroids such as prednisone (DELTASONE) or prednisolone (METICORTEN) for extended periods of time for conditions such as asthma, skin disorders, or arthritis.

Clinical Data (Fosamax)

Fosamax has been shown to reduce the risk of hip fracture by 1% in women who had previously experienced at least one vertebral fracture (2% of women on placebo had hip fractures versus 1% of women on Fosamax, a 50% relative reduction). We are still waiting for the results of a study evaluating the effects of Fosamax on hip fracture in postmenopausal women who have never experienced a vertebral fracture. Most women who took the placebo (over 85%) in the three-year clinical trials did not have a fracture of any type. Fewer studies have been done on men taking Fosamax.

An update on Fosamax use for up to 10 years has left many questions unanswered. Three groups of postmenopausal women were studied: (1) those who had been on Fosamax for 5 years and been discontinued for 5 years, (2) those who had been on 5 milligrams per day for 10 years, and (3) those who had been on 10 milligrams per day for 10 years. The main study endpoint was bone mineral density (BMD) at the lumbar spine, not fractures.

Although there were increases in BMD with increasing dose, this increase was not related to fracture rate: the 5 milligram group had eight times the increase in BMD of the spine of the discontinued group but twice the number of new vertebral fractures. Women who had discontinued the drug for five years had about the same number of fractures as those taking 10 milligrams for five years. (New “fractures” were defined by examining radiographs and measuring loss of height of the vertebrae.) As noted in the drug profile for raloxifene (EVISTA), BMD and fracture reduction are not clearly related; that appears here as well. Yet, women are often treated based on BMD alone.

Questions raised in an accompanying commentary to the 10-year trial include worries about what happens to bone structure with continuing increases in BMD, since there is evidence from animal studies that with time, bones become more brittle and susceptible to fracture. Unfortunately, at what point that occurs in people is unknown. Thus, it is unknown how long women should stay on Fosamax as well as how long benefits might last after the drug is stopped.

Clinical Data (Actonel)

Actonel, like Fosamax, is associated with a modestly favorable effect on the risk for vertebral fracture, a type of spinal fracture that may or may not be symptomatic. The absolute reduction in the risk of a new vertebral fracture in women taking Actonel is 5% compared to women taking an inactive placebo. The most benefit was seen in women with two or more vertebral fractures before they started taking Actonel.

A published study sponsored by Procter & Gamble, the maker of Actonel, suggests that Actonel may reduce the risk of hip fracture, the most serious consequence of osteoporosis, in elderly women with low bone mineral density by about 1% (the same result as Fosamax). However, this study has been criticized on a number of grounds, including the fact that follow-up information was not available for 3,324 of the 9,331 women in the study. This could have biased the results in favor of Actonel by leaving out women who had fractures.

Actonel is retained in bones for many years, but long-term effects remain uncertain. Concern exists because some bisphosphonates increase the occurrence of spontaneous fractures in animals.9

Common Problems When Taking Bisphosphonates

Since bisphosphonates can irritate the esophagus (the tube that connects the mouth and stomach), causing ulcers and bleeding, they must be taken with water on an empty stomach. Stay upright for at least half an hour to ensure that the tablet does not get stuck in your esophagus before reaching the stomach. You should not eat or drink anything but water during this half hour to get the maximum absorption of the drug.

Since Fosamax came on the market, there have been reports of serious adverse effects associated with its use. Several cases of bone, joint and/or muscle pain that developed after starting therapy with the drug have been reported. In 2004, the FDA updated the adverse reaction section of the product label of Fosamax to include post marketing experiences of bone, joint and/or muscle pain

Actonel, in post marketing experience, has been associated with reports of very rare hypersensitivity (allergic reactions) and skin reactions, including hive-like swelling under the skin, especially around the face and mouth (angioedema), generalized rash, and blistering of the skin (bullous skin reactions), some severe. Severe musculosketal pain and death of the bone tissue of the jaw (osteonecrosis) have been reported. In 2006 the FDA required manufacturers to add this information to the adverse reaction section of their product label.

The typical signs and symptoms of osteonecrosis of the jaw may include pain, swelling or infection of the gums, loosening of the teeth, poor healing of the gums, numbness or a feeling of heaviness in the jaw, drainage and exposed bone. Patients with the least serious form of this condition may not show any symptoms, but in the most serious cases, some patients may require the removal of sections of the jaw.

A review of medical literature shows there have been 368 reported cases of osteonecrosis of the jaw linked to drugs commonly used to treat osteoporosis. According to the review, published in the May 16 2006, Annals of Internal Medicine, osteonecrosis was more common in the lower jaw (mandible) than the upper jaw (maxilla). More than half of all cases (60%) occured after dentoalveolar surgery (such as tooth extraction) to treat infections, and the remaining 40% are probably related to infection, denture trauma, or other physical trauma.

Ninety-four percent of the patients who developed osteonecrosis of the jaw were those with cancers such as multiple myeloma, as well as patients with cancers that have spread to bone who are receiving intravenous (IV) bisphosphonate. However, the remaining cases were in people using oral bisphosponates such as alendronate (FOSAMAX) or risendronate (ACTONEL).  The authors stated that, “The concern is that with more women aging and taking bisphosphonates for longer periods of time, more cases of osteonecrosis may develop even in patients receiving Fosamax or ibandronate therapy."

Bisphosphonates are not to be used by people with mild osteoporosis, with severe kidney problems, or in women before menopause. It should not be given to people with dementia or who are otherwise unable to follow the instructions on how to take the medication. Bisphosphonates should not be used in pregnant or breast-feeding women. Safety and effectiveness is not known in children under the age of 18 years.

For use in Paget’s disease, Fosamax is given daily for six months. If a relapse occurs, Fosamax is sometimes resumed; Actonel is given for two months and repeated if necessary.

Parlodel is derived from “ergot,” and has several uses. Here we discuss its use for Parkinson’s disease, for  which it is the second-choice drug, after a combination of levodopa and carbidopa (SINEMET, SINEMET CR). If you have Parkinson’s disease, your doctor should first try levodopa with carbidopa and should prescribe Parlodel only if the combination drug does not decrease your symptoms or if it causes too many adverse effects. Parlodel often works best when given with levodopa. If you are over 60, you should generally be taking less than the usual adult dose.

In older adults, Parlodel often causes dizziness, nausea, constipation, and tingling in fingers or toes when exposed to the cold. It can also cause more serious adverse effects called choreiform movements—unusual and uncontrolled movements in the body, face, tongue, arms, hands, and upper body. About 25% of Parlodel users in all age groups experience this adverse effect. If you have any of these symptoms, especially if they are severe or persistent, call your doctor and ask if your dose of Parlodel should be reduced. Do not take less Parlodel than your doctor prescribed unless he or she instructs you to do so.

In 2005, the FDA revised the product package insert of Parlodel (Bromocriptine) regarding post marketing safety data relating to sudden onset of sleep and possible problems involving the membranes that line and surround the heart and lungs.

Physicians from the Mayo Clinic in Rochester, Minn., publishing in the September 2005 Archives of Neurology, examined the relationship between the drugs used to treat Parkinson’s disease known as dopamine agonists and pathological gambling. The dopamine agonist group of drugs includes Parlodel (Bromocriptine), pergolide (PERMAX), pramipexole (MIRAPEX), and ropinirole (REQUIP).

The Mayo Clinic physicians identified 11 patients between 2002 and 2004 who met the definition of pathologic gamblers. All had Parkinson’s disease, and all were being treated with levodopa and a dopamine agonist. The Mayo Clinic physicians also searched the world’s medical literature for other reports of pathological gambling associated with the use of dopamine agonists. They found six published reports involving an additional 17 patients. The authors commented that “The relationship of pathological gambling to dopamine agonist therapy in these cases is striking.”