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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1998  |  Volume : 9  |  Issue : 4  |  Page : 397-415
Osteodystrophy in Chronic Renal Failure Patients

Department of Nephrology and Hypertension, University of Antwerp, Belgium

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How to cite this article:
D'Haese PC, Couttenye MM, De Broe ME. Osteodystrophy in Chronic Renal Failure Patients. Saudi J Kidney Dis Transpl 1998;9:397-415

How to cite this URL:
D'Haese PC, Couttenye MM, De Broe ME. Osteodystrophy in Chronic Renal Failure Patients. Saudi J Kidney Dis Transpl [serial online] 1998 [cited 2021 Apr 15];9:397-415. Available from: https://www.sjkdt.org/text.asp?1998/9/4/397/39098

   Introduction Top

In patients with chronic renal failure a number of events involved in mineral homeostasis are disturbed. When the renal function deteriorates to less than 50% of its normal capacity, the kidneys are no longer capable to fully excrete the daily phosphorus load. In addition there will be a decreased capacity to produce lα-hydroxylase; the enzyme responsible for the renal synthesis of the active form of vitamin D; i.e. calcitriol (lα, 25-(OH) 2 vitamin D3) which in turn leads to a decreased calcium absorption from the gut and ultimately the development of hypo­calcemia.

Both hypocalcemia and hyperphosphatemia stimulate parathormone (PTH) secretion. Over time there is also a characteristic increase in the calcium concentration required to suppress PTH secretion (shift in calcium 'set-point'). [1],[2] The net result of these changes is that the parathyroid glands become hypertrophied and hypersecretory. [3]

The changes in mineral metabolism due to renal failure inevitably lead to metabolic bone disease. Already in the early stages of renal impairment, histologic changes can be observed in the bone, so that by the time glomerular filtration rate (GFR) falls to 50% of normal, 50% of the patients exhibit abnormal bone histology. [4]

Renal osteodystrophy is a general term encompassing abroad spectrum of metabolic bone diseases. The state of secondary hyper­parathyroidism as described above, without interference of other metabolic factors, leads to a high turnover bone disease either expressed as a mild lesion without distortion of osteoid organization (lamellar osteoid) or the more pronounced form known as osteitis fibrosa in which the osteoblasts function in a more 'chaotic' way resulting in 'woven osteoid. In osteomalacia the effects of secondary hyperparathyroidism are overridden by other factors that induce a mineralization defect in combination with a low bone turnover. With the mixed bone lesion, which is considered a transitional state, characteristic features of both hyperparathyroidism and osteomalacia are concomitantly present. Finally, adynamic hone (disease), is a type of renal osteodystrophy, the prevalence of which within the dialysis population has grown rapidly during the last years. It is characterized by low bone formation, but in contrast to osteomalacia, in the absence of an increased osteoid volume. An overview of the histological qualification of the various types of renal osteodystrophy is presented in [Table - 1]. [5],[6],[7],[8],[9],[10]

   Phosphorus Retention Top

There is general agreement that phosphorus plays an important role in the pathogenesis of hyperparathyroidism. The mechanism by which this effect occurs is complex and to a certain extent controversial. It has been demonstrated that a rise in serum phosphorus can evoke an increase in PTH secretion [11] . Humans with normal renal function given an oral phosphorus load showed increases in serum phosphorus, decreases in ionized calcium and increased serum PTH. Whether this sequence of events also occurs in early renal failure has been questioned. Indeed, in these patients, despite relative hyperpara­thyroidism, low phosphorus levels are often observed due to a phosphaturic effect of increased PTH levels. [12] The role of phosphorus intake on the production rate of lα,25-(OH) 2 vitamin D 3 (lα-hydroxylase activity in the roximal tubule) is still controversial [13],[14],[15] . With further loss of renal function and its ensuing inappropriate phosphate excretion, phosphate levels undoubtedly increase. This hyperphosphatemia exerts a direct stimu­lating effect on the parathyroid glands as shown by Kilav et al. [16] It also stimulates PTH indirectly through a decreased lα-hydroxylase activity [13],[14] and physiochemical reduction of the calcemia via the calcium x phosphate solubility product. To what extent other mechanisms, such as an effect on phospholipid composition of the parathyroid cell membrane, calcium fluxes in the para­thyroid cell and/or regulations of calcium and/or calcitriol receptors on the parathyroid cell may influence the role of phosphorus in the PTH secretion is not yet fully understood. [17]

   1α,25-(OH) 2 Vitamin D 3 (Calcitriol) Deficiency Top

The kidney is the major site for the production of calcitriol. Here, this important metabolite of vitamin D is biosynthesized under the enzymatic l α-hydroxylase activity, localized in the proximal tubular epithelial cells.

As renal mass decreases with progression of renal failure and the GFR decreases to below 80 ml/min [18] , the ability to generate the active l α ,25-(OH) 2 vitamin D3 compound may also decrease whereas median concen­trations of inactive PTH will increase. Hence, relative (in incipient renal failure) or absolute (with more advanced loss of functional renal mass) deficiency of calcitriol are considered key events in the development of secondary hyperparathyroidism.

Calcitriol deficiency leads directly and indirectly to reduced parathyroid gland suppression and thus higher levels of PTH; directly through its genomic action on the parathyroid cell, and indirectly through reduced intestinal calcium absorption. Thus, a number of patients with reduced serum calcium levels, as may be seen at the onset of renal failure, may present with elevated serum PTH levels despite calcitriol levels within the normal range. Since serum PTH levels and calcitriol do not correlate.[19] the important triggering ability of calcitriol in the development of hyperparathyroidism is thought to be further determined by other underlying biological events yielding to a servocontrol mechanism. [20]

The issue of reduced vitamin D receptors (VDR) at the level of the parathyroid cell, as described before in renal failure patients [21] , remains controversial, at least as long as nodular transformation of the parathyroid gland with increasing duration of renal failure [3],[23] has not developed.[15] Concerning the possible involvement of the VDR gene polymorphisms in the pathogenesis of hyperparathyroidism and other bone lesions continuing controversial results have been reported. [24],[25],[26]

   Altered Parathyroid Function Top

At the transcriptional level, PTH mRNA is increased by lowering serum calcium concentration. [27] By virtue of their VDRs parathyroid cells also respond to increased calcitriol levels through a decreased PTH mRNA production; an effect that has been shown to override a possible simultaneous hypocalcemia induced stimulation. [27] Whether phosphorus either up-regulates or inhibits PTH mRNA synthesis is still a matter of debate. [16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28]

The secretion of PTH which occurs by exocytosis is controlled by the extracellular calcium concentration involving a recently cloned calcium sensing receptor; [29],[30] the calcium versus PTH relationship being sigmoidal. The cellular events underlying the calcium regulated PTH secretion are presented in [Figure - 1], Hypercalcemia activates the calcium receptor with subsequent production of inositol triphosphate which in turn raises the intracellular calcium concentration by a transient spike in the element's concentration derived from the endoplasmic reticulum, and a more sustained increase due to influx of calcium through voltage sensitive and insensitive channels. An increase in the diacylglycerol concentration leads to an increase in protein kinase C activity that will then inhibit PTH secretion. How hypo­calcemia leads to an increased secretion of PTH is less well documented but increased cAMP levels and protein-kinase-A have been implicated [31] [Figure - 1]. Evidence has been presented recently that similar mechanisms are at work in the regulation of the PTH gene transcription {synthesis) by extracellular calcium [33] Both in vitro [3] and in vivo [16] the secretion of PTH has also been shown to be influenced by the extracellular phosphate concentration, independent from serum calcium and vitamin D. With regard to parathyroid cell proliferation, stimulatory effects induced by hypocalcemia and hypovitaminosis D have been suggested'. Recent data also indicated a stimulatory effect of hyperphosphatemia on parathyroid gland hyperplasia. It remains to be shown however, whether phosphate regulates cell growth directly or indirectly. [24]

The issue of parathyroid cell apoptosis ah remains controversial. Whereas some groups were unable to find any evidence of prosrammed cell death, [34],[33] others reported various degrees of apoptosis [36],[37] Given the preset technical difficulties in demonstrating apoptosis particularly in slowly growing tissues, remains to be seen whether this is real c caused by technical artifacts, as recently demonstrated in both the myocardium [38] an the kidney. [39]

The PTH-induced alterations on the circulating calcium concentration are the results of the hormone's actions on various target organs In bone the cells of the osteoblastic lineage are the primary targets. Here, increased levels of PTH, together with other factors such as interleukin-1 (IL-1) and tumor necrosis factor a (TNF-α), will activate the remodeling cycle through actions on the layer of osteoblasts covering the bone surface. In addition, stimulated osteoblasts and other cells in the bone micro environment (i.e. marrow stromal cells) will produce various cytokines and growth factors; i.e. granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M­CSF), interleukin-6 (TL-6), interleukin-II (IL-II). These will, through cell-to-cell communication, stimulate the proliferation and differentiation of osteoclast precursor cells which after fusion to multinucleated osteoclasts will ultimately end-up in an increased bone resorption and release of calcium from the bone. [10],[40]

At low intermittent doses PTH has been shown to stimulate bone formation with an increased number of osteoblasts and higher alkaline phosphatase activity, a feature useful in the design of new therapies for osteoporosis. [41]

At the level of the kidney, the PTH inhibits phosphate re-absorption, increases fractional re-absorption of calcium, and stimulates the la-hydroxylase activity, which results in higher levels of active vitamin D.

New insight has also been gained, using refined knockout technology and in-vitro osteoblast culture models, in the major role played by parathyroid hormone related peptide (PTHrP) and the PTH/PTHrP receptor in bone development and its possible impli­cations in adult bone disorders such as renal osteodystrophy. [24] In addition to the stimulating effects of PTHrP on osteoblast activity, C-terminal fragments of this peptide have most recently been shown to exert anti-proliferative effects on osteoblasts as well, [42] and to inhibit bone resorption in vivo [43] .

   Other Factors Contributing to Renal Osteodystrophy Top

In addition to the systemic factors, a number of other substances may also play a role in the development of renal osteo­dystrophy. In patients with chronic renal failure accumulation of aluminium originating from inadequately treated water used to prepare the dialysis fluid or from the intake of aluminium-containing phosphate binding agents may exert a toxic effect on bone at three levels. Firstly, accumulation of the element at the calcified bone boundary may induce a mineralization defect. Whether this is due to a direct effect on the physicochemical process of hydroxyapatite formation or occurs indirectly by affecting osteoblast function [44],[45] is not yet fully understood. Secondly, as indicated by histomorphometric bone biopsy examination of aluminium­intoxicated patients, aluminium reduces the overall activity of the osteoblast which at the cellular level has been shown to be due to the transferrin-mediated anti-proliferative effect of the element on the osteoblast. To what extent aluminium also affects the proliferation/differentiation rate of osteoblast precursors remains to be established. [47]

Thirdly, it has recently been shown that the uptake of aluminium by transferrin­mediated endocytosis also suppresses the PTH secretion, not synthesis. [48] Whether the so-called aluminium-related bone disease will ultimately be expressed as osteomalacia, the mixed lesion or adynamic bone will depend on whether the effect of aluminum on mineralization, osteoblastic activity, or parathyroid gland function prevails. [5] It will also depend on the situation of the bone tissue at the onset of the intoxication.

Aside from aluminium, other (trace) elements, such as iron, silicon, zinc, lead, vanadium, sulphur and fluoride have also been associated with the development of bone lesions. [7],[49],[50],[51],[52],[53],[54]

At present their role in the development of particular types of renal osteodystrophy however, remains controversial. Recently, increased levels of strontium were observed in dialysis patients with osteomalacia. [55] Support for its role in the development of this bone disease was provided by an experimental study in which strontium administration to chronic renal failure rats resulted in the development of osteomalacic lesion. [56]

Clinical factors that may contribute to renal osteodystrophy include diabetes mellitus which, because of its concomitant deficiency of bone growth factors and lower PTH levels, is typically characterized by a low turn-over state. [57] Renal failure is associated with a state of gonadal dysfunction in both sexes and gonadal steroids are critical to bone remodeling through their potential effects on IL-1 and IL-6 production. Hence they have been considered a contributing factor to renal osteodystrophy. [58],[59] As lα,25­-(OH) 2 vitamin D 3 is deficient in renal failure and since i) this compound has been shown to induce a strong transcriptional up­regulation of the genes of osteocalcin and osteopontin [60] ii) these matrix proteins are secreted at the time of mineralization, their deficiency would be expected to affect matrix organization and mineralization. [10]

Metabolic acidosis is associated with a negative skeletal calcium balance, [61] which results from either the direct dissolution of bone [62] or the stimulation of cell-mediated bone resorption. [63] To what extent metabolic acidosis contributes to the development of renal osteodystrophy is not yet clearly understood. [64] Some evidence has been presented that at the cellular level, the acidotic state stimulates osteoclastic activity while osteoblastic activity is decreased. [62],[64],[65] Also, an additive effect of PTH and acidosis on osteoclastic bone resorption has been suggested. [66] Acidosis may also have an inhibitory effect on lα-hydroxylase activity, thereby contributing to a low calcitriol level. [67]

   The Spectrum of Renal Osteodystrophy Top

Renal osteodystrophy is a general term encompassing both high and low bone turnover forms of bone disease. Mild secondary hyperparathyroidism and osteitis fibrosa belong to the former group, while osteomalacia and adynamic bone disease belong to the low turn over group. In between these two groups, patients may present with a more or less normal histology or a mixed lesion showing the features of both hyperparathyroidism and osteomalacia.

Hyperparathyroid bone disease

As outlined above this disorder is caused by excessive levels of PTH and other activating factors on the skeleton. In hyperparathyroid bone disease, both formation and resorption of bone take place at an accelerated rate. As a result the number of osteoblasts and osteoclasts are increased. Hyperparathyroid bone disease can further be divided in the mild lesion with a high bone turnover but where the osteoid is properly laid down (lamellar) and mineralized, and osteitis fibrosa in which osteoblasts function in a more chaotic way resulting in the deposition of the so-called woven osteoid which is further characterized by the development of a typical marrow fibrosis consisting of fibrous tissue occupying the peritrabecular spaces. Although the mineralization rate is also increased it can not completely keep up with the increased osteoid deposition which will ultimately result in an increased amount of osteoid which mineralises poorly and consists of mechanically deficient woven bone resulting in fragile bone prone to fractures. [68]


In osteomalacia the effects of secondary hyperparathyroidism on bone are overridden by other factors that induce a mineralization defect and a low rate of bone turnover. This type of renal osteodystrophy is characterized by an excess of un-mineralized lamellar osteoid producing wide osteoid seams. The number of osteoblasts and osteoclasts are both reduced. Remaining osteoblasts however continue to produce osteoid, which does not get mineralized readily as assessed by tetracycline labeling. The total bone volume may vary whereas mineralized bone volume is always low [68] . Patients suffer from bone deformities, bone pain and fractures.

In end-stage renal failure patients, osteomalacia mostly results from aluminium exposure which is known to inhibit bone minerali­zation by a mechanism that, at the present, is still poorly understood. [5],[44],[45] In osteomalacic patients specific stains for aluminium [69],[70],[71] together with micro-analytical techniques [72] have demonstrated the element to be present at the osteoid calcified bone boundary. Aside from aluminium, other factors such as vitamin D deficiency and perhaps other (trace) elements such as strontium [56] may also play a role in the development of the disease.

Mixed uremic osteodystrophy

In this type of renal osteodystrophy characteristic features of both hyperpara­thyroidism and osteomalacia are present. In the mixed lesion a predominant pathogenic cause is lacking. It is caused primarily by hyperparathyroidism and defective minerali­zation with or without decreased bone formation; features that may co-exist in varying degrees. Marrow fibrosis is present together with increased amounts of osteoid, which can either be of the lamellar or woven type. [68]

Adynamic bone disease

Adynamic bone is characterized by hypo­cellular bone surfaces with decreases in both osteoblastic surfaces and numbers. Osteoclast surfaces may be decreased or normal. [3] The reduced amount or even absence of osteoid together with a decrease in trabecular bone volume are two key aspects of this disorder and in this respect differs from osteomalacia; the other low turnover form of renal osteo­dystrophy.

Neither the exact pathogenesis nor the clinical implications of this type of renal osteodystrophy are at present well understood. Adynamic bone disease has primarily been associated with aluminium intoxication. In contrast to its deleterious effect on bone mineralization as noted in osteomalacia, in the case of adynamic bone disease aluminium is suggested to act at the level of either the osteoblast by reducing its cellular activity and/or proliferation [46],[74],[75],[76] or by suppressing PTH secretion by the parathyroid gland; [48],[77] actions which are thought to be transferring-mediated. [46],[48] The discrepant observation of a growing number of patients with adynamic bone disease concomitantly with a drastic reduction in the exposure to aluminium implies, however, that other pathogenic factors must be active. Here, besides to diabetes mellitus [78] a role has also been attributed to over treat­ment with calcium and vitamin D. Also age, time on dialysis, CAPD and male gender [79],[80],[81],[82],[83] have been reported to hold an increased risk for the development of adynamic bone disease.

Although in dialysis patients with adynamic bone disease serum PTH levels are reduced for the degree of renal failure, the levels are still above the upper normal limit compared to subjects with normal renal function [79] . This suggests that the production of one or more suppressors of bone formation must be increased or that promoters of bone formation must be decreased. [10] Here, a potential role for interleukin-II, interleukin­IV and endothelin, respectively inhibiting bone formation, [84] bone resorption [85] and osteoclast function [73] has been put forward. As osteogenic protein-1 (also called bone morphogenic protein-7) is produced by renal tubular cells [86] and is considered a potent osteoblast growth factor, [87] its deficiency may also contribute to the development of adynamic bone disease in end-stage renal failure. [10] It has been suggested that calcitriol might also lead to a relative resistance of bone on the remodeling effect of PTH. [88] Therefore, its seems that calcitriol may lead to the development of adynamic bone not only by suppressing PTH secretion but also by rendering the bone unresponsive to the effect of PTH. [89],[90] Recently, the provocative hypothesis based on experimental evidence [91],[92] has been put forward stating that by the relative iron depletion noted in the current dialysis population secondary to the intro­duction of erythropoietin, there will be an increase in: (i) number of binding sites for aluminium on transferrin, (ii) the affinity of transferrin for aluminium and (iii) the number of transferrin receptors. This in turn will increase the cellular uptake of the aluminium-transferrin complex via endocytosis [46],[48] making transferrin receptor expressing tissues, such as the parathyroid gland and osteoblast, prone to the deleterious effects of aluminium even when present at relatively low concentrations.

It has been a matter of controversy whether adynamic bone disease represents a clinically relevant disease or is merely a histological diagnosis with no clinical consequences. As low bone turnover implies a failure of the normal homeostatic mechanisms responding to biomechanical stresses in bone, one may reasonably assume that in individuals with adynamic bone, the healing of microfractures and the renewal of areas of bone that have become unstable would be impaired and that this would lead to clinical symptoms [89] , Literature data also point to an increased fracture rate in comparison to that seen in the general population and increased mortality rate as compared with that among patients with other forms of renal osteodystrophy. [93]

   Renal Osteodystrophy: An Evolving Disorder Top

As renal osteodystrophy has a dynamic nature as demonstrated in studies involving serial bone biopsies, [73] one would expect, decreasing prevalence of low turnover bone disease with the withdrawal of aluminium containing phosphate binding agents and the diminished exposure to aluminium containing dialysis fluids. However, whereas concomi­tantly with the decreasing proportion of patients with stainable aluminium, the incidence of osteomalacia indeed decreased [82],[94] a growing number of patients with adynamic bone disease (up to 61% of the dialysis population) has repeatedly been reported. [80],[82],[83],[94],[95] Adynamic bone not only emerges at the expense of osteomalacia, but also goes along with a decreasing prevalence of hyperparathyroid bone disease. [80],[82],[96] The exact physiopathological mechanisms behind a dynamic bone disease are not yet clearly understood and thus reason(s) for its increasing prevalence remain largely unknown. As already outlined in this paper, epidemio­logical and experimental studies have put forward a number of factors contributing to the development of the disorder. Further studies are needed however, to unravel the pathogenetic mechanisms underlying their potential role.

   Diagnosis and Treatment of Renal Osteodystrophy Top

Invasive versus non-invasive diagnosis of renal osteodystrophy

Histological, histomorphometric and in some cases histochemical examination of a bone biopsy must still be considered the gold standard for diagnosis of renal osteodys­trophy. Here classification of the various types of renal bone disease in general is based on the quantification of osteoid deposition, bone formation rate, the presence of marrow fibrosis and histochemical staining of aluminium at the osteoid calcified bone biopsy. Iron deposition, however, has to be excluded beforehand, since it may interfere with aluminium staining [97],[98],[99] Nevertheless, standard clinical practice in diagnosing renal osteodystrophy has evolved away from taking a bone biopsy as it requires invasive procedures. In recent years various non­invasive alternatives making use of bio­chemical indices of bone formation as well as bone resorption [Table - 2] have been evaluated which are essentially all equally and fairly well correlated with histological parameters of bone turn-over. [95],[100],[101],[102] These degrees of correlation do not imply, however, that they are useful to make a diagnosis of renal osteodystrophy. Therefore, evaluation and validation of the diagnostic performance of these biochemical markers in terms of sensitivity, specificity and positive and negative predictive values, as was done recently for bone alkaline phosphatase, osteocalcin and PTH in the diagnosis of aluminum bone disease, [79],[95] remains a challenge for the clinical nephrologists. [24],[102],[103],[104]

Recently, a strategy for the diagnosis and differentiation between aluminium overload/ increased risk for toxicity/aluminium-related bone disease based on baseline serum aluminium values in combination with a low-dose desferrioxamine test and serum PTH measurement has been established. [105]

Aside from biochemical markers, some studies also focused on the diagnostic value of instrumental techniques such as dual X-ray absorptiometry (DEXA) for measurement of the bone mineral density (BMD), hand X­rays by radiographic analysis or ultrasono­graphy for parathyroid imaging. [106],[107],[108] Although these techniques may to a certain extent provide some useful information, their diagnostic values in renal osteodystrophy remains questionable and in general do not add much to the information provided by biochemical markers of bone turnover. Much research needs to be done applying these techniques to end-stage renal disease patients if they are ever to be clinically useful in the renal osteodystrophy population.

Treatment of renal osteodystrophy

The mainstays of the prevention and treatment of renal osteodystrophy continue to be phosphate restriction/binding and calcium supplementation. [109] Phosphate control should start with a low phosphate diet. As it is impractical to reduce the daily phosphorus intake to below 8OOmg/day [1] a phosphate binder, either calcium carbonate or calcium acetate taken with each meal in proportion to its phosphate content is usually also required.

Aluminium containing phosphate binders should be avoided by all means. However, they may be the only available alternative in hypercalcemic patients particularly those in whom vitamin D treatment is contra­indicated. Here, the concomitant intake of citrate (Shohl's solution, fruit juices..) should be avoided since this will increase gastrointestinal absorption of phosphate [111] . The use of magnesium salts in the presence of low magnesium dialysate may allow both the control of serum phosphate concen­trations and higher doses of calcitriol. They can also be used to reduce the required dose of aluminum phosphate binders. As magnesium inhibits mineralization, however, its use requires careful monitoring of serum magnesium concentrations. [113],[114]

Uremic patients may be in negative calcium balance because they often ingest 500 mg/day or less. Also, gut absorption of calcium may be reduced because of decreased serum calcitriol levels. In order to prevent or suppress over secretion of parathyroid hormone, serum calcium levels in end-stage renal failure patients need to be maintained at the upper limit of the normal range. Therefore, the calcium level in the dialysate should be between 6 and 7 mg/dl (1.5-1.75 mM) providing an influx of approximately 800 mg per treatment. [110] Lower calcium levels may exacerbate hypocalcemia and stimulate PTH secretion. As the positive calcium balance is usually greater in CAPD patients, the standard dialysis solution (1.75 mm) is usually adequate within this population. Lower calcium dialysate solution are useful to treat patients in whom hyper­calcemia develops because of supplemental calcium administration or vitamin D therapy Here the dialysate calcium concentration should be reduced to 5 mg/dl (1.25 mM) [10] The efficacy of oral calcium supplementation importantly depends on the timing of intake; calcium taken between meals is more a calcium supplement than a phosphate binder. [10]

Several studies have confirmed the potent inhibitory effect of calcitriol on PTH synthesis and secretion in dialysis patients by both raising serum calcium and inhibiting 1 parathyroid hormone gene transcription. [115],[116] Hence calcitriol and other vitamin D analogues (vitamin D, alfacalcidol, dihydro­tachysterol, calcifedol..) have been widely used to treat secondary hyperparathyroidism, as well as to correct deficient endogeneous production of lα,25-(OH) 2 Vitamin D3. These agents lessen bone pain and improve bone histological features. Since the effe­ctiveness of vitamin D preparations appear to be dependent on peak serum levels achieved, adequate dosing is essential and may obviate the need for surgical intervention of hyperparathyroidism with parathyroidectomy. Revised guidelines for calcitriol dosing according to the severity of hyperpara­thyroidism have recently been presented by Llach et al. Vitamin D preparations are contraindicated in hyperphosphatemic patients because they will further increase the calcium­phosphorus product. [110] Also the use of these compounds should be avoided in the presence of adynamic bone since, aside from their effect on parathyroid gland function, they are also known to decrease osteoblast proliferation. [118]

In patients with aluminium-related bone disease the first line of therapy should consist of withdrawing all sources of aluminium, including aluminium-containing phosphate binders and dialysate with high aluminium content. Although these measures will prevent exacerbation of the aluminium overload they will not remove the element from bone. Here, the use of desferioxamine is recommended. To reduce the risk for side effects associated with the use of this chelator [119],[120] desferrioxamine should be administered at doses as low as 5 mg/kg once weekly during the last hour of dialysis. [121],[122],[123] To ensure adequate removal of both the aluminium and iron desferrioxamine chelates (i.e. aluminoxamine and ferrioxamine) either high-flux polysulphone dialyzers or a charcoal hemoperfusion column should be used during the dialysis session following desferrioxamine administration. [124] Strategies for treatment of aluminium-related bone disease have recently been outlined [121],[122]

The treatment of renal osteodystrophy still poses substantial problems. Therefore, efforts are undertaken continuously to further optimize treatment modalities. Research has been directed towards the development of non-hypercalcemic drugs that are able to interfere with excessive PTH synthesis in the absence of major side effects. A novel class of drugs, the so-called 'calcimimetics' is now being developed. [125] These speci­fically act on the calcium receptor thereby suppressing PTH secretion without affecting plasma calcium or phosphorus levels. The ideal phosphate binder is still lacking, and various compounds are still being evaluated [126],[127] . To which extent bone growth factors such as insulin growth factor may play a role in the therapy of renal bone disease in the near future is still a matter of debate. [128]

   Renal Bone Disease in Hemodialysis versus CAPD Top

There are several differences between CAPD and haemodialysis, which can affect mineral homeostasis. Various studies have indicated that the dialysis modality has a major impact on bone turnover and the progression of uremic bone disease. It has repeatedly been shown that CAPD is an independent risk factor for the development of the adynamic form of renal bone disease.

This finding has been explained by;

i) the lower response of calcium turn over to the action of PTH

ii) the greater positive calcium balance in CAPD vs. haemodialysis providing a more effective suppression of PTH secretion

iii)the greater phosphate removal. [83],[129],[130],[131]

Bone mineral density studies (BMD) have suggested a better bone metabolism and preservation of cortical bone in patients treated by CAPD as opposed to those undergoing haemodialysis treatment; a phenomenon which, at least in part, might be explained by the higher residual renal function generally observed with the former treatment. [132],[133] Others however, have not been able to demonstrate any difference in BMD between CAPD and haemodialysis patients. [134] Histologic findings have provided some evidence for a better therapeutic improvement of metabolic bone disease in CAPD. [135]

In view of the fact that hyperphosphatemia can more easily be controlled in CAPD than by hemodialysis, CAPD patients require less aluminium containing phosphate binders, which together with the lower intradialytic transfer of aluminium put these patients at a lower risk for bone aluminium accumu­lation. [136] Nevertheless, even with the latter treatment modality, care should be taken when treating younger and smaller children, since this population is known to be at an increased risk for aluminium toxicity. [137],[138]

   Acknowledgments Top

The authors are grateful to Erik Snelders for expert desk editing and Dirk De Weerdt for his excellent drawing

   References Top

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138.Roodhooft AM, van de Vyver FL, D'Haese PC, van Acker KJ, Visser WJ, de Broe ME. Aluminum accumulation in children on chronic dialysis: predictive value of serum aluminum levels and desferrioxamine infusion test. Clin Nephrol 1987;28:125-9.  Back to cited text no. 138    

Correspondence Address:
Marc E De Broe
Department of Nephrology-Hypertension, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Antwerp (Edegem)
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