Adynamic bone disease--bone and beyond

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]. NKF/KDOQI guidelinesa and renal osteodystrophy classification ahttp://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm. NKF/KDOQI guidelinesa and renal osteodystrophy classification ahttp://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm. 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]. Mixed uraemic osteodystrophy: high resorptive activity, osteoid accumulation, peritrabecular fibrosis (Goldner stain) (courtesy of Dr. G. Lehmann, Jena). Mixed uraemic osteodystrophy: high resorptive activity, osteoid accumulation, peritrabecular fibrosis (Goldner stain) (courtesy of Dr. G. Lehmann, Jena). Adynamic renal osteodystrophy: absence of cellular activity and osteoid, low cancellous bone volume (osteopenia) (Goldner stain) (courtesy of Dr. G. Lehmann, Jena). Adynamic renal osteodystrophy: absence of cellular activity and osteoid, low cancellous bone volume (osteopenia) (Goldner stain) (courtesy of Dr. G. Lehmann, Jena). The NKF-KDOQI guidelines suggest a number of histomorphometric parameters for the classification of ROD (Table 2). Frequently applied histomorphometric parameters and normal levels according to K/DOQI ABD is diagnosed in the presence of subnormal values in criteria 2–6 in the absence of fibrosis. aSee the text for comment. Frequently applied histomorphometric parameters and normal levels according to K/DOQI ABD is diagnosed in the presence of subnormal values in criteria 2–6 in the absence of fibrosis. aSee the text for comment. 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). Commonly applied definition criteria for ABD. Commonly applied definition criteria for ABD. 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. 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). Possible indications for an iliac crest bone biopsy in renal osteodystrophya aModified after [1] and http://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm. Possible indications for an iliac crest bone biopsy in renal osteodystrophya aModified after [1] and http://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm. 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. 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. Example of tetracycline labelling in patients with suspected renal osteodystrophy Several alternatives from the tetracycline family are available, e.g. tetracycline hydrochloride (250 mg TID/BID depending on renal function on days 25–23 before biopsy) followed by demeclocycline (days 4–2 before biopsy) (note: demeclocycline capsules or tablets are not available in parts of the European Community). Alternatively, two doses of tetracycline hydrochloride 10 days apart may be used. Example of tetracycline labelling in patients with suspected renal osteodystrophy Several alternatives from the tetracycline family are available, e.g. tetracycline hydrochloride (250 mg TID/BID depending on renal function on days 25–23 before biopsy) followed by demeclocycline (days 4–2 before biopsy) (note: demeclocycline capsules or tablets are not available in parts of the European Community). Alternatively, two doses of tetracycline hydrochloride 10 days apart may be used. 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. 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] in the presence of A chronic with high of may to ABD than osteomalacia. the aluminium-induced ABD forms particularly to bone and A current that have to the underlying aluminium is the by from Brazil a high of low-turnover bone disease in these patients substantial aluminium aluminium bone in contrast to about a of the patients with high-turnover bone disease. to of used to be a major of aluminium for dialysis patients [35]. Aluminium has also been described in CKD patients aluminium been with dialysis phosphate has substantially in about a of patients aluminium bone and in a published in of the dialysis patients been with aluminium the aluminium overload or to be a clinical is a in the clinical relevance of aluminium-induced bone disease between and to the different Especially in aluminium is used more and as a in the of the bone in to in aluminium levels not aluminium and not well with of aluminium A test the diagnostic accuracy (Table to a test to a test on the of the aluminium in as diagnostic from to The guidelines recommend the test of possible and The and of the test to disease are and respectively, if at the time iPTH levels are for are patients with aluminium levels and and clinical of aluminium to of aluminium in the and are for should also be since aluminium-related bone disease can after The latter may also apply if are used in such patients, but this is not bone biopsy using the or the is required in order to aluminium <5% are usually not considered to be are considered to be ABD before is reached Bone in patients on dialysis or with CKD ± ABD in of the patients None of these patients or aluminium during the of higher ABD prevalence of in predialysis CKD patients was reported The prevalence of ABD was in patients with a of ± are available on the of ABD in patients from CKD to The prevalence of ABD has over the the that aluminium-induced low-turnover bone disease has more and more (Figure ABD has now emerged as the lesion in a mixed of and dialysis patients and in particular in patients, to have been In the of hyperparathyroid bone disease has diminished The in ABD prevalence two major in dialysis the of and patients is many patients to high and It is to the relative of these two potentially not studies a high ABD For example, used the static parameters, surface/bone surface and surface/bone surface to patients versus high-turnover this only of both and dialysis patients from low-turnover of ROD distribution over time after of ROD distribution over time after or bone turnover and bone remodelling activity (Table bone turnover is not to but also in that are frequent in dialysis such as and A relative is as an for ABD It may be to low levels or to a relative excess of antagonistic PTH (e.g. that bone metabolism In a bone biopsy in dialysis patients, iPTH plasma levels by of ABD if levels virtually ABD the osteoblast surface and the absence of fibrosis, the defined an iPTH between and as (in patients not with In agreement with this bone in dialysis patients with a iPTH plasma level low turnover or ABD at 1 after the associated with a high prevalence of ABD associated with a high prevalence of ABD from or relative ABD is characterized by to PTH a of the on osteoblasts In patients with ABD, the parathyroid to is As a PTH an parameter for PTH bone is impaired in ABD. bone In type 1 with bone trabecular and osteoid bone and in of bone formation and resorption dialysis patients are also particularly to aluminium accumulation and PTH and as for ABD will be discussed in the It is clear from the above that the of ABD is may include uraemic as well as in and In on the of relative PTH in a uraemic and there is only a thin line in CKD between sufficient to sufficient bone metabolism versus of PTH to low-turnover bone disease may in subtypes of but is in patients with osteomalacia [10]. with and of the and has been described as of aluminium-induced osteomalacia [35]. However, these and may also in the absence of aluminium overload in patients with bone lesions (Figure The of dialysis and aluminium is It has been that bone disease is the only of low-turnover and [10]. This from that of low-turnover bone disease associated with aluminium of the bone surface [10]. 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