Treatment of established bone loss after renal transplantation with etidronate

BACKGROUND: Osteoporosis is a well-documented complication of organ transplantation. Bisphosphonates have been shown to be effective in preventing corticosteroid-induced osteoporosis in renal transplant recipients, but data are lacking for treatment of established osteoporosis. This study reports our clinical experience of treatment with the bisphosphonate etidronate in a single renal transplant center. METHODS: To establish the effectiveness of etidronate in treating established low bone mineral density (BMD), all newly transplanted patients treated with etidronate were compared with controls. Twenty-five patients treated with etidronate (14 males, 11 females) and 24 controls (15 males, 9 females) were identified from the cohort of patients who underwent transplantation between January 1, 1994, and December 31, 1996. RESULTS: There was no difference in mean age, weight, or cumulative dose of corticosteroids between the treatment and control groups. The baseline BMD measurement was performed at 10.4 +/- 5.3 months after transplantation for treated patients and at 10.7 +/- 4.5 months for controls (P=0.78). Over the subsequent 1-year study period, patients treated with etidronate demonstrated a greater increase in BMD at sites with a preponderance of trabecular bone. Lumbar spine BMD increased 4.3 +/- 6.1% in the treatment group versus 0.55 +/ -5.3% in controls (P<0.03) and trochanter BMD increased 10.3 +/- 11.9% and 2.2 +/- 5.7%, respectively, in the treatment and control groups (P<0.02). CONCLUSIONS: This study establishes the effectiveness of etidronate for treatment of low BMD in renal transplant recipients. Patients selected for treatment had lower baseline BMD than control subjects, yet still showed a clinically important increase in BMD.     

The Prevalence of Osteopenia in Pediatric Renal Allograft Recipients Varies with the Method of Analysis

BACKGROUND: Pediatric renal allograft recipients often suffer from osteopenia and the potential for increased fractures. Although modern densitometers are widely available, their use in children is complicated by lack of optimal interpretive criteria. METHODS: We reviewed dual energy X-ray absorptiometry (DEXA) studies in 33 patients with functional renal allografts 4.4 +/- 3.6 years after transplantation. We interpreted our data using three previously described methods of assigning bone mineral density (BMD) Z scores. RESULTS: BMD was directly related to age, height, weight, body surface area, and pubertal status (p < 0.001). Using gender-mixed reference data matched by chronological age, the mean BMD Z score was -0.9 +/- 1.3 vs. 0.4 +/- 1.4 when matched by height-age (p < 0.001). Height-age adjustment particularly increased the BMD Z score of pubertal adolescents. In a subset of 22 patients, gender-matched reference data led to different results from the gender-mixed reference population (mean BMD Z score 0.0 +/- 1.7 vs. -0.8 +/- 1.4, p < 0.001). CONCLUSIONS: The perceived prevalence of osteopenia among pediatric kidney transplant recipients differs using analysis based on chronological age, height-age, or gender-matched reference data. Further studies are necessary to determine the clinical significance of measured bone density in this population.     

Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis.

Some studies have indicated that the risk of fragility fractures in men increases as bone mineral levels decrease, but there is an overlap in the bone mineral density (BMD) measurements between patients with or without fractures. Furthermore, it has been suggested that the biomechanical competence of trabecular bone is dependent not only on the absolute amount of bone present but also on the trabecular microarchitecture. In the present study, 108 men (mean age 52.1 years) with lumbar osteopenia (T score < -2.5) were recruited to examine the relationships between BMD, architectural changes in trabecular bone, and the presence of vertebral fractures. Lumbar BMD was assessed from L2 to L4 in the anteroposterior view with dual-energy X-ray absorptiometry. At the upper left femur, hip BMD was measured at the transcervical site. Spinal X-ray films were analyzed independently by two trained investigators, and vertebral fracture was defined as a reduction of at least 20% in the anterior, middle, or posterior vertebral height. Transiliac bone biopsy specimens were obtained for all patients. Histomorphometric studies were performed on an image analyzer, and the following parameters were determined: trabecular bone volume (BV/TV), trabecular thickness (Tb.Th), number (Tb.N), and separation (Tb.Sp), interconnectivity index (ICI), characterization of the trabecular network (node count and strut analysis), and star volume of the marrow spaces. Spinal radiographs evidenced at least one vertebral crush fracture in 62 patients (group II) and none in 46 patients (group I). After adjusting for age, body mass index, and BMD, there were no significant differences between the two groups in BV/TV, Tb.Th, or star volume. In contrast, the mean values of ICI, free end-to-free end struts (FF/TSL), and Tb.Sp were significantly higher, whereas Tb.N and node-to-node struts (NN/TSL) were lower in patients with at least one vertebral fracture. Logistic regression analysis showed that only ICI, FF/TSL, NN/TSL, and Tb.N were significant predictors of the presence of vertebral fracture: odds ratios for an alteration of 1 SD ranged from 1.7 (1.0-3.2) for NN/TSL to 3.2 (1.1-10.1) for ICI. Patients with at least three vertebral fractures (n = 23) were categorized as "multiple fractures." The results of logistic regression showed that spine BMD, BV/TV, and all architectural parameters were significant predictors of multiple vertebral fractures: odds ratios for an alteration of 1 SD ranged from 2.2 (1.1-4.6) for star volume to 3.7 (1.4-9.7) for ICI. These results strongly suggest that bone trabecular microarchitecture is a major and independent determinant of vertebral fractures in middle-aged men with osteopenia.     

Prevalence of osteoporosis, osteopenia, and vertebral fractures in long-term renal transplant recipients

BACKGROUND: Osteopenia and osteoporosis are frequent complications early after transplantation. Their long-term prevalences and associations with the risk of fractures are not well known. The objective of the present work was to determine the incidence of osteopenia and osteoporosis versus vertebral fractures in renal transplant recipients with stable graft function and with a follow-up of at least 10 years. PATIENTS AND METHODS: Forty renal transplant recipients, 24 men and 16 women, were included in the study. The mean age was 41.8 years and the follow-up was 130 +/- 14 months. Initial immunosuppression consisted of cyclosporine with or without an antiproliferative agent. Measurements of bone mass density (BMD) were performed by dual-energy X-ray absorptiometry (DEXA). The assessment of vertebral fracture using conventional radiography was evaluated by semiquantitative criteria. RESULTS: Eleven patients (27.5%) displayed lumbar spine osteoporosis (T-score < -2.5); 21 (52.5%), osteopenia (T-score > -2.5 and < -1) and 8 (20.0%), normal BMD. However, BMD was better preserved at the femoral neck: 14 patients (35.0%) had normal BMD; 20 (50.0%) osteopenia, and 6 (15.0%), osteoporosis. When analyzed together, patients with osteoporosis or osteopenia showed worse graft function at 1 and 8 years compared with normal BMD patients (1.75 +/- 0.634 vs 1.32 +/- 0.33 mg/dL at 1 year; P < .014) and (1.7 +/- 0.4 vs 1.2 +/- 0.2 mg/dL at 5 years; P < .01) and a greater number were prescribed vitamin D (50% vs 23%). Mild vertebral fractures were observed in 60.0% patients with osteoporosis; 70% with osteopenia; and 43% with normal lumbar BMD. Peripheral fractures were more common in patients with osteoporosis (P = .053). CONCLUSIONS: Osteoporosis and osteopenia are common among long-term renal transplant recipients are associated with poorer graft function. Lumbar spine BMD osteoporosis is associated with peripheral fractures. However, mild vertebral deformities are not associated with the presence of osteopenia or osteoporosis.     

Bone mineral density changes within 11 months of renal transplantation in Iranian patients

BACKGROUND AND AIM: We studied bone mineral density (BMD) changes in Iranian patients with end-stage renal disease (ESRD) within 11 months after renal transplantation. METHODS: Among 68 ESRD candidates for renal transplantation, the BMD at the femur and the spine were assessed using a DEXA Norland scanner. Linear regression analysis was used to identify risk factors associated with low bone density. RESULTS: Mean BMD, T-score and Z-score of femur and spine were significantly reduced (at femur, 0.78 +/- 0.14, -2.4 +/- 1.1, -1.6 +/- 1.0; at spine, 142.25 +/- 105, -1.09 +/- 1.1, -1.07 +/- 0.9). Osteoporosis and osteopenia were found 55.2% and 36.2% at the femur and 8.6% and 58.6% at the spine, respectively. The BMD showed a significant negative association with age (r=0.615), female gender (r=0.394), and corticosteroid intake (r=0.286), and a positive association with weight (r=0.394) and body mass index (r=0.626). There was no significant association between BMD measurements and calcium, phosphorous, or parathyroid hormone levels. At 11 months follow-up, in 20 patients, the subject had lost a mean of 2.4% T-score and 2.8% Z-score at spine (P=.027 and .13, respectively), but did not experience significant declines at the femur. BMD showed a decrease in 80% of recipients in the spine area; there was a 15% BMD increase at the hip. CONCLUSION: Low bone density is common among ESRD Iranian patients. Early screening and treatment of this group is recommended. Significant loss in lumbar density occurred within 11 months of transplantation in more than one third of a prospective cohort of renal transplant recipients.     

Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: I. Two-dimensional histology

While osteoporosis is characterized by a low bone mass there is a well-recognized overlap in bone mineral density (BMD) measurements between groups of subjects with and without vertebral fracture. To investigate whether differences in trabecular architecture may contribute to the presence or absence of fractures independent of the bone mass, fracture and nonfracture groups matched for age, gender, and BMD were assembled. Transiliac biopsies and corresponding lumbar spine BMD measurements from 31 women and 16 men with vertebral fracture were compared with those from 22 women and 11 men without fracture. Lumbar BMD (L1-4) was measured using a Hologic 2000 densitometer. The lumbar BMD was similar in women with and without fracture (0.63 g/cm(3) +/- 0.10 SD and 0.71 g/cm(3) +/- 0.17 SD, n.s.) and in men with and without fracture (0.72 g/cm(3) +/- 0.12 SD and 0.76 g/cm(3) +/- 0.17 SD, n.s.). Undecalcified iliac crest biopsy sections, 8 microm thick, were analyzed for remodeling variables and trabecular architecture using OsteoMeasure and TAS image analysis systems. No significant difference was found in either gender between fracture and nonfracture groups in percent bone volume (mean 10% in all groups), or in the wide range of remodeling and architectural variables measured, including the trabecular width, number, and separation, mean trabecular plate density and fractal dimension, as well as several indirect indices of connectivity including the node:terminus ratio, marrow star volume, and trabecular pattern factor. On the basis of this evidence it was concluded that there is no difference in the trabecular architecture between patients with crush fracture and controls when account is taken of bone mass. This suggests that microanatomical disruption is a predictable intrinsic feature of bone loss. However, there remains the possibility that the two-dimensional character of the structural deterioration measured indirectly is not sufficiently sensitive for the complex cancellous system. This is considered further in part II.     

胸腰椎骨质疏松性骨折自固化磷酸钙骨水泥椎体成形的实验研究

目的探讨自固化磷酸钙骨水泥(calciumphosphatecement,CPC)注射椎体成形术后对胸腰椎骨质疏松性骨折椎体的力学影响。方法自愿捐赠的4具甲醛固定的老年尸体,取胸腰椎骨质疏松标本,平均年龄69岁,男、女各2具。每具标本随机取6个椎体,制备24个单椎体标本,建立前屈方向加载单椎体骨折模型。将CPC粉末与固化液以2.5g∶1ml调和制备CPC骨水泥,对骨折标本行CPC成形强化,每个椎体注射CPC约4ml。分别进行骨折前、成形后屈曲压缩力学检测。结果骨质疏松椎体标本骨折前最大载荷为1954±46N,位移长度为5.60±0.70mm,刚度为349±18N/mm;骨折间隙CPC填塞成形后最大载荷为2285±34N,位移为5.35±0.60mm,刚度为427±10N/mm,各指标骨折前和成形后比较差异均有统计学意义(P<0.05)。CPC加强成形后单椎体的承载能力强度较骨折前提高16.92%,刚度较骨折前提高22.31%。结论椎体内注射CPC能明显恢复骨质疏松骨折椎体的力学性能。     

Intervertebral disc degeneration can predispose to anterior vertebral fractures in the thoracolumbar spine.

Mechanical experiments on cadaveric thoracolumbar spine specimens showed that intervertebral disc degeneration was associated with reduced loading of the anterior vertebral body in upright postures. Reduced load bearing corresponded to locally reduced BMD and inferior trabecular architecture as measured by histomorphometry. Flexed postures concentrated loading on the weakened anterior vertebral body, leading to compressive failure at reduced load. INTRODUCTION: Osteoporotic fractures are usually attributed to age-related hormonal changes and inactivity. However, why should the anterior vertebral body be affected so often? We hypothesized that degenerative changes in the adjacent intervertebral discs can alter load bearing by the anterior vertebral body in a manner that makes it vulnerable to fracture. MATERIALS AND METHODS: Forty-one thoracolumbar spine "motion segments" (two vertebrae and the intervertebral disc) were obtained from cadavers 62-94 years of age. Specimens were loaded to simulate upright standing and flexed postures. A pressure transducer was used to measure the distribution of compressive "stress" inside the disc, and stress data were used to calculate how compressive loading was distributed between the anterior and posterior halves of the vertebral body and the neural arch. The compressive strength of each specimen was measured in flexed posture. Regional volumetric BMD and histomorphometric parameters were measured. RESULTS: In the upright posture, compressive load bearing by the neural arch increased with disc degeneration, averaging 63 +/- 22% (SD) of applied load in specimens with severely degenerated discs. In these specimens, the anterior half of the vertebral body resisted only 10 +/- 8%. The anterior third of the vertebral body had a 20% lower trabecular volume fraction, 16% fewer trabeculae, and 28% greater intertrabecular spacing compared with the posterior third (p < 0.001). In the flexed posture, flexion transferred 53-59% of compressive load bearing to the anterior half of the vertebral body, regardless of disc degeneration. Compressive strength measured in this posture was proportional to BMD in the anterior vertebral body (r2 = 0.51, p < 0.001) and inversely proportional to neural arch load bearing in the upright posture (r2 = 0.28, p < 0.001). CONCLUSIONS: Disc degeneration transfers compressive load bearing from the anterior vertebral body to the neural arch in upright postures, reducing BMD and trabecular architecture anteriorly. This predisposes to anterior fracture when the spine is flexed.     

Effect of ibandronate on bone loss and renal function after kidney transplantation.

Severe osteoporosis frequently is observed after organ transplantation. In kidney transplantation, it adds to pre-existing renal bone disease and strategies to prevent osteoporosis are not established. Eighty kidney recipients were included in a randomized controlled prospective intervention trial. Treated patients (n = 40) received an injection of ibandronate, a bisphosphonate, immediately before and at 3, 6, and 9 mo after transplantation. The primary outcome measured was the change in bone mineral density. Secondary measures included graft outcome, spinal deformities, fracture rate, body height, and hormonal and metabolic data. Loss of spongy and cortical bone after transplantation was prevented by ibandronate. Changes of bone mineral density (ibandronate versus controls) were as follows: lumbar spine, -0.9 +/- 6.1% versus -6.5 +/- 5.4% (P < 0.0001); femoral neck, +0.5 +/- 5.2% versus -7.7 +/- 6.5% (P < 0.0001); and midfemoral shaft, +2.7 +/- 12.2% versus -4.0 +/- 10.9% (P = 0.024). Fewer spinal deformities developed with ibandronate (7 patients with 7 deformities versus 12 patients with 23 deformities; P = 0.047). Loss of body height was 0.5 +/- 1.0 cm versus 1.1 +/- 1.0 cm in control subjects (P = 0.040). Two bone fractures occurred in each group. There were fewer acute rejection episodes with ibandronate (11 versus 22; P = 0.009). Graft function after 1 yr was comparable. Bone loss, spinal deformation, and loss of body height during the first year after kidney transplantation are prevented by injection of ibandronate at intervals of 3 mo. The smaller number of rejection episodes of the ibandronate-treated group should be confirmed and its mechanism should be explored in additional studies.     

Leptin is a negative independent predictor of areal BMD and cortical bone size in young adult Swedish men.

The association between leptin and areal BMD has been controversial, and the predictive role of leptin on cortical volumetric BMD and bone size has not previously been studied. We show that leptin is a negative independent predictor of aBMD (DXA), at several measured sites, and of cortical bone size (pQCT) in a large population of young men. INTRODUCTION: Recent findings suggest that both adipose tissue (AT) and bone mass are regulated by leptin. Previous reports studying the association between leptin and areal BMD (aBMD) have yielded conflicting results. The role of leptin on volumetric BMD (vBMD) and bone size of the cortical and trabecular bone compartments has not previously been studied. MATERIALS AND METHODS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based study of 1068 men (age, 18.9 +/- 0.6 [SD] years). aBMD of the total body, lumbar spine, femoral neck, both radii, and trochanter, as well as total body AT and lean mass (LM) were measured using DXA, whereas cortical and trabecular vBMD and bone size were measured by pQCT. RESULTS: Total body LM could explain a larger magnitude of the difference in the variation in aBMD and cortical bone size than what total body AT could (total body aBMD: LM 37.4% versus AT 8.7%; tibia cross-sectional area [CSA]: LM 46.8% versus AT 5.6%). The independent role of leptin on bone parameters was studied using a multiple linear regression model, including age, total body LM and AT, height, present physical activity, calcium intake, and smoking as covariates. Leptin was found to be a negative independent predictor of aBMD (total body: beta = -0.08, p = 0.01; lumbar spine: beta = -0.13, p < 0.01; trochanter: beta = -0.09, p = 0.01), as well as of the cortical bone size (CSA and thickness) of both the radius (CSA: beta = -0.12, p < 0.001) and tibia (CSA: beta = -0.08, p < 0.01), but not of the cortical or trabecular vBMD of these bones. CONCLUSION: Our results indicate that LM has a greater impact on bone mass than AT. Our findings further show that leptin is a negative independent predictor of aBMD at several measured sites and of bone parameters reflecting cortical bone size, but not vBMD, in a large population of young Swedish men.     

Bone mineral density in pediatric transplant recipients

BACKGROUND: Reduced bone mass and fragility fractures are known complications after transplantation in adults. Far less is known about the skeletal effects of transplantation in children and adolescents. METHODS: This cross-sectional study examined the skeletal status of children (ages 9-18 years) who were at least 1 year post-cardiac (n=13), post-renal (n=8), or post-bone marrow (BMT; n=15) transplantation. Bone mass at total hip, femoral neck, spine (L2-4), and whole body (WB) was determined by dual energy x-ray absorptiometry and compared with age, sex, and ethnic-specific reference data. Standard deviations (z-scores) were calculated for both areal bone mineral density (BMD) and estimated volumetric bone density (bone mineral apparent density [BMAD]). RESULTS: Cardiac transplant patients had significantly lower BMD z-scores compared with the reference population at all skeletal sites. BMT recipients had significantly reduced BMD z-scores at total hip, spine, and WB. Kidney transplant patients had a significantly reduced WB BMD z-score only. Spine BMAD z-scores remained significantly reduced in cardiac and BMT subjects. Three of 36 patients had radiographic evidence of spinal fracture after transplantation. No correlation between steroid dosage and any measure of bone mass was observed. CONCLUSIONS: Cardiac and BMT recipients had reduced BMD at multiple skeletal sites, and renal transplant recipients had reduced WB BMD for age. Deficits in spine bone density persisted after correcting for small bone size using BMAD. Low bone density and the occurrence of vertebral fractures indicate that cardiac, renal, and bone marrow transplantation in children is associated with reduced bone health.     

Age-related changes in trabecular architecture differ in female and male C57BL/6J mice.

We used microCT and histomorphometry to assess age-related changes in bone architecture in male and female C57BL/6J mice. Deterioration in vertebral and femoral trabecular microarchitecture begins early, continues throughout life, is more pronounced at the femoral metaphysis than in the vertebrae, and is greater in females than males. INTRODUCTION: Despite widespread use of mice in the study of musculoskeletal disease, the age-related changes in murine bone structure and the relationship to whole body BMD changes are not well characterized. Thus, we assessed age-related changes in body composition, whole body BMD, and trabecular and cortical microarchitecture at axial and appendicular sites in mice. MATERIALS AND METHODS: Peripheral DXA was used to assess body composition and whole body BMD in vivo, and microCT and histomorphometry were used to measure trabecular and cortical architecture in excised femora, tibia, and vertebrae in male and female C57BL/6J mice at eight time-points between 1 and 20 mo of age (n = 6-9/group). RESULTS: Body weight and total body BMD increased with age in male and female, with a marked increase in body fat between 6 and 12 mo of age. In contrast, trabecular bone volume (BV/TV) was greatest at 6-8 wk of age and declined steadily thereafter, particularly in the metaphyseal region of long bones. Age-related declines in BV/TV were greater in female than male. Trabecular bone loss was characterized by a rapid decrease in trabecular number between 2 and 6 mo of age, and a more gradual decline thereafter, whereas trabecular thickness increased slowly over life. Cortical thickness increased markedly from 1 to 3 mo of age and was maintained or slightly decreased thereafter. CONCLUSIONS: In C57BL/6J mice, despite increasing body weight and total body BMD, age-related declines in vertebral and distal femoral trabecular bone volume occur early and continue throughout life and are more pronounced in females than males. Awareness of these age-related changed in bone morphology are critical for interpreting the skeletal response to pharmacologic interventions or genetic manipulation in mice.     

Bone mineral density in prepubertal obese and control children: relation to body weight,lean mass,and fat mass

The aim of the study was to determine the influence of obesity on bone status in prepubertal children. This study included 20 obese prepubertal children (10.7 +/- 1.2 years old) and 23 maturation-matched controls (10.9 +/- 1.1 years old). Bone mineral area, bone mineral content (BMC), bone mineral density (BMD), and calculation of bone mineral apparent density (BMAD) at the whole body and lumbar spine (L1-L4) and body composition (lean mass and fat mass) were assessed by DXA. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) at the calcaneus were measured with a BUA imaging device. Expressed as crude values, DXA measurements of BMD at all bone sites and BUA (69.30 versus 59.63 dB/MHz, P < 0.01) were higher in obese children. After adjustment for body weight and lean mass, obese children displayed lower values of whole-body BMD (0.88 versus 0.96 g/cm2, P < 0.05) and BMC (1190.98 versus 1510.24 g, P < 0.01) in comparison to controls. When results were adjusted for fat mass, there was no statistical difference between obese and control children for DXA and ultrasound results. Moreover, whole-body BMAD was lower (0.086 versus 0.099 g/cm3, P < 0.0001), whereas lumbar spine BMAD was greater (0.117 versus 0.100 g/cm3, P < 0.001) in obese children. Thus, it was observed that, in obese children, cortical and trabecular bone displayed different adaptation patterns to their higher body weight. Cortical bone seems to enhance both size and BMC and trabecular bone to enhance BMC. Finally, considering total body weight and lean mass of obese children, these skeletal responses were not sufficient to compensate for the excess load on the whole body.     

Lateral spine densitometry is a more sensitive indicator of glucocorticoid-induced bone loss.

Osteoporosis is a common complication of glucocorticoid therapy. Bone density measurement is now commonly used in assessing which steroid-treated patients require specific interventions to reduce fracture risk. The recently developed techniques for the measurement of bone mineral density (BMD) of the vertebral body alone, by dual-energy x-ray absorptiometry (DXA) in the lateral projection, may be particularly useful in this context since steroid-induced bone loss is most marked in trabecular-rich regions like the vertebral body. This possibility has been assessed in the present study by the measurement of BMD in the lateral and anterioposterior (AP) projections in 28 women receiving chronic glucocorticoid treatment. The two BMD measurements were significantly related (r = 0.62, p < 0.001). When expressed in relation to age-appropriate normal values, lateral BMDs were lower than AP BMDs both in percentage terms (70.8 +/- 4.4 versus 90.3 +/- 2.6%, p < 0.001) and in terms of Z scores (-1.42 +/- 0.22 versus -0.91 +/- 0.24, p = 0.027). AP BMD Z scores classified 12 patients as osteopenic, whereas a further 7 were so categorized by lateral BMD Z score. It is concluded that lateral DXA scanning is a more sensitive indicator of glucocorticoid-induced osteopenia than conventional BMD measurement in the AP projection.     

Comparison of the humoral markers of bone turnover and bone mineral density in patients on haemodialysis and continuous ambulatory peritoneal dialysis

Renal osteodystrophy is an important complication in patients with end-stage renal disease on maintenance dialysis. The aim of this study was to compare the biochemical markers of bone formation (serum collagen type I C-terminal propeptide) and resorption (serum deoxypyridinoline - DPD - and pyridinoline - PYR) with the bone mineral density (BMD) at lumbar spine, femoral neck, and forearm in patients with end-stage renal disease on haemodialysis (HD) versus continuous ambulatory peritoneal dialysis (CAPD). Fifty-nine adult patients, 45 on CAPD (18 females, 27 males) and 14 on HD (2 females, 12 males), were studied. The mean age was 44 +/- SEM 1.6 and 54.4 +/- 4.8 years, respectively. No significant differences in serum calcium, phosphorus, creatinine, and parathyroid hormone were found between patients on HD and CAPD in predialysis samples. Serum urea was significantly lower (p = 0.02) in the CAPD group. Serum PYR (nmol/l) and DPD (nmol/l) were significantly higher in patients on HD as compared with those on CAPD: 105 +/- 23.3 versus 43.7 +/- 3.47 (p = 0.007) and 31.0 +/- 2.4 versus 24.4 +/- 1.4 (p = 0.027), respectively. The results were still significantly higher in the HD patients following correction for serum creatinine and body mass index. There was a close correlation between dialysate DPD and creatinine in both dialysis modalities (HD r = 0.9, CAPD r = 0.76). The clearance of DPD did not differ significantly between the CAPD membrane and the HD membrane (p = 0.22). Serum collagen type I C-terminal propeptide was not significantly different between the HD and CAPD patients. The results were unaffected following correction for age and gender. The BMD was measured in 38 (65%) of the patients (HD n = 8, CAPD n = 30) by dual-energy X-ray absorptiometry and expressed as 'Z' scores. This was reduced at all sites in the patients with end-stage renal disease. The BMD was significantly lower at the ultradistal forearm (mostly trabecular bone) in HD patients as compared with CAPD patients (n = 0.02). A similar trend was observed at the lumbar spine, although the results failed to reach significance. In the whole population (n = 38), linear regression analysis revealed a significant negative correlation between BMD at the ultradistal forearm and serum PYR (r = -0.35, p = 0.04) and DPD (r = -0.33, p = 0.049). Combined measurements of BMD and biochemical markers of bone resorption may have potential in the identification of patients at high risk of bone loss who may require further evaluation of bone remodeling by bone histomorphometry.     

Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation.

A significant proportion of patients will be long-term survivors of bone marrow transplantation (BMT) and little is known about their risk of late bony complications. We therefore evaluated bone mineral density (BMD) prior to BMT, post-transplantation changes in BMD, and mechanisms of bone loss in long-term survivors. We performed two analyses. The first was a cross-sectional study of 83 consecutive BMT patients (38 F, 45 M), examining the relationship between BMD and bone turnover, measured immediately prior to transplantation, and a number of disease and patient variables. The second was a prospective study of 39 patients (19F, 20 M) followed for a median of 30 months (range 5-64 months) following either allogeneic (allo, n = 29) or autologous (auto, n = 10) BMT to determine if bone loss was related to treatment of graft versus host disease (GVHD) with glucocorticoids and cyclosporine A, high bone turnover rates, or hypogonadism. Auto BMT recipients acted as a control group for effects of GVHD therapy on BMD. Prior to BMT, spinal and femoral neck (FN) BMDs were 8.6% and 14% lower in female auto BMT recipients than in female allo BMT recipients, respectively (p = 0.12 and p = 0. 003). Urinary bone resorption markers were higher than in normal gender- and age-matched control subjects. Patients treated previously with glucocorticoids also had 8% lower FN BMD. Glucocorticoid-pretreated women with amenorrhoea had lower lumbar spine (LS) and FN BMDs than eumenorrheic women and women receiving HRT. Post-allo BMT, patients lost 11.7% of FN BMD compared with a nonsignificant decrease of 1.1% post-auto BMT (p < 0.001). Spinal BMD and total body bone mineral content (TBBMC) decreased by 3.9% and 3.5%, respectively, post-allo, compared with an increase (1.5%, p = 0.03) or nonsignificant decrease (-3.7%, p = NS), respectively, post-auto BMT. Post-allo BMT bone loss correlated best with the cumulative prednisolone dose at the LS and FN, and with average daily prednisolone dose for TBBMC. At the spine, the rate of bone loss was 4%/10 g of prednisolone, while the rate of bone loss at the FN was greater (9%/10 g of prednisolone). Bone loss was also negatively related to the duration of cyclosporine therapy for GVHD and baseline deoxypyridinoline concentrations. Avascular necrosis of the femoral head occurred in four, and vertebral and rib fractures occurred in one of the allo BMT patients, but in no auto BMT patients. In conclusion, BMT recipients are at risk of osteoporosis secondary to bone loss associated with their underlying illness and/or chemotherapy, particularly in female autograft recipients, and in allograft recipients secondary to GVHD and its treatment.     

Bone density and cortical structure after pediatric renal transplantation

The impact of renal transplantation on trabecular and cortical bone mineral density (BMD) and cortical structure is unknown. We obtained quantitative computed tomography scans of the tibia in pediatric renal transplant recipients at transplantation and 3, 6, and 12 months; 58 recipients completed at least two visits. We used more than 700 reference participants to generate Z-scores for trabecular BMD, cortical BMD, section modulus (a summary measure of cortical dimensions and strength), and muscle and fat area. At baseline, compared with reference participants, renal transplant recipients had significantly lower mean section modulus and muscle area; trabecular BMD was significantly greater than reference participants only in transplant recipients younger than 13 years. After transplantation, trabecular BMD decreased significantly in association with greater glucocorticoid exposure. Cortical BMD increased significantly in association with greater glucocorticoid exposure and greater decreases in parathyroid hormone levels. Muscle and fat area both increased significantly, but section modulus did not improve. At 12 months, transplantation associated with significantly lower section modulus and greater fat area compared with reference participants. Muscle area and cortical BMD did not differ significantly between transplant recipients and reference participants. Trabecular BMD was no longer significantly elevated in younger recipients and was low in older recipients. Pediatric renal transplant associated with persistent deficits in section modulus, despite recovery of muscle, and low trabecular BMD in older recipients. Future studies should determine the implications of these data on fracture risk and identify strategies to improve bone density and structure.     

Mapping quantitative trait loci for vertebral trabecular bone volume fraction and microarchitecture in mice.

BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable; however, little is known about the specific genetic factors regulating trabecular bone. Genome-wide linkage analysis of vertebral trabecular bone traits in 914 adult female mice from the F2 intercross of C57BL/6J and C3H/HeJ inbred strains revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 QTLs associated with each of the traits. Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton. INTRODUCTION: Both cortical and cancellous bone influence the mechanical integrity of the skeleton, with the relative contribution of each varying with skeletal site. Whereas areal BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable, little is known about the genetic determinants of trabecular bone density and architecture. MATERIALS AND METHODS: To identify heritable determinants of vertebral trabecular bone traits, we evaluated the fifth lumbar vertebra from 914 adult female mice from the F2 intercross of C57BL/6J (B6) and C3H/HeJ (C3H) progenitor strains. High-resolution microCT was used to assess total volume (TV), bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp), and number (Tb.N) of the trabecular bone in the vertebral body in the progenitors (n = 8/strain) and female B6C3H-F2 progeny (n = 914). Genomic DNA from F2 progeny was screened for 118 PCR-based markers discriminating B6 and C3H alleles on all 19 autosomes. RESULTS AND CONCLUSIONS: Despite having a slightly larger trabecular bone compartment, C3H progenitors had dramatically lower vertebral trabecular BV/TV (-53%) and Tb.N (-40%) and higher Tb.Sp (71%) compared with B6 progenitors (p < 0.001 for all). Genome-wide quantitative trait analysis revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 quantitative trait loci (QTLs) associated with each of the vertebral trabecular bone traits, exhibiting adjusted LOD scores ranging from 3.1 to 14.4. The variance explained in the F2 population by each of the individual QTL after adjusting for contributions from other QTLs ranged from 0.8% to 5.9%. Taken together, the QTLs explained 22-33% of the variance of the vertebral traits in the F2 population. In conclusion, we observed a complex pattern of genetic regulation for vertebral trabecular bone volume fraction and microarchitecture using the F2 intercross of the C57BL/6J and C3H/HeJ inbred mouse strains and identified a number of QTLs, some of which are distinct from those that were previously identified for total femoral and vertebral BMD. Identification of genes that regulate trabecular bone traits may ultimately yield important information regarding the mechanisms that regulate the acquisition and maintenance of mechanical integrity of the skeleton.     

Differences in anthropometric parameters and the IFG-I-IGFBP3 axis between liver and renal transplant children

BACKGROUND: Growth can be differently altered after liver and renal transplantation (Tx) in childhood. METHODS: We compared graft function, linear growth, immunosuppression and serum IGF-I (RIA) and IGFBP3 (IRMA) concentrations in 15 liver (5.6+/-1.1 years old) and 17 renal (7.4+/-0.1 years old) Tx patients who were followed for 4-6 years. RESULTS: Graft function was normal post-liver Tx, although in renal recipients creatinine clearance decreased significantly during follow-up. Liver Tx children presented an increase in mean height of 0.92+/-0.2 SDS (P<0.01) beyond the 2nd year post-Tx, although in renal Tx patients height SDS did not improve. Immunosuppressive corticoid dosage could be decreased and discontinued in liver Tx patients, while in renal recipients it was maintained between 0.18+/-0.01 and 0.16+/-0.02 mg/kg/day. At 3.7+/-0.4 years post Tx, liver Tx patients presented higher mean serum IGF-I level, lower mean serum IGFBP3 value, leading to a higher mean IGF-I/IGFBP3 molar ratio, P<0.001. CONCLUSIONS: We found that while catch up growth coud be achieved after liver Tx, height SDS did not improve after renal Tx. This may be related to a reduced renal graft function and/or to differences in immunosuppressive corticoid dosage. In children with renal transplants a challenge for the future will reside in making it possible to substitute steroid therapy without altering graft function.     

Fractal analysis of radiographic trabecular bone texture and bone mineral density: two complementary parameters related to osteoporotic fractures.

Trabecular bone microarchitecture and bone mineral density (BMD) are two main factors related to osteoporotic fractures. Currently, however, microarchitecture is not evaluated. We have developed and validated a trabecular bone texture analysis from radiographic images. The objective was to determine if the fractal analysis of texture was able to distinguish osteoporotic fracture groups from control groups, either in vertebrae, hip, or wrist fractures, and to determine if this indicator and BMD were independent and complementary. In this cross-sectional unicenter case-control population study in postmenopausal women, 107 fracture cases were enrolled and age-matched with 197 control cases. This population comprised 40 vertebral fractures (with 70 controls), 30 hip fractures (55 controls), and 37 wrist fractures (62 controls). Hip and lumbar spine BMD were measured by double-energy X-ray absorptiometry. Fractal analysis of texture was performed on calcaneus radiographs and the result was expressed as the H parameter (H = 2-fractal dimension). The H parameter showed a lower value (0.679 +/- 0.053 SD) in fracture cases versus control cases (0.696 +/- 0.030; p = 0.007), the statistical significance persisting after adjustment for age and for lumbar spine (LS) or hip BMD. This result was confirmed in vertebral fractures (p = 0.0001) and hip fractures (p = 0.003) but not wrist fractures (p = 0.07). We determined the threshold between high and low H values and then the odds ratios (OR) of fracture for low H for BMD < or = -2.5 SD in T score and for the combinations of both parameters. The OR of fracture for low H was 1.6 (95% CI, 1.1-2.6). For LS BMD < or = -2.5 SD the OR of 6.1 (3.4-10.8) shifted to 9.0 (4.0-20.4) when we added low H and for hip BMD it shifted from 5.6 (3.3-9.4) to 8.1 (4.0-16.8). In vertebral, hip, and wrist fracture cases the results were also significant. These data have shown that the fractal analysis of texture on calcaneus radiographs can distinguish osteoporotic fracture groups from control groups. This analysis and BMD provide independent and complementary information. These data suggest that we can improve the fracture risk evaluation by adding information related to microarchitecture, derived from analysis of conventional radiographic images.