Treating the epidemic

At the International Osteoporosis Foundation World Congress in Rio De Janeiro, Brazil in May this year, leading experts in the field reported on the latest research in drug treatments.

During the next 50 years, the number of osteoporotic fractures, already numbering in the millions, is expected to more than double, worldwide. Facing this anticipated epidemic, researchers are putting considerable resources into finding medications that will stop bone loss, or even rebuild weakened bone, in order to reduce fracture risk.

Currently there are several classes of drugs that are approved for treatment of osteoporosis, including bisphosphonates or selective estrogen receptor modulators (SERMs) and parathyroid hormone. Valued at around $7 billion in 2002, and forecast to double by 2011, the osteoporosis market is expected to see a rush of new drugs in the next five to ten years.

Bisphosphonates ... and kidney function

Dr Paul Miller, from Colorado Center for Bone Re s e a rch, Lakewood, Colorado, USA, reported that the established bisphosphonate risedronate is well tolerated in patients with reduced kidney function. Miller and colleagues analysed placebo controlled, phase III clinical trial data from over 9,000 patients with varying degrees of renal insufficiency. Even those patients with severe kidney impairment achieved significantly reduced frac-Osteoporosis.

Treating the epidemic ture risk on risedronate, without compromising renal function.

... and for Paget’s Disease

Miller, newly elected to the IOF international Board, and colleagues also investigated the use of bisphosphonates to treat a rare condition called Paget’s disease. In this disease the bones become weak due to an accelerated bone turnover-the continuing loss and replenishment of bone minerals. Miller and colleagues reported that one dose of zoledronic acid, a bisphosphonate that is given intravenously, may be slightly more effective than daily dosing with risedronate in patients with Paget’s. Six months after receiving zoledronic acid, bone turnover in volunteers was still much lower than in those who received a placebo, or who had taken risedronate for 60 days but then stopped.

Compliance challenges

Compliance has been a problem with many patients prescribed bisphosphonates, particularly those medications requiring daily or weekly dosing. “Only 50% of patients prescribed bisphosphonates are still
! taking them a year later,” noted Dr David Kendler, from the Providence Health Care Center, Vancouver, Canada.

Kendler and colleagues reported that when patients stop taking risedronate the control of their bone remodelling rapidly disappears. This means that within a few months of stopping treatment, patients are back to where they started and bone is being lost as fast as it was before treatment.

“People who are on risedronate need to know that the therapeutic effect would be rapidly reversed once they stop,” said Kendler. Doctors can play their part helping patients maintain their medication regimens, stressed IOF President Pierre Delmas, from the INSERM Resarch Unit, Lyon, France. Delmas led the IMPACT study, designed to assess the effect of how physician feedback affects
patients’ willingness to continue drug therapy.

Positive or neutral reinforcement by physicians helps patients to keep up with risedronate medication, Delmas and colleagues reported. This was discovered by monitoring bone turnover markers, small molecules that can be detected in the blood or urine and which indicate response to treatment.

Based on measurements of these markers, patients who were told their condition was improving were more likely to continue with their medication than those whose condition continued to deteriorate. “We found that persistence in patients is improved by 30% over the course of a year, if patients know they are getting better,” said Delmas.

Those who persisted with medication were also found to have better improvement in bone mineral density (BMD), a commonly used measure of bone strength. Patients who stayed on their medication showed greater improvement in BMD than people who stopped taking the drug.

Strontium ranelate

Results from two clinical trials suggest that strontium ranelate can reduce the risk of hip fractures in women with osteoporosis, and reduce the risk of both hip and vertebral fractures in women with osteopenia.

Osteopenia, which is defined as low bone mineral density, is a condition that precedes osteoporosis and is generally considered an important risk factor for fractures. Major studies to determine whether strontium ranelate is effective include the TROPOS (for TReatment Of Peripheral OSteoporosis) and SOTI (for Spinal Osteoporosis Therapeutic Intervention) studies. Both were andomised, doubleblind, placebo controlled trials enrolling a total of over 5,000 volunteers. Subsets of the data were analyzed by two collaborative efforts led by Dr Jean.

Yves Reginster, WHO Collaborating Center in Liège, Belgium and Dr Ego Seeman at Austin Hospital, University of Melbourne,
Australia. Both Reginster and Seeman are IOF Board members. “The data showed that strontium ranelate significantly reduces the risk of experiencing a hip fracture by 36% in at-risk patients,” said Reginster, executive secretary of IOF and coauthor of both studies. “And for the first time, in patients with osteopenia, or low bone mass (measured at their spine) but who were not yet osteoporotic, we have a treatment that is capable of reducing the vertebral fracture risk by 59%,” he continued.

Hormones and hormone modulators

Estrogen plays a major role in bone formation in both women and men. For this reason postmenopausal women are at increased risk for osteoporosis and hormone replacement therapy has become widely used both as a prophylactic and a treatment. However, because estrogen therapy carries an increased risk for some cancers and cardiovascular disease, researchers have turned to alternate approaches such as the use of selective estrogen receptor modulators (SERM), drugs that mimic some of the actions of estrogens.

One promising drug under study is a next generation SERM called lasofoxifene. Dr Michael Bolognese, from the Bethesda Health Research Center, Bethesda, USA, and colleagues reported the results of a second phase II clinical trial to determine the safety and efficacy of low doses of this SERM.

Healthy postmenopausal women, aged between 50 and 74, were given lasofoxifene for one year. Doses as low as 17 microgrammes per day resulted in an increase in BMD over the time of the trial. At the highest dosestested, 500 microgrammes, BMD increased by an average of 2.2%, while those on placebo saw a drop in BMD of 0.25% over the same time frame.

The drug was well tolerated and has an acceptable safety profile, the authors report.

Other potential benefits are also under investigation. For example, some doses tested resulted in a statistically significant lowering of low-density lipoprotein cholesterol, the so-called “bad cholesterol”. This level fell from an average of 129 mg/dL in the placebo group, to 106 mg/dL in the group receiving the highest dose of lasofoxifene. “Lasofoxifene, a next generation SERM, may play an important role in the health of postmenopausal women,” said Bolognese.

Not everything works

One treatment patients can stop, without missing out on any benefit, is topical natural progesterone creams. From analysis of a two-year, double blind, placebocontrolled trial, Dr Gill Pearson and colleagues at Southampton General Hospital, and elsewhere in the UK, conclude that these creams do not prevent boneloss in postmenopausal women.

Pearson began the research because she questioned widely-promoted claims in women’s magazines and the Internet that these creams can prevent bone loss and even increase BMD by as much as 5-7% per year. Results of the twoyear trial showed that though the progesterone (40 - 80 mg applied per day) was absorbed through the skin, BMD actually fell over the two-year period of the study. In contrast, women taking hormone replacement (50 microgrammes estradiol and 170 micrograms of norethisterone)z=increased BMD by an average of 10% over the two years.

“Despite strong marketing claims to the contrary, doctors should advise women not to use these progesterone creams as protection against osteoporosis,” said Pearson. Perhaps a different dose or delivery system could be more effective on bone, she added, noting that progesterone has been shown to stimulate bone formation in animalstudies.

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