The Modern Approach to the Prevention and Treatment of Spine Fractures

1. Osteoporosis: A Public Health Problem
2. Treatment of Osteoporosis
3. Kyphoplasty
4. Results of Kyphoplasty
5. Timing of Kyphoplasty
6. Kyphoplasty Complications
7. Future Opportunities with Kyphoplasty
8. Medical Management of Osteoporosis
9. Q & A Session

Stephen A. Paget, MD: It is a pleasure today to introduce one of our own, Dr. Joseph Lane, who is an internationally recognized expert in the area of metabolic bone disease, particularly osteoporosis. He has a very long interest, shown in his 200 peer-reviewed papers on many aspects of bone disease, including more recently the use of bone morphogenic protein both in surgery and various types of animal models. Joe did his undergraduate years at Columbia and went to Harvard Medical School, has been Chief of Orthopaedic Surgery both at Memorial Sloan Kettering and at UCLA and, wonderful for us, came back and is now a Professor of Orthopaedic Surgery at the Weill Medical College at Cornell University.

He will focus today on the general issue of osteoporosis, specifically, a wonderful and innovative new technique to improve pain in patients who have fractures. Hopefully, it will make a change in the multi-planar changes that can occur in the elderly. Joe, it's a pleasure to have you here.

Osteoporosis: A Public Health Problem

Joseph Lane, MD: Thank you very much for allowing me to come here and to share with you some new and exciting approaches to osteoporosis. Clearly, 20 years ago we were very realistic about this whole issue and watched people develop compression fractures and deformity and offered very few medications for protection. There has been a revolution in terms of pharmacological agents that are now out there that can really stop osteoporosis dead in its tracks and now actually reconstruct the skeleton.

A problem is fractures that still can occur - no medicine is 100% effective. I am going to share with you a methodology to treat one of the most troublesome issues that still revolves around osteoporosis, and that is the compression fracture. Osteoporosis is a wide-spread disease, and I'm going to concentrate basically on the spinal area.

There are about 700,000 fractures that take place in the United States per year. One-third are painful, but two-thirds are painless, and patients will not recognize it, but the only thing they know is that they are getting shorter and rounder as time goes on. Anybody who has lost two inches in height should be suspected of having a compression fracture. Other etiologies would be scoliosis or kyphosis.

Now what are the consequences of a compression fracture? In the acute phase, these people obviously have severe pain, and this is well noted. More common is the problem of deformity; they will end up being stooped over. Notice the woman on the right hand side; her center of gravity is shifted to the front. So they become unbalanced or what I call "noncompensated kyphosis". They also have a loss of respiratory function - their diaphragm is elevated into their chest cavity, and they have respiratory dysfunction.

Because they are off balance, they frequently have some scoliosis associated with this kyphosis. Their gait ability is dramatically decreased, and that is why we have developed a Tai-Chi program at the hospital. They are embarrassed by their performance, and they are basically home dwellers with a marked degree of clinical depression. And the quality of life, by any questionnaire that is out there, whether it is the SF-36 or others, demonstrates that these people are doing poorly, particularly compared to their peers.

We try to be a little bit more scientific about this and get some numbers. It's difficult. There are some investigators who have looked at actually the degree of lung capacity that seems to be compromised. When we look at their food log, they eat less food, their albumin levels are lower, they are in chronic pain. It is very difficult for them to sleep because they cannot lie on their backs. There is functional loss of independence, and most importantly, they do fall. And with falls, not only can they fracture their spines, but they can fracture their hips.And there is a dramatically increased risk of hip fractures once you have had vertebral fractures.

Now there are a number of studies by Cooper, reinforced even further by a person named Deborah Cato, at the University of California San Francisco from the Osteoporosis Surveillance Program. What they have noted is that, certainly in the middle registry or after a hip fracture, 20% of people will die within six months. After that, they followed the line of everybody else. There is a short window of increased mortality.

With Colles' fractures in the bottom registry, there is no increased mortality; it just happens, and, in fact, wrist fractures do not increase rapidly as one gets older. They sort of plateau, and there are the same numbers for people in their 70s, 80s, and 90s, unlike hip fractures and vertebral fractures.

And finally, there are the vertebral fractures. Now here was a big surprise to everybody. If you follow these people -- and on the far right is five years -- people who have two or more vertebral fractures have up to a 34% increased mortality rate. So vertebral fractures, by some mechanism, clearly indicate increased mortality. So it is, in fact, a lethal disease.

Now, what have we done? In treatment of vertebral fractures, the traditional method is to hope somebody else will take care of them. But you give them an analgesic, and there are problems with analgesics that they can give a patient -- we recently had another perforated diverticulum from overuse of narcotics. These elderly people do not tolerate narcotics well. They obviously can be treated with osteoporosis medication, but even in the most optimistic view, it would take six months, if not a year, to gain the benefit of these medications.

With bed rest, which is a double-edged sword, they feel a bit better, but then they lose their physical strength. External bracing in most elderly people -- they either don't wear the brace or they wear it loosely and it is a waste of $2000. And then there is physical therapy, and it's usually taught wrong, because many of the exercises for back pain actually increase the risk of collapse of the vertebral body.

So we have had a very poor track record in treating these kind of issues. The traditional method that everybody really should do is clearly the day a fracture is recognized, regardless of the bone density, put everybody on calcium, vitamin D and exercise and adequate nutrition, and I have to emphasize nutrition. There is a number of drugs out there. We are going to come back to them, including the estrogens, the bisphosphonates, which are alendronate, risedronate, the intravenous bisphosphonates, zoledronate. Then there is calcitonin and raloxifene and a number of agents which are basically out there to treat patients, but there is a time lag in this individual. We will come back at the end of the kyphoplasty issue.

Treatment of Osteoporosis

What you are seeing on the right is a patient with osteoporosis, and they get narrowing of the vertebral body. Osteoporosis takes a shark bite out of that trabeculate, leads to disconnectivity, and with most of the approved drugs other than the newly involved PTH, which will be coming along, we cannot reconstruct the connectivity. So the minute you see this disease, you have to treat it.

Now, while this was going on, work was being carried out in Europe by the French and also by the Spanish. And as they noted patients who had compression fractures of the spine, particularly due to pathologic conditions such as cancer of various forms, the French tried a technique of percutaneous stabilization of malignant pathological fractures. Going through the pedicle, they placed a needle through the pedicle into the vertebral body, (it was done by interventional radiologists) and then injected methyl methacrylate (cement for hips, knees and joints), and used this as a temporary bridge or strutto hold up the vertebral body.

This started in the 1980s, and then the French said "We can treat various forms of pathological fractures, why don't we include osteoporosis?" So they started treating osteoporosis, and the method is noted as a vertebroplasty. So the method involves this insertion of the needle, and then, under image control, you take a bolus of cement and inject the bolus of cement -- anywhere from 3 to 6 cc inserted per side. And there now has been an array of studies which have shown that as long as you get 3 cc into a vertebral body, you dramatically increase the mechanical strength. This has been performed by evaluating cadaver studies and looking at bones and crushing them, but just a small amount of fluid into a fixed body will improve it.

There are some problems with this I'm going to talk about. Now the results of this technique were dramatic. What they noticed in a series of cohort studies -- there were no randomized studies-- about 80% of patients claimed some level of pain relief, but they have anything from 'the patient says they are better' to more sophisticated studies using HAQ parameters. Particularly the Europeans have done this. So there is a pain relief phenomenon. No vertebral body which is filled with cement will go on to further collapse. That has been documented, and the complication rate was about 6%.

Now what are these complications? Well, anywhere from 30 to 60% of patients will have cement that leaks out of the vertebral body, because you are pushing material in and it is coming out at the same time. And you have not created a protective haven to hold the cement; you usually stop pushing when you see it on the fluoroscopy. So that if you are a slow finger, you may push a lot more cement in before your eye tells your finger to stop pushing. So there has been a problem of expansion of the cement coming out.

Another problem is that you go into a closed space, and as the 3 to 6 cc of cement comes in the marrow goes out -- and sometimes with the cement -- and goes directly to the lung. Our experience at Hospital for Special Surgery is that we have watched the blood gases go down temporarily, and the oxygen saturation may drop to as low as 80% of normal for about 20 minutes and then they gradually return. So if you are good and you do not inject too quickly and you are not greedy and you only take a few levels, and you have excellent radiographic skills, you can keep your complications very low.

If you do multiple levels in an unsupervised environment, each time you do it, you are adding to a problem called Adult Respiratory Distress Syndrome. There has been documented mortality from the procedure, and usually those occur when you have done six or seven levels at the same setting in an elderly individual. The advantages of this technique are that it gives pain relief and it can be done under local anesthesia, so the way to do this in a very difficult patient is to keep them awake and let them know what is going on. In the best centers, they only do two levels, i.e., Hopkins and University of Maryland, which have pioneered this program.

So the complication is roughly 6%, with some mortalities. But while it does give pain relief, it does not reduce the fracture. So it does not address the kyphosis. You take it as it is. Whatever the deformity is, you lock it in place at that particular period of time. It is a high-pressure fill, there are leaks and there are issues regarding the safety. We will be doing this procedure at this institution, but it will be done on one level. It will be done carefully. It will be done under excellent image control in a non-greedy fashion. In that setting, I think it is safe, but you cannot reduce the fracture.

Kyphoplasty

Now recognizing this was a problem, there is an issue -- could this be done in a safer way and actually reduce the fracture? Basically, a technique was done borrowing from angioplasties as a model. What you do here is you are going to put in a device and try to reduce the fracture. Let me demonstrate how this works.

Here is a compression fracture. You take this compression fracture and you then enter through the pedicle, similar to the vertebroplasty. You now place a needle, under image control, down into the vertebral body. Once you have it in the body, you then place a balloon, and you make a core large enough to get your device in. You insert a balloon. Now this balloon is made out of Kevlar, and you blow it up with a pressure that is equivalent to 12 times the pressure of a bus tire, which is 360 pounds per square inch. This is very significant pressure. And then as you gradually do it, you watch it on the image as you blow it up in a very controlled fashion. And you watch potential reduction as well as the potential to expand laterally or more a fragment posteriorly; everything is done slowly.

Because you are rebreaking the spine, we do this under general anesthesia. You can do this under conscious sedation -- in Detroit they do it under conscious sedation -- it is not necessary to put them to sleep. So that's an issue to be brought up with the internist -- how you want to approach this. Once you blow this balloon up, you have created a cavity, and because there is weight on their chest and on their pelvis, they are hyperextended, you retain the correction for about 20 to 50 minutes, so you can take out the balloon and you have a cavity. You know how many cc's you have taken to do it and you can put exactly that same amount of material back. You are not going to insert an extra 3 cc into the lung. You then insert it.

Now here is a typical example of a patient. On the left is an individual who developed a very significant curve. The anterior column of the vertebral body is 12 mm and the posterior is 37. So they have lost approximately 2/3 of the anterior height in this wedge fracture. You now go ahead and you do a kyphoplasty, and the anterior column is now up to 29 mm, meaning you have reversed this by over 50%. You have corrected about 50% of the deficit and then you are putting in cement. Notice, by the way, a little cement off to the side. Once you break the vertebral body, the cement can drift out a little bit. There are now techniques using a more viscous material to control exactly where you put your cement. It is not a guarantee that you are going to avoid losing cement out in some space, but you can prevent it from going out posteriorly, which is the area of concern.

Now there is a study group that looks at these. I'm going to share our data from that experience, tell you our indications, how we have made the choice of the patients, what are the functional results, what are the complications, and where this technique may fit into your armamentarium of treatment for these patients.

If you look at any series, and this is one of the initial series, you will find that these patients are about 70 years of age. We have gone as high as into the early 90s and some people have reported, in the most recent review of the data, up to about 95. It is the physiological age of the patient, not the chronological age, that matters. We have also treated younger patients for unique problems, and these people have almost always been on things like steroids, or have had myeloma or some deleterious disease. Vertebral fractures do not occur in people under the age of 65 unless they have another reason.

Three out of four will be women, but there will be men. We now know that men have a problem. In fact they are often sicker, and they do not tolerate the fractures very well, so the men we have done have been very sick individuals. At our institution, when we reviewed our material, they had 3.7 major morbidities and many of you have taken care of these patients -- these are not average walk-off-the-street osteoporotic patients. They come in with a lot of baggage, and that is probably why they are getting into this problem. They have had osteoporosis; they have steroids. Many of them have had steroid osteoporosis, and they now gradually are increasing our experience with liquid tumors. And while this number had been 5%, last week, I did three multiple myelomas, and I would say now that about 20% of my practice are these liquid tumors that are coming to be treated by this particular technique.

Who is eligible? Nobody is treated in my hands or by most people within the first two weeks of a fracture. Remember, two-thirds of people with a fracture have no symptoms. The other group will rapidly improve their symptoms. So don't rush to do a kyphoplasty. Give patients a chance to get better by themselves. The number two would be if a person has persistent pain, pain score 5/10 that just doesn't go away. Or every time you take an x-ray, you see that the fracture is getting further and further crushed, particularly in the thoracolumbar direction, which leads to the greatest deformity and flattening of the lumbar lordosis. Those are the patients we revisit.

So loss of control while we are waiting for the medicine to work, or lack of improvement in terms of the pain are the indications. We rarely treat patients with a single fracture. It is usually a fracture in the setting of multiple other fractures. That means you have a window of opportunity to treat them medically to prevent this.

Results of Kyphoplasty

Now what happens if you treat these patients? Well there have been studies of the group by Frank Philips. Our experience, the group at the Cleveland Clinic with Isabelle Lieberman, has shown that within 24 hours, once they get through the anesthesia and get up and around, there is some significant improvement in the majority of these patients. If you do multiple levels, it may take up to a week because they may have a couple of incisions that they have to recover from.

There are some people who show no improvement, and, in turn, if you go and look at these individuals four months down the line, there is a large holding benefit. 90% of people will tell you they are still better. At this institution it is 88%. So it is that kind of number we are talking about. There is a small group that get worse, and what they often will have is either a second fracture or things like spinal stenosis and other issues of the spine that have not been fully addressed.

Number two -- how do they do in terms of outcomes? There a bunch of outcome studies have been performed on these patients. Here is one that was done by Frank Phillips, the pre-op and then later what their level was within 24 hours. Remember that within this elderly group, they never get up to 100%. They are not normal individuals. They have very significant disabilities. So improvement is what we look for in that group.

Here is a study done by Lieberman. What we are looking at here on the left is physical function, a dramatic increase from before to after on the SF-36, the left column. I want to go back. There is another parameter that we looked at to show that they have improved. At our institution, we have a little different population, but again it appears by the SF-36almost every patient has improved by some parameters. The mental health is unaffected by this, but other issues such as social functioning and other issues have all shown dramatic improvement. So we have objective evidence, at least by health outcome parameters, that they have improved.

Now, what about the height of the vertebral bodies? If you look at a number of series, they all basically say the same thing. You can restore the height and the anatomy of the vertebral body with a kyphoplasty. Here is an example. In terms of the angulation of the patient, we missed part of the angle that was pre-op kyphos, local kyphos 36 degrees, changed to 18 degrees, and the reason is that, particularly in the thoracolumbar area, a very small anterior height restoration translates itself into bringing patients back and making them erect. So that they really can have dramatic height restoration though the actual vertebral height is very minor, depending on where you go after this particular area.

Timing of Kyphoplasty

The biggest question occurs when Mrs. Jones has a fracture that is less than three months or over three months. Can you fix something that is older versus something that is newer. Well, a recent study of a combined group, headed by Steve Garvin at the University of California San Diego, looked at these questions and showed that up to 3 months, about 71%, here is the percent reduction, they start at 71% disability, but went up to 92%. So they had about 80% of patients showing a significant improvement. If they were more than three months, 78% of patients show improvement in height. The difference is -- if you wait over three months, the height restoration is halved. So the longer you wait, the less the benefit; in both, the number of patients that can be moved is exactly the same.

We have had better results in patients who have been on steroids. We can make improvements after up to three years if the patient remains on steroids, because the bones are so soft. Or, if they come in with a very low bone mass, you can break it with a balloon. If they have a marginal osteoporosis and it's an old fracture and they are strong, we can't move the bone at all. So the key here is to pick it earlier rather than later; but even the later patients, if they are very disabled, can be improved.

So let's review again: early vs. late. If it's less than three months, 90% partial pain relief, height restoration and angular correction. So as you are watching patients and they are not improving, and they are collapsing before your eyes, this is the time to take advantage of the situation. And if it's more than three months, your improvement is less and your pain relief is not as good as the group that's done fresh, but it still can be a benefit if you can clearly identify those vertebral fractures. Our best results, again, are with patients exposed to steroids, chemotherapy, significant bad bone mass -- those are the ones that respond even in the late period.

Kyphoplasty Complications

Now what are the complications? I mean, you can't do things for free. There are complications. There is no question about it. I went back over our personal experience at Hospital for Special Surgery. In the first 100 to 115 patients, 230 levels, we averaged about 2 levels per patient. We had one dural leak from a needle as it was being placed to get alignment, and the patient had no symptoms. It just cleared, but we had seen some dural liquid and we repositioned our needle. It's just like doing a spinal tap basically. We did have one patient who had a very dramatic improvement in the height of the vertebral body. It was T5, a dramatic increase, and then went on within ten hours to develop a hemothorax on that side and lost about a unit and a half of blood into the chest. It was recognized, we stopped the bleeding, and we had to put a chest tube in and do a mini thoracotomy to get this material out. She stayed a week in the hospital to get through recovery.

So that was my worst complication. However, across the country, two people out of 5,000 have had significant spinal nerve damage, and one person required a laminectomy for an epidural bleed that was so big she became paralyzed. She had a full recovery by doing an emergent laminectomy. So there are complications in this particular procedure. This is the balloon technique, not the vertebroplasty.

So I think that the kyphoplasty offers pain relief. It is not assured. I have now become more cautious as time goes on, and I look upon this as a low-risk procedure, and I tell patients it should be a low-risk procedure. If I can't get a good view, if the anesthesiologist is not happy with what the patient is doing, and if I'm not moving the bone, I may not continue the procedure. Or I may only do one or two levels and not do a third level. And I keep saying I may want to avoid complications, and we are getting better at this specific technique. I want to make sure that the worst that happens is 20% of people have not gotten better; they have a little hole in their back, its just like a failed epidural.

So I think there is a great future in terms of the kyphoplasty. I think, though, that the overwhelming number of patients with osteoporosis does not need this procedure. I think most of them will get better with medical management, and you have to use medical management. It is the ones who are usually sicker, and you have all seen them because you have all cleared these patients. Not everybody gets better with this technique.

Future Opportunities with Kyphoplasty

One last thing -- there are future opportunities in terms of kyphoplasty. We are now going to add to the cement materials that can do local control, particularly for cancer. We are thinking very seriously about using zoledronate or pamidronate or other techniques, which will ooze out into the area and add better control of tumors at the same time. We have not talked about using specific agents to enhance bone, but I think there is a big opportunity. And we are also moving toward bone ceramics, such as hydroxyapatitein the younger individual, which can then be remodeled and disappear and be converted over to bone, because I'm not happy to put cement in a 40-year-old individual and worry about the whole life. In the 5,000 patients, nobody has had an infection, and we use antibiotics.

Medical Management of Osteoporosis

Okay, I just want to go on to make a couple of comments about the drugs that we are currently using for osteoporosis. Remember that kyphoplasty is done in the setting of excellent medical management. You must treat the osteoporosis. By the way, at New-York Presbyterian Hospital, 80% with an osteoporotic fracture, who come in because of the fracture, leave the hospital without major medical alteration. That is our experience. I think we probably do better than most hospitals. You can imagine we have a long way to go.

We are going to talk about osteoporotic medications. There are high- and low-turnover osteoporosis. The major drugs that are currently available for us are antiresorptive agents, which are the estrogens, calcitonins, bisphosphonates, alendronate, risedronate etc. There is a new agent coming out in terms of parathyroid hormone, and that was discussed by Bob Lindsay recently. I'll come back to that in a second to tell you where there is an opportunity for this.

Number 1 -- everybody needs calcium and vitamin D. Calcium and vitamin D are often inadequate. In NewYork-Presbyterian Hospital, 8% of people with a fragility fracture have osteomalacia. It may be subtle. There is a tremendous amount of malnutrition. The skinnier the patient, the greater the chance of malnutrition.

Number 2 -- we now know that 5% of people with osteoporosis have, in fact, sprue. How many of you are looking for sprue? And the majority of them do not have diarrhea. The majority do not have diarrhea. Are you looking for sprue in your population? All this irritable bowel syndrome -- check for sprue. Now, it turns out that calcium and vitamin D will, in fact, decrease fractures by up to 25%, so that even though the bone may not increase, it will in fact decrease the fracture rate. Anybody with a nursing home population should treat patients with calcium and vitamin D. One comment for you, in the group here, is you treat your patients and they often have indigestion. You put them on H2 blockers; calcium carbonate goes in one door and out the other with an H2 blocker. You cannot give Tums or OsCal or Caltrate with those agents, because they will not be absorbed unless they are chewed up -- so I prefer a calcium citrate unless the patient guarantees they are going to chew up the pill, because it will not be absorbed if there is no acid in your stomach.

So that is why I think you have to revisit your calcium preparations, particularly in the rheumatoid patient, who has so much indigestion. The next one is about estrogen. No question estrogen will increase a bone mass by measuring your bone mass. If you don't take it, you lose bone. There are issues about estrogen. It is uncertain as to how good it is. These are case-controlled studies. No randomized control on estrogen. So the Federal government has made a change in how it approaches estrogen. There are issues that have concerned the government.

There is no question of increase risk of breast cancer, 2% per year over the population. And the decrease in the hip and spine fractures are not quantifiable. The improvement of lipid profile has not translated itself into cardiac benefits. There is no clear evidence that it prevents Alzheimer's disease. And now, with osteoporosis in question and Alzheimer's in question and heart in question, why are you giving estrogen? You are giving it because of symptoms. The Federal government says that it is no longer recommended for the treatment of osteoporosis.

So if the patients are taking estrogen, they should take it for reasons other than osteoporosis. Now the endocrinologists clearly feel there is a benefit for it. You can't budge the drug companies to do the right kind of trial. So it is still a questionable issue about estrogen. One point is that estrogen leads to clots. You should consider, if a patient comes in on estrogen, ideally you would stop it a month before orthopaedic surgery because of increased risk of thrombophlebitis.

So its main use according to all these people is for what it was there for -- post menopausal symptoms. And when the symptoms stop, stop the estrogen. Now it turns out that the bone cells cannot tell the difference between estrogen and non-estrogen, and Tamoxifen appears to be recognized by the bone cells. They think it's estrogen, and 70% of people on Tamoxifen have increased bone density. We don't have fracture data on it, but that gave rise to the use of the SERMs and Evista is clearly one of these.

What do these things do? They are bound by the estrogen receptors, that think it's an estrogen. It unequivocally decreases spinal fractures 40%. It has no uterine cancer, and there is now strong interest in using this to prevent breast cancer; the data would be something on the order of about 70%. The problem with Evista is that it does not prevent hip fractures. So if hip fractures are important, you are not getting the benefit from Evista. Also, if the patient is on Evista, they can also get clots. So again, if they walk into your door with Evista and you have some time line, you should stop the Evista before they have orthopaedic surgery and increased risk of phlebitis.

Nasal calcitonin is a tricky agent. Its benefit is uncertain. There is one randomized, controlled study demonstrating a decrease in spine fractures at the usual nasal dose spray. It does not protect against hip fractures, however. But more important is the general consensus and feeling, though the data is shaky, that there is an analgesic benefit provided by calcitonin. So it is very popular now in the use of osteoporotic pain. We often will give it until the pain goes away, but again, it will not protect the hip. It is a second drug that you can use. But if your hip fractures are important, then you really want to move on to another drug in addition to the calcitonin. You have more experience than I in pain relief with calcitonin.

The big key is really on the bisphosphonates. I have chosen alendronate. I could have chosen risedronate. Alendronate has been out longer, so I have a little bit more data on it. Basically, these are paraphosphate analogues that get onto the surface of bone and get under the osteoclast, bind to the bone and cannot be resorbed. Their half-life is ten years. So once they get into the bone, you've got them for a very, very, very long time. They have a second effect by killing the osteoclast. So that anywhere you want to prevent osteoclast function or giant cells are working, these agents will kill them. That is why there is interest in the prevention of osteolysis, as well as disuse osteoporosis, in rheumatoid arthritis where you want to prevent regional osteoporosis.

No question, in every study that is out there, whether it is alendronate or risedronate, you get something on the order of about 50% prevention of hip fractures, and it is the only agent that will prevent it. If you are worried about hip fractures, these are the agents you have got to use. If you can't get oral, then you've got to go the intravenous form if this is what is important to you in your treatment of the patient.

All right now, what are the benefits? Basically, it improves bone mass. It decreases every fracture that has been tested by all of these particular agents, and they are all comparable, but there are other unique opportunities for us at HSS. I do believe it prevents osteolysis, and there are animal studies that clearly demonstrate it. So in the revision joint or in the young adult who is getting a joint at 60 or 55, these people should be put on a bisphosphonate, because it will prevent osteolysis; it will delay it.

Once they are loose, it is of no benefit, but clearly, if you do it early, it is of great benefit. In osteonecrosis, you get dead bone, the body comes in and removes the dead bone. You get a fatigue fracture, and it collapses, and the head goes to death. If you treat them with bisphosphonates, the body cannot remove the dead bone and what it does is it puts living bone on top of the dead bone and incorporates it like a casting technique.

Dr. Cornell and I have for years treated patients with this and we have decreased the conversion from avascular necrosis to joint replacement dramatically in our population, which is often made up of cancer patients with chemotherapy. I don't have the alcoholics or the steroids, but it probably would work in all those individuals by using this specific technique. It's not an all-answer, and it will not prevent osteonecrosis, but it prevents the collapse or delays the collapse in this technique. So I would revisit this in all your patients with lupus, and your steroid patients, (consider) using these agents.

Now the other point is do bisphosphonates work in men? No problem with men as in women, and if you've got a man you should be treating him certainly at that time. The other thing is that the feeling now is a single weekly dose really works comparably to a daily dose. Now I know that Linda has been pushing enormously the use of this early -- the day you think of steroids is the day you start the treatment, and clearly you guys know more about this than I do.

The question in my mind is how much steroids before you start doing it? The issue really is you lose your bone within the first three months. So if you are dilly-dallying around for three months, you've lost your window. The promising information now is that the bisphosphonates start working within three weeks, so you don't need to use intravenous. You can get your benefit very quickly with the oral agents, and I think you have to start on them right away in these particular patients.

The last one, of course, is chemotherapy, and the chemotherapists do not think about this. Lupron is the single worst agent. It is the ultimate castration, and these patients lose their bone before your eyes. If you are called in consultation, these patients basically need this.

All right, here is the problem that is not resolved, and the latest data are still uncertain. If you look at animals that are treated with the bisphosphonates, they acquire microdamage in the bone, and they are little cracks in little areas. The issue with this inability to correct these microfractures is - is this going to lead ultimately to a crash of your skeleton. They have now followed patients up to seven years on a placebo versus treatment drug. They treated these patients a long period of time, and there is the same protection against fractures, as long as these agents have been used with no fall-off. So in spite of the cracks, it seems to be still compensated by better quality bone and other issues, which seem to overcome these little holes that you see.

By the way, the dog studies were done with doses ten times what you use in patients; so these were very high doses in animals. I am going to say that Actonel is exactly the same. In fact I can see no difference between Actonel and Fosamax. There are issues that still have to be resolved about whether Actonel has less indigestion than Fosamax at daily dose, no question. At weekly doses, you know we've had discussions among ourselves, and none of us can really come to a clear answer. Some people have failed on one drug; so it's nice to go to another. You've done this all the time in rheumatology, switching one drug, and you can never tell why one is better.

Now the last point is that it's hard to believe that a 1% change in bone mass is going to prevent a 50% drop in hip fractures. So this is impossible. Tim Wright cannot design and model for me a change in the skeleton to account for a 1% change. So it is the turnover of the bone that is changing, the surface chemistry. The surface activity accounts for most of this and not actually increased bone mass. So that if you treat a patient and the bone mass does not go up, but the turnover parameters are flat and low, you are probably getting exactly the same benefit, and you don't have to pull your hair out and say "I've got to change the drug." It's not necessary as long as the turnover has not occurred.

Lastly is this new drug parathyroid hormone. This probably is going to be a hot ticket for rheumatology. It is a very powerful agent because it is the only agent which makes bone. So now you've got a patient and you can prevent bone loss. . Now you can make bone, and a number of studies by Bob Neer and others has consistently shown that you can decrease the number of fractures 6% versus 3% in the aft of the spine, vertebral, 14% down to 5%. So a big decrease and a dramatic increase in bone mass.

What was interesting was that Bob Lindsay came by and said there was a peculiar observation that he couldn't explain. In the patients treated with parathyroid hormone who had vertebral fractures, those who were on the drug ultimately lost only 1/3 of the height compared to those who were on the placebo. Either the patient's bone mass was stronger, or they healed their fracture faster.

Mathias Bostrom, in this institution, has shown consistently in animal models that parathyroid hormone speeds up fracture healing. Does that mean we should use it for all fractures? Does that mean it will increase porous ingrowth and give up porous ingrowth in patients we have been unhappy with, such as rheumatoid patients? So it may change the agenda by which we are looking at the drug and at rheumatoid patients who are used to injections.

So I think there is a clear element and a call here to use it, and it may change spine fusion rates and increase their improvement. Basically these are the vertebral fractures, dramatic improvement in a series of studies, and here is one by Costman and another study which shows it is extremely effective in decreasing fractures and increasing bone mass.

So, in conclusion, I am embarrassed to say this little simple thing: that everybody gets calcium, vitamin D, and consider estrogen I think now mainly for post-menopausal symptoms. I don't know how many people walk into our doors who still have never even gotten the simplest fundamental, and the orthopaedists do very poorly in this area. The other point is prevention by exercise. If they can't walk a straight line, they have balance problems and we are not going to try to do balance training. We have a program, including Tai-Chi, which in our institution has been effective in women. It decreases falls 47%. It is the single most effective way to prevent falls. And if they do fall, we now have these pants called Safe Hips and others, hip protectors. If they fall on a hip, it is almost impossible to fracture it. The reason it is not 100% is that people don't wear the pants, but if they wear the pants --, 31% wear them --you can't fracture your hip.

So get an NTX (ed. note: Urinary N-Telopeptide)to see where you are basically going, and the key element is if you think osteoporosis and you have evidence of osteoporosis, treat the osteoporosis.

Q & A Session

Question: You said that you were surprised about getting through the IRB, which is a standard control trial. I'm stunned that you get your kyphoplasty through an IRB without controls. Do you have any idea, I'm not saying that you have to do sham operations, but you must have some control data that says the kyphoplasty works as opposed to non-kyphoplasties.

Joseph Lane, MD: A lot of people have done operations and cohorts and used historical controls. This is a challenge in this particular area, and it has been a major deficit. There is a limited, randomized, controlled study done by the kyphoplasty study group. In that group, they found that the patients who were treated on the medical arm -- this was a crossover study which allowed patients to come out of the medical arm after three months of treatment-- there was a dramatic, statistically different health outcome parameter in these patients. Now, the numbers were limited. They didn't follow them very long. Whether it made a difference in the long run is not clear. But there was a study of about 50 to 55 patients performed in a randomized study. Now the government recognizes this, and they are now going to do a randomized study where they are going to have three arms. One arm is going to be medicine, the second arm is going to be vertebroplasty, (even though I make a strong statement of this, it would really make a difference if pain is the big parameter) and the third arm is going to be a kyphoplasty. The placebo arm will get a sham operation. They will actually have an incision made and the suture placed.

The dilemma in presenting this is the methyl methacrylate is not FDA approved. You cannot do an NIH study with a non-approved drug without an IDE (ed. note: independent drug evaluation)It took them two years to get a manufacturer willing to do the IDE for the study. So this is now in the planning stage where the planning grants are. And you are absolutely right, Mike, I think there will be a controlled study. It may turn out that all this height restoration is of no benefit as long as you get the pain relief to the patients and keep it safe.

Question: I don't understand something about the biology. What makes the spine different from the hip from the point of view of how these agents act? Also, practically, we see so much osteoarthritis in the spine, how do you get a handle on whether you are getting a true reading from your DEXA in the spine and does it matter if its true reading? Does the osteoarthritis actually protect your spine? And lastly, do the bisphosphonates work as well in the spine as they do in the hip?

Joseph Lane, MD: Steve raises the artifact of DEXA. When you do a DEXA examination, you look at the spine and you look at the hip. This is not a true density. This is what we call an apparent or an aerial density. You are drawing a circle around an area and measuring everything that is within the column of the circle. And when you get osteophytes or arthritis, you are going to clear this in your number and you'll get an artificially higher value than you would if you could look directly at the spine. So the way to get around that problem is when you do the DEXA, you look at both the spine and the hip and you take the worst reading, which is usually the hip in patients with arthritis, as your number. The reason we like the spine is that it has trabecular bone, which is metabolically more active. The hip is more cortical bone and slower to respond, and the precision is not as clear as with the spine. Therefore, to see changes, you have to wait longer periods of time, but you take whichever is the worst. There are other methods to try to get into the vertebral body by a lateral DEXA or using a quantitative CAT scan, but the easiest way is to shift down to the hip, because the hip is probably more valid in that area.

The other one is, again, more trabecular. Bone responds on its surface. Bone that has bigger surface will respond faster and will lose bone quicker and will regain bone faster. So, therefore, these drugs work best in the vertebral body or the calcaneus or in the triangle of the hip, which is trabecular bone, and they work slower in the cortical bone, which is the femoral neck. So there are differences between diaphyseal bone and metaphyseal bone and cancerous bone in terms of how these drugs work.

Question: Joe, I just want to bring to your attention and the attention of the group the lead article in the JBMR for February 2002. It says that not all vertebral fractures are the same, and also there is a very strong suggestion that it is the unstable vertebral fracture that might be responding best to this form of therapy. They argue that routinely patients should be x-rayed hyperextended to see whether there is mobility and whether you succeed in reducing the amount of compression that is seen. I wonder if (a) do you do that routinely to look at hyperextend? And (b) does that partly explain the particular patients you said you thought the procedure was most successful in, which are the steroid-induced patients, who are most likely to have this mobility or what they call osteolysis. Before you comment on that, I just want to make a comment about the alendronate study that was reported. That was not a randomized prospective trial with placebo for five years or seven years. What happened was that after the first three years, patients who were in the placebo arm were given the option to go on therapy. And, in a sense, what happened was I think about 60 to 70% of the patients chose to do that. And then they used the patients who did not go as the controls. So it was not really a randomized prospective trial with placebo for 7 years.

Joseph Lane, MD: I think Richard is absolutely right. There are vertebral bodies that will respond better than others. We are not really clear how we can pick those patients out. Certainly, the ones that have a central deficit and have a lot of marrow edema -- if you see a cleft. These are the ones, exactly as Richard said, that you can expand and stabilize, that will do better. Those without edema or those who have more of a total collapse are less likely to benefit. We have tried to move these people around on the operating table with the image and watch what happens in terms of motion. Most of these we do not move sufficiently for us to recognize it with our eye at this time. There is a need for a better way to discriminate one versus the other. Clearly, there are some that respond and some that do not.

Stephen A. Paget, MD: I want to expand on Joe's response to Steve's question. The density machines measure 1 through 5. They usually give you an answer that averages for them. But the numbers are there for the individual ones and if you look down and L1, 2, 3 is all 0.9 grams per cm and L4 is 1.2 you certainly know that something is going in L4 and you have to use a different average. Usually the computer will give you an average for L1-2, L1-4, L2-3 and give you all the possibilities. Sometimes you have to pick the more appropriate vertebra.

Question: As you know, as we all know, the youngsters are very busy playing basketball and so forth and so on, and the incidence of stress fractures is a significant one. What I want to ask you is whether you think a stress fracture in a 15-year-old or 16-year-old girl is something to worry about in terms of the problems that you talked about today. And when would you start to protect them against the consequence?

Joseph Lane, MD: Well, Linda and others would argue very strongly about when you start the process of good nutrition and good calcium. I think if a person has an inappropriate fracture, where trauma was done that has to drive you to do a careful analysis. Some of these people will have had rickets. Some of these people will have had an underlying collagen disease. Some of these people will have had anorexia nervosa or primary amenorrhea, and there is an array of issues that have to be answered. But clearly, any stress fracture should be reviewed by you and go through a more rigorous approach, and Jo Hannifin and Lisa Callahan have developed an array. I think it doesn't stop at 50. It stops at any age. If you get metatarsal fractures or other inappropriate fractures, you've got to go through the same array of saying this is inappropriate and should be evaluated.

Question: If a patient has severe osteoarthritis and is bed ridden, is there any role for IV pamidronate?

Joseph Lane, MD: Yes, Dr. Zackson has pioneered at this institution. Linda and I must have 150 patients that are getting intravenous bisphosphonates. If your patients have GERD or esophageal dysfunction and you really want to give a bisphosphonate, we have had outstanding results. We have reviewed the material at our institution with a controlled group getting Fosamax. We have found exactly the same amount of bone density. The numbers are too small to comment about the fractures, but there is no question that those agents will give you the bone density improvement that you can get with the oral agents. I use 30 mg four times a year. Dr. Zackson uses 60 mg twice a year. Dr. Bockman is now using zoledronate 4 mg once a year. So these agents are out there, and I think you have to use it as it unfolds. Pamidronate is our biggest experience.