Bone Quality Versus Quantity in Osteoporosis

1. How New Therapies Reduce Fractures in High Risk Individuals
2. The Paradox of Bone Quantity Versus Bone Quality
3. Calcitonin Preserves Microarchitecture
4. The QUEST Trial
5. Effects of Calcitonin
6. The Impact of Parathyroid Hormone
7. The Future of Osteoporosis Measurement

How New Therapies Reduce Fractures in High Risk Individuals

It is a pleasure to come to Manhattan. I should acknowledge the sponsorship of Novartis for this presentation. Note also that we have done work with calcitonin, which I will discuss today in my presentation, for perhaps the last 20 years.

Now, with that as a background, we can start off here by making the point that it is not a bad time to have osteoporosis. As you know, it's a common and expensive disease, causing fractures of the spine, hip and wrist, etc. But the good news in the year 2002 is that we now have the ability to reduce fracture in women, at high risk of fracture, after the menopause, by about one-third to one half.

As you look at this slide, which is simply an observational assessment with a histogram of the reduction of risk of new vertebral fractures as noted above in women with high risk, with prevalent fracture as the baseline, we can say across the four approved therapies for osteoporosis -- alendronate (Fosamax), calcitonin (Miacalcin), raloxifene (Evista), and risedronate (Actonel), we can now reduce fracture by 30% to 47%.

Now these are all post menopausal women. These are studies in peer reviewed, double blind, controlled studies. You might say where is estrogen? Estrogen is now approved for prevention of osteoporosis, but at this time no longer for treatment. The question, however, and what I am going to spend the remainder of my time on, is how do we reduce fracture? Because as you remember, one of our major work horses of osteoporosis management -- bone quantity measurements by dual photon absorptiometry at hip and spine -- has disparate results for each of these particular therapies. The bisphosphonates have very robust effects on bone quantity and bone density, while the two hormonal or hormone like agents, calcitonin and raloxifene, have more modest effects. So the question has arisen, how are these treatments working to reduce the risk of fracture?

In general, it goes back to this particular slide, which is noted as quite old, dating from 16 years ago. In 1986, David Dempster at Columbia, Helen Hayes, noted with scanning electron micrographs (normal bone to your left, osteoporotic bone to your right) that osteoporosis is a problem with quantity i.e., not enough bone present. As you see in the scanning electron micrograph (to your right, osteoporotic bone), there is a paucity of bone compared to normal bone (on your left.)

But as well, Dr. Dempster reminded us in this particular paper that there is also a micro-architectural abnormality of bone with osteoporosis, i.e., if you look at that trabecular strut going across the middle of the slide to the right, you see it is beginning to perforate. There is that crack about half way through and that particular trabecular rod or strut is beginning to disconnect.

While down in the lower left hand corner, there is already a disconnection or a perforation of that trabecular strut. And indeed, osteoporosis is both a quantitative and a qualitative problem leading to fractures of spine, hip and wrist and many other skeletal sites.

Now what is quite new, new in the sense of our awareness over the past two to three years, is that the approved antiresorptive therapies we have in 2002 -- bisphosphonates, SERMs such as raloxifene (with more coming for each of those therapies in the future), and calcitonin -- may have differing effects on quantity and quality. And it may be -- and I will show you some early data from studies from our laboratory to indicate -- that at least one of these therapies has its primary effect in reducing fracture by preserving the microarchitecture, by preserving the structure of bone rather than by dramatically improving the bone quantity.

Many of the questions that have arisen regarding how these therapies are working in osteoporosis fracture reduction arose from a study that our group is very involved in, a trial with calcitonin nasal spray over five years, using the typical tribal rituals that we jump through in terms of study design -- multi-center, double-blind, randomized, five year trial in women with an average age of 68, post menopause. Approximately 2000 women were involved in this five year trial, and it was designed to look at the ability of calcitonin by nasal spray to reduce future risk of vertebral fracture.

And as some of you who may have seen the paper in the year 2000 in the American Journal of Medicine may remember, 200 units of nasal spray, salmon calcitonin, compared to placebo with survival curve analysis, significantly reduced the risk of a new compression fracture at the spine by about 36%. In women with one to five prevalent vertebral fractures, in other words, salmon calcitonin significantly reduced the risk of a future fracture by approximately one-third.

So, there was a significant effect on reducing fracture in women at high risk of fracture through five years. But when the investigators of the so-called PROOF trial looked at the effects of calcitonin on quantity, determined by lumbar spine vertebral bone density through five years (you may remember that we looked at multiple dosages) we saw that through five years there was a modest effect on bone densitometry with the 200 unit dosage. That is, the 200 unit group through five years had about a 1.2% improvement in bone density. Those of you who are managing and seeing a lot of osteoporosis know that, typically, with bisphosphonates, (alendronate or risedronate and other bisphosphonates yet to come, probably zoledronate, avandronate -- a lot of -dronates running around so to speak) at three years, the data from the trial and others have indicated an approximately 5% to 7% improvement in bone density.

So when we first saw these data from the PROOF study, we raised the question 'How is an agent working to reduce fracture by one-third -- 36% through five years, with such a modest effect on the quantity of bone?' Because I think our expectations in osteoporosis over the past ten to 15 years have been that to reduce fracture you need to see a substantial improvement in bone quantity.

Then we saw the data with the raloxifene studies, the so-called MORE study, coming out shortly after we had the PROOF data, and it showed, interestingly, with that hormonal or hormone-like medication, a similar effect to calcitonin, i.e., a modest improvement in bone density -- about 2% as again compared to the 5% to 7% that one might see with the bisphosphonates.

Not only was there a modest effect on the quantity of bone -- bone densitometry in the PROOF trial -- but as markers of type I collagen break-down and osteoclast- resorbed bone, the telopeptides are released from the broken-down bone, simplistically speaking, move into the serum where they can be measured and then into the urine. And when we looked at serum C-telopeptide, a sensitive and specific marker of bone resorption, we saw a significant reduction at one year with salmon calcitonin with the 200 unit group (in the yellow). But as compared to what we would have expected with bisphosphonates, again, this is comparatively modest, because alendronate produces perhaps, with a serum marker at one year, an approximately 40 to 50% reduction.

The Paradox of Bone Quantity Versus Bone Quality

So we begin wondering how these agents could be working to reduce fracture in the face of modest effects on bone quantity and bone densitometry and turn over of bone resorption markers. We are beginning to find that not only is it the calcitonin group and our group at the University of Washington saying that there may be a paradox of bone quantity as compared to bone quality and defining how antiresorptive therapies work to reduce fracture, but now we have other particular allies, typically the Mayo Clinic with Graves and Melton raising similar questions, due to recent data coming out with raloxifene.

For those of you who don't wake up every morning wondering about bone quantity and bone quality, as I do, to give you a little background on exactly how these therapies may be working, we need to go back and remember that certainly bone quantity is most important in predicting fracture risk at baseline.

In vitro studies have shown, with removal of a vertebra from a cadaver, 60% to 80% of the compressive strength of bone is due to its mineral content. As well, in epidemiologic observational studies, cross-sectional, usually baseline, predicts osteoporotic fracture risk in post-menopausal women, and I think that again reiterates the use of bone densitometry as a baseline measurement to define risk. We know there is an exponential relationship from the data from Wasnich and Ross back in the early '90s -- that as bone densitometry drops, fracture risk increases, and at low bone levels, such risk increases exponentially.

The trials have indicated that anti-resorptive therapies increase or preserve quantity of bone and reduce fracture risk. I think many of us have always assumed through the '80s and the '90s that a change in BMD a surrogate endpoint for treatment effects on fracture risk. However, such an assumption may be incorrect. It may be that, for certain therapies, we cannot use bone mineral density as a definite surrogate for therapeutic effect, particularly with agents such as calcitonin and raloxifene.

I have quoted a recent paper from our specialty osteoporosis and metabolic bone disease journal, The Journal of Bone and Mineral Research from January from the raloxifene data that I would share with you. It is a paper with an accompanying editorial from the Mayo Clinic group, as noted in January of 2002. Now let's go back a little bit and again review some of the evolution of this apparent dichotomy/ paradox between quantity and quality. Up there sort of faded into the sunset a little bit, both literally and figuratively, is fluoride. Some of you are old enough to remember when we used fluoride for something other than dental caries. In the '70s and '80s, sodium fluoride was used. It wasn't approved by the FDA, but there was a 35% improvement in bone density when you gave sodium fluoride at a pharmacologic dose, and the study is from Riggs, reference #1 -- up to 65 to 75 mg of sodium fluoride a day. You could see a substantial effect on bone densitometry, perhaps 35% over four years.

But, as noted over in the percent decrease in the vertebral fracture risk, there was no effect on reducing fractures at the spine. Some of you who may have read the New England Journal of Medicine paper back in 1990 would remember there was actually an increase in fractures at appendicular sites i.e., humeral shaft, femoral shaft and a non-significant, but nevertheless an increase in hip fractures when fluoride was given.

This was probably the first example of this disconnect between quantity and quality, because we know sodium fluoride has a mitogenic effect on the osteoblast to actually cause new bone to be made. But with fluoride you have a new bone crystal for apatite rather than hydroxy apatite, and it appears at least from the lack of reduction in vertebral fracture risk -- and if we consider an extrapolation of quality to fracture risk -- that indeed the quality of bone being made with sodium fluoride is inferior, more prone to fracture, and therefore no reduction and possibly even an increase in fracture risk.

That is then followed by the data I have already shown you but here, the effect that calcitonin, raloxifene, risedronate and alendronate, that the papers have published below, have shown a number of observations in their relationships to the decrease in vertebral fracture risk.

The first point (from the yellow down through the orange), calcitonin through to alendronate, is that there is, across those four agents, a 1% to 8% improvement in vertebral bone mineral density, but with a 30% to 47% reduction in fracture risk. So that in itself says, across all four agents, a bit of a disconnect between the magnitude of improvement in quantity and presumably the improvement in quality. This is seen in the decrease in vertebral fracture risk and the extent to which, if indeed fracture risk is being reduced by that much you would expect it across all of these four agents, even alendronate, and risedronate, a greater magnitude of improvement in bone density, perhaps 25% to 30%.

Or on the other side of the coin, even with alendronate's 6% to 8% improvement in bone density, fractures reduced by 47%. We would expect a 6% to 8% improvement, perhaps only a reduction of 10% to 15% in fractures. So that is the first observation. The second observation of these data, again looking at it post- hoc, is the dichotomy between hormonal or hormone-like agents, calcitonin and raloxifene, as compared to the bisphosphonates. The fact is that the first two in the yellow show only a 1% to 3% improvement in bone density compared to the bisphosphonates 3% to 8% with generally rather similar reduction of fracture risk.

We don't really know if alendronate is better than raloxifene in reducing fracture, because the two have not been compared head to head in fracture reduction studies. It is probably more potent as a bisphosphonate, but in general I think we can say there are comparable effects, one-third to one-half reduction of fracture risks. Then to sum this up, which actually a number of us have noted in an editorial in our specialty journal back in December, we need to be aware of these particular discordances between the magnitude of change in density and the magnitude of risk reduction, as well as the discordance between calcitonin and raloxifene as compared to bisphosphonate and reduction of fracture.

Now we have additional data coming out, and when you see data that might agree with your hypothesis, it makes your heart sort of go pitty-pat. When we first saw these data with raloxifene, we felt that we are now on the right track to try to define the action -- specifically of calcitonin and possibly raloxifene in reducing fracture. The data that we had known about from the alendronate trials, again, was an approximately 47% to 50% reduction of fracture, with an approximately 5% to 7% improvement in bone density. Steve Cummings and Dennis Black, at the University of California San Francisco, have been the major purveyors of alendronate publications over the years. They went back and did a post hoc analysis asking the question 'what percent of the decrease in vertebral fracture rate with alendronate, how much of that fracture reduction of say 50% is due to the improvement in bone mineral density?'

With that admittedly post hoc analysis, regression analysis, only 16.4% of the reduction of fracture reduction with alendronate is due to the improvement in bone density. We've known this for about two years because until the paper got published in the American Journal of Medicine in March of this year, it had been available in abstract form since about 1999. What is equally fascinating -- obviously we are a bit biased because we think it agrees with our hypothesis -- our data with raloxifene from the so-called Moore study that show the increase in bone mineral density -- the increase in bone density with raloxifene in the MORE trials accounted for only 4% of the decrease in vertebral fracture rate. It is probably true not only at the spine as well as the femoral neck -- if you read the paper there was some confounding due to treatment interactions at the spine -- but I think it is probably true not only of hip but also of the vertebral column.

What this simplistically says for us, is that if you look at fracture reduction with either alendronate or raloxifene, only 4% to 16% in those two therapies is due to that improvement in bone density. It obviously says 96% to 84% is due to something else, and the big question is, what is this something else, what is this substance X that may be accounting for fracture risk reduction with these two treatments?

With those data in hand and the observation with calcitonin, we are going back with the PROOF study doing again a regression analysis post hoc to see what percent of the reduction of fractures in calcitonin is due to bone density. And we are also including in it a combination with resorption markers, what percent is due to a reduction in bone turnover and what percent is due to the two together. So hopefully those data should be out, as well as the data with raloxifene and alendronate, some time in the fall.

We can then say, and I think for clinicians this is important, if we are taking care of women and men with osteoporosis, we now have to factor into our thinking the contributions of bone quality as well as bone quantity to the effects of these antiresorptive therapies in reducing fracture. It is not to denigrate BMD. Even though the scale is obviously tipped towards bone quality, BMD remains our major workhorse for managing osteoporosis. But this is to let you know that in the future there is going to be greater focus on what we have termed bone quality in both the research area of osteoporosis and day-to day management. This includes turnover, damage state, micro-cracks, particularly with bisphosphonates, the degree of mineralization and material properties.

Calcitonin Preserves Microarchitecture

Architecture is an area that I will share with you because we are particularly focused on it in our laboratory. Our particular hypothesis is that calcitonin is working to preserve microarchitecture -- to prevent fracture even though there is a less than robust effect on the quantity of bone.

At our institution at the University of Washington, I still use bone density as our major work horse day to-day to define risk. In other words, a person who has low bone density in combination with positive risk factors -- steroid exposure, cigarette smoking, family history of osteoporosis, prevalent fracture, etc, -- and I would like to add in a high level of resorption by a marker - should be treated.

However, we need now to remember for raloxifene and calcitonin, and other SERMs coming in the future, lasofoxafine, besadoxafine, we may not need to see these substantial effects on bone density. We should only need to see preservation, i.e., no loss of bone density, to assure us over one to two years that these therapies are effective.

So we are now evolving new hypotheses as to how these therapies work to reduce fracture. Of increasing importance are the abilities of these therapies to decrease the perforations of those trabecular rods and struts at cancellous sites, which of course, are the sites of osteoporosis.

We would like to say that for bisphosphonates, it seems that we do need an increase in bone mineral density. For all of them, we need a decrease in turn-over of some magnitude and I would like to think that there are mechanisms other than decreasing turn-over or decreasing quantity of bone that may be operative with calcitonin -- such things as apoptosis, going a bit upstream from both structure and quantity, and the fact that calcitonin does not produce apoptosis of the osteoclast, in terms of essentially stopping it in its tracks, as bisphosphonates do, but as a transient effect. And then the osteoclast recovers from that effect of calcitonin within 24 hours and goes merrily about its business resorbing bone.

Could it be related to apoptosis? Could it be related to a cell that many of us in the bone field have not really thought much about? The osteocyte that may control mechanical stimuli being translated to bone in terms of remodeling -- can there be effects of calcitonin there? But the bottom line is that we feel calcitonin's effect may be to decrease trabecular perforation. I think we have some early data in a very preliminary fashion to support that hypothesis.

The QUEST Trial

Now those early data come from the QUEST trial, which looked at the effects of calcitonin, specifically on what we have termed the quality, structure and microarchitecture of bone. It was a study with our group in collaboration with Novartis, and NIH sponsored at least the biopsies, and the CRC at the University of Washington. But this trial is directed at trying to define an action of calcitonin on the architecture of bone. For that particular clinical study, we recruited 91 post- menopausal women, mean age of 67. They are similar to the women in the PROOF study, a five year trial of calcitonin in reducing fracture, looking at women only who had a prevalent fracture and in general a low bone density as determined by densitometry.

So QUEST was a two-year trial calcitonin plus calcium versus calcium alone. I am sure when you see this trial you will agree that the women give of themselves both literally and figuratively to the clinical research. We started with 91 women. I believe we finished with 73 or 74 at two years, back in November. It looked at bone quantity, because obviously that is important and its relationship to quantity is important as well. DEXA determinations were performed at the spine, hip and wrist and os calcis, ultrasound at the os calsis. As you know, we can now look preferably with both DEXA and ultrasonography, say at the heel, as an example.

We looked at turnover throughout the entire skeleton. What is comparatively unique is that we did iliac crest bone biopsies at the beginning and end of the study with the typical histomorphometry that had been done for years on those particular, small approximately half-inch specimens from the iliac crest.

We then proceeded to do three dimensional micro-CT, as seen here on the slide, and that provides us an improved resolution of structure at the iliac crest at predominately trabecular bone. But as I like to say, facetiously, since not everyone wishes to have an iliac crest bone biopsy every year or two to determine what their bone quality is and since we do all the bone biopsies and then send them off to Denmark to have the histology done, I think they are comparatively easy to do but they are invasive and can occasionally be painful, we have been very interested in defining a noninvasive technology for determining the structure of bone, trabecular structure, at the tissue level. We think high resolution magnetic resonance imaging in collaboration with our colleagues at the University of California San Francisco, Dr. Majumdar, provides a potential technology for the future that we will be using. I'll show you some of the first data with MRI from this trial.

First, this is a three-dimensional microcomputerized tomographic assessment of an iliac crest bone biopsy from a woman in the QUEST trial at baseline. She is then randomized to calcitonin plus calcium or calcium alone plus placebo and then re-biopsied at two years. What we see here, in the middle of the picture, is a trabecular strut that is moving across that area that is perforated and that is baseline. These are women with osteoporosis prevalent fractures, etc. In the one below it, about four struts down again, a trabecular strut that looks like it is getting ready to disconnect. And indeed our particular hypothesis is entering the study; calcitonin with micro CT and with MRI will show preservation of the trabecular architecture over two years compared to loss of trabeculae in the placebo group at that same period of time.

Now we have approximately 70 biopsies, which says that biopsies are acceptable (particularly if the women agree to them at the end of the study as well as the beginning). And about half of them have been analyzed, but we don't have the data yet. We are waiting until the full data set is available before we can confirm what we are saying with two-dimensional histology and then the three-dimensional follow-up micro CT.

We look at bone volume over total volume. The number of trabeculae, obviously we prefer that the number not decrease unless the thickness is increasing dramatically. We look at trabecular thickness with micro CT. Are they maintaining the width of the trabecular struts, and down below is something called trabecular spacing. And you would assume if a trabecular number is dropping out, your spacing would increase. You would not like to see an increase in spacing if you are maintaining the structure of bone.

As I said, we would like to hope that MRI could be of advantage in the future to replace the use of biopsies to look at what is going on in terms of structure. We use a typical General Electric 1.5 Tesla assessment to look at the radius in terms of various cuts through the distal radius, predominately trabecular bone. We look at four regions. There are three seen here. As you can see, there is a nice network, a honeycomb of trabecular structure that can be analyzed at that particular site.

We can look at the hip with the so-called T2-Star analysis. None of this is quite yet ready for prime-time, but I can assure you it is coming, and we can look at the hip in various regions as predominately, although not exclusively, trabecular bone. We can look at the heel, as noted, at the calcaneus at a number of sites to determine the trabecular microarchitecture of these sites. We would do this non-invasively, without having to do a biopsy.

Now these were baseline data that we had just when we started the study. Again, what we were asking is what is the trabecular bone fraction, how much bone is there at these sites of radius, of hip, and of the heel? How much bone is there -- bone volume (BV) over total volume (TV), the number of trabeculae, the spacing -- how far they are apart, and thickness.

[Note: This section has been edited to summarize some of the data discussed, as data from the QUEST Trial have not yet been published. The gist was that there was not major change, although preservation did occur in the calcitonin-treated group and trabecular number seems to be maintained with calcitonin. Details of the MRI vs. biopsy findings and within group changes are expected to be presented at the ASBMR. ]

It may be difficult for us to get thickness with micro CT, but even here we see approaching differences between the two to suggest that thickness is being lost in the placebo group. And the P-within is significant in the sense that it shows that thickness is being lost in the placebo group. I can add that we are seeing similar effects at the hip with the so-called T2-Star, the K-time, preservation of architecture at the hip with loss of architecture at the spine, and, to a lesser extent, similar effects at the heel, but we don't have those data analyzed yet.

Now, why might this be important? We know that if you look at the lattice work of osteoporosis, say, in a vertebral body or at the hip or at the distal radius, you can see normal bone (to your right) and again I am indebted today to Dempster. You see maintenance of the normal honeycomb network of bone.

We have known from data from the Danish group back in the '70s and '80s, that if we go to the simplistic approach of what is happening with osteoporosis, horizontal struts seem to be preferentially hit with bone resorption, as seeing a resorption cavity beginning and one of these horizontal struts between the vertical struts, it is eroded, or these trabecular rods drop out. We are left with little stubs that eventually, due to disuse, go away as well.

You can look at this, if you are not into looking at microarchitecture a lot and say gee "looks pretty good to me, I have maintained the vertical trabeculae." However, we know from Eular's theorem that the loss of those horizontal trabeculae are similar to what would happen with a bridge, with a building, a vertebral body, the femoral neck. The loss of preferentially important struts, and particularly the horizontal struts, seems to lead to deterioration of the structural integrity and presumably can contribute to a microfracture becoming a macrofracture.

As noted here from Eular's theorem, the buckling load of the unsupported trabeculae on the right without the horizontal struts in this case is 16 times less than the supported trabeculae on the left. In other words, preferential loss of these horizontal struts dramatically increases the risk of a macrofracture. Presumably, preservation, even through quantity is not being improved, even through resorption is not being dramatically reduced, may explain how calcitonin is working to reduce fracture and potentially for the future how other agents, including raloxifene, may work.

Dr. Dempster's slide I appreciate: In medieval cathedrals, if you don't have a flying buttress, much as if you don't have a horizontal strut, presumably the entire structure collapses, even though flying buttresses don't add much volume to the whole structure.

Then in summary, this is some of the early, and preliminary, data from the QUEST study. We haven't seen the biopsy finality slides. We haven't seen the micro CT. We would like to think that it will confirm what we are finding so far, and we see no reason why it shouldn't. Although again you are looking at iliac crest compared to hip, compared to heel, compared to radius, we've got some site interaction, but we are going to be able to get a lot of the same questions answered regarding interrelationships between quantity, turnover, quality, and architecture. I have to mention strength also, but we can do a formatted assessment of strength with my finite element analysis, both Micro CT and MRI. We think we have now at least started confirming, or at least defining the mechanisms by which calcitonin is reducing fracture and with that, I'll answer any questions.

Effects of Calcitonin

Question: Would I be correct in determining from this data that the calcitonin doesn't rebuild struts and doesn't increase quantity very much, but it is a drug that may be more effective in preventing osteoporosis than treating it?

Dr. Chesnut: I think we can preserve the trabecular microarchitecture. I agree with you, we don't have a reason to suspect that calcitonin or any of the other antiresorptive therapies dramatically increase the number of trabeculae or their thickness. The only exception being data from Dempster and Lindsay, to indicate that parathyroid hormone may increase thickness of the trabecular strut and may possibly improve activity, but I am not sure how you roll a strut back once its already perforated. But it may essentially prevent that perforation. I think you are quite right that calcitonin only preserves -- much as we would assume we effected with bisphosphonates and SERMs.

However I would indicate that we do have clinically a 36% reduction of fractures in women at high risk, and therefore I feel if we can simply keep the trabecular structure we have, we will avoid future fractures. Could we produce a greater effect on fracture reduction clinically? Let's say how about 75% reduction, could we combine these agents and get a greater than 30 to 50% reduction of fracture, a 75% to 80% reduction of fracture by use of a therapy that increases the overall amount of bone there and perhaps increases thickness etc.? I think that is reasonably something to consider.

As well for prevention: right now calcitonin is approved for treatment of the disease. I see no reason not to, although there is a paucity of data in using it in women shortly after menopause. However, are women without a disease who are only taking it for risk factors and potentially a slightly low bone density going to use a nasal spray? I am particularly happy to say that Novartis, along with other investigators, is working on an oral calcitonin and the initial data looked very impressive in the first Phase II trials. So I think an oral calcitonin for prevention would be worthwhile.

Should we combine these therapies? Not right off the bat, but I think we can say there seems to be a rationale for combining agents that stimulate formation, such as parathyroid hormone. If we could ever get an oral PTH rather than the injectable that will probably be approved this summer along with an oral calcitonin, could that be of value? Or, even now, if bisphosphonates have a different mechanism than say calcitonin, could the two of those have additive or synergistic effects? This is a point to consider.

Question: Is it a weight-bearing phenomenon that preserves the vertical struts longer?

Dr. Chesnut: That is a very good question. I really can't answer it well. I'm sure many of the biomechanics people, there is a long list of folks working in this area right now, would probably have an answer to that. But I assume, as you have indicated, it is related to things such as gravity, the various forces being placed on vertebral bodies, femoral neck, etc, as well as the radius. Why are these particular struts more important? I really can't answer that question. I would have to defer to the biomechanics area.

One very good question I have been asked before. How do you know what is horizontal and vertical in some of these slices, and that again is a very good question that I am still dealing with.

The Impact of Parathyroid Hormone

Question: Two quick questions. Number one: your compensation skills allow you now to distinguish between struts and plates - so are the plates important? The second question: you just briefly mentioned the parathyroid hormone. Could you expand on what the parathyroid hormone does in this structural analysis?

Dr. Chesnut: The last question first, what does parathyroid hormone do in the structural analysis. Obviously the people with the greatest knowledge of this would be Robert Lindsay and David Dempster and that group. The data at the bone meetings last year indicated that in a small number of biopsies with micro CT, (they have no MRI data) -- I think 10 to 15 biopsies at most, there seemed to be an improvement in connectivity with what is called the VEDI number. I'm not quite sure what that means, and as well an increase in trabecular number, a decrease in spacing, again not significant because only a small number of samples were available and as well an increase in trabecular structure. I expect PTH is probably going to do that. For some of those who don't know a lot about PTH you can say, how about hyperparathyroidism and all those good things. If you give parathyroid hormone simplistically, intermittently rather than continuously, and endogenously it has an anabolic effect. We have been waiting a year for it to be approved from Lilly. It will be injectable. It will be expensive. We will have to wait and see how that is going to sort out. All PTH is under development at a number of places and as I like to say, if some of my colleagues at Novartis in Basel can come up with an oral calcitonin 32 amino acid without dissolution in the gastrointestinal tract, they can probably do it with a fragment of PTH or an 84 amino acid fragment as well. So I think that PTH probably will have structural effects that will be greater than we would anticipate with an antiresorptive therapy.

The other point is a very good one. At the iliac crest as you saw on those micro CTs, you are going to see a lot of plates that have not yet perforated and become rods and struts. However, at the radius and as well at the os calcis are regions of analysis that are primarily trabecular rods and struts rather than plates.

It's going to be one of the problems we are going to have to look at -- the two- dimensional MRI in terms of structure and with the micro CT as well because there are going to be a lot of plates in there as well as the rods and struts. And can we extrapolate the data on rods and struts to what is going on at plates? I haven't even started thinking about that. It's a good question.

The Future of Osteoporosis Measurement

Question: How do we test for bone quality and what is the role of BMD?

Dr. Chesnut: We in this area have not made the lives of practitioners any easier. Just when you were finally dragged yelling and screaming into T- and C-scores, which is the most arcane and confusing way to ever look at anything ever devised, now we are asking another question, 'how important is BMD?' It is still very important. I think you continue to use that for two reasons. One is to confirm in your own mind two years later that a preservation or an improvement will translate into a reduction of fracture across the four approved therapies that we have at this time.

However, I would like to make the point that in the future, we will probably be looking at risk factors, at bone quantity. I use turnover markers a lot -- not everyone uses those but I like to see what those are -- if they are high there is increased risk and for the future we will probably need to assess bone quality. With MRI you have to be kidding, you can't even get on it unless you have a brain tumor or some orthopaedic problem. It's not accessible and its $1,200 for us to do these, which, of course makes our radiology department very happy, but the sponsor is very unhappy.

The bottom line is that portable MRI is coming. A lot of it is coming out of NASA, because they are concerned about a flight to Mars, i.e., that there may not only be a problem with quantity of bone but also with quality, and so they are defining ways to look at the quality of bone in space. Where we are now is that if you have preservation of bone density, no significant loss with calcitonin or raloxifene, and -- I like to hedge my bets because I like to see a suppressor of a marker resorption as well -- I am comfortable. I can tell this woman or man that we think we are preserving your bone structure and quality, so let's keep this therapy going. So preservation and again with the reduction in marker I am comfortable with.

Question: How do you deal with DEXA, supposing the average is okay but one bone is low, for example some parts of the hip are low compared to the other part of the hip.

Dr. Chesnut: I look at the hip total and I look at the femoral neck, if it is greater or less than what the total is. But you will see disparate changes across sites across time and discrepancies between the two and that is one of the problems we are going to deal with in the QUEST study.

We said when we set the QUEST study up, we are looking at multiple sites. We are going to cover the waterfront. This is an exploratory expedition to define what is going on there. I think you have to say for a clinician what is the most important site and with bone densitometry, the bottom line is, it's the hip, it's the hip, it's the hip, particularly in a woman over 65 or a man who has arthritis that may falsely elevate the spine. So if I see a change in the total hip after 65 I am very comfortable that that is a true measurement. Due to arthritis, you can't put a lot of dependence on the spine measurement in a person over 65, but the hip should probably give you a pretty good measurement over all.

A very important question that the orthopaedists at our place asked me, if somebody has a hip fracture, do I have to stop bisphosphonates or other antiresorptive therapies? Could they deter healing? Do they aid in fracture? Not to my knowledge, even though some say calcitonin may improve healing. One of my colleagues has suggested that calcitonin has the effect of stimulating healing and formation, but I am not sure that those data have been confirmed at other sites as well.

Thank you very much.