lunes, 14 de junio de 2010
domingo, 13 de junio de 2010
PREVENTION
Genetic counseling is recommended for couples considering pregnancy if there is a personal or family history of this condition. Genetic counselors can help people with OI and their family members further understand OI genetics and assist in prenatal diagnosis.
INTERVIEW
Strengthening Brittle Bones -- In-Depth Doctor's Interview
What does osteogenesis imperfecta mean?
Dr. Orwoll: Osteogenesis imperfecta (OI) means that the bone is not formed perfectly, and it's a disease that results in brittle bone, so fractures happen much more commonly than they should.
What are the severities?
Dr. Orwoll: People can have the disease with a wide variety of severities, sometimes very severe with multiple fractures that result in deformities, other times very mild so that fractures happen more commonly than usual, but not much.
I think most people have heard of osteoporosis. Is it similar to that and it just manifests earlier in life?
Dr. Orwoll: Right. Osteoporosis is a disease that has lots of causes, so it's an umbrella diagnosis, and osteogenesis imperfecta is one of the diseases that presents like osteoporosis, or presents as osteoporosis, so it is a kind of osteoporosis.
What is the genetic cause?
Dr. Orwoll: The mutation that causes the disease is in type 1 collagen, which is one of the very important proteins in bone, and the mutation causes the collagen to not fold appropriately. Our bone is very complicated, and the proteins and minerals have to be arranged in a very careful way. This mutation prevents that organization, so the bone simply can't form as effectively as it should.
So are some people born without certain bones in their body, or...
Dr. Orwoll: No. Osteogenesis imperfecta doesn't result in missing bones. It results in bones that are simply not as strong. There isn't as much bone there because it can't be formed as normal bones. So the bones are there, they just aren't strong. If you have a severe form of osteogenesis imperfecta, there are multiple fractures present, and the bone can't support normal growth, then one ends up with quite a lot of deformity.
What are the treatments?
Dr. Orwoll: Treatments for osteogenesis imperfecta are few. In childhood, in the last 5 or 10 years, we've begun to understand how to utilize a kind of drug called disphosphonates, which prevent bone breakdown more than anything else, but they allow bone to be formed better. So in childhood, we use those drugs. We're just beginning to understand whether we can use them in adults. There's almost no information about how to treat adults with osteogenesis imperfecta.
Why is it you can use it in children, but not in adults?
Dr. Orwoll: The treatments have just been pioneered in children, because that's when the severe forms become obvious. And treatment becomes necessary early in life. It turns out that osteogenesis imperfecta, for some reason, becomes a little less severe after growth ends, and so there just hasn't been the demand to treat the adults with the disease, despite the fact that they continue to break bones.
Are the disphosphonates effective?
Dr. Orwoll: They are effective. They don't cure the disease. They don't prevent fractures, but they strengthen the bones, and they reduce the risk of fracture.
What is the hope for Forteo?
Dr. Orwoll: Well, Forteo is a drug that works differently than the disphosphonates, because it forms new bone. The disphosphonates prevent bone breakdown. So in a disease that is a disorder of bone formation, we hope that Forteo will allow a direct attack on the problem that causes the disease.
Do you have evidence that that might be the case with its use in osteoporosis?
Dr. Orwoll: In osteoporosis, Forteo does work by forming new bone, strengthens the bone, and reduces fracture. But, of course, in osteoporosis there isn't this mutation, and collagen is normal. The disease is caused by something else, so the question we're asking is whether Forteo will work like it does in osteoporosis in osteogenesis imperfecta.
How long has Forteo been approved for osteoporosis?
Dr. Orwoll: About two years.
Have doctors already tried this anecdotally, or...
Dr. Orwoll: Yes. People have tried, or there have been a few instances in which Forteo has been tried in osteogenesis imperfecta, but there is virtually no published evidence about whether it's useful.
What phase is this trial?
Dr. Orwoll: This is phase 3 -- phase 4, actually, since it's approved.
Is there any evidence at all that it would work, or is the theory just that it would work exactly as it does in osteoporosis?
Dr. Orwoll: We've treated several patients with osteogenesis imperfecta with Forteo and appeared to get good results, so that has stimulated us to go on to do this in a formal way and specifically test whether this is going to be a good treatment for the disease.
What are the down sides, I know that there have been concerns about Forteo used for a long period.
Dr. Orwoll: It's a complicated question. Forteo is a drug that is relatively easy to use. Patients don't have much in the way of side effects, but studies that were done to result in the approval of Forteo went on for only two years, and there's some information in animal studies that prolong therapy with Forteo may be detrimental. So we don't know what to do after two years of therapy right now.
When you say detrimental, what was the problem?
Dr. Orwoll: Basically people, or rats got osteosarcoma, but they were treated.
Tumors on the bone?
Dr. Orwoll: Bone cancer, yes. They were treated with very high doses of Forteo for the rats' entire lives, so from baby ratdom to old age, and only then did the osteosarcomas appear. So lots of debate went on about that within the FDA and the community in general. Eventually it was decided that that probably wasn't relevant for the human situation, and the drug went on to approval. Nevertheless, there's this warning that one shouldn't use it for more than two years.
Have there been cases with osteoporosis patients where they've developed the bone?
Dr. Orwoll: No, no.
Even after?
Dr. Orwoll: Right.
So patients can only use it for two years, correct?
Dr. Orwoll: Well, that's the recommendation -- that they only use it for two years, but the field is just uncertain about, at this point, what to do after two years of therapy right now. There's a lot of study going on right now to figure out how to preserve the bone that is built after two years and to some extent, lots of interest in cyclic parathyroid hormone, or Forteo therapy. So use it for awhile, build up bone, stop for awhile. Use it again, build up more bone, and in that way, actually, get to the point of having pretty normal bone.
If this works, is this going to be an incremental improvement, or is it going to be a big deal?
Dr. Orwoll: We don't know. Of course, we are doing the study to see how much of a benefit there will be. It's our hope, based on how Forteo works and what patients with osteogenesis imperfecta need, that it will be a major improvement.
What does osteogenesis imperfecta mean?
Dr. Orwoll: Osteogenesis imperfecta (OI) means that the bone is not formed perfectly, and it's a disease that results in brittle bone, so fractures happen much more commonly than they should.
What are the severities?
Dr. Orwoll: People can have the disease with a wide variety of severities, sometimes very severe with multiple fractures that result in deformities, other times very mild so that fractures happen more commonly than usual, but not much.
I think most people have heard of osteoporosis. Is it similar to that and it just manifests earlier in life?
Dr. Orwoll: Right. Osteoporosis is a disease that has lots of causes, so it's an umbrella diagnosis, and osteogenesis imperfecta is one of the diseases that presents like osteoporosis, or presents as osteoporosis, so it is a kind of osteoporosis.
What is the genetic cause?
Dr. Orwoll: The mutation that causes the disease is in type 1 collagen, which is one of the very important proteins in bone, and the mutation causes the collagen to not fold appropriately. Our bone is very complicated, and the proteins and minerals have to be arranged in a very careful way. This mutation prevents that organization, so the bone simply can't form as effectively as it should.
So are some people born without certain bones in their body, or...
Dr. Orwoll: No. Osteogenesis imperfecta doesn't result in missing bones. It results in bones that are simply not as strong. There isn't as much bone there because it can't be formed as normal bones. So the bones are there, they just aren't strong. If you have a severe form of osteogenesis imperfecta, there are multiple fractures present, and the bone can't support normal growth, then one ends up with quite a lot of deformity.
What are the treatments?
Dr. Orwoll: Treatments for osteogenesis imperfecta are few. In childhood, in the last 5 or 10 years, we've begun to understand how to utilize a kind of drug called disphosphonates, which prevent bone breakdown more than anything else, but they allow bone to be formed better. So in childhood, we use those drugs. We're just beginning to understand whether we can use them in adults. There's almost no information about how to treat adults with osteogenesis imperfecta.
Why is it you can use it in children, but not in adults?
Dr. Orwoll: The treatments have just been pioneered in children, because that's when the severe forms become obvious. And treatment becomes necessary early in life. It turns out that osteogenesis imperfecta, for some reason, becomes a little less severe after growth ends, and so there just hasn't been the demand to treat the adults with the disease, despite the fact that they continue to break bones.
Are the disphosphonates effective?
Dr. Orwoll: They are effective. They don't cure the disease. They don't prevent fractures, but they strengthen the bones, and they reduce the risk of fracture.
What is the hope for Forteo?
Dr. Orwoll: Well, Forteo is a drug that works differently than the disphosphonates, because it forms new bone. The disphosphonates prevent bone breakdown. So in a disease that is a disorder of bone formation, we hope that Forteo will allow a direct attack on the problem that causes the disease.
Do you have evidence that that might be the case with its use in osteoporosis?
Dr. Orwoll: In osteoporosis, Forteo does work by forming new bone, strengthens the bone, and reduces fracture. But, of course, in osteoporosis there isn't this mutation, and collagen is normal. The disease is caused by something else, so the question we're asking is whether Forteo will work like it does in osteoporosis in osteogenesis imperfecta.
How long has Forteo been approved for osteoporosis?
Dr. Orwoll: About two years.
Have doctors already tried this anecdotally, or...
Dr. Orwoll: Yes. People have tried, or there have been a few instances in which Forteo has been tried in osteogenesis imperfecta, but there is virtually no published evidence about whether it's useful.
What phase is this trial?
Dr. Orwoll: This is phase 3 -- phase 4, actually, since it's approved.
Is there any evidence at all that it would work, or is the theory just that it would work exactly as it does in osteoporosis?
Dr. Orwoll: We've treated several patients with osteogenesis imperfecta with Forteo and appeared to get good results, so that has stimulated us to go on to do this in a formal way and specifically test whether this is going to be a good treatment for the disease.
What are the down sides, I know that there have been concerns about Forteo used for a long period.
Dr. Orwoll: It's a complicated question. Forteo is a drug that is relatively easy to use. Patients don't have much in the way of side effects, but studies that were done to result in the approval of Forteo went on for only two years, and there's some information in animal studies that prolong therapy with Forteo may be detrimental. So we don't know what to do after two years of therapy right now.
When you say detrimental, what was the problem?
Dr. Orwoll: Basically people, or rats got osteosarcoma, but they were treated.
Tumors on the bone?
Dr. Orwoll: Bone cancer, yes. They were treated with very high doses of Forteo for the rats' entire lives, so from baby ratdom to old age, and only then did the osteosarcomas appear. So lots of debate went on about that within the FDA and the community in general. Eventually it was decided that that probably wasn't relevant for the human situation, and the drug went on to approval. Nevertheless, there's this warning that one shouldn't use it for more than two years.
Have there been cases with osteoporosis patients where they've developed the bone?
Dr. Orwoll: No, no.
Even after?
Dr. Orwoll: Right.
So patients can only use it for two years, correct?
Dr. Orwoll: Well, that's the recommendation -- that they only use it for two years, but the field is just uncertain about, at this point, what to do after two years of therapy right now. There's a lot of study going on right now to figure out how to preserve the bone that is built after two years and to some extent, lots of interest in cyclic parathyroid hormone, or Forteo therapy. So use it for awhile, build up bone, stop for awhile. Use it again, build up more bone, and in that way, actually, get to the point of having pretty normal bone.
If this works, is this going to be an incremental improvement, or is it going to be a big deal?
Dr. Orwoll: We don't know. Of course, we are doing the study to see how much of a benefit there will be. It's our hope, based on how Forteo works and what patients with osteogenesis imperfecta need, that it will be a major improvement.
COSTS-ECONOMICS
Due to the perception that only 20,000 to 50,000 people in the United States have OI, the National Institute of Health (NIH) has labeled OI as an Orphan Disease. This label means not enough people in the USA have this disorder to justify a significant research budget. This year the NIH will invest only $5,000,000 for OI research. To have the Orphan label removed, at least 200,000 in the USA or 5% of the world’s population must have this disease. We believe this is the case.
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