Percutaneous bone biopsy in the diagnosis of renal osteodystrophy

Renal failure is associated with many complex bone and mineral complications. The spectrum of diseases is wide, encompassing defects in bone turnover, remodeling, and mineralization. Disease is currently defined in terms of whether a high or low turnover lesion is present. Measurement of serum parathyroid hormone levels (PTH) remains an important aspect in the management of renal bone disease, however, is limited by its lack of sensitivity in many clinical settings. Multiple biochemical markers are also available both commercially and experimentally to assist in assessing the degree of bone formation or resorption. However, when definitive diagnosis is important, when the clinical setting is confusing or complex, or when parathyroidectomy is being considered, the use of percutaneous bone biopsy is an essential tool in the understanding of underlying bone pathology and in directing therapy intervention.     

Differences in bone quality in low- and high-turnover renal osteodystrophy

Abnormal bone turnover is common in CKD, but its effects on bone quality remain unclear. We qualitatively screened iliac crest bone specimens from patients on dialysis to identify those patients with low (n=18) or high (n=17) bone turnover. In addition, we obtained control bone specimens from 12 healthy volunteers with normal kidney function. In the patient and control specimens, Fourier transform infrared spectroscopy and nanoindentation quantified the material and mechanical properties of the specimens, and we used bone histomorphometry to assess parameters of bone microstructure and bone formation and resorption. Compared with high or normal turnover, bone with low turnover had microstructural abnormalities such as lower cancellous bone volume and reduced trabecular thickness. Compared with normal or low turnover, bone with high turnover had material and nanomechanical abnormalities such as reduced mineral to matrix ratio and lower stiffness. These data suggest that turnover-related alterations in bone quality may contribute to the diminished mechanical competence of bone in CKD, albeit through different mechanisms. Therapies tailored specifically to low- or high-turnover bone may treat renal osteodystrophy more effectively.     

Therapy of bone and joint changes in renal osteodystrophy in adulthood

The renal osteoarthropathy in patients with chronic renal disease undergoing hemodialysis is characterized by increased bone turnover. This is the consequence of secondary hyperparathyroidism and leads to fibro-osteoclasia and osteomalacia. Mineralization of the atypical bone fibers is diminished and the collagen texture is altered. The biomechanical properties of such bone are reduced, which means that the incidence of fractures is increased and fracture healing seems to be disturbed. Therapy given for renal failure leads to segmental necrosis of the epiphyses. In the growing skeleton longitudinal growth is diminished and deviations in the axes of long bones are often observed. Corrective osteotomies, treatment of fractures and artificial joint replacements are therefore necessary in patients with renal failure. Observations recorded in 13 patients (aged 16-67 years) with chronic renal insufficiency who underwent 21 surgical interventions and were followed up for 6 years have led to formulation of the following general recommendations. Corrective osteotomies should only be performed when they are absolutely essential; the rate of nonunions is very high. The same is true for fixation of fractures with plates and nails. When joint replacements are inserted because of segmental necrosis and fractures the course is almost the same as in patients without renal osteoarthropathy when bone cement is used for fixation.     

Multiple bone fractures following an epileptic seizure in renal osteodystrophy

Seizure induced bone fractures in patients with renal osteodystrophy are uncommon. A case is described where multiple bone fractures occurred following convulsions which appeared shortly after haemodialysis.     

Value of the 99mTc-methylene diphosphonate bone scan in renal osteodystrophy

The value of radionuclide bone scanning in the diagnosis of renal osteodystrophy is still debated. In order to re-examine this issue, 25 uremic patients treated by intermittent hemodialysis underwent 99m-Technetium Methylene Diphosphonate (99mTc-MDP) bone scan. They were subdivided into three groups according to quantitative bone histology. Group 1 (N = 8) had pure dialysis osteomalacia, group 2 (N = 7) mixed lesions, and group 3 (N = 10) pure osteitis fibrosa. The scintigraphic studies were interpreted by means of a five point semi-quantitative scale. Using this quantification, all but one group 1 patients had decreased bone tracer uptake, and all patients of group 3 had an increased uptake (chi square test of Yates, P less than 0.001). Among patients of group 2, bone uptake was decreased in the three patients with clearly reduced mineralization front and moderate osteitis fibrosa, but it was increased in all patients with severe osteitis fibrosa and subnormal mineralization front. A quantitative analysis of regional tracer uptake into bone was performed in two patients: one of group 2 and one of group 3. The results obtained clearly corroborated the semi-quantitative findings. Thus, in hemodialysis patients with symptomatic bone disease, the 99mTc-MDP bone scan provides useful information for the differential diagnosis between dialysis-related osteomalacia and secondary hyperparathyroidism. In patients with mixed lesions, the importance of bone tracer uptake appears to depend on the extent of the mineralization front and on the intensity of osteitis fibrosa.     

Fractures and vertebral bone mineral density in patients with renal osteodystrophy

We investigated the relationship of CT determined vertebral bone mineral density (BMD), type of renal osteodystrophy, N terminal PTH levels and fracture history in 31 dialysis patients. BMD for patients with bone biopsy documented osteitis fibrosa was 1.6 standard deviation (SD) above the normal value for age and sex matched controls, while those patients with low turnover osteodystrophy had a mean BMD 1.2 SD below normal (p less than 0.0001). Three patients with osteitis fibrosa who had previously been treated with prednisone had a low BMD (1.8 SD below normal, different than O, p = 0.0015). There was no correlation between BMD and time on dialysis (r = 0.1). An N terminal PTH level greater than 150 pg/ml was a sensitive (94%) and specific (100%) method of separating those patients with osteitis fibrosa from those with low turnover osteodystrophy, while BMD was much less useful in this differentiation. A low BMD was not predictive of fracture history but the type of renal osteodystrophy was. Patients with low turnover osteodystrophy had a fracture rate of 0.2 fractures/dialysis year in comparison to those with osteitis fibrosis who had 0.1 fractures/dialysis year. Patients with the former bone disease fractured mainly axial rather than appendicular bones in contrast to those patients with osteitis fibrosa. In conclusion we found that patients with osteitis fibrosa had increased BMD compared to normal while those with low turnover osteodystrophy had decreased BMD, but that the N terminal PTH level was a better predictor of the type of bone disease present than was BMD.     

25-hydroxyvitamin D levels and bone histomorphometry in hemodialysis renal osteodystrophy

BACKGROUND: The importance of 25-hydroxyvitamin D (25-OHD) serum levels in hemodialysis chronic renal failure has not been so far histologically evaluated. Information still lacking relate to the effect of 25-OHD deficiency on serum parathyroid hormone (PTH) levels and on bone and its relationship with calcitriol levels. METHODS: This retrospective study has been performed on a cohort of 104 patients on hemodialysis from more than 12 months, subjected to transiliac bone biopsy for histologic, histomorphometric, and histodynamic evaluation. The patients, 61 males and 43 females, mean age 52.9 +/- 11.7 years, hemodialysis length 97.4 +/- 61.4 months, were treated with standard hemodialysis and did not receive any vitamin D supplementation. Treatment with calcitriol was not underway at the time of the biopsy. Transiliac bone biopsies were performed after double tetracycline labels. In addition, serum intact PTH (iPTH), alkaline phosphatase, and 25-OHD were measured. Calcitriol serum levels was also measured in a subset of patients (N= 53). The patients were divided according to serum 25-OHD levels in three groups: (1) 0 to 15 (15 patients), (2) 15 to 30 (38 patients), and (3) >30 ng/mL (51 patients). RESULTS: There was no significant difference in average age, hemodialysis age, serum PTH [490 +/- 494, 670 +/- 627, and 489 +/- 436 pg/mL, respectively (mean +/- SD)], alkaline phosphatase, and calcitriol between the three groups. The parameters double-labeled surface, trabecular mineralizing surface, and bone formation rate were significantly lower in group 1 than in the other groups (P < 0.03, < 0.03, and < 0.02, respectively). Osteoblast surface and adjusted apposition rate were borderline significantly lower in group 1 (P < 0.06 and < 0.10). There was no statistical difference in the biochemical and bone parameters between groups 2 and 3. A positive significant correlation was found between several bone static and dynamic parameters and 25-OHD levels in the range 0 to 30 ng/mL, showing a vitamin D dependence of bone turnover at these serum levels. However, actual evidence of an effect on bone of 25-OHD deficiency was found at serum levels below 20 ng/mL. With increasing 25-OHD levels beyond 40 ng/mL, a downslope of parameters of bone turnover was also observed. CONCLUSION: Since PTH serum levels are equally elevated in low and high 25-OHD patients, while calcitriol levels are constantly low, an effect of 25-OHD deficiency (group 1) on bone, consisting of a mineralization and bone formation defect, can be hypothesized. The effect of vitamin D deficiency or bone turnover is found below 20 ng/mL. The optimal level of 25-OHD appears to be in the order of 20 to 40 ng/mL. Levels of the D metabolite higher than 40 ng/mL are accompanied by a reduction of bone turnover.     

Bisphosphonates in renal osteodystrophy

The present review considers the role that bisphosphonates might have in patients with renal failure. Although bisphosphonates are widely used to reduce fracture risk in patients with osteoporosis, few studies have documented their effect in patients with renal osteodystrophy. The pathogenesis of bone loss after renal transplantation and the role of the recently identified osteoprotegerin/receptor activating nuclear factor-kappaB system is described. Inhibition of bone resorption may prove beneficial when high bone turnover is present, but there are potential drawbacks to widespread use of bisphosphonates. These issues are discussed, with emphasis placed on reports published within the past 18 months.     

Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy

Renal osteodystrophy alters metabolic activity and remodeling rate of bone and also may lead to different bone composition. The objective of this study was to characterize the composition of bone in high‐turnover renal osteodystrophy patients by means of Fourier transform infrared spectroscopic imaging (FTIRI). Iliac crest biopsies from healthy bone (n = 11) and patients with renal osteodystrophy (ROD, n = 11) were used in this study. The ROD samples were from patients with hyperparathyroid disease. By using FTIRI, phosphate‐to‐amide I ratio (mineral‐to‐matrix ratio), carbonate‐to‐phosphate ratio, and carbonate‐to‐amide I ratio (turnover rate/remodeling activity), as well as the collagen cross‐link ratio (collagen maturity), were quantified. Histomorphometric analyses were conducted for comparison. The ROD samples showed significantly lower carbonate‐to‐phosphate (p < .01) and carbonate‐to‐amide I (p < .001) ratios. The spatial variation across the trabeculae highlighted a significantly lower degree of mineralization (p < .05) at the edges of the trabeculae in the ROD samples than in normal bone. Statistically significant linear correlations were found between histomorphometric parameters related to bone‐remodeling activity and number of bone cells and FTIRI‐calculated parameters based on carbonate‐to‐phosphate and carbonate‐to‐amide I ratios. Hence the results suggested that FTIRI parameters related to carbonate may be indicative of turnover and remodeling rate of bone. © 2010 American Society for Bone and Mineral Research     

Primary bone oxalosis: the roles of oxalate deposits and renal osteodystrophy

Primary oxalosis is a rare congenital disorder. The excessive oxalate biosynthesis induces deposits in many organs, particularly in kidney and bone. The late onset of primary oxalosis is reported in a 50-year-old man. His chronic renal failure was treated by maintenance hemodialysis for 3 years. He then developed a diffuse bone disease with osteosclerosis and roentgenographic features of hyperparathyroidism. A parathyroidectomy was performed, with debatable improvement of bone lesions. Laboratory results and histologic and histomorphometric studies before and after parathyroidectomy suggest a double histopathogenetic mechanism for this bone disease: renal osteodystrophy and massive bone oxalate deposits. Such deposits may induce both a heterogeneous osteosclerosis with dense metaphyseal bands and histologic bone lesions similar to those of hyperparathyroidism. The crystalline deposits induce in the bone tissue a granulomatous macrophagic reaction. These macrophages are unable to phagocytize the crystals and may be involved in active bone resorption. Bone lesions of oxalosis occur in patients with chronic renal failure, and hyperparathyroidism has a worsening role.     

Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy

INTRODUCTION: Trace elements are known to influence bone metabolism; however, their effects may be exacerbated in renal failure because dialysis patients are unable to excrete excess elements properly. Our study correlated bone quality in dialysis patients with levels of bone fluoride, magnesium, and aluminum. A number of studies have linked trace elements, including fluoride, magnesium, and aluminum, to the development of renal osteodystrophy (ROD). However, little is known about the relationship between trace elements and changes in bone quality in ROD patients. The purpose of this study was to examine bone quality in ROD patients, and correlate differences in bone quality to trace element concentrations in bone. Bone quality encompasses parameters that contribute to the mechanical integrity of the bone. METHODS: One hundred fifty-three anterior iliac crest bone biopsies from patients with ROD were examined and subdivided into five groups based on the pathological features. Parameters contributing to bone quality, such as bone structure and remodeling, connectivity, mineralization, and microhardness, were assessed and correlated to bone chemical composition. In addition, clinical symptoms of ROD were assessed and correlated with bone composition. RESULTS AND CONCLUSIONS: There were no differences in bone architecture between the different ROD bone groups; however, differences in bone mineralization and microhardness were observed. Increase in bone fluoride was associated with increased osteoid parameters and decreased bone microhardness. Bone mineralization and microhardness decreased with increasing bone magnesium content and intact parathyroid hormone (PTH) level. Moreover, bone magnesium increased with intact PTH levels. The relationship between PTH, bone magnesium, mineralization, and microhardness was primarily observed in aplastic bone disorder. Furthermore, bone magnesium and aluminum contents were positively associated with bone pain and proximal myopathy in these patients. Most importantly, fluoride, magnesium, and aluminum showed significant correlations with one another. These results suggested that in ROD, bone fluoride may diminish bone microhardness by interfering with mineralization. Magnesium may be involved in the suppression of PTH secretion, lowering bone turnover thus leading to an increase in bone mineralization profile and microhardness in aplastic bone disorder. The effects of fluoride and magnesium on bone quality may be exacerbated by their interaction with aluminum.     

Cell biology of renal osteodystrophy

Renal osteodystrophy, a well-recognized complication of chronic renal failure, encompasses a spectrum of skeletal disorders ranging from high-turnover lesions of secondary hyperparathyroidism, the most common histologic lesion in pediatric patients with end-stage renal disease, to low-turnover lesions of adynamic renal osteodystrophy, which has become a common skeletal lesion in adults with chronic renal failure. Several advances have been made in the understanding of the pathogenesis of secondary hyperparathyroidism, particularly the critical roles of calcium, phosphorus, and vitamin D in promoting excess parathyroid hormone (PTH) synthesis and secretion, and parathyroid gland hyperplasia in renal failure. These insights will guide the development of more effective strategies for the prevention and management of renal bone disease.