Disturbances in mineral metabolism play a central role in the development of renal bone disease. In a 54-wk, randomized, open-label study, 119 hemodialysis patients were enrolled to compare the effects of sevelamer hydrochloride and calcium carbonate on bone. Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). Serum phosphorus, calcium, and intact parathyroid hormone were well controlled in both groups, although calcium was consistently lower and intact parathyroid hormone higher among patients who were randomly assigned to sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover (e.g., activation frequency) after 1 yr in either group. Osteoid thickness significantly increased in both groups, but there was no significant difference between them. Bone formation rate per bone surface, however, significantly increased from baseline only in the sevelamer group (P ϭ 0.019). In addition, of those with abnormal microarchitecture at baseline (i.e., trabecular separation), seven of 10 in the sevelamer group normalized after 1 yr compared with zero of three in the calcium group. In summary, sevelamer resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation increased and trabecular architecture improved with sevelamer. Further studies are required to assess whether these changes affect clinical outcomes, such as rates of fracture. 19: 405-412, 200819: 405-412, . doi: 10.1681 Patients with chronic kidney disease (CKD) typically have abnormal bone histology. Alterations in bone turnover, mineralization, and volume in renal patients depend on several factors. In particular, disturbances in calcium-phosphate, parathyroid hormone (PTH), and vitamin D metabolism are important in the development of renal osteodystrophy (ROD). J Am Soc NephrolThe pattern of ROD observed in patients with stage 5 CKD has changed in recent years. Previously, observed bone conditions in renal patients in order of prevalence were mixed uremic osteodystrophy (MUO), predominant hyperparathyroid bone disease (HPBD), and aluminum-related os-

There is no correlation between iPTH and bone turnover in African Americans with ESRD. A substantial number of African American patients with low bone turnover have very high serum PTH levels. Bone histomorphometric results reveal differences in remodeling dynamics and responses to PTH between African American and Caucasian patients. Further studies utilizing newer PTH measurement assays are needed to better delineate the correlation between PTH and bone turnover in the various racial groups.

Insulin-like growth factor I (IGF-I) is an important growth factor for bone, yet the mechanisms that mediate its anabolic activity in the skeleton are poorly understood. To examine the effects of locally produced IGF-I in bone in vivo, we targeted expression IGF-I to osteoblasts of transgenic mice using a human osteocalcin promoter. The IGF-I transgene was expressed in bone osteoblasts in OC-IGF-I transgenic mice at high levels in the absence of any change in serum IGF-I levels, or of total body growth. Bone formation rate at the distal femur in 3-week-old OC-IGF-I transgenic mice was approximately twice that of controls. By 6 weeks, bone mineral density as measured by dual energy x-ray, and quantitative computed tomography was significantly greater in OC-IGF-I transgenic mice compared with controls. Histomorphometric measurements revealed a marked (30%) increase femoral cancellous bone volume in the OC-IGF-I transgenic mice, but no change in the total number of osteoblasts or osteoclasts. Transgenic mice also demonstrated an increase in the osteocyte lacunea occupancy, suggesting that IGF-I may extend the osteocyte life span. We conclude that IGF-I produced locally in bone osteoblasts exerts its anabolic effect primarily by increasing the activity of resident osteoblasts.

Background and objectives: Racial differences in mineral metabolism exist in the chronic kidney disease population, especially as it relates to intact parathyroid hormone (iPTH) levels. Few data exist on the relationship of these markers to bone biopsy findings in African-American (AA) hemodialysis patients across the spectrum of renal osteodystrophy (ROD).Design, setting, participants, & measurements: In prevalent AA hemodialysis subjects, we prospectively evaluated subjects by performing transiliac bone biopsy and correlating biochemical and clinical data to bone histology.Results: Study patients (n ‫؍‬ 43) had an average age of 53.7 (؎11.6) yr, with dialysis vintage of 40.4 (؎24.5) mo, 30% with diabetes, and 51% male. Bone histology revealed adynamic bone disease (ABD) (16%), mild to moderate hyperparathyroidism (HPT) (72%), severe (12%) HPT, and no osteomalacia or mixed uremic osteodystrophy. At the time of biopsy, mean corrected calcium was 9.1, 8.9, and 9.4 mg/dl (P ‫؍‬ 0.344); calcium-phosphorus (Ca ؋ PO 4 ) product was 42, 55, and 62 mg 2 /dl 2 (P ‫؍‬ 0.002); phosphorus was 4.6, 6.2, and 6.7 mg/dl (P ‫؍‬ 0.005); and iPTH was 225, 566, and 975 pg/ml (P ‫؍‬ 0.006), respectively. Median values for bone-specific alkaline phosphatase (BS-AP) were 16, 34, and 64 ng/ml (P < 0.0001) among the three groups.Conclusions: These data demonstrate that across the spectrum of ROD, iPTH levels are higher than expected in AA hemodialysis subjects. iPTH, PTH peptides, and bone-specific alkaline phosphatase correlated directly with histomorphometric measurements of bone turnover and when subjects were grouped by histologic diagnosis. Only 9.5% of subjects were simultaneously within suggested Kidney Disease Outcomes Quality Initiative (K/DOQI) ranges for Ca ؋ PO 4 , phosphorus, and iPTH, of which 75% demonstrated ABD on biopsy.

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.