Hanna Mawad

Renal Osteodystrophy in the First Decade of the New Millennium: Analysis of 630 Bone Biopsies in Black and White Patients

Renal osteodystrophy occurs early during loss of kidney function. There are 26 million American patients with chronic kidney disease (CKD), and almost all patients with CKD stage 5 have abnormal bone histology. Six hundred and thirty bone biopsies from adult CKD‐5 patients on dialysis were evaluated by histomorphometry and analyzed using the turnover (T), mineralization (M), and volume (V) classification. There were racial differences; whites exhibited predominantly low turnover (62%), whereas blacks showed mostly normal or high turnover (68%). A mineralization defect was observed in only 3% of patients. In whites, cancellous bone volume was low, normal, or high in approximately the same number of patients, whereas in blacks, cancellous bone volume was high in two‐thirds of the patients. More than 80% of blacks and whites with low cancellous bone volume had thin trabeculae owing to low bone formation. Cortical thickness was low in half the whites, whereas it was normal in three‐quarters of blacks. Cortical porosity was high in 50% of whites, whereas three‐quarters of blacks had high porosity. In summary, the TMV system gives relevant information. It should be expanded to include the architecture of cancellous and cortical bone. There are racial differences. Low bone volume and low bone turnover are more frequent than heretofore appreciated, whereas mineralization defects nowadays are observed rarely in adults. These findings call for an adjustment of the current therapeutic paradigm that takes into consideration race and risk of low bone volume and turnover. The latter have been shown to be associated with increased vascular calcifications.

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.

Effects of treatment of renal osteodystrophy on bone histology.

Renal osteodystrophy is characterized by abnormalities in bone turnover, mineralization, and bone volume. The effects of treatment modalities for renal osteodystrophy on bone should be analyzed with respect to these abnormalities. The major treatment modalities for renal osteodystrophy include phosphate binders, vitamin D compounds, and calcimimetics. Aluminum-containing phosphate binders have been shown to be toxic to bone secondary to their effects on bone turnover, mineralization, and bone volume. The use of calcium-based phosphate binders has been associated with the development of adynamic bone disease (low bone turnover), bone loss, and worsening of vascular calcifications. New nonaluminum, noncalcium phosphate binders have been developed (sevelamer hydrochloride and lanthanum carbonate). These agents show a potential for improvement in bone turnover and bone volume. Patients with renal osteodystrophy are deficient in calcitriol and often in calcidiol. Calcidiol deficiency has been underappreciated and deserves to be addressed in the treatment of patients with renal osteodystrophy. Calcitriol replacement therapy by daily oral administration is associated with frequent episodes of hypercalcemia and suppression of bone turnover in patients with stages 3 to 5 chronic kidney disease. Pulse oral or intravenous calcitriol administration induces frequent episodes of hypercalcemia or hyperphosphatemia, respectively, and achieves the same degree of correction of bone abnormalities. There are no data on the effects of paricalcitol or doxercalciferol on human bone. Experimental data, however, show that these two analogues and maxacalcitol may control serum parathyroid hormone levels without suppressing bone turnover. Calcimimetics lower parathyroid hormone levels and bone turnover.

Intact PTH Combined With the PTH Ratio for Diagnosis of Bone Turnover in Dialysis Patients: A Diagnostic Test Study

BACKGROUND Determination of parathyroid hormone (PTH) level is the most commonly used surrogate marker for bone turnover in patients with stage 5 chronic kidney disease on dialysis therapy (CKD-5D). The objective of this study is to evaluate the predictive value of various PTH measurements for identifying low or high bone turnover rate. STUDY DESIGN Diagnostic test study. SETTINGS & PARTICIPANTS 141 patients with CKD-5D from 15 US hemodialysis centers. INDEX TESTS Intact PTH, PTH 1-84, and PTH ratio (ratio of level of PTH 1-84 to level of large carboxy-terminal PTH fragments). REFERENCE TEST OR OUTCOME Bone turnover determined using bone histomorphometry. OTHER MEASUREMENTS Demographic and treatment-related factors, serum calcium and phosphorus. RESULTS Patients presented histologically with a broad range of bone turnover abnormalities. In white patients with CKD-5D (n = 70), PTH ratio <1.0 added to intact PTH level <420 pg/mL increased the positive predictive value for low bone turnover from 74% to 90%. In black patients (n = 71), adding PTH ratio <1.2 to intact PTH level <340 pg/mL increased the positive predictive value for low bone turnover from 48% to 90%. Adding PTH ratio >1.6 to intact PTH level of 340-790 pg/mL increased the positive predictive value for high bone turnover from 56% to 71%. LIMITATIONS Because the research protocol called for carefully controlled blood specimen handling, blood drawing and routine specimen handling might be less stringent in clinical practice. By limiting study participation to black and white patients with CKD-5D, we cannot comment on the roles of intact PTH, PTH 1-84, and PTH ratio in other racial/ethnic groups. CONCLUSION In black patients with CKD-5D, the addition of PTH ratio to intact PTH measurements is helpful for diagnosing low and high bone turnover. In white patients with CKD-5D, it aids in the diagnosis of low bone turnover.

Influence of the parathyroid glands on bone metabolism

Bone is a classic target tissue for parathyroid hormone (PTH), whose calciotropic effect is mediated largely via catabolic actions on this tissue. Paradoxically, PTH also exerts anabolic actions, with intermittent injections of PTH or its amino‐terminal fragments causing an increase in bone formation and bone mass, actions that form the basis for the use of PTH in the treatment of osteoporosis. Besides vitamin D, PTH is the only other known bone anabolic agent. High‐affinity PTH receptors (PTH‐1R) have been detected on osteoblasts and osteoclasts (albeit in lower numbers).

Low-energy fractures without low T-scores characteristic of osteoporosis: a possible bone matrix disorder.

BACKGROUND Osteoporotic fractures commonly occur after low-energy trauma in postmenopausal women with reduced bone quantity documented by low bone mineral density (BMD). Low-energy fractures, however, have also been reported to occur in premenopausal women with normal or near-normal BMD, suggesting the existence of a bone quality abnormality. METHODS Bone quality and quantity were evaluated in a cross-sectional study of three groups of premenopausal white females: (1) twenty-five subjects with low-energy fracture(s) and BMD in the normal range (t-scores > -2.0), (2) eighteen subjects with low-energy fracture(s) and BMD in the osteoporotic range (t-scores ≤ -2.5), and (3) fourteen healthy volunteers (controls). Bone quality was assessed with use of Fourier transform infrared spectroscopy and histomorphometry in iliac crest bone samples obtained from all subjects; bone quantity was assessed by dual x-ray absorptiometry and histomorphometry. RESULTS The collagen crosslinking ratio in the non-low-BMD subjects with fractures was 13% greater than the ratio in the low-BMD subjects with fractures and 14% greater than the ratio in the controls (p < 0.001 for both). Cancellous bone volume was 29% greater (p < 0.01) and trabecular separation was 31% less (p < 0.01) in the non-low-BMD subjects with fractures than in the low-BMD subjects with fractures; the values in the non-low-BMD subjects did not differ from those in the controls. Bone turnover did not differ among the groups, and osteomalacia was not present in any subject. Thus, the non-low-BMD subjects with fractures maintained bone quantity, but the collagen crosslinking ratio, a parameter of bone quality, was abnormal. In contrast, the low-BMD subjects with fractures did not have this collagen crosslinking abnormality but did have abnormal bone quantity. CONCLUSIONS This study highlights a collagen crosslinking abnormality in patients with low-energy fractures and nonosteoporotic t-scores. Reports have indicated that altered collagen crosslinking is associated with subnormal fracture resistance. A finding of nonosteoporotic bone mass in a patient with low-energy fractures would justify assessment of bone material quality, which currently requires a bone biopsy. Further studies are needed to search for possible noninvasive tests to diagnose abnormal crosslinking. Since no specific therapies for abnormal collagen crosslinking are currently available, studies are also needed to explore novel therapeutic modalities to reverse the underlying collagen crosslinking abnormality. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Interventional Nephrology and Dialysis: Bone Biopsy: Indications, Techniques, and Complications

Abstract Bone biopsy is the gold standard for diagnosing the type and severity of renal osteodystrophy (ROD) in end‐stage renal disease (ESRD) patients. In this article we review the indications, techniques, and complications of this minimally invasive procedure. The importance of careful preparation is emphasized.

The five most commonly used intact parathyroid hormone assays are useful for screening but not for diagnosing bone turnover abnormalities in CKD-5 patients.

BACKGROUND/AIMS Assessment of bone turnover for management of renal osteodystrophy is part of routine care in chronic kidney disease Stage 5 (CKD-5) patients. Measurement of intact parathyroid hormone (iPTH) is the most commonly used surrogate marker for bone turnover in these patients. The current study was conducted to evaluate the predictive value of the five most commonly used iPTH assays for bone turnover. METHODS In a cross-sectional study, 84 CKD-5 patients underwent bone biopsy and blood drawings for determination of iPTH and total serum alkaline phosphatase (AP). RESULTS Histologically, patients presented with a broad range of bone turnover abnormalities as determined by activation frequency and bone formation rate/bone surface. Results of the five iPTH assays in each patient correlated but were significantly different. There were also significant differences between iPTH measurements at the same bone turnover level. Using Kidney Disease Outcome Quality Initiative recommended iPTH ranges, all assays showed comparably poor diagnostic performance. At 80% specificity, cut-off values of the 5 iPTH assays for low bone turnover varied from 165 to 550 pg/ml and for high bone turnover from 404 to 1,003 pg/ml. Sensitivities at these cutoffs remained below acceptable standards. Addition of AP measurements to iPTH did not improve diagnostic accuracy. CONCLUSIONS Precise assessment of bone turnover will require utilization of established and novel bone markers reflecting effects of bone turnover rather than measuring only iPTH or other effectors.

Opposite Effects of Calcitriol and Paricalcitol on the Parathyroid Hormone-(1-84)/Large Carboxy-Terminal-Parathyroid Hormone Fragments Ratio in Patients with Stage 5 Chronic Kidney Disease

BACKGROUND AND OBJECTIVES The effects of calcitriol and paricalcitol on circulating levels of intact parathyroid hormone, parathyroid hormone-(1-84), the large carboxy-terminal-parathyroid hormone fragments, and the parathyroid hormone-(1-84)/carboxy-terminal-parathyroid hormone fragments were studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In the longitudinal study, 31 hemodialysis patients who were receiving intravenous calcitriol or paricalcitol were followed for 6 to 8 wk. After a washout period, patients were treated with the other vitamin D compound for 6 to 8 wk. Plasma intact parathyroid hormone and parathyroid hormone-(1-84) were measured, and the parathyroid hormone ratio was calculated. In the cross-sectional study, results of intact parathyroid hormone, parathyroid hormone-(1-84), and parathyroid hormone ratio were compared between patients who were treated with paricalcitol (n = 49) versus no vitamin D therapy (n = 44). RESULTS In the longitudinal study, the parathyroid hormone ratio was significantly lower in patients who were treated with calcitriol and higher with paricalcitol treatment compared with values that were obtained during washout. In the cross-sectional study, intact parathyroid hormone levels were identical in both groups, whereas parathyroid hormone-(1-84) and thus parathyroid hormone ratio values were higher in patients who were given paricalcitol than in patients who were not receiving vitamin D. CONCLUSIONS These data show that at similar intact parathyroid hormone values, the active parathyroid hormone-(1-84) compound is lower with calcitriol than with paricalcitol treatment. This finding might be relevant for choice of vitamin D compound in patients with stage 5 chronic kidney disease.

FGF-23 serum levels and bone histomorphometric results in adult patients with chronic kidney disease on dialysis

Background: Fibroblast growth factor-23 (FGF-23) is a hormone principally produced by osteocytes/osteoblasts. In patients with chronic kidney disease (CKD), FGF-23 levels are usually elevated and can reach up to 300 – 400 times the normal range. FGF-23 is regulated by local bone-related and systemic factors, but the relationship between circulating FGF-23 concentrations and bone remodeling and mineralization in CKD has not been well characterized. In the current study, we examined the relationship between FGF-23 levels and bone histomorphometry parameters in adult patients with renal osteodystrophy. Material and methods: 36 patients on dialysis (CKD-5D) underwent bone biopsies after tetracycline double labeling. Blood drawings were done at time of biopsy to determine serum levels of markers of bone and mineral metabolism. Results: Patients with high bone turnover had higher values of serum FGF-23 than patients with low bone turnover. FGF-23 levels correlated with activation frequency (ρ = 0.60, p < 0.01) and bone formation rate (ρ = 0.57, p < 0.01). Normal mineralization was observed in 90% of patients with FGF-23 levels above 2,000 pg/mL. Furthermore, FGF-23 correlated negatively with mineralization lag time (ρ = –0.69, p < 0.01) and osteoid maturation time (ρ = –0.46, p < 0.05) but not with osteoid thickness (ρ = 0.08, ns). Regression analysis showed that FGF-23 was the only independent predictor of mineralization lag time. FGF-23 correlated with cancellous bone volume (ρ = 0.38, p < 0.05) but did not predict it. Conclusion: Circulating FGF-23 concentrations may reflect alterations in ongoing bone formation along with active mineralization, but not exclusively in bone formation or mineralization. Abnormal mineralization lag time (> 100 days) was mainly seen in patients with FGF-23 levels less than 2,000 pg/mL, while very high levels of FGF-23 are associated with normal mineralization lag time.