Serum osteoprotegerin and renal osteodystrophy.

BACKGROUND: Numerous growth factors and cytokines are known to modulate bone turnover. An important, recently discovered complex involved in osteoclastogenesis is the osteoprotegerin/osteoprotegerin-ligand (OPG/OPGL) cytokine complex, which is produced by osteoblasts. Many factors, including parathyroid hormone (PTH), appear to affect bone turnover through this pathway. In this disorder, the role of the OPG/OPGL system in the pathogenesis of renal osteodystrophy, a disease with either low or high bone turnover, has not been investigated so far. METHODS: Thirty-nine chronic haemodialysis patients had bone biopsies, including histomorphometric and histodynamic examinations. In addition, the following serum biochemistry parameters were measured: serum OPG, intact PTH, PTH 1-84, total PTH, osteocalcin, total and bone alkaline phosphatases, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. RESULTS: On average, serum OPG levels were above the normal range. They were lower in adynamic bone disease (ABD) patients, than in patients with predominant hyperparathyroidism (HP) or mixed osteodystrophy (MO). Significant negative correlations were found between serum OPG and PTH levels, and between serum OPG and parameters of bone resorption (ES/BS) and bone formation (ObS/BS and BFR/BS) in HP and MO patients with PTH values < or =1000 pg/ml. For intact PTH levels < or =300 pg/ml, serum OPG was significantly lower in the group with ABD than in those with HP or MO (P<0.05). CONCLUSION: In renal osteodystrophy the OPG/OPGL system is involved in the regulation of bone turnover induced by PTH. The determination of serum OPG levels could be of use in the diagnosis of low turnover bone disease, at least in association with PTH levels < or =300 pg/ml.     

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.     

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.     

Zinc nutritional status modifies renal osteodystrophy in uremic rats.

BACKGROUND: Previous studies from our laboratories suggested that zinc depletion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25(OH)2D, calcitriol) in calcium- and phosphorus-depleted rats with normal renal function, and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D metabolites, PTH response, mineral balance and bone histomorphometry in animals with different zinc nutritional and renal functional status. METHODS: Fifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -deplete (-) diets for two weeks. Thereafter, half of each paired group underwent nephrectomy (N), while half had sham (S) operations. Animals were observed for eight weeks after surgery. External mineral balances of zinc, calcium, phosphate and magnesium were determined before surgery, and 1, 2 and 7 weeks after surgery. Plasma creatinine, zinc, calcium, phosphorus, magnesium, 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrifice. Static and dynamic bone histomorphometry was determined by standard techniques. RESULTS: After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels, and nephrectomized animals had lower creatinine clearances than respective controls at sacrifice. Plasma calcium and phosphorus concentrations were similar in all four groups at sacrifice. Plasma magnesium concentrations were similar in groups with renal insufficiency, regardless of zinc nutritional status. Plasma 25-hydroxycholecalciferol and calcitriol levels were similar in all groups. There was no difference between mean PTH concentration in sham-operated animals, regardless of zinc nutritional status. Although nephrectomized groups' PTH levels were increased compared to S controls, PTH levels were increased in +Zn/N animals compared to the -Zn/N group. Zinc-deplete groups had consistent negative net zinc balance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of different zinc nutritional status were compared. Nephrectomized animals had histomorphometric changes indicative of higher bone turnover and abnormal mineralization. Zinc deficiency was associated with less evidence of increased parathyroid hormone activity on bone in nephrectomized rats. CONCLUSIONS: Zinc depletion limits the increase in plasma PTH concentration and the expression of secondary hyperparathyroid bone disease during the development of renal insufficiency in the renal ablation model of uremia in rats. The mechanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PTH on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight the potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.     

Oxalosis in bone causing a radiographical mimicry of renal osteodystrophy

We report a patient on maintenance dialysis with oxalosis and radiographical signs typical of hyperparathyroid bone disease in patients with end-stage renal insufficiency. The patient underwent a subtotal parathyroidectomy. Because his bone pain worsened during long-term dialytic therapy, a bone biopsy was performed and revealed crystalline deposits in trabecules and the bone marrow characteristic of oxalate. Trabecular destruction and signs of defective mineralization of bone were also found. When the diagnosis was made, the patient had become addicted to narcotic analgesics; he died from an overdose. The case underscores the limits of skeletal radiographs for the diagnosis of oxalosis in bone. Furthermore, the radiographic findings may lead to erroneous conclusions in patients with renal osteodystrophy because the radiographic signs of oxalosis can mimic those of hyperparathyroid bone disease.     

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.     

The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling

BACKGROUND: Loss of bone mass after transplantation begins in the early periods after transplantations and may persist for several years, even in patients with normal renal function. While the pathogenesis of these abnormalities is still unclear, several studies suggest that preexisting bone disease, glucocorticoid therapy, and alterations in phosphate metabolism may play important roles. Recent studies indicate that osteoblast apoptosis and impaired osteoblastogenesis play important roles in the pathogenesis of glucocorticoid-induced osteoporosis. OBJECTIVES: To examine the early alterations in osteoblast number and surfaces during the period following renal transplantation. METHODS: Twenty patients with a mean age of 36.5 +/- 12 years were subjected to bone biopsy 22 to 160 days after renal transplantation. In 12 patients, a control biopsy was performed on the day of transplantation. Bone sections were evaluated by histomorphometric analysis and cell DNA fragmentation by the methods of terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL), using immunoperoxidase and direct immunofluorescence techniques. RESULTS: The main alterations in posttransplant biopsies were a decrease in osteoid and osteoblast surfaces, adjusted bone formation rate, and prolonged mineralization lag time. Peritrabecular fibrosis was markedly decreased. None of the pretransplant biopsies revealed osteoblast apoptosis. In contrast, TUNEL-positive cells in the proximity of osteoid seams or in the medullary space were observed in nine posttransplant biopsies of which four had mixed bone disease, two had adynamic bone disease, one had osteomalacia, one had osteitis fibrosa, and one had mild hyperparathyroid bone disease. Osteoblast number in posttransplant biopsies with apoptosis was lower as compared with posttransplant biopsies without apoptosis. In addition, most of them showed a marked shift toward quiescence from the cuboidal morphology of active osteoblasts. Serum phosphorus levels were lower in patients showing osteoblast apoptosis and correlated positively with osteoblast number and negatively with the number of apoptotic osteoblasts. In addition, posttransplant osteoblast surface correlated positively with parathyroid hormone (PTH) levels and negatively with glucocorticoid cumulative dose. CONCLUSION: The data suggest that impaired osteoblastogenesis and early osteoblast apoptosis may play important roles in the pathogenesis of posttransplant osteoporosis. The possible mechanisms involved in the pathogenesis of theses alterations include posttransplant hypophosphatemia, the use of glucocorticoids, and the preexisting bone disease. PTH seems to have a protective effect by preserving osteoblast survival.     

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.     

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.