OSTEOPENIA IN RENAL PATIENTS: DIAGNOSIS, TREATMENT AND PREVENTION

K. Olgaard, Copenhagen, Denmark

Chair: T. Drueke, Paris, France

J. Cannata-Andia, Oviedo, Spain

Prof. K. Olgaard Nephtology Department Rigshospitalet Copenhagen, Denmark

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Slide 1

Prof Olgaard: Thank you very much Chairmen, Ladies and Gentlemen. The topic today is osteopenia in renal patients and I have to cover in a short time both diagnosis, treatment and prevention.

Slide 2

You know osteopenia reduces bone mass really, is or can be a consequence of a large number of different conditions and I will, in this talk, turn my focus upon the consequences of renal osteodystrophy and not touch osteoporosis of post transplant bone disease or the special patient groups listed.

Slide 3

You know that renal osteodystrophy might be a high bone turnover state, a low bone turnover state, it might be the adynamic bone or it might really be a condition which has components from all of this and all these different stages might be followed by osteopenia and that means that it is very, very difficult just for the state of having osteopenia to tell what is the underlying bone disease, what is the underlying bone condition.

Slide 4

So, what I will do in the following is just to try to follow the K/DOQI guidelines and try to tell you about how they can be implemented. You know osteodystrophy and the consequences are a large number of different and you have heard already this morning a number of these symptoms mentioned but especially it is followed by osteopenia, bone pain, periarthritis, joint pain, fractures, cysts in the bone, myopathy, extra-skeleton vascular calcifications and especially growth failure in children. So, there are a number of consequences, which can be accompanying this osteopenia in renal patients.

Slide 5

Slide 6

But if we now go to my task and that is really to look upon the diagnosis and first look upon the non-invasive illustrations of bone disease in chronic renal failure and if you look upon the x-rays, here are a couple of hands.

Slide 7

A couple of patients were severe, secondary hyperparathyroidism at least estimated from extremely high PTH levels. Then you will see that the tips of the fingers are completely destroyed, they are beginning cysts but you will also see there are huge extra skeletal calcifications and if you look at the skeleton, if you look at the fingers, the bone and the fingers then it is nearly impossible to tell whether these fingers are osteopenic or not and the general concept is that you need approximately this or you need a reduction of the bone renal content in the bone of approximately 30% before you are able to estimate that there is osteopenia on x-rays.

Slide 8

If you look at this other example, then you will see it's clear that you can use x-rays as a good indicator of calcium deposition in the vessels but it is really very, very difficult even in much better x-rays than this one to tell how much is in the bone and how much has been lost during time.

Slide 9

So just very shortly the K/DOQI guidelines, they indicate or recommend that bone radiographs are not indicated for the assessment of bone disease in CKD but they are useful in detecting severe peripheral vascular calcifications and/or bone disease secondary to beta-2-microglobulin amyloidosis.

Slide 10

If we now turn to the bone mineral density determinations, then I would like to refer to this paper by Mariane Rix from our group. She looked upon a large number of patients with pre-dialysis uraemia according to the status of the K/DOQI guidelines and you will see that at all places where she measured the BMD, she found a decline in the BMD according to the reduction in TFR and that has been confirmed in several other studies.

Slide 11

She also looked upon the reduction in bone mineral content in relation to three groups of elevated parathyroid hormone levels. At all places she found that reduction in bone mineral content related to the severity of the degree of secondary hyperparathyroidism.

Slide 12

Bone mineral density (BMD) measurement should be measured by DEXA scans in patients with fractures and in those with known risk factors for osteoporosis. But that means also that it should not necessarily be measured in all our dialysis patients and it has to be stressed once again that a low BMD does not provide us with any information on what is the type of bone disease and what is the structure of bone.

Slide 13

Slide 14

This is the old classical paper by Sherrard showing that you can't distinguish by the use of intact PTH assays between a high turnover bone disease and a low turnover bone disease and in his material he used the limits of about 500 picograms/ml or below 100 picograms/ml as it is also repeated really in the K/DOQI guidelines.

Slide 15

That is the standard we have been using with all the limitations there are in using PTH assays. So you know not recently but within the last ten years we have realised that the intact PTH assay commeasures a rather huge peak of C-terminal fragments mainly the long C- terminal fragment 7-84. That can explain the huge variation that is seen when you are using different intact PTH assays. But this also underlines, this is an indication of the amount of PTH 7-84 that is commeasured with a PTH assay.

Slide 16

This also underlines the difficulty we have in comparing PTH determinations from one lab or one department to another really. They're huge variations. So recently there was the introduction of this new assay only measuring PTH 1-84. That is, I'm sure a huge advantage for the future but we have to realise that all the studies that have been performed until now, they are performed on the basis of the knowledge we have obtained by the use of intact assays.

Slide 17

So this group from Doctor Malluche's lab, they looked upon the relationship between bone formation or bone turnover and intact PTH, the old assay, the specific assay PTH 1-84 And then they took in that 7-84 might affect the response of bone to PTH 7-84, let me say in this way, so they created a ratio between PTH 1-84 and C-terminal PTH fragments and found that this relationship gave a better indication for the bone turnover status of the patients than the use of either intact PTH or the more specific PTH 1-84.

Slide 18

I have to say that this concept has been discussed a lot and a large number of studies do not agree with the beneficial effect of using this ratio, so right now I will not recommend it for any practical purposes. If you look upon the relationship between intact, 2 intact PTH assays, then it's beautiful. If you look upon the relationship between the intact PTH and the specific PTH 1-84, then it's beautiful too but the slope of the line is much lower and the general concept is that the intact assay commeasures about 40% of non-specific PTH fragments.

Slide 19

So the K/DOQI give us recommendations, levels for the PTH we should aim at in the different stages.

Slide 20

So let me just go through the other bone markers. The problem with many of these bone markers is that it is eliminated by the kidneys and that you will have elevated levels according to the reduction in kidney function and that goes for all the markers which I will not mention according to the time.

Slide 21

But it is shown here by Mariane Rix once again that most of these markers, they just follow the reduction in kidney function and that means that it is very, very difficult really to tell at least in population whether the marker is the expression of a reduction in kidney function or is a question really of severe skeletal problems.

Slide 22

You know if you take these two examples, then you have one example of hyperparathyroid bone disease in a patient with skeletal factor, PTH levels around 300.

Slide 23

Or you might have a severe adynamic bone disease in a patient with a skeletal factor and PTH maybe about 200 and it is very, very difficult just on the basis alone of PTH levels to tell what the underlying bone disease is. So in a certain number of patients we need bone biopsies.

Slide 24

The K/DOQI guidelines state that the most accurate diagnostic test for determining the type of bone disease associated with CKD is iliac crest bone biopsy with tetracycline labelling and histomorphometric analysis.

Slide 25

They also stress that it is not necessary, I would like to understress not because we all have problems I think by using bone biopsy in the clinical practise, so it's not necessary to perform bone biopsy in most situations in the clinical practise but it should be considered in a patient with stage 5 who has pathological factors due to minimal or no trauma who has intact PTH levels between 100-500 picograms/ml with a coexisting condition such as unexplained hypercalcemia, severe bone pain or unexplained increases in bone alkaline phophatases or in patients who are suspected of aluminium bone disease.

Slide 26

So I will now look at the treatment.

Slide 27

I will do it just as short and if I start with the K/DOQI guidelines for phosphorus levels, what should we aim at of phosphorus levels? Then it is stated that in CKD patients, stage 3 and 4 we should go for a phosphate level between 2.7 and 4.6 mg/decilitre or 0.87 millimolar and 1.49 millimolar in these patients. In patients on dialysis or stage 5 we could allow a little higher phosphate levels between 3.5 and 5.5 mg/decilitre or in millimolar between 1.13 and 1.78 millimolar and that is a good thing. In our unit it would reduce the phosphate level or the aim at least just a little bit.

Slide 28

But if you look at this paper from JASN in 2005 where they have looked at the large number of uraemic patients with relatively mild reduction in the kidney function and with phosphorous levels between in millimolar between 0.8 and 1.6 millimolar, then you will see that also within the documented recommended range of the K/DOQI guidelines, there's a significant increase in mortality at least correlating with the increase in phosphate.

Slide 29

So there's a good, good reason really to try to have a focus on phosphate.

Slide 30

You all know the type of phosphate binders I will not touch on the classical phosphate binders but just show you this slide on the sevelamer, which is an effective phosphate binder, does not affect calcium and of course, you will have the same reduction in the calcium-phosphorous product as you have in the phosphate levels by use of sevelamer.

Slide 31

The other more recently introduced phosphate binder, is the lanthanum carbonate which is similarly effective in binding phosphate levels and is marketing at this meeting. I just have one concern about lanthanum levels and that is that if we look at the experimental studies that have been performed and published by Doctor Drueke's group but also confirmed from Doctor Fouad Al-Baaj, then in 2 different types of experimental uraemia they found accumulation of lanthanum in the liver, significant accumulation of lanthanum in the liver and at the same time a reduction of the liver volume by approximately 20%.

Slide 32

Lacour further found an increase in the hepatic enzymes.

At this meeting we saw or heard that there is now experience from 3 years use with lanthanum in uraemic patients without any effects on the kidney function but still I would like to have these results confirmed before really recommending this new phosphate binder.

Slide 33

The vitamin D analogues. Of course there are the classical analogues and then there are less calcemic analogues 19-nor, 22-Oxa and 1-alpha vitamin D2.

Slide 34

The classical effects of calcitriol or 125 has been shown in enormous papers on bones since 1989 and even before that time. It has a significant improvement effect on bones but we don't have bone biopsies in general, so what we're doing is we are using the circuit marker for PTH levels and that is what they have done in this study where they have compared 19-nor or simpler with calcitriol on the treatment of secondary hyperparathyroidism.

Slide 35

And as you'll see in this study from Doctor Sprague then both vitamin D analogues were able to suppress PTH levels at really the same weight and level but also they demonstrated that the hypercalcemic and/or the calcium-phosphorous product above 75 occurring at least once during treatment occurred at exactly the same weight using the 2 vitamin D analogues. So right now, still I'm not convinced that there's any benefit from using, clinical benefit, let me say that from using the less calcemic analogues of vitamin D in treatment of our patients.

Slide 36

K/DOQI guidelines and I'll not take you through this, provide us with recommendations for the use of the different vitamin D analogues at stage 3 or 4 and at stage 5 where you have, it is related to the levels of parathyroid hormone.

Slide 37

Slide 38

So just one word about calcimimetics.

Slide 39

I think that calcimimetics and the introduction of cinacalcet has been one step ahead really, a great advantage and you will see in this study by Doctor Moe how it has been able to really suppress PTH levels to within the recommended range. At the same time you will have a suppression of plasma phosphorous and you will have a normalisation of plasma calcium levels that means that the calcium-phosphorous product is also normal.

Slide 40

So there is a great advantage of this. By the provision of vitamin D you are introducing a long-term suppression of the synthesis of parathyroid hormone but while you are introducing a change, shift in the short-term in the PTH levels by the use of calcimimetics and that might of course, affect the anabolic effects of PTH and not only the catabolic effect of PTH. Probably we are going to see how to use a combination of these two types of drugs in the future.

Slide 41

Bisphosphonates. Just one word of caution really, bisphosphonate is used in secondary, primary osteoporosis a lot, more and more.

Slide 42

In patients with reduced kidney function and in transplanted patients it has also found its way but there are publications of a number of patients with severe, severe problems after the introduction of bisphosphonates and this is just one example of a patient developing a severe nephrotic syndrome with a really severe destruction of both the glomeruli and the tubuli in these patients.

Slide 43

So, the recommendations of the European guidelines for transplantation is really what I'm alluding to here and they're not based upon solid evidence but really the use of these phosphonates might be considered as treatment of severe osteopenia factors in patients with a good and stable kidney function as in all other patients. If we have patients with really severe osteoporosis, then of course, we might consider the beneficial effects on the risk of introducing some complications. It should, however, probably not be used in patients with reduced kidney function and that is also recommended by the FDA who will not accept that kind of use. It should not be used in the presence of secondary or tertiary hyperparathyroidism, not in the case of hyper-vitaminosis D and not be used to pre-menopausal women due to the risk of the foetus, it will be transferred by the placenta. So there are many, many, many limitations leaving only a few indications for the use of these phosphonates in our patients. So also we had the same kind of ideas, same kind of source.

Slide 44

I just want to end this talk by looking at the future and I think that PTH 1-34 might really be a drug which in some way will find its way into also our circles I'm not aware of anybody who has done that but it will be a very, very difficult balance but it might be as someone said that it has beneficial effects. One of the most promising things, one that has happened recently is the introduction of bone morphogenic protein 7 and I would just show you one picture of bone it has beneficial effects on kidneys.

Slide 45

Chairman: Congratulations for this nice overview. I would like to ask you whether you considered as a presently clinically relevant to measure end-vertebral plate x-ray attenuation to predict fractures and if not at which site would you recommend the DEXA measurement of bone mineral density in order to critically assess specifically the cortical bone and not only the trabecular bone since risk of fractures is mainly femoral like fractures has mainly been related to a decrease in cortical bone?

Prof Olgaard: I think that you really answered a lot of your questions yourself indirectly. I would use bone mineral density as a continuous follow in the single patient but it would be very difficult to use the different levels, the different degrees of demineralisation in our dialysis population. I would go for probably the hip, if you want to use cortical bone because fractures in the hip have the most severe consequences but today with the use of DEXA you will often get the whole skeleton within no time so but my focus would be on the hip due to the clinical consequences.

Question: What do you think also of the site of the distal third of the radius?

Prof Olgaard: I think that there have been a lot of comparisons you know not lately but previously between the bone mineral density in the radius and the rest of the skeleton. As you saw in this study from Mariane Rix well, it correlates rather nicely, if you have a large population but I would be more cautious about using the arm than I would about using the hip mainly because the arm is exposed for in dialysis patients to so many things, fistulas and blood pressure and blood sampling so I would use the hip.