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.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.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.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.
Abstract The parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor (denoted as PTH-1R) is a key signaling factor through which calcium-regulating hormones PTH and PTHrP exert their effects on bone. There are contradictory reports regarding the capability of osteoclasts to express PTH-1R. To address this issue in humans, bone biopsy specimen samples from 9 normal controls and 16 patients with moderate to severe secondary renal hyperparathyroid bone disease (2°HPT) with elevated PTH levels were studied to determine whether osteoclasts in the bone microenvironment express PTH-1R messenger RNA (mRNA) and protein. We report that osteoclasts express the PTH-1R mRNA but the protein is detected only in patients with 2°HPT. The PTH-1R mRNA and protein also were found in osteoblasts, osteocytes, and bone marrow cells. Receptor expression was higher in osteoclasts and osteoblasts of patients with 2°HPT than normal controls (98.0 ± 1.1% vs. 65.7 ± 14.3% and 65.8 ± 3.4% vs. 39.1 ± 6.2%; p < 0.01, respectively). Approximately half of osteoclasts found in bone of patients with 2°HPT have the PTH-1R protein. In patients with 2°HPT, a positive relationship exists between erosion depth, a parameter of osteoclastic activity, and the percentage of osteoclasts with PTH-1R protein (r = 0.58; p < 0.05). In normal controls, an inverse relationship exists between the percentage of osteoblasts with receptor mRNA, mRNA signals/cell, and serum PTH levels (r = −0.82 and p < 0.05 and r = −0.78 and p < 0.01, respectively). The results provide the novel evidence of PTH-1R in human osteoclasts and suggest a functional role for the receptors in 2°HPT.
Epidemiological studies suggest that moderate consumption of alcoholic beverages may be beneficial for bone in postmenopausal women. To investigate prospectively these uncontrolled obsewations, female rats were divided in four groups of 10 animals each and treated with 1) ovariectomy (OVX) and 2.5% ethanol diet (OVX‐ETOH group), 2) OVX and control diet (OVX‐C group), 3) sham surgery and 25% ethanol diet (SHAM‐ETOH group), or 3) sham surgery and control diet (SHAM‐C group). Three weeks after surgery, bone histomor‐phometfy revealed that the OVX‐C group, as expected, had lower trabecular bone volume and higher parameters of bone formation and resorption than the SHAM‐C group (p < 0.01). Intake of ethanol did not change these parameters in the SHAM rats, but in the OVX rats it was associated with sharp reduction in parameters of bone resorption (p < 0.01) without a concomitant effect on parameters of bone formation. The cytokines are believed to contribute to accelerated bone resorption during the early postmenopausal period. Indeed, the peripheral blood monocybc cells (PBMC) from the OVX‐C rats produced higher amounts of TNF‐α than the PBMC from the SHAM‐C rats (p < 0.05) and administration of ethanol prevented this increase in OVX rats but had no effect in SHAM rats. In summary, short‐tetm intake of moderate doses of ethanol was associated with markedly different eftects in rats with and without ovarian function. Although ethanol had no significant effect on the bone tissue and TNF‐α production of the SHAM rats, it was associated with markedly lower parameters of bone resorption and less TNF‐α production in the OVX animals. This suggests that exposure to low‐dose ethanol may protect from osteopenia following cessation of ovarian function.
Low bone mass, vertebral osteopenia, and fractures have been recognized in patients with ankylosing spondylitis (AS). However, there are few data about bone histology and histomorphometric changes in these patients. To shed light on bone alterations of these patients, we carried out a study including static and dynamic variables of bone of patients with AS, using iliac crest bone biopsy.16 white men with AS, mean age 34 +/- 3 years (15 to 55), mean duration of disease 11 +/- 2 years (6 months to 27) underwent bone biopsy for mineralized bone histology and evaluation of histomorphometric variables.14 patients presented osteopenia, 10 mineralization defects, and 3 osteomalacia. Trabecular bone mass, trabecular wall thickness, trabecular plate, and wall thickness were significantly lower than the control values. Comparing bone formation variables we found that the relative osteoid volume and the thickness of osteoid were significantly greater than control values (p < 0.05); comparing bone resorption variables we found that the bone osteoclast interface and the eroded surface were similar to that obtained in male controls. Analyzing dynamic variables, we observed that mineral apposition rate and doubly labeled osteoid were significantly less than the control group (p < 0.05), and mineralization lag time was statistically greater than the control group (p < 0.01). There was positive correlation between the duration of disease with relative (r = 0.513, p < 0.05) and absolute osteoid volume (r = 0.590, p < 0.05). There was negative correlation between disease duration and eroded surface (r = -0.616, p < 0.01) and bone osteoclast interface (r = -0.481, p < 0.05). There was positive correlation between duration of disease and singly labeled trabeculae (r = 0.680, p < 0.01), duration of disease and singly labeled osteoid seam, and duration of disease and mineralization lag time (r = 0.439, p < 0.05).Low bone mass in male patients with AS may also be related to mineralization defect. As bone resorption variables were normal in our patients, it is possible that the reduced bone mass seen in AS is due to a depression in bone formation rather than an increase in bone resorption.
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.
Cinacalcet lowers plasma parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism (sHPT), but the bone histologic response has not been described. This prospective, double-blind, placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT.Patients with intact PTH (iPTH) > or = 300 pg/ml were randomly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and/or phosphate binder therapy. Cinacalcet (30 - 180 mg/day) was used to achieve iPTH levels < or = 200 pg/ml. Bone biopsies were performed before and after one year of treatment.Baseline and end-of-study data were available from 32 patients (19 cinacalcet, 13 placebo). Baseline bone turnover was elevated in 27, reduced in 3 and normal in 2 patients. Serum bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTx) were elevated. Cinacalcet treatment decreased PTH and diminished activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (< 100 pg/ml). The histomorphometric parameter changes in bone corresponded to PTH, BSAP and NTx reductions. Bone mineralization parameters remained normal.Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT.
In dialysis patients, there is an increasing evidence that altered bone metabolism is associated with cardiovascular calcifications. The main objective of this study was to analyse, in hemodialysis patients, the relationships between bone turnover, mineralization and volume, evaluated in bone biopsies, with a plain X-ray vascular calcification score.In a cross-sectional study, bone biopsies and evaluation of vascular calcifications were performed in fifty hemodialysis patients. Cancellous bone volume, mineralized bone volume, osteoid volume, activation frequency, bone formation rate/bone surface, osteoid thickness and mineralization lag time were determined by histomorphometry. Vascular calcifications were assessed by the simple vascular calcification score (SVCS) in plain X-Ray of pelvis and hands and, for comparison, by the Agatston score in Multi-Slice Computed Tomography (MSCT).SVCS≥3 was present in 20 patients (40%). Low and high bone turnover were present in 54% and 38% of patients, respectively. Low bone volume was present in 20% of patients. In multivariable analysis, higher age (p = 0.015) and longer hemodialysis duration (p = 0.017) were associated with SVCS≥3. Contrary to cancellous bone volume, the addition to this model of mineralized bone volume (OR = 0.863; 95%CI: 0.766, 0.971; p = 0.015), improved the performance of the model. For each increase of 1% in mineralized bone volume there was a 13.7% decrease in the odds of having SVCS≥3 (p = 0.015). An Agatston score>400 was observed in 80% of the patients with a SVCS≥3 versus 4% of patients with a SVCS<3, (p<0.001).Higher mineralized bone volume was associated with a lower plain X-ray vascular calcification. This study corroborates the hypothesis of the existence of a link between bone and vessel and reinforces the clinical utility of this simple and inexpensive vascular calcification score in dialysis patients.
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