NDT Plus 2008 1(3):135-147; doi:10.1093/ndtplus/sfn040
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Adynamic bone disease—bone and beyond
Vincent M. Brandenburg and
Jürgen Floege
Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Pauwelsstrasse 30, Aachen, D-52057, Germany
Correspondence: Vincent M. Brandenburg, Department of Nephrology and clinical Immunology, RWTH University Hospital Aachen, Pauwelsstrasse 30, Aachen, D-52057, Germany. Phone: +49-241-80-36072; Fax: +49-241-80-82446; E-mail: Vincent.Brandenburg{at}post.rwth-aachen.de
Key Words: adynamic bone disease • calcification • chronic kidney disease • low-turnover osteodystrophy
Received for publication January 27, 2008. Accepted for publication March 18, 2008.
 |
Renal osteodystrophy: definition, nomenclature and classification
|
|---|
Disturbances of bone and mineral metabolism are a hallmark of
chronic kidney disease (CKD). Renal osteodystrophy (ROD) is
the traditional term for bone lesions in conjunction with CKD
and is now considered a part of the ‘
chronic kidney disease—mineral and bone disorder’ (CKD-MBD) [
1]. ROD comprises various
subtypes with substantial differences in aetiology and fundamental
differences in treatment strategies. In long-term dialysis patients
the prevalence of some types of ROD is virtually 100% [
2].
A simple, easy to apply but still sophisticated and comprehensive descriptive system of ROD is the TMV system [1]. The TMV system comprises bone turnover (T), bone mineralization (M) as well as bone volume (V). Bone turnover and bone volume may both be classified as high, normal or low. Bone mineralization may be categorized as normal or abnormal. As an alternative to volume, the bone balance may be considered [3,4].
Based on the above system, the NKF/KDOQI guidelines distinguish six types of bone pathology in CKD-MBD (Table 1) (Figures 1 and 2). The focus on cancellous bone parameters in this classification system has been questioned regarding the importance of cortical bone quality for structural integrity [5]. Moreover, bone histomorphometric parameters comprise a continuum, and categorization may be an oversimplified approach [5]. Nevertheless, categorical CKD-MBD classification is helpful for clinical practice and widely used as the basis for therapeutic decision making. In this review we will focus particularly on adynamic bone disease (ABD), which is increasing in prevalence and, in many CKD populations, now represents the most frequent type of bone lesion [6].
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What is ABD?
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The term ‘aplastic’ or ‘adynamic’ bone
disease was introduced in the early 1980s [
7,8]. ABD is characterized
by a low-bone turnover without osteoid accumulation, i.e. with
a thin osteoid seam. Both the rate of collagen synthesis by
osteoblasts and the subsequent mineralization of bone collagen
are subnormal. The latter distinguishes ABD from the second
low-turnover form, i.e. osteomalacia, where a mineralization
defect exceeds the defects in bone formation, resulting in a
relative osteoid excess [
9,10]. In ABD, there are few or no
osteoblasts, and minimal or no peritrabecular fibrosis or marrow
fibrosis (in contrast to osteitis fibrosa). Especially the bone
formation rate (BFR) is substantially diminished and the number
of remodelling sites is low [
9].
|
ABD in bone histomorphometry
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The NKF-KDOQI guidelines suggest a number of histomorphometric
parameters for the classification of ROD (Table
2).
Bone turnover may be assessed by the activation frequency or
by BFR [
3]. The activation frequency is defined as the reciprocal
of the total remodelling time. The latter is the net result
of bone resorption, reversal, formation and quiescent periods.
Therefore, the activation frequency assesses both osteoclast
(resorption) and osteoblast (formation) activity [
11,12]. In
contrast, BFR focuses only on osteoblast activity [
11,
13]. However,
in ROD the correlation between these two parameters of bone
turnover is excellent (
r = 0.95 in dialysis and
r = 0.97 in
predialysis patients) [
12] and both the activation frequency
and BFR may be used for assessment of bone turnover.
Especially bone turnover, fibrosis quantification and bone mineralization assessment are required to differentiate between hyperparathyroid bone disease, osteomalacia and mixed and adynamic bone disease. Many previously published ROD studies thus rely on three histomorphometric parameters: BFR (µm2/mm2/day), osteoid accumulation (%) and the presence or absence of fibrosis [13–22]. For example, based on these three parameters, normal histology was defined as the absence of fibrosis, osteoid volume <12%, and BFR >97 but <613 µm2/mm2/day [16]. However, cut-off levels are inconstant. Concerning BFR, cut-off levels varying from 97 to 108 µm2/mm2/day have been applied to separate normal from low bone turnover. Other studies used one standard deviation below normal levels, or <5% of normal levels, to define adynamic BFR [13–23]. Similarly, cut-off levels for osteoid volume separating osteomalacia from ABD vary from 12% [16,21] to 15%, [13–15,17–20,23] (Figure 3).
Parfitt has challenged such a high threshold for osteoid accumulation,
since 5% is already ‘generous’, assuming that normal
osteoid volume is 1.5 ± 1.2% [
5]. If the lower 5% cut-off
is used, more patients will be diagnosed with osteomalacia than
with ABD [
24]. In contrast, a fibrous tissue volume of <0.5%
is a non-disputed criterion for ABD [
13–21,
23].
Within ABD, it is of major therapeutic importance to distinguish aluminium-induced and non-aluminium-induced forms [10,25,26]. Recently, a variant of ABD has been described (so-called ABD-V) [23], which is characterized by high osteoclastic resorption (osteoclast surface/bone surface more than two standard deviations higher than in controls). Its clinical relevance remains to be defined.
|
How to diagnose the subtype of renal osteodystrophy
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The gold standard for the diagnosis and classification of ROD
is histomorphometric analysis of an undecalcified bone sample
[
1]. Pre-biopsy
in vivo tetracycline labelling as well as amyloid
and aluminium stains are required for complete diagnostic work-up.
A combination of dynamic and static bone parameters, both of
cortical and trabecular bone, gives a complete overview upon
bone metabolism [
3,
5]. The preferred site of biopsy is 2 cm
posterior and 2 cm inferior to the anterior iliac crest
using an instrument designed to obtain a core of bone of at
least 4–5 mm diameter [
9] (e.g. Meunier® bone biopsy
device).
KDIGO and NKF-KDOQI guidelines recommend a bone biopsy in the following cases (Table 3).
The indications for a bone biopsy after renal transplantation
are less clear and not explicitly discussed in current guidelines.
Basically, the above-mentioned indications also apply for the
posttransplant situation.
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Bone biopsy and the role of tetracycline labelling
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It is mandatory to distinguish between static and dynamic bone
parameters in histomorphometry. Static histomorphometric parameters
include bone volume/tissue volume, osteoid thickness, osteoid
surface/bone surface, osteoblast surface/bone surface, osteoclast
surface/bone surface, and fibrosis volume/tissue volume. In
contrast, BFR, activation frequency and mineralization lag time
are dynamic bone parameters.
In order to evaluate the underlying dynamics of bone morphology, in vivo tetracycline labelling is necessary [4,25]. Tetracyclines show fluorescence in ultraviolet light and bind to actively forming bone areas. Calcium-containing phosphate binders should not be given in parallel to tetracycline. In patients with severely impaired renal function, one possible scheme for tetracycline labelling is shown in Table 4 [27]. Information is enhanced by using two different tetracylines with different fluorescence [27]. After the second labelling period, 4–6 days should elapse to give the second tetracycline line sufficient time to get buried by osteoid, in order to protect it from washout during in vitro staining. A modified, short-term ‘emergency’ labelling scheme is possible [9,27]. The most appropriate labelling scheme should be chosen in agreement with the local bone pathologist.
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Assessment of renal osteodystrophy without a bone biopsy
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Measurements of bone mineral density or plain bone radiographs
are not suitable for a diagnosis of ROD [
25], although the latter
may identify Looser's zones. None of the known biochemical markers
for parathyroid status, bone formation and bone resorption have
reached a sufficient level of diagnostic accuracy (reviews in
[
1,
25,
28]), and none so far can replace the diagnostic power
of a bone biopsy.
Whereas plasma iPTH levels at the extremes, i.e. <50 pg/ml and >800 pg/ml, are usually associated with ABD and high-turnover bone disease, respectively, in particular levels between about 100 and 500 pg/ml exhibit variable associations with types of bone lesions. This diagnostic uncertainty of intermediate, K/DOQI target-compliant PTH levels has recently been confirmed by bone biopsy studies from Brazil [29] and Portugal [30]. The situation is complicated further by wide variations in iPTH results if different test assays are employed [31,32] and by potentially variable ratios of agonistic (PTH1–84) and antagonistic (PTH7–84) PTH forms [33].
Bone alkaline phosphatase (BAP) is probably the single most useful biochemical parameter for the assessment of bone formation. Elevated levels of bone alkaline phosphatase virtually exclude an adynamic renal bone disease [25,28]; however, elevations of BAP along with total AP may be seen in cases of severe osteomalacia. Combinations of biochemical markers hold promise [22], at least for the differentiation for high-turnover versus adynamic forms. Such combinations could be, for example, iPTH plus osteoprotegerin [2] or iPTH plus bone-specific alkaline phosphatase [28]. Another approach is to measure the ratio of PTH(1–84) to PTH(7–84) [33].
Currently, the domain of biochemical markers is the long-term monitoring of ROD evolution. Changes of bone markers, such as bone-specific alkaline phosphatase, over time, may be suitable indicators for the assessment of therapeutic effects.
|
Aluminium bone disease
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|---|
Hyperaluminaemia in end-stage renal disease (ESRD) patients
was reported as early as 1970 [
34]. The true dimension of aluminium-related
complications in dialysis patients, including bone disease,
emerged in the 1980s [
35,36]. In the 1980s, aluminium overload
was the predominant cause for the development of low-turnover
bone disease in dialysis patients [
35,
37]. In aluminium-treated
dialysis patients with osteitis fibrosa, the distribution of
aluminium in bone is diffuse, whereas in aluminium-induced osteomalacia,
or ABD, there is a predominant localization along the mineralization
front [
35]. Aluminium causes mineralization defects, and markedly
reduces both osteoclast resorption and osteoblast surface [
10].
It profoundly decreases PTH synthesis and release [
38,39] even
in the presence of excessive hyperphosphataemia [
40]. A chronic
low-dose exposure with concomitant high dosages of vitamin D
may preferentially lead to ABD [
10] rather than osteomalacia.
Clinically, the aluminium-induced ABD forms appear particularly
prone to causing bone pain, hypercalcaemia and fractures [
10,
26].
A current example that even recent trial findings have to take
into account the underlying aluminium exposure is the study
by Barreto
et al. from Brazil [
29]. They recorded a high proportion
of low-turnover bone disease (
2/3) in their entire cohort. Of
these patients
60% had substantial aluminium staining (>25%
aluminium bone staining) in contrast to about a third of the
patients with high-turnover bone disease.
|
Sources of aluminium
|
|---|
Prior to widespread usage of reverse osmosis, water contamination
used to be a major source of aluminium for dialysis patients
[
35]. Aluminium toxicity has also been described in CKD patients
ingesting aluminium hydroxide who had never been treated with
dialysis [
41]. Although aluminium-containing phosphate binder
usage has substantially declined, in 1995 about a quarter of
patients exhibited positive aluminium bone staining, and in
a study published in 2004, 57% of the dialysis patients had
been treated with aluminium ‘in the past’ [
42].
Thus, aluminium overload or intoxication continues to be a clinical
concern. There is certainly a difference in the clinical relevance
of aluminium-induced bone disease between ‘developing’
and ‘developed’ countries simply due to the different
prescription patterns. Especially in emerging countries aluminium
is used more generously, and as a consequence in the year 2000,
95% of the bone biopsies contained Al in Uruguay compared to
19% in Spain [
43].
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How to diagnose aluminium bone disease
|
|---|
Serum aluminium levels do not correctly reflect body aluminium
stores and do not correlate well with signs of aluminium toxicity.
A desferrioxamine (DFO) test increases the diagnostic accuracy
(Table
5).
Depending on the dosage of DFO administered, the aluminium increase
in serum regarded as diagnostic varies from exceeding 50 µg/L
[
44] to 200 µg/L [
45]. The NKF-K/DOQI guidelines recommend
performing the low-dose test because of possible DFO side effects
(ophthalmologic damage and mucormycosis). The sensitivity and
specificity of the low-dose DFO test to diagnose Al-bone disease
are 87% and 95%, respectively, if at the same time iPTH levels
are <150 pg/mL [
46]. Candidates for DFO testing are patients
with elevated serum aluminium levels (between 60 and 200 µg/L)
and clinical symptoms and/or signs suggestive of aluminium toxicity.
Patients exposed to significant amounts of aluminium in the
past and who are scheduled for parathyroidectomy should also
be tested, since aluminium-related bone disease can worsen after
parathyroidectomy. The latter concern may also apply if calcimimetics
are used in such patients, but this is not proven yet.
Upon bone biopsy staining using the aluminon reagent or the acid solochrome azurine (ASA) stain is required in order to detect aluminium [47,48]. Aluminium-positive surfaces <5% are usually not considered to be significant, while those >25% are considered to be strongly positive [49].
|
When does ABD occur in the course of CKD?
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ABD frequently occurs before ESRD is reached [
21,
50,
51]. Bone
biopsies in patients new on dialysis or with advanced CKD (mean
age 54 ± 12 years) revealed ABD in 23% of the patients
[
21]. None of these patients had received calcitriol or aluminium
during the course of CKD. An even higher ABD prevalence of 49%
in predialysis CKD stage 5 patients was reported [
19]. The prevalence
of ABD was 13% in patients with a creatinine clearance of 20
± 12 ml/ min [
51]. No data are available on the evolution
of ABD in patients who progress from CKD stages 3 to 5.
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Evolution of ABD prevalence over the last decades
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The prevalence of ABD has increased over the last 15–
20 years, despite the fact that aluminium-induced low-turnover
bone disease has become more and more infrequent [
6,
18] (Figure
4). Non-aluminium-induced ABD has now emerged as the dominant
lesion in a mixed cohort of adult haemodialysis and peritoneal
dialysis patients [
18], and in particular in diabetic ESRD patients,
prevalences up to 67% have been observed [
21]. In parallel,
the former predominance of hyperparathyroid bone disease has
diminished [
6,
52]. The increase in ABD prevalence parallels
two major developments in dialysis patients. First, the proportion
of elderly and diabetic patients is steadily growing. Second,
many patients were exposed to relatively high vitamin D and
oral calcium dosages. It is currently impossible to quantify
the relative impact of these two potentially causative factors.
Of note, not all studies confirm a high ABD prevalence. For example, Lehmann et al. [20] used the static histological parameters, osteoclast-covered surface/bone surface (OcS/BS <1%) and osteoblast-covered surface/bone surface (ObS/BS <1%), to stratify patients into low- versus high-turnover osteopathy. With this classification, only 7% of both pre- and dialysis patients suffered from low-turnover osteopathy.
|
What are risk factors for the development of ABD?
|
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Besides aluminium, several other factors or conditions decrease
bone turnover and bone remodelling activity (Table
6). Low bone
turnover is not limited to advanced CKD, but also occurs in
other conditions that are frequent in dialysis populations such
as advanced age, glucocorticoid-induced osteoporosis, diabetes
and hypoparathyroidism. A relative ‘hypoparathyroidism’
is regarded as an important risk factor for ABD [
14,
18,
50,
53].
It may be due to low iPTH(1–84) levels or to a relative
excess of antagonistic PTH fragments (e.g. PTH(7–84))
that negatively affect bone metabolism [
54]. In a bone biopsy
study in dialysis patients, iPTH plasma levels determined by
immunoradiometric assay (Nichols Allegro) were highly predictive
of ABD if <120 pg/mL, while levels >450 pg/mL virtually
excluded ABD [
19]. When considering the optimal osteoblast surface
(1.5%) and the absence of fibrosis, the authors defined an iPTH
range between 120 and 250 pg/mL as desirable (in patients not
treated with calcitriol). In agreement with this report, bone
biopsies in parathyroidectomized dialysis patients with a persistent
iPTH plasma level <70 pg/mL uniformly revealed low turnover
or ABD at 1 year after the operation [
55].
Apart from absolute or relative hypoparathyroidism, ABD is frequently
characterized by skeletal resistance to bone-anabolic PTH actions,
presumably via a down-regulation of the PTH/PTHrp receptor on
osteoblasts [
56,57]. In patients with ABD, the parathyroid gland
responsiveness to hypocalcaemia is diminished. As a consequence,
PTH pulsatility, an important parameter accounting for PTH anabolic
bone actions, is impaired in ABD.
Diabetes mellitus negatively affects bone metabolism. In type 1 diabetics with ESRD bone biopsies exhibited reduced trabecular and osteoid bone volumes and marked reductions in indices of bone formation and resorption [58]. Diabetic dialysis patients are also particularly prone to aluminium accumulation and PTH resistance [59].
Calcium administration and vitamin D as triggers for ABD will be discussed in the ‘treatment’ section.
It is clear from the above that the pathophysiology of ABD is certainly multifactorial. Further mediators may include uraemic toxins as well as derangements in cytokines and growth factors [10, 60]. In summary, on the background of relative PTH resistance in a uraemic milieu and presumably several other factors, there is only a thin line in CKD between allowing sufficient hyperparathyroidism to maintain sufficient bone metabolism versus oversuppression of PTH leading to low-turnover bone disease [61].
|
Low-turnover bone disease and clinical symptoms
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Skeletal pain may occur in all subtypes of ROD, but is especially
common in patients with (aluminium-induced) osteomalacia [
10].
Proximal muscle weakness together with axial skeletal pain and
fractures of the ribs, vertebral bodies, pelvis and hips has
been described as common features of aluminium-induced osteomalacia
[
35]. However, these signs and symptoms may also occur in the
absence of aluminium overload in patients with osteomalacic
bone lesions [
68] (Figure
5). The classical triad [
35] of dialysis
encephalopathy [
69], microcytic anaemia and osteopathy suggesting
aluminium toxicity is very rare nowadays. It has been claimed
that ‘aluminium-induced bone disease is the only form
of low-turnover producing symptoms and ultimately death’
[
10]. This idea came from observation that side effects of low-turnover
bone disease (pain, hypercalcaemia, fractures) were associated
with aluminium covering >20% of the bone surface [
10]. However,
non-aluminium induced ABD also carries significant morbidity
and mortality [
42] (see below) and it is now clear that any
type of ABD may cause bone pain. However, there is no pathognomonic
clinical sign of ABD.
|
ABD and calcium metabolism
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ABD is characterized by a reduced ability to incorporate serum
calcium into the bone compartment [
70]. In calcium isotope experiments
in dialysis patients with biopsy-proven ROD, calcium accretion
in bone was significantly lower in ABD compared to hyperparathyroid
bone lesions [
70]. Patients with reduced bone turnover exhibited
a higher systemic calcium exposure while enteral calcium absorption
did not differ between high- and low-turnover bone lesions [
70].
In agreement with this, low biochemical markers of bone turnover
predicted the development of hypercalcaemia after the initiation
of calcium carbonate [
71]. The reduced bone capacity to buffer
calcium loads in ABD has now been widely confirmed [
72].
|
ABD and ectopic calcification
|
|---|
Cardiovascular calcifications and associated mortality are prominent
clinical problems in patients with ESRD [
73–75]. Several
studies noted a relation between bone metabolism and such calcifications.
In 224 prevalent Turkish haemodialysis patients, low turnover
was detected in 75% of the bone biopsies [
76]. Patients with
the lowest bone activation frequencies, i.e. the lowest bone
turnover, exhibited the most pronounced coronary artery calcification
(CAC) scores. Similar findings were obtained in 101 Brazilian
haemodialysis patients [
15]. London
et al. [
42] quantified vascular
calcifications of the common carotid arteries, the abdominal
aorta, iliofemoral axis as well as legs. Increasing calcification
score levels were associated with decreasing mean iPTH, tetracycline
double-labelled surface and osteoblast surface, while the aluminium-stained
surface predicted the calcification score in a multiple stepwise
regression analysis [
42]. All these findings point to an association
of low-bone turnover with cardiovascular calcifications (Figures
6 and
7).
Calcific uraemic arteriolopathy (CUA), formerly called calciphylaxis,
has also been linked to ABD [
77]: five out of seven patients
with CUA had biopsy-confirmed ABD (Figure
8).
The above human data are supported by animal studies performed
in LDL receptor knock-out mice (LDL-R
–/–). These
mice, when fed a high-fat or diabetogenic diet, also exhibit
the combination of low-turnover osteodystrophy and vascular
calcifications [
78,79]. This is accelerated by superimposed
experimental CKD [
78,79]. Administration of anabolic bone stimulating
agents such as bone morphogenic protein 7 (BMP-7) [
78] or synthetic
PTH(1–34) [
79] improved bone turnover and skeletal mineralization
and decreased calcium deposition in the aorta.
|
Low iPTH and increased mortality
|
|---|
The causal relation between ABD and vascular disease may at
least in part explain why iPTH plasma levels <150 pg/mL
led to a significant, 1.4-fold increase in mortality in 58 000
ESRD patients after extensive multivariate adjustments [
80].
Ganesh
et al. confirmed a U-curve relationship in their 2-year
follow-up study in 12 800 dialysis patients: Both very
low (<32 pg/ml) and high iPTH levels (>496 pg/ml)
increased the risk for sudden death [
81]. Similar findings were
reported in other smaller studies [
82;
83]. In particular the
combination of low iPTH and high serum calcium levels (plus
high serum phosphate), a combination typical for ABD, was associated
with substantial mortality [
84]. However, such a U-curve-shaped
relationship between PTH and mortality has not been uniformly
confirmed. After multiple adjustments, Block
et al. revealed
a linear association of the two parameters [
85].
|
ABD and bone stability
|
|---|
ABD is associated with a diminished ability to repair microdamage
[
5]. Accumulated microdamage may result in an increased fracture
risk [
53,
86]. In a retrospective study in 9000 haemodialysis
patients, a U-curve relationship between fracture risk and plasma
iPTH levels was indeed detectable [
87]. Fracture risk was comparable
for hip, vertebrae and pelvis in patients with iPTH levels <150
pg/mL and those with iPTH exceeding 800 pg/mL and was lowest
around
300 pg/mL [
87]. Another study determined that, compared
to the normal population, hip fracture incidence was 17 times
higher in ESRD patients [
88]. One of the significant predictors
of fracture risk was an iPTH level <195 pg/mL. Atsumi
et al. [
86] retrospectively showed that the lowest tertile of
iPTH, in particular in men, was associated with a 22% increase
in the risk of vertebral fractures. However, all these studies
have significant limitations and may only serve to create a
hypothesis rather than to establish evidence, since none assessed
bone histologies or parathyroidectomy rates and they were retrospective
and uncontrolled.
In prepubertal children, ABD was associated with decreased linear growth and worsened growth retardation [89].
|
Management of the patient with ABD
|
|---|
General considerations
In contrast to high-turnover bone disease, the management of
ABD is not well investigated and large-scale prospective randomized
trials are absent [
90]. The treatment currently follows two
principles: first, to reduce calcium and vitamin D load and
second, to restore PTH activity (Table
7). Using these approaches,
ABD is reversible in a substantial number of patients [
13,
91].
However, while the approaches mentioned above appear intuitive,
the situation clearly is more complex given data from large
databases indicating that treatment with active vitamin D is
associated with a survival benefit even in patients with very
low PTH levels [
92]. Thus, potential bone benefits of avoiding
active vitamin D in ABD patients may be offset by the resulting
lack of other beneficial actions of a pleiotropic compound such
as vitamin D, emphasizing the need for large controlled prospective
trials in this area.
Aluminium removal in cases of significant exposure
DFO mobilizes aluminium from bone and decreases the proportion
of protein-bound aluminium in plasma, thereby facilitating removal
by dialysis. Discontinuation of aluminium and administration
of DFO improved signs of aluminium-induced bone lesions
in vivo [
93,94]. Human data with serial biopsies after DFO treatment
have shown marked declines in stainable bone-surface aluminium
that were associated with increases in BFR [
17]. Long-term application
of DFO (11 ± 4 months, dosage 42 ± 17 mg/kg administered
once weekly) also improved signs of dementia and increased erythrocyte
mean corpuscular volume, but side effects were common [
95].
Polysulfone dialyzers offer maximum clearance of DFO-aluminium
complexes [
96]. Parathyroidectomy should be avoided in patients
with aluminium-induced bone disease, since the decrease in bone
turnover after surgery may be associated with an accelerated
accumulation of aluminium in bone [
97]. A repeat bone biopsy
with quantification of stainable aluminium on the trabecular
surface may help to guide the duration of chelation therapy
[
27].
Reduction of intradialytic calcium loading
Serum ionized calcium levels are probably the most powerful regulator of PTH synthesis and excretion. Especially in conjunction with vitamin D treatment a positive calcium balance depresses bone turnover [63]. For both haemodialysis and CAPD patients there are convincing laboratory data and first histomorphometry results showing that lowering dialysate calcium concentration improves ABD [13,98–100]. Reducing the dialysate calcium concentration from 1.75 or 1.5 mmol/L to 1.25 mmol/L reduced serum ionized calcium, diminished episodes of hypercalacemia and increased iPTH (fourfold), bone-specific alkaline phosphatase and TRAP-5b levels within 3–6 months [100]. In a prospective trial in 51 CAPD patients with biopsy-proven ABD, two batch calcium concentrations (1.62 mM or 1.0 mM) were compared [13]. Repeat bone biopsies after 16 months showed that the low-calcium batch led to a normalization of BFR, which increased from 18.1 ± 5.6 to 159 ± 59 µm2/mm2/day. The low-calcium group experienced a decrease in serum ionized calcium levels resulting in a 300% increase in serum iPTH values (from 57 ± 15 to 237 ± 34 pg/mL). In 40% of the patients, ABD had resolved after 16 months.
The current NKF K/DOQI guidelines recommend limiting daily oral calcium intake (dietary calcium plus phosphate binder) to <2000 mg. Dialysate calcium concentrations of 1.75 mmol/L should not be used routinely. In cases of ABD, reduction of dialysate calcium to 1.25 or 1.00 mmol/L is advisable and usually tolerated well clinically.
Usage of calcium-free phosphate binders
Oral calcium-containing phosphate binders are the other major source of calcium. Recently developed calcium- and aluminium-free phosphate binders now offer alternatives. Two prospective bone biopsy studies have compared the effects of calcium-free versus calcium-containing phosphate binders on bone metabolism and histology in dialysis patients [30,91]. D'Haese et al. [91] compared the bone effects of lanthanum carbonate versus calcium carbonate in 63 dialysis patients. The median intake of calcium carbonate and lanthanum carbonate was 2000 (n = 30) and 1250 mg/day (n = 33), respectively. After 1 year of treatment, the number of patients increasing their bone turnover after an initial diagnosis of ABD was similar in both groups (3/6 calcium carbonate versus 4/6 lanthanum). However, during the follow-up, bone turnover decreased to ABD after an initial diagnosis of high-turnover ROD in six patients of the calcium carbonate group versus one patient in the lanthanum group. Regarding sevelamer, Ferreira et al. analysed repetitive bone biopsies in 68 patients after 1 year of treatment with either sevelamer (dosage increased from 3.3 ± 2.0 to 5.0 ± 2.7 g/day) or calcium carbonate (dosage increased from 3.8 ± 2.2 to 4.0 ± 2.5 g/day) [30]. Only the sevelamer group exhibited a significant increase in BFR per bone surface. At the end of the study three patients (9%) had developed de novo ABD in the sevelamer group compared to six (17%) in the calcium group. However, the comparability between these two bone biopsy studies is limited due to different histomorphometric criteria of ABD [30,91]. Several additional lines of evidence also point towards an improved bone turnover following a switch from calcium-containing phosphate binders to sevelamer [101,102]. In the Treat-to-Goal study, 200 haemodialysis patients were randomized either to 6.5 g/day sevelamer or 4.6 g/day calcium acetate or 3.9/day g calcium carbonate (mean intake) over 53 weeks. Mean iPTH remained stable in the sevelamer group (220 pg/mL), whereas it dropped significantly from 200 to 138 pg/ml in the calcium group. In a post hoc analysis of this study, it was shown that calcium-treated subjects showed a decrease in thoracic vertebral trabecular bone attenuation, a surrogate marker of bone density, whereas sevelamer-treated subjects exhibited stable values [102]. Similar data were obtained in a 2-year prospective study that also compared calcium carbonate-treated (4.3 ± 1.7 g/day) with sevelamer-treated (6.9 ± 2.6 g/day) haemodialysis patients [103]. The calcium carbonate group in comparison to the sevelamer group exhibited decreasing iPTH levels, significantly more hypercalcaemic episodes, and a loss of trabecular bone density [103] (Figure 9).
These human data are in line with experimental results indicating
that high dosages of calcium supplementation in uraemic rats
suppress osteoclastic and chondroclastic activity [
104].
Avoidance of vitamin D over-treatment
The administration of active vitamin D compounds reduces bone turnover in CKD patients. One hundred and seventy-six CKD patients (GFR 15–50 ml/min) were randomized to alphacalcidol (0.25 µg every other day to 1.0 µg/day) or placebo treatment over 2 years [49]. Bone biopsies were performed at the study entry and end. In patients with ROD at baseline (75%), alphacalcidol treatment significantly reduced osteoblast surface, number of osteoblasts, eroded surface and BFR while these parameters changed insignificantly with placebo. Biopsy studies indicate that high dosages of active vitamin D (calcitriol) in patients with ESRD may eventually lead to the development of ABD. In a prospective 12-month study with serial bone biopsies in 14 children on peritoneal dialysis, all exhibited hyperparathyroidism-associated bone lesions at baseline and 11 overt osteitis fibrosa [63]. Intermittent oral or intraperitoneal calcitriol decreased BFR by 60% and six children developed ABD (43%) [63]. Similar results emerged from another 12-month repeat biopsy study in 16 peritoneal dialysis children, who, after an initial diagnosis of osteitis fibrosa (n = 9) or mild lesions of secondary HPT (n = 7), developed ABD under calcitriol in 25% of the cases [89]. However, in all these studies high-dosage active vitamin D treatment was associated with higher incidences of hypercalcaemia and higher mean serum calcium levels. Therefore, it is difficult to assess the particular impact of non-calcaemic versus calcaemic vitamin D actions upon bone metabolism. Moreover, the high dialysate calcium content of 1.75 mmol/L certainly contributed to ABD development in the two studies.
Preliminary in vitro data point towards a lower osteoblast activity suppression of novel vitamin D receptor (VDR) agonists (paricalcitol) [105]. Additionally, paricalcitol increased while calcitriol decreased the PTH(1–84)/PTH C-fragment ratio in haemodialysis patients indicating a positive effect by paricalcitol on skeletal PTH resistance [106]. However, no human bone biopsy data are available to verify whether newer VDR agonists indeed affect bone turnover in a better way than calcitriol.
Teriparatide as a bone-stimulating agent
The daily subcutaneous application of PTH(1–34), teriparatide, is a powerful anti-osteoporotic treatment. In theory, teriparatide offers the chance to restore bone metabolism in patients with ABD ([79] see above). The administration of PTH(1–34) in patients with ‘non-renal’ hypoparathyroidism (mostly post-surgical or with gain-of-function mutations in the calcium-sensing receptor) over 3 years led to significant elevations of bone turnover markers [107]. However, controlled human trials in CKD have not been performed so far. Nevertheless, in anecdotal reports, teriparatide (e.g. 20 µg s.c. three times per week after haemodialysis) has been used in bone biopsy-confirmed ABD patients with severe fracturing osteoporosis. Reductions of bone pain and transient increases of bone-specific alkaline phosphatase have been reported.
Restoring the pulsatile PTH secretion pattern
The biological action of PTH on bone largely depends on pulsatile PTH secretion [108]. This may explain the risk for ABD in patients receiving active vitamin D or peritoneal dialysis, since in the former case vitamin D activity builds up over days and then continuously suppresses PTH release, whereas in PD patients there is often a constant exposure to high calcium dialysate levels, in contrast to the fluctuating calcium level in HD patients.
Two classes of compounds may help re-establish a pulsatile, oscillatory secretion pattern of PTH in patients with ABD: the calcimimetics and the calcilytics. The calcimimetic agent cinacalcet has a half-life of <24 h and initially reduces iPTH levels markedly, but this is followed by a strong iPTH rebound in plasma so that circadian swings of plasma iPTH increase [109]. In vivo experiments already showed a bone protective, bone anabolic effect of calcimimetics [110]. Untreated rats with adriamycin-induced CKD developed a low-turnover bone disease resembling osteomalacia [110]. Two treatment arms with NPS-568, a short-acting calcimimetic agent, were tested: one with daily oral gavage, the other with a continuous subcutaneous infusion. While the continuous infusion normalized PTH-levels in the previously hyperparathyroid CKD animals, large fluctuations of PTH were detectable in the gavage group: at 1 h after gavage, PTH decreased by 78%, while levels had returned to baseline after 14 h. After 57 days, several parameters of bone formation were significantly improved in the daily gavage arm compared to the animals treated continuously.
Finally, calcilytic agents, which temporarily block the calcium sensing receptor at the parathyroid gland and thereby promote PTH secretion, may also help to stimulate bone turnover by increasing the pulsatile PTH secretion pattern. The oral calcilytic agent NPS 2143 has been applied to a model of bone loss and osteopenia (ovarectomized rats) [111] and compared with the action of s.c. PTH(1–34). Increases of plasma PTH after the administration of NPS 2143 were prolonged (>4 h) in contrast to short increases with s.c. PTH(1–34). Indeed, both agents stimulated bone turnover. However, NPS 2143 resulted in a dramatic increase in both bone formation and resorption, with no net effect on bone mass. In contrast, PTH(1–34) also increased both resorption and formation, but formation exceeded resorption, resulting in increased bone mass. Only the coapplication of the calcilytic agent plus estradiol led to an increase in bone mass, presumably due to the hormonal antiresorptive effect in this experiment. Calcilytic agents therefore need further proof of bone protective properties.
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ABD: closing remarks
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|---|
ABD is not an innocent bystander in CKD [
65]. It is possibly
the most prevalent bone lesion in advanced CKD, is associated
with impaired calcium metabolism and linked to cardiovascular
disease and mortality in CKD patients. ABD is, at least in part,
often iatrogenic and it is this part in particular, which lends
itself to prevention or therapeutic intervention. Reducing the
calcium load is the best investigated preventive or therapeutic
option in non-aluminium induced ABD.
|
Acknowledgements
|
|---|
Conflict of interest statement. The results presented in this
paper have not been published previously in whole or part. J.F.
is a regular consultant for Amgen and Genzyme and has received
honoraria for lectures and panels from the following companies:
Abbott, Amgen, Genzyme and Shire. V.B. has received travel grants
and honoraria for lectures from Genzyme, Abbott and Shire.
|
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Renal osteodystrophy:...
What is ABD?
