A comparative study of bone biopsies from the iliac crest, the tibial bone, and the lumbar spine

‘Chronic kidney disease - mineral and bone disorders’ (CKD-MBD) are diseases, which can be subdivided by bone histological parameters of bone turnover (T), mineralisation (M) and bone volume (V) [4]. For example, osteoporosis as a frequent disease with high fracture risk is presented by reduced bone volume, whereas mineralisation and turnover can be altered in different directions. Therefore, current guidelines recommend a bone biopsy before induction of treatment [2]. The therapeutic goal is the prevention of patient relevant endpoints, especially fractures. In patients on dialysis the prevalence of fractures is four times higher and they occur about 10–15 years earlier than in the general population. Furthermore, these patients have a dramatically elevated 1-year mortality risk after fracture [10]. Unfortunately, it is not clear how to predict fracture risk in CKD patients. In the general population bone density measurement by dual x-ray absorptiometry (DXA) is the gold standard for osteoporosis diagnostics and fracture risk prediction. While osteoporosis is clearly one major contributor to the elevated fracture risk of the CKD population DXA was not recommended for CKD patients so far [2]. One reason was that DXA cannot predict the CKD-MBD subtype. However, recent studies show that DXA can nevertheless predict fracture risk of patients with chronic kidney disease [11] and will presumably be an inherent part of the CKD-MBD diagnosis in the future.

Concerning bone biopsies there is uncertainty whether an improvement in the bone biopsy parameters, which is often used to show treatment effects, results in reduced fracture risk or not. For example, in the Bonafide study the treatment with the calcimimetic drug cinacalcet resulted in a normalisation of elevated bone turnover but has no effect on the bone volume [12]. Nevertheless, in another trial with cinacalcet, a reduction of fracture risk was shown, even if this was only pronounced when adjusting to baseline differences [13].

In the present study bone specimens of embalmed cadavers were used for the histomorphometric assessment. The median bone volume of all 10 body donors was comparable between the three biopsy sites (Fig. 1) but revealed severe intraindividual differences (Fig. 2). Only a few biopsy studies investigated bones from two or more skeletal sites. Their results are very heterogeneous. While some groups showed a more or less pronounced correlation [14] other studies could not confirm this [15] or showed different results depending on the sites [16]. Biopsy studies including histomorphometric measurements from the human tibia are not known so far whereas the proximal tibia is one of the common investigation sites for bone diseases in rats. In animal studies the iliac bone structure and metabolism showed an average between those of the tibia and the lumbar vertebra [17]. Those findings could not be confirmed in our human samples where no relation could be seen between the biopsy sites at all.

High-resolution imaging methods can determine bone strength and quality in-vivo. Furthermore, they can be used for bone biopsy analyses. For example, Borah and colleagues used micro-computed tomography of bone biopsies to describe effects of long-term bisphosphonate treatment on BV/TV results [18]. In our study, we wanted to validate our histomorphometric findings by micro-computed XtremeCT-analysis of the same specimen. For this, we chose two sample sets that revealed very different results in the histomorphometric analysis. For donor number 3 the BV/TV-ratio between the proximal tibia and the iliac crest were comparable with the ratio between the lumbar spine and the iliac crest. In contrast, donor number 8 was chosen for the great difference between those BV/TV ratios. By confirming our histomorphometric results with the imaging method (Table 2), we could exclude that the measured BV/TV-heterogeneity was due to method-derived failures.

The intra-individual differences seen in our study may reflect the variability of skeletal sites due to requirements of each individual and the anatomic position. The skeleton shows a region-specific difference of the two osseous tissue types, i.e. trabecular and cortical bone. Depending on the anatomic site, these two bone types exhibit distinct microstructure characteristics and mechanical properties that, furthermore, differ between the anatomic sites [19]. In our study we used bone biopsy samples from three skeletal regions with different requirements of strength and consecutively specific amounts of trabecular and cortical bone. For example, the vertebral body mainly consists of trabecular bone, whereas the tibia as a long bone of the lower limbs is predominantly built up of cortical bone [20].

Trabecular bone is composed of irregularly distributed rods and plates [21] and the cortical bone consists of regular, cylindrically shaped lamellae [19]. Due to diverse directions of these structures, which is called the anisotropy of the bone, the mechanical properties of the bone are very variable. Thus, cortical bone has directional properties in pressure and traction strength, as well as in elastic modulus, that could be confirmed in bone specimen analysis which were sampled either in longitudinal or transverse direction [22].

Another explanation of the intra-individual variability of bone volume is the different level of mechanical load at each anatomic region, which results in either weakening or strengthening of the bone. Thus, the dominant hand becomes usually stronger with growth leading to a limb bilateral asymmetry [23] and one-sited exercise, e.g. tennis, can result in a higher bone mineral content at this site [24].

In addition, CKD-MBD have an impact on the two bone types. For example, early hyperparathyroidism leads to a reduced bone volume pronounced at the cortical sites [25]. Unfortunately, clinical information about the renal function from the body donors was not available in our study. On the other hand, the mean age of the body donors was 81 years where an average kidney function below GFR 60 ml/min and therefore early changes in mineral and bone metabolism could be supposed [2]. Nevertheless, even if we cannot directly transfer the results of this study into the CKD population, the shown limitation of the bone biopsy should create awareness and encourage further studies.

In summary, our data show that trabecular bone volume (BV/TV) results of one skeletal site are not always representative of that of other sites, hence it is no pars pro toto. The heterogeneity of the skeleton must be known by the physician interpreting bone biopsy results. Thomson et al. suggest that taking a biopsy from the site of a fracture might deliver the patient relevant information about the bone metabolism and structure [26]. Unfortunately, this might not be practicable in the clinical setting and taking biopsies from skeletal regions at higher fracture risks like the lumbar spine is not feasible. Therefore, we consider using imaging measurements, e.g. bone mineral density results, which can be taken at several skeletal sites for an individual fracture risk assessment.

Future studies will have to evaluate our results in the CKD population and whether parameters of mineralisation and turnover show the same intraindividual heterogeneity compared to bone volume.