| LOW BONE TURNOVER: SHOULD WE STIMULATE BONE TURNOVER IN DIALYSIS PATIENTS |
| Tilman B. Drueke, Paris, France |
Chair: T.B. Drueke, Paris, France |
J. Cannata-Andia, Oviedo, Spain |
|
Prof T.B. Drueke |
Slide 1
Slide 2
Prof Drueke: Thank you Jorge. We all know that there is a wide spectrum of renal bone disease in chronic kidney disease (CKD) patients. When going along the line of intact PTH to the left side, we have more and more low turnover bone disease, adynamic or osteomalacia; in contrast, the more we are going along the line to the right side we have high turnover bone disease, either mixed lesions or pure osteitis fibrosa. Today I would like to focus on the left side here, that is oversuppression of PTH and probably many other associated factors which lead to low bone turnover disease, and see if we can change this condition.
Slide 3
Let us start with a definition: low turnover bone disease or more precisely adynamic bone disease is characterized by defective bone matrix formation plus defective bone mineralisation and decreased bone resorption. Thus osteoid thickness is either normal or low although osteoid surface may be high.
Slide 4
I couldn’t resist the pleasure to show two nice histological features demonstrating what I am speaking about. This slide shows adynamic bone disease. You see that there is no bone activity at all, there are no osteoblasts or osteoclasts. Following tetracycline administration at two subsequent time points, there is actually no double tetracycline labelling.
Slide 5
Let us compare this dramatic low bone turnover feature with that of a dramatic high bone turnover, namely hyperparathyroid bone disease. Here you see nice double tetracycline labellings, together with a large number of osteoblasts, osteoclastic reabsorption, and myelofibrosis. This very active feature is extremely different from the previous one which looks like dead bone in advanced stages of the disease.
Slide 6
Of interest, adynamic bone is characterized by the presence of hump-like structures on lamellar bone which are thought to reflect a minimodeling process, in an attempt to confer at least some degree of activity to a highly inactive bone.
Slide 7
The diagnosis of adynamic bone disease cannot be made based on clinical criteria alone. It most often relies on biochemical criteria, in particular a low serum PTH. Whether “whole” or “biointact” PTH assays, as opposed to the so-called “intact” PTH assay presently used in the majority of our centres, allows a more precise diagnosis of adynamic bone disease remains to be seen. This is also true for the whole PTH/PTH 7-84 ratio. To date, the gold standard of the diagnosis still relies on the histomorphometric assessment of a bone biopsy.
Slide 8
Dr De Broe’s group in Antwerp, Belgium reported some years ago that low serum levels of bone-specific alkaline phosphatase had the best predictive value for the diagnosis of adynamic bone disease. In our experience, however, the measurement of this enzyme does not allow a clear-cut distinction between low and normal bone turnover.
Slide 9
The causes underlying adynamic bone disease are multiple. To date, the most frequent cause is hypoparathyroidism, be it induced surgically or medically. In the seventies and eighties of the last century aluminium intoxication was the predominant cause in many dialysis centres.
Slide 10
Skeletal resistance to PTH is another possible cause which may be due to down-regulation of the PTH/PTHrp receptor and/or an inhibitory action of PTH fragments on bone turnover.
Slide 11
Other favouring conditions are shown on this slide, the most prominent being age and diabetes.
Slide 12
Now, why should we stimulate bone turnover in dialysis patients? Many colleagues would argue that there is no harm having bones which are a bit lazy if there are not any clinical consequences of low bone turnover. Well, we know that, first of all, in presence of excessively low bone turnover the calcium, phosphorus and magnesium which enter the body via the oral route cannot be deposited in the bone. The turnover is so low that the bone cannot fulfil any more its normal buffer function. Therefore, these ions will be immediately deposited in the soft tissues. Maybe this view is an oversimplification. However, it appears ton fit well clinical observations. We have to consider that the normal compartments for calcium in the body are the entry compartment, namely the gut, of large size, the extracellular compartment, which is rather small, and the bone compartment, which is extremely large. When we then consider that in CKD patients with adynamic bone disease the skeletal compartment does not participate anymore effectively in the exchange between the intestinal and the extracellular compartment, and that the kidney does not excrete any longer excessive calcium amounts taken up via the gut it is easy to understand that the only way the calcium can go is to a new compartment, namely the soft tissues, und extraosseous calcification ensues.
Slide 13
In contrast to the belief of some people, there is reported evidence of an increased propensity to fractures in patients with low serum PTH levels, say low bone turnover, as shown on this slide. It demonstrates that haemodialysis patients with very low PTH levels are the ones with the highest fracture rate.
Slide 14
In this study by Coco et al, there was a significant difference in fracture-free survival between the haemodialysis patients with low as compared to medium and high PTH levels, which means that the patients with low bone turnover are at increased risk of fracture. One can easily imagine that these patients, when receiving a kidney transplant and high doses of corticosteroids, are exposed to a particularly high fracture risk.
Slide 15
Another issue of concern linked to adynamic bone disease is the observation of marked growth retardation in the pediatric patient population with chronic renal failure.
Slide 16
This slide illustrates the relation between the PTH status and bone turnover status on the one hand and the propensity towards soft tissue calcification on the other hand. It is somewhat ironic that both high and low bone turnover favour the occurrence of hypercalcaemia, hyperphosphataemia, and hypermagnesemia, obviously seoncdary to opposite mechanisms, and thereby favour the deposition of these ions as apatite crystals in extraosseous tissues.
Slide 17
Now, what are the means at hand allowing us to stimulate bone turnover in CKD patients?
Slide 18
Giorgio Coen has already addressed this issue to some extent. I would like to further extend on it. First of all, we know that in the past aluminium overload was a major condition inducing low bone turnover. This has been shown in animals and this unfortunately has also been our personal experience in many patients, with sometimes dramatic consequences. At present, hypoparathyroidism is the dominant factor in most patients with low bone turnover disease, be it in the presence or absence of a concomitant, minor residual aluminium overload. We have seen that there are a number of other factors, in particular advanced age and diabetes mellitus. Malnutrition, protein and phosphate deficiency, and iron overload have been proposed as other possible factors. Glucocorticoid treatment of course also depresses bone turnover, and maybe also hypothyroidism.
Slide 19
A first means to stimulate low bone turnover is to decrease the dialyzate calcium concentration, as shown by Dr Jehle’s group in Germany. Haemodialysis patients exposed to the low calcium dialyzate for 18 months experienced an increase in plasma PTH and a decrease in plasma Ca x PO4 product. Concomitantly, circulating markers of bone formation and resorption increased, reflecting an increase of bone turnover.
Slide 20
Sanchez et al from Spain used a similar procedure to stimulate bone turnover. They compared two groups of 44 peritoneal dialysis patients, one treated with standard calcium dialyzate concentration and the other with low calcium dialyzate. As expected, they observed an increase in serum PTH in the group on low dialyzate calcium, compared with the group on standard dialyzate calcium.
Slide 21
Sanchez et al also found indirect evidence of increased bone turnover in the low calcium dialyzate group, as shown here by an increase in serum osteocalcin. However, they could not confirm this observation by concomitantly performed histomorphometric analyses, based on bone biopsies done at start and twelve months after exposure to one or the other dialysis solutions.
Slide 22
Finally, I would like to show you possible future ways of stimulating bone turnover in CKD patients. They are based on studies performed in experimental animals with CKD and in patients with osteoporosis but without CKD. The first aspect deals with the effects of bone morphogenetic protein-7 (BMP-7), and the second with the effects of intermittent, as opposed to permanent, administration of PTH.
Slide 23
This work from Keith Hruska’s group in Saint Louis, Missouri has already been alluded to by Giorgio Coen. This slide shows bone formation rate assessed by histomorphometry in different types of bone disease, and in response to the injection of BMP-7 into non uraemic and uraemic mice. Actually the authors did not use wild type mice, but a very special breed of transgenic mice, namely LDL receptor knockout mice with severe hypercholesterolemia. They administered BMP-7 to sham-operated mice on either normal or low-phsophate diet, mice with CKD having secondary hyperparathyroidism, and mice with CKD having adynamic bone disease, in presence or absence of BMP-7 treatment. Adynamic bone disease was induced by a high calcium and vitamin D diet. The slide shows that the latter could be entirely prevented by the administration of BMP-7.
Slide 24
The same was true for another histomorphometric parameter, namely mineral apposition rate: thus again, adynamic bone disease could be prevented in mice treated with BMP-7. Surprisingly, not shown here, the injection of BMP-7 into mice with hyperparathyroid bone disease also led to a reversal of the disorder towards normal. It would be good to have these findings confirmed by an independent group before accepting the claim that BMP-7 may be one of the most important proteins in controlling both low bone turnover and high bone turnover and allowing full correction of both low and high bone turnover in CKD.
Slide 25
Hruska et al also showed in the CKD mice with adynamic bone disease that BMP-7 was able to correct serum phosphorus, serum calcium, and serum Ca x PO4 product.
Slide 26
Finally, they observed a decrease in soft tissue calcification, namely calcification of the aorta, in LDL-receptor knock-out mice with CKD put on a high-fat diet, in response to BMP-7, as shown on the right side of this slide. No such beneficial effect of BMP-7 was observed in non-uraemic, sham-op. control mice, as shown in columns 2 and 3.
Slide 27
A more classic way to increase bone turnover would consist in the administration of PTH since this hormone is the major determinant of bone disease in CKD patients. High PTH means high turnover, and low PTH means low turnover. A relatively recent finding is that the intermittent administration of PTH can cure osteoporosis since intermittent PTH injections are able to reactivate lazy bone and thereby increase bone turnover. The authors of the work shown on this slide injected PTH intermittently into diabetic LDL-receptor knock-out mice with the purpose to stimulate skeletal bone mass. This animal model therefore is the same as in the previous work but here we deal not with uraemic, but with diabetic mice. They have a low bone mineral content when treated with vehicle, whereas the intermittent administration of PTH 1-34, which is also called teriparatide, is able to increase bone mineral content significantly.
Slide 28
It is very interesting to note that teriparatide is also able, at the same time, to decrease the extent of vascular calcification, as shown here isat the level of the aortic valves. Compared to vehicle-treated animals there is a tremendous decrease in vascular calcification in response to intermittent injections of parathyroid hormone.
Slide 29
Intermittent injections of teriparatide also increase the bony expression of osteopontin (OPN), a marker of bone formation.
Slide 30
In contrast, the vascular expression of osteopontin is down-regulated by teriparatide. It is interesting to see that a given marker may evolve into opposite directions in response to the same stimulus, depending on the tissue in which it is expressed. This also goes along with the inverse relation between bone turnover and calcification.
Slide 31
Let me summarize. At present, many of our patients are oversuppressed by massive doses of either calcium or vitamin D, the latter given either orally or intravenously. Clearly, we have to bring them back in some way from the left side of low turnover bone disease towards the middle representing normal bone turnover. Obviously we have to pay much attention not to overstimulate PTH and bring the patients back to the right side, that is where we started 30 years ago in the majority of the patients. It will be clinical skill which finally will allow us to control bone turnover in an optimal way.
Chairman: Thank you Tilman, Doctor Drueke. It’s time for questions. Please are there short questions and short answers?
Question: Well, I have to express my complete disagreement with Tilman’s conclusion and he knows why. First, because you are based on non-evidence. Histological evidence reviewed by the KDOQI has shown that the optimal PTH range based on histological data is the limit for differentiating normal bone from adynamic bone, namely 60 pg/ml of intact PTH measuring also the 7- 84 fragment, and the upper limit was between 150 and 200 pg/ml. So the the KDOQI recommendations are not based on evidence. Second, you showed as the only clinical evidence of the deleterious effect of low adynamic bone the experience by Cocco et al and you know where the dialysis patients come from. They come from which hospital? In which conditions of nutrition? They are all malnourished because they are mostly infected with HIV, you see and they have very low proteins and you showed that it is very important to have good nutrition, isn’t it? With high IGF or IGF-4, so what do you think of that? What is your clinical evidence, the only one is actually the last published data of sevelamer against calcium and there is in favour both for the trabecular bone and also for the cortical bone which is quite completely unique up to now but of course, it is a new technique which has never been evaluated to predict fracture whereas all the studies that have shown that showing that increase in cortical bone at the femoral neck, you decrease the risk of fracture and I think Dr Cannata will not disagree with me. It is well known that it is related to hyperremodelling, high PTH, so why do you want to stimulate PTH to keep bone healthy and strong against fracture?
Prof Drueke:Thank you for this mini lecture, Dr Fournier. I think there is no time to answer to all you concerns. We are running out of time.
Question: We are here to debate because we are clinicians responsible for the bone of our patients and of the calcification.
Chairman: Yes but what Tilman has been doing is to give an overview of the issues. His task is not to discuss one specific paper in great detail.
Question: The only paper that supports actually your hypothesis of stimulating bone remodelling.
Prof. Drueke: There are of course other papers but I did not have time to show them, there are at least two other papers.
Question: We all know that keeping low PTH and high PTH without changes in the I would say rhythm of PTH is bad for the bone. O.K. Because both high and low produce high fracture rates so what do you think about the likely effect of the calcimimetics that really can pick a big PTH and in some way is not pulsatile and permanent?
Prof Drueke: Since calcimimetics lead to an intermittent change of PTH this is a very interesting suggestion. What we do not know is whether when PTH goes up intermittently or when it goes down intermittently, as is the case with the calcimimetics, this will give rise to the same result. We do not know whether this has similar implications for bone turnover. It would be a very interesting way to stimulate bone turnover, of course, but whether such an intermittent decrease in PTH levels with calcimimetics works in a way similar to the intermittent increase in serum PTH by exogenous PTH administration remains in the domain of speculation.
Question: Tilman, I think it’s a little bit simple to reflect the bone turnover also by parathyroid hormone I think we have more data to estimate bone turnover. In my own centre I have a lot of patients with PTH lower than 150 pg/ml, yet with normal bone turnover, they have normal osteocalcin levels, they have normal TRAP and normal bone alkaline phosphatase levels, and have no signs of osteodystrophy. I never have agreed to stimulate such patients according to the so-called guidelines. I can also not accept, like Albert Fournier.
Prof Drueke: It is true that it is an oversimplification to consider only PTH; as we have seen by Dr Coen’s intervention there may be different situations depending on different ratios between 1-84 PTH and 7-84 PTH fragments with opposite actions, depending on how the patients are treated, namely with high calcium or low calcium intakes or dilayzates, high or low vitamin D supplements, and it may well be that depending on each centre’s habits or strategies we have to envisage that similar PTH levels will not reflect similar conditions. This is why there’s such a big need for other circulating markers of bone turnover which directly stem from bone but do not have themselves an influence on bone. Unfortunately we know that we have no excellent markers at present which can distinguish between normal and low bone turnover. That’s the problem.
Question: A last practical question if I can. Judging from the last result, I would say that the results are new but the idea of manipulating the calcium dialysate to increase PTH is 20 years old. Then we never had really data to support this that we use in the clinical practise. Judging this, judging the coming evidence and more evidence about fractures, will you use it prudently in patients with very low bone turnover once you have already excluded aluminium toxicity in the clinical practise for a short period for example, to stimulate the PTH I would say just your opinion a very practical clinical question.
Prof Drueke: I would say that for me the most attractive potential indication is for patients who have low bone turnover disease and at the same time massive vascular calcification, I mean extraosseus calcifications including tumour-like calcifications. In these patients we know that we can remove calcium massively from the soft tissues, especially of course in patients with the tumour-like calcifications. I’m not quite sure for the other types of calcifications but at least we could avoid these patients to aggravate vascular calcifications; however, this has to be shown in prospective studies.
Chairman: I quite agree with you, Tilman, especially for patients who are intoxicated by vitamin D, with ulcerations of the skin due to calcifying arteriolosclerosis. We had such a patient in whom we decreased the calcium of the dialysate and were able to cure his lesions on both thighs.
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