Injection for Better Bones -- In-Depth Doctor's Interview
Reported July 13, 2005

TOPIC: Injection for Better Bones

What is the name of the new drug for osteoporosis?

Dr. McClung: The new drug is named AMG162.

How is it different than what is on the market already for osteoporosis?

Dr. McClung: AMG162 is a human antibody that is directed against a specific molecule that is the major regulator of bone loss in people. So the antibody interferes with the molecule's activity. As a result, activity of bone dissolving cells slows bone loss and helps preserve bone structure. Its end effect is similar to other drugs, but the mechanism by which it does that is different than drugs like Fosamax (alendronate) or Actonel (risedronate). It’s different in that it specifically inhibits the major regulator of bone absorbtion.

What do they do that’s different?

Dr. McClung: The drugs we have to treat osteoporosis come in two categories. There are antiresorptive drugs, and that includes most of the drugs that doctors use like Fosamax, Actonel, calcitonin and estrogen. All of those work by turning down the activity of bone-dissolving cells. These drugs don’t restore the bone, they don’t make bone grow, and they don’t restore the abnormal structure that has occurred in older patients with osteoporosis. There’s a different category of drugs, that’s called anabolic or growth-promoting agents. One medicine, Forteo, is given by daily injection and actually stimulates new bone growth, increases bone mass, and helps restore some of the disordered architecture. But most of the drugs that we use are in the anti-resorption category, and AMG162 fits in that same category.

So, basically they stop bone loss rather than promoting new bone growth?

Dr. McClung: Correct.

The anabolic drugs don’t target the same protein that we’re talking about right?

Dr. McClung: Right. So drugs like Fosamax and Actonel are incorporated into the bone-dissolving cells that interfere with the activity of the cells. The AMG162 finds the regulator of the cells and is a very powerful and effective way to turn down the activity in those bone-dissolving cells.

Can you explain what happens to bone as we get older?

Dr. McClung: Bone is a very dynamic tissue that has this marvelous dance of bone-dissolving cells and bone-forming cells. The bone-dissolving cells are osteoclast. They break down old bone, and that’s replaced with healthy, new young bone. That’s the way we maintain the structure and viability of our skeleton, so that’s a good process. After menopause in women, and with aging in both men and women, the activity of the bone-dissolving cells increases and outstrips the ability of the bone-forming cells to keep up. That results in bone loss and destruction of bone tissue in what we call osteoporosis. AMG162 decreases the activity of osteoclasts.

What is the biggest advantage to this new drug?

Dr. McClung: I think the advantages fall into two categories. First, all of the medicines that are currently used have some side effects. Fosamax and Actonel are perceived to result in stomach upset and irritability in some patients, and that limits its usefulness. By administering the drug subcutaneously, or through a shot in the skin, those GI symptoms are avoided. Maybe more importantly, the ability to administer AMG162 only twice yearly, provides the opportunity to get away from the difficulty that we have with people stopping their medication. With osteoporosis medications, it’s clear that fewer than 50 percent of the people who are given the prescription continue their treatment beyond a year, and that’s not the effective way to treat this disorder.

Why do they stop?

Dr. McClung: They stop because of side-effects, the inconvenience of daily dosing, or they simply forget to take their medicine. Oftentimes, patients aren’t aware of how important it is to continue therapy for a long time to get the full benefit of treatment. By having a drug that is administered just twice a year where the patient would come to his doctor’s office to have it administered, at least in principal, it would provide the opportunity to improve the persistence and compliance with treatment. Lastly, AMG162 works more quickly than other medicines that we have, like within hours after its administration. The activity of bone-dissolving cells is substantially reduced, whereas with drugs like Fosamax and Actonel, it takes a few weeks before the full effect is seen. For most patients, that’s not a very big issue. For some patients, who are at really high risk for fracture, to have a drug that works quickly and that can be administered conveniently, would provide an advantage.

Is there risk of infection at the injection site?

Dr. McClung: In the studies we’ve performed, we’ve not observed any unusual side effects with the medication, but that study is small. Much larger studies are ongoing, and that will be explored further. The injection is into the skin like an insulin shot, and if done correctly, the probability of having an infection from injection or side effects from injection is very small.

With traditional drugs, how often to patients take their doses?

Dr. McClung: For Fosamax and Actonel, most people take their medicine once a week. For other medicines, it has to be taken every day.

What would the cost of the new drug be?

Dr. McClung: Well, it’s way too early to know what the manufacturer is going to do about the pricing of the drug.

Tell me about your study of this new drug's effect on osteopororsis.

Dr. McClung: The study we’ve performed was a phase II study that had two objectives: One was to evaluate various doses or various dosing intervals to figure out which was the optimal regimen. What we learned was that all of the doses that were administered from small to large, and whether it was given every three months or every six months, all of the doses were very effective in turning down the activity of bone-dissolving cells. The second objective was to compare the effects we saw with AMG162 with the responses to Fosamax. What we observed was that in both the spine and the hip, the density changes were at least as great with AMG162 as were seen with Fosamax. So it’s unlikely that any antiresorptive drug will be very much more effective than our current drugs which are very effective. The advantages have to do with the dosing regimen, with the tolerability, and with the speed of onset of action.

What did you see with the bone density measurements in your study?

Dr. McClung: In menopausal women who are not on estrogen, the number of places in the bone where bone dissolving is actively happening is increased. When we administer these antiresorptive drugs and turn down the activity of the cells, many of those cavities that have been dissolved away will fill in over time, and we can observe that and measure that with our bone density test. So in the first year of treatment, there is a modest increase of 4 percent to 5 percent in the bone density values in the spine and hip. After that, the values tend to plateau.

It seems like when you see an increase in bone density, that means you’re actually building the bone?

Dr. McClung: Not exactly. In post-menopausal women, when the activity of the osteoclast is increased, there are more cavities, and the cavities that the bone-dissolving cells dig out are deeper than normal. With treatment, fewer cavities wind up existing, and the cavities that are there are more shallow. So the filling in of that space is what we measure as an increase in bone density, so it’s filling in some of the holes of the cavities that were there, but it doesn’t make the structure of the bone get better, and it doesn’t stimulate new bone growth.

Since most women do not know they have osteoporosis until they break a bone, how do you get them passionate about preventing it?

Dr. McClung: We know that low bone density, or osteoporosis, is a powerful risk factor for fractures. The whole objective for treatment is to reduce the likelihood of fractures happening, and the two fractures that are most devastating to women are spine fractures and hip fractures. Spine fractures result in height loss, curvature of the back, multiple fractures, and both physical and psychological disability. Many women, particularly whose mothers or aunts have had osteoporosis, are aware that this can be a very devastating clinical problem. When women have their first fracture, they suddenly realize that they feel old, and the concern of those fractures is what makes many women interested in knowing if they have osteoporosis and if they are a candidate for therapy.

How many women are at risk?

Dr. McClung: All women and men are at risk for osteoporosis because bone loss happens in all of us with aging. In the United States, there is an estimated 8 million women who now have osteoporosis and somewhere in the range of 2 to 3 million men with osteoporosis. Another 20 or 30 million have low bone density, who are at risk for developing osteoporosis. We now have ways to identify those people who are at risk, with a combination of measurement of bone density, which is a very powerful predictor of fracture risk, and other risk factors that include age and body size. Small people or thin people are more likely to fracture than heavy people. Those with a family history of fracture and once somebody has had a fracture are determinants of future fracture risk. So the combination of bone density and those important clinical risk factors allow us to identify the specific individuals who are at risk for fracture who would benefit from treatment.

Who is a potential candidate for AMG162?

Dr. McClung: The person who is a candidate for AMG162 would be a post-menopausal woman who has osteoporosis, which are generally women in their late 60s or 70s, who’ve had a bone density test, and who have been found to have low bone density. Most often, low bone density is found in smaller, rather than larger women, and in those women who have a family history. So, the poster girl for AMG162 would be a woman who’s in her late 60s or 70s with a family history, particularly if she’s had a fracture herself since menopause.

What are the things younger women can do now to prevent osteoporosis from occuring?

Dr. McClung: There are maybe three or four things they can do. Probably the most important is to have chosen your parents well. We inherit how much bone we make, and that’s the major determinant of who is going to develop osteoporosis. The other three things are to maintain an adequate and appropriate diet, especially a diet that is adequate in calcium and vitamin D, or the sunshine vitamin. Secondly, to maintain a regular program of physical activity. That’s important in maintaining both muscle strength and for elderly people, is important in slowing the rate of bone loss. Lastly, to avoid the lifestyle factors that are detrimental to bone health, the most important of which is smoking.

What are the current recommendations for calcium?

Dr. McClung: The recommendation for calcium in post-menopausal women is a total daily intake of 1500 milligrams a day. So, that would be one quart of milk, plus three servings of dairy products a day. Most adults have to take a supplement to get to that point. More important is vitamin D. The current recommendation is 400 units a day, which is the amount in a quart of milk or a multivitamin, up until age 65. If you are over age 65, the recommendation is 600 units a day. Most of us feel those recommendations are actually too low, and that often older men and women require intakes of up to 1000 units a day to provide adequate vitamin D. My recommendation is for men and women 65 and older their intake of vitamin D be in the range of 800 units to 1000 units per day and then 1500 milligrams of calcium. It’s important to note that 1500 milligrams of total calcium, so that’s the amount of calcium in one’s diet plus the amount in the supplement. We’re not recommending that everybody supplement their diet with 1500 milligrams of calcium. If their calcium intake is high because of dairy product intake or because they eat soy-based products, then they don’t need to take extra supplements.

Do you think the awareness of osteoporosis is growing? Why do you think it does not get as much attention as it should?

Dr. McClung: Well, it’s not as dramatic as a heart attack, but osteoporosis does kill people. The mortality following a hip fracture is very high. Even after having spine fractures, mortality rates are increased. But more importantly, especially after spine fractures, the disability, the discomfort and the marked change in lifestyle that happens has had major impact on the quality of life of men and women. The awareness of osteoporosis in this country has improved and increased dramatically in the last 20 years. Before 1985, no one ever knew about osteoporosis. With the activities of the National Osteoporosis Foundation, of the International Osteoporosis Foundation, and a whole variety of interested people, the awareness of osteoporosis around the country has increased substantially. And appropriately, awareness is now focusing on identifying which women beyond menopause are those at risk. Not everyone is at high risk, but it’s important to identify and find those women at high risk who would be the perfect candidates for current and new treatments.

END OF INTERVIEW

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If you would like more information, please contact:
Paula Gunness
Providence Portland Medical Center
4805 NE Glisan
Portland, OR 97213
(503) 215-6433