Slide 1

Thank you very much. Now, this is a very important question and that implies that there’s a very important answer as well. The difficulty is that I’m not sure I can give you the answer that you want. I’ll have to leave you to judge that at the end of the talk. This won’t be an exhaustive review of the field and for that I must apologise to the people in the audience who may have contributed to the field and have not been acknowledged in my summary. That in no way implies that their work is any less worthy. It’s just the constraints of time. So we’ll move on here.

Slide 2

Now, I thought I’d start off with the current guideline position. This is KDOQI from 2003. There have been other attempts since then but, of course, KDOQI still in some sense represents the current standard of care that is practiced in many parts of the world. So there is not a lot to be said about transplantation bone disease, look at this. So kidney transplant patients should have a BMD measurement by DEXA to assess the development of osteoporosis OPINION. DEXA scans should be obtained at the time of transplantation and 1 and 2 years post-transplant (OPINION). If a t-score is equal or less than -2 at the time of transplant or at subsequent evaluations therapy with a parenteral amino bisphosphonate should be considered (OPINION). So at least there’s the humility there I think to express these views as opinions only and a recognition that there’s considerably uncertainty there.

Slide 3

Now, the bisphosphonates, of course, come in various shapes and forms. I’ve just listed some of them here. This again, is not an exhaustive list. These are all agents that are familiar to you, they are not all available, licensed in all of Europe or in the US necessarily. They fall into 3 main groups and they differ enormously in their potency. But in fact, this is the most striking area of difference between them and qualitative differences in what they actually do is less striking. They’re all potent antiresorptive agents and there are certain detailed differences that can be identified as well but potency is a major factor. They all have a long duration of action. They may have a short half life in plasma or relatively so but a very long duration of action in bone and they stay in bone a long time. A single injection of zoledronate, for example, in post-menopausal women modifies the biochemical markers of bone metabolism briskly and the disturbance remains present for up to a year after the injection. So these are very long acting drugs in some cases. But that of course, means that if you are giving the drug and inducing side effects the side effects maybe very prolonged as well. So we need to be quite cautious there.

Slide 4

Now why use bisphosphonates at all in this post-transplant setting? Well, there’s an enormous body of evidence out there attesting to the benefits of bisphosphonates in non-renal patients with osteoporosis and we know that bisphosphonates in that group can protect BMD and can slow the loss of bone and also reduce fracture rate. There’s a massive body of evidence supporting that view. That also extends to patients in whom treatment with glucocorticoids has been initiated. This study goes back a bit 2001 from Boutsen and colleagues comparing pamidronate with calcium (in blue and red) versus calcium alone (in yellow ) in patients started on glucocorticoids when you can see that the calcium alone patients experience considerable loss of bone, whereas those given either a single dose of bisphosphonate or multiple dose of bisphosphonates were largely protected.

Slide 5

There’s a lot of other evidence out there that’s broadly in agreement with that. So these agents are not only effective in preventing bone loss in a post-menopausal setting but they’re also effective in preventing bone loss with the initiation of glucocorticoids. Following transplantation as we’ve heard there’s a very rapid phase of early bone loss and the early studies of Julian was supported by subsequent observations by Grotz amongst others showing this extraordinarily fast loss of bone during the first 6 months following transplantation with 5- 7% BMD going over that period of time and work from our group a while back showed a rather similar pattern of early bone loss with a tendency to stabilise from 6 months on and in some cases even to recover at least partially.

Slide 6

So this was tempting therapeutic target. The fact that there was such a very rapid period of bone loss triggered the thinking that if one could intervene right at the beginning one might achieve something useful. We did a study a number of years ago, a small study and it was not a very powerful study, but you have to start walking before you run. This study looked at patients who had kidney transplantation and were given two very small doses of IV pamidronate one at the time of the transplant and the other a month later. The dose was extremely small 0.5 mg/kg only. No further intervention made. This was an open randomised study. Bone loss in the control patients is shown in red. Very substantial loss both at the femoral neck and at the lumbar spine was largely eliminated in the bisphosphonate groups. So even with these relatively small numbers quite a startling difference emerged. Subsequent work by other groups has tended to confirm these observations that the bisphosphonates given in that way work well to prevent the loss of BMD early after transplantation.

Slide 7

This is Grotz’s work, lumbar spine here, here’s the bisphosphonates treated group. Here you’re using ibandronate not pamidronate and can see rapid loss in the control group and a similar level of protection observed at the hip. So these are all very encouraging observations. It quite quickly, I think, it drew the renal community to the view that we should be giving bisphosphonates to most and perhaps even all patients following transplantation. But it wasn’t quite as simple as that. I’ll come back to that later on.

Slide 8

More recent work looking at risedronate in patients already with established transplantation. Risedronate given orally 35 mg/week in transplanted patients. This is looking at femoral neck, BMD changes and you can see that there’s really not a great deal of difference here and no significant impact of the bisphosphonates given that way at that site.

Slide 9

In contrast at the lumbar spine using a similar same protocol some protection of bone loss seen at 12 months in the risedronate group. Here are the risedronate patients and there are the controls.

Slide 10

So the conclusion from that work by Torregrosa and colleagues, sorry about the misspelling here, is that risedronate protected BMD at the spine but not at the hip and bone density actually increased at the lumbar spine in risedronate treated patients. This is an interesting point in that the bisphosphonate was associated with a significant reduction of self-reported bone pain in these patients. No effects on fracture and indeed none of the studies that I’ve allluded to so far have shown a statistically significant effect on fracture, although the Grotz study showed the beginnings of a trend.

Slide 11

Now this brings us then on to some metanalyses of some of the available work out there and this one was published fairly recently 2006. Mitterbauer and colleagues looking at a number of studies including our one here, there’s the Grotz one and one here also by Coco and colleagues that I’ll talk about a bit more in a moment. But you can see here looking at the changes at the femoral neck after a bisphosphonate, the type of bisphosphonate not specified, versus control and you can see that there is clearly the beginnings of a trend here. These are BMD measurements and not fracture we’re talking about by the way but even so, strictly speaking we don’t quite achieve statistical significance here.

Slide 12

Although I think there’s certainly a strong suggestion that BMD is protected there. If one does the same analysis, same group looking at the lumbar spine, here there is a clear cut and a quite significant protection of BMD from this small metanalysis of these studies.

Slide 13

Now these Cochrane reviews if you’re on the receiving end of them, can be quite a disturbing experience because they rather tend to dismiss your work as being completely irrelevant or fundamentally flawed in various ways. I’ve had that experience more than once, it’ll probably happen again from time to time. But anyhow just to summarise the results of this one, which is well worth a read, this is 2008 looking at interventions for preventing bone disease in kidney transplant patients. The interventions being bisphosphonates, vitamin D metabolites or calcitonin and it points out that no individual intervention has been shown to reduce fracture risk after kidney transplantation. I would certainly not disagree with that I think that’s absolutely right. These agents provide a significant improvement in bone mineral density when given after transplantation but the clinical significance is not at all clear and that’s largely because the role of bone densitometry in CKD is also unclear at the moment. I’ll say a word or two about that in a minute as well. So, they clearly have a good effect on protecting BMD and they’re rather better, the bisphosphonates that is, than vitamin D sterols in what limited head to head studies there are available.

Slide 14

Now not included in that Cochrane review is a study that we have done which has not yet been published, but it has been presented and I’ll just run through this quickly because it’s a reasonable sized study, it’s intravenous pamidronate again but it’s one of the biggest studies out there. So this was a multicentre study that we did non-blinded and the patients were randomised at the time of transplantation to receive IV pamidronate or not. They all received supplemental calcium and they all got vitamin D supplementation in a rather modest dose, which incidentally hardly changed the 25- hydroxy vitamin D concentrations at all from the beginning to the end of the study which is another point worth noting there. We excluded patients whose PTH was low, our hope being that we would weed out at least some of the patients who might have low turnover bone disease. We thought that that was a group that potentially could be harmed by the bisphosphonates. We accepted that by choosing that cut off we might well have a number of patients with low turnover included disease, however. So the intention-to-treat populations, 46 versus 47 standard immunosuppression. These patients all had steroids at low dose and a cyclosporine as their CNI.

Slide 15

The results look like this. If we start at the top left, BMD at the lumbar spine is significantly protected in the bisphosphonate group. Moving on to the total hip, significant benefit there from the bisphosphonate, less obvious at the femoral neck specifically, but quite obvious in the Ward’s triangle area.

Slide 16

So again in this rather larger study showing results broadly compatible with what we’ve seen before. Changes in bone markers did not differ between the two groups at all. Here is reduction of phosphate and serum creatinine, calcium no change here, and I’m not going to go through these in detail in the interests of time in fact, but the bone markers, osteocalcin and bone specific alkaline phosphatase and c-telopeptide did not differ appreciably between the 2 groups.

Slide 17

Facture is a crucial end point of course, and the fractures encountered in this study were quite infrequent 5 in the control group, 2 in the treatment group. Fracture rates calculate at 5% and 2%, way short of significance. These are very small numbers. So even with a study of approaching 50 per group the fracture event rate was far too low to have any chance of showing anything interesting.

Slide 18

Now why is this then? Well, I’m just going to give you some assertions here quickly and start to explain a bit about why I think these studies struggle to show a change in fracture rate. BMD is a predictor of bone fracture risk and in the non-renal population it’s clearly a good predictor. In CKD stage 2 and 3 it is an adequate predictor, albeit not as good as in the general population. CKD stages 4 and 5 it’s almost useless as a predictor of bone fracture and in the transplanted patient group it’s almost useless as well. That seems to be the information that is emerging.

Slide 19

Why should that be? Well, I think it can be at least partly explained in this way. Here’s bone density down the right hand side as one of the determinants of bone strength and fracture risk. We can measure that with a DEXA scanner, so that’s what we actually measure in these studies but what we don’t measure is what’s down the left hand side here the bone quality issue. This is where bone histology comes in, we’re not really able to get a good view of that in any way other than by biopsy at the moment so there’s a big dark area that we largely ignore in these studies. I’ll put it to you that in the transplanted patients and in the CKD patients there’s so much variation in the quality side that that essentially masks any more robust measurements we make of bone density.

Slide 20

So we don’t get the correlation with bone density that we might expect. We know that there is a big variation in bone histology in patients at the time of transplantation from mild hyperparathyroidism, adynamic, osteomalacia and a fair number of osteomalacics in this study. Other studies have all shown in differing ways this level of heterogeneity, so it’s a mixed bag that we’re trying to treat with a single agent which is a bit naïve.

Slide 21

Now, this is an important work. This is Maria Coco and colleagues, again showing that the use of pamidronate largely prevents bone loss. Nothing new there. So here’s the pamidronate group, control group and also at 12 months a similar observation. But the important thing about this study is the histology because this study shows changes in histology from the time of the transplant and the initiation of the bisphosphonate and 6 months later.

Slide 22

Look at this. We’ve got a mixed picture at the time of transplantation and most of these lines are going down and a lot of them are ending up in the adynamic sector which they did not before. It’s by no means certain therefore that these patients who were given bisphosphonates have ended up with healthy bone. Many people could argue that to be down here is to ask for trouble in the future. So a big question mark about the safety there.

Slide 23

Quite a lot of experimental work about ways in which bisphosphonates may damage bone or interfere with the ability of bone to repair itself. This was done in dogs looking at canine rib. You can see there’s a microfracture here picked out by the arrows and the study used risedronate and alendronate and showed suppressed intracortical remodelling of quite a substantial degree with both those bisphosphonates, increased micro damage accumulation in both to a substantial degree, no effect on strength or stiffness but there was an effect on toughness in the alendronate patients only. So evidence of quite important or potentially important toxicity there. Low turnover disease in hypercalcemia with hyperparathyroidism. This again is another illustration to me that the things we tend to look at measure easy things like PTH, calcium etc. and although we might use them to say that a particular patient should have high turnover bone disease, it’s not that simple.

Slide 24

This study by Borchhardt and colleagues is a good one and well worth reading. Bone biopsies were done after double tetracycline labelling here in 17 patients. These patients had hypercalcemia and hyperparathyroidism and reasonable function. So high turnover disease was present in 9 and low turnover disease in 8. So about an equal split of high and low turnover disease despite PTH being high. I think this just reinforces the notion that we can’t predict what’s going on in the skeleton at the moment without getting a piece of the bone out. Neither PTH nor FGF-23 - I won’t talk about the FGF-23 story here - was associated with changes in phosphate handling or in any histological bone parameter.

Slide 25

So to conclude then, where are we with the bisphosphonates? Well, I think there are some important pitfalls out there which I have listed here. There’s no doubt in my view that we can protect BMD with bisphosphonates in this setting but we almost certainly can’t protect strength because no study has yet shown a reduction in fracture. Nor has it been possible to show a reduction in fracture with metanalyses. There is a distinct possibility in my view of long term bone toxicity from the bisphosphonates. It’s speculative, hard evidence is lacking but there are a number of pointers in that direction so we have to be cautious. Nephrotoxicity I’ve not touched on. I don’t think that’s a big issue for our sort of patients. Low bioavailability when given orally in my view means if you’re going to use these drugs, we ought to be using them parentally and not orally. The bioavailability is so low and so variable when given orally that I think that doesn’t make much sense. Furthermore the use in transplantation is unlicensed in most countries and so we are really leaping out in the dark with little evidence and little support in the event that things go wrong.

Slide 26

So to conclude then current recommendations here are the bisphosphonates down at the bottom to be taken in the context of the other things that we might be doing. Again the evidence that these make any real differences might be pretty thin I have to say but with bisphosphonates, insofar as one could express a view, I think you could argue in favour of giving early IV bisphosphonates, probably not in patients who have a particularly high likelihood of having low turnover bone disease, though don’t fool yourself into thinking that by doing that you’re necessarily going to reduce fracture rate. A big study’s going to be needed to show that and I think it’s perfectly valid to take the view that we should not be using bisphosphonates at all in these patients at the moment. That’s the level of uncertainty that exists at the moment.
Thank you.