Forms Of Renal Osteodystrophy Research Articles

ЗНАЧЕНИЕ МЕТОДА РЕНТГЕНОВСКОЙ ДЕНСИТОМЕТРИИ ПРИ ПЛАНИРОВАНИИ ДЕНТАЛЬНОЙ ИМПЛАНТАЦИИ У ЛИЦ СРЕДНЕГО ВОЗРАСТА ПРИ РАЗЛИЧНЫХ ФОРМАХ ПОЧЕЧНОГО ОСТЕОПОРОЗА

The subject of the study is the prospects of implementing the method of X-ray densitometry in preparation for dental implantation (DI) in patients with chronic kidney disease (CKD). 
 The aim of the study was to determine the diagnostic significance of densitometry results (frequency and severity of BMD) in middle-aged patients with various stages of CKD and healthy controls when choosing a method of dental implantation.
 Methodology. We selected 203 ambulatory charts of middle-aged patients which underwent dual-energy X-ray absorptiometry (DXA) with DTX 200 densitometer (Denmark) on the basis of Saratov Regional Center of Osteoporosis Prevention and Treatment and osteoporosis centers. 
 Results and discussion. The somatic pathology of the examined persons was represented by: diseases of cardiovascular system, kidney diseases, rheumatologic diseases, combination of cardiovascular diseases and kidney diseases and cardiovascular and rheumatologic diseases. Data on the periodontal status of those examined were unknown. Twelve groups of examinees were distinguished according to gender, glomerular filtration rate (GFR). Two other gender groups were patients on outpatient hemodialysis. 
 BMD in CHD depends on patient's sex, somatic pathology and the nature of treatment, stage of the disease. As the disease severity increases, the number of patients with normal BMD decreases, the number of patients with low BMD increases, with osteopenia diagnosed in every third of both genders, and osteoporosis (OD) in every third man and every second woman. The pathology itself, regardless of the patient's gender, is of decisive importance in the development of a decreased BMD in patients with somatic pathology. It is important for MDI to distinguish forms of renal osteodystrophy (ROD), but X-ray densitometry cannot distinguish OP from several forms of ROD. 
 Conclusions. In middle-aged individuals, X-ray densitometry should be performed as a mandatory examination for the timely detection of OP. For outpatient dental patients with CKD, we suggest not to test for MPCT by this method prior to MDI.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

Bone Biopsy for Histomorphometry in Chronic Kidney Disease (CKD): State-of-the-Art and New Perspectives.

The use of bone biopsy for histomorphometric analysis is a quantitative histological examination aimed at obtaining quantitative information on bone remodeling, structure and microarchitecture. The labeling with tetracycline before the procedure also allows for a dynamic analysis of the osteoblastic activity and mineralization process. In the nephrological setting, bone biopsy is indicated to confirm the diagnosis of subclinical or focal osteomalacia and to characterize the different forms of renal osteodystrophy (ROD). Even if bone biopsy is the gold standard for the diagnosis and specific classification of ROD, the use of this approach is very limited. The main reasons for this are the lack of widespread expertise in performing or interpreting bone biopsy results and the cost, invasiveness and potential pain associated with the procedure. In this regard, the sedation, in addition to local anesthesia routinely applied in Italian protocol, significantly reduces pain and ameliorates the pain perception of patients. Concerning the lack of widespread expertise, in Italy a Hub/Spokes model is proposed to standardize the analyses, optimizing the approach to CKD patients and reducing the costs of the procedure. In addition, new tools offer the possibility to evaluate the osteogenic potential or the ability to form bone under normal and pathological conditions, analyzing mesenchymal stem cells and their ability to differentiate in the osteogenic lineage. In the same way, circulating microRNAs are suggested as a tool for exploring osteogenic potential. The combination of different diagnostic approaches and the optimization of the bioptic procedure represent a concrete solution to spread the use of bone biopsy and optimize CKD patient management.

Sclerostin and DKK1 circulating levels associate with low bone turnover in patients with chronic kidney disease Stages 3 and 4.

Background Disordered mineral and bone metabolism is a common complication of chronic kidney disease (CKD). Bone biopsy remains the gold standard tool for evaluating renal osteodystrophy (ROD), but it is an invasive procedure. Despite a growing interest in the ability of newer bone biomarkers to discriminate between different forms of ROD, data on pre-dialysis patients are scarce.MethodsA cross-sectional study was conducted in a cohort of 56 patients with CKD Stages 3 and 4. Participants underwent a transiliac bone biopsy after a course of double tetracycline labelling. Circulating levels of Wnt signalling inhibitors sclerostin and Dickkopf-1 (DKK1), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin were measured and correlated with histomorphometric analysis results.ResultsMost patients had abnormal bone histology and low-turnover bone disease was the predominant form of ROD. Characteristics associated with high bone turnover were worse renal function, lower serum calcium and higher intact parathyroid hormone and fibroblast growth factor-23 levels. Patients with low bone turnover, on the other hand, presented with higher sclerostin along with lower DKK1 and sRANKL levels. In the multivariable logistic regression analysis, sclerostin and DKK1 levels were independently associated with low-turnover bone disease.ConclusionsOur results suggest that circulating levels of Wnt signalling inhibitors sclerostin and DKK1 are predictive of low-turnover bone disease in patients not yet on dialysis. Further research is needed to assess the performance of these bone turnover biomarkers, compared with histomorphometric analysis, in the diagnosis and treatment monitoring of ROD.

Safety of denosumab in patients with chronic kidney disease.

Chronic kidney disease (CKD) is associated with bone and mineral disturbances in the form of renal osteodystrophy. The American College of Rheumatology Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis 2017 recommend against treatment with denosumab in adult patients who have received an organ transplant and who are continuing treatment with glucocorticoids due to lack of adequate safety data on infections in adults treated with multiple immunosuppressive agents. Therefore, this study was conducted to compare the safety of denosumab in patients with CKD, especially in a group of patients who received immunosuppressive medications, and to assess the rate of infections in such group in comparison to patients with normal renal function. We retrieved all data of patients who are receiving denosumab in our institute through search in the medical record system (Al-Shifa System). We excluded all patients with malignancy and all patients who were prescribed denosumab but did not receive it. During the period from 2006 to 2018, 314 patients were treated with denosumab therapy. Out of 84 patients who were fulfilling the inclusion criteria, 24 (28.5%) patients had normal kidney function and 60 (71.4%) patients had CKD. Forty-three percent of all patients with CKD developed side effects after taking denosumab. In comparison, only 17% of patients with normal kidney function developed side effects. Of patients with CKD and infections, 50% of them had moderate infections and required admission. Out of these patients, 76% were in immunosuppressive medications and 61% of the patients were receiving steroids more than 2.5 mg per day. Using Chi-square test and the nonparametric independent samples Kruskal-Wallis test, there was a significant association between the dose of steroids and the rate of side effects with a significance level of <0.014 and 0.009, respectively. Hypocalcemia was detected in two patients (3.3%), and they had CKD stage V. Denosumab is associated with increased risk of infection in CKD patients on steroids or multiple immuno-suppressive medications. There was no deterioration in renal function while using denosumab. In this regard, close monitoring of this group of patients is essential, as well as medication adjustments.

P1395FIBROLAST GROWTH FACTOR 21 CORRELATES POSITIVELY WITH AND PREDICTS TO OSTEOPOROSIS IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) has been recognized as a common complication and arises early in the course of CKD. Osteoporosis can be one form of renal osteodystrophy, one component of the bone abnormalities of CKD-MBD. Fibroblast growth factor 21 (FGF21) is increased progressively with a decline of renal function and higher FGF21 levels predict high all-cause mortality in hemodialysis patients. In recent studies, FGF21 has been approved to exert an inverse effect on bone mineral density. Hence, our study was performed to investigate the relationship and role of FGF21 in osteoporosis in our hemodialysis (HD) patients cohort. Method We screened HD patients in Nanjing Zhongda Hospital and The First People’s Hospital of Changzhou according to a strict inclusion criteria and exclusion criteria. We recorded demographic information, blood data before dialysis and serum FGF21, FGF23 levels and measured the CT-attenuation values (in Hounsfield units (HU)) of trabecular bone in L1 on axial images to evaluate the severity of osteoporosis. We used univariate analyses to compare the differences between two groups. Meanwhile, bivariate correlation analyses were performed to assess the correlation of L1 attenuation with serum FGF21, FGF23 and other clinical parameters. Stepwise multivariate linear regression analyses were employed to evaluate variables independently associated with attenuation values. We constructed ROC curves to calculate the AUC and compared the prognostic value of every independently associated factor or united factor to osteoporosis. All analyses were two-tailed, and a P &amp;lt; 0.05 was considered to be statistically significant. SPSS Software, version 18.0 was used for all statistical analyses. Results 339 HD patients from two big HD centers in China that met our standards were screened. The mean age of HD patients was 56.79 ± 15.60 years. 339 HD patients were divided into two groups osteoporosis (n = 98) and non-osteoporosis (n = 241) on the basis of HU level (L1 attenuation ≤ 135 HU). Remarkably, serum FGF21 were higher in osteoporosis compared to non- osteoporosis in HD patients (median 640.86 pg/ml vs. 245.46 pg/ml, P &amp;lt; 0.01). We also divided HD patients into two groups according to tertiles of serum FGF21 levels. Moreover, attenuation levels were negative associated independently with serum FGF21 (r=-0.136, P&amp;lt;0.05). To evaluate the different values of independent associated or united factors in predicting osteoporosis, receiver operating characteristic (ROC) curves was constructed. The area under the curve (AUC) for FGF21 combined with age yielded a marked increment (AUC=0.836, P=0.000) with a good sensitivity (93.8%). Conclusion In conclusion, elevated FGF21 level has a positive relationship with the incidence of osteoporosis in HD patients. Simultaneously, FGF21 in combination with age can be a predictive parameter of osteoporosis in HD patients.

We Use Too Much Vitamin D in Hemodialysis Patients

Current Kidney Disease Improving Global Outcomes guidelines for chronic kidney disease-mineral and bone disorder recommend maintaining the PTH level between 2 and 9 times the upper limit of normal. PTH levels function as a surrogate for bone turnover to differentiate forms of renal osteodystrophy. Vitamin D receptor agonists are primarily used to treat osteitis fibrosa in hemodialysis patients. However, there is concern that overtreatment may put HD patients at risk for adynamic bone disease, which has been associated with fracture and vascular calcification. This raises the issue as to whether "we use too much vitamin D in hemodialysis patients."

Bone histomorphometry: a concise review for endocrinologists and clinicians

Bone histomorphometry is a quantitative histological examination of an undecalcified bone biopsy performed to obtain quantitative information on bone remodeling and structure. Labeling agents taken before the procedure deposit at sites of bone formation allowing a dynamic analysis. Biopsy is indicated to make the diagnosis of subclinical osteomalacia, to characterize the different forms of renal osteodystrophy and to elucidate cases of unexplained skeletal fragility. Bone histomorphometric parameters are divided into structural and remodeling subgroups, with the latter being subdivided into static and dynamic categories. Metabolic bone disorders such as osteomalacia, hyperparathyroidism, hypothyroidism, osteoporosis and renal osteodystrophy display different histomorphometric profiles. Antiresorptive and anabolic drugs used for the treatment of osteoporosis also induce characteristic changes in the bone biopsy. Bone histomorphometry is an important research tool in the field of bone metabolism and provides information that is not available by any other investigative approach.

Bone mineral density and bone histomorphometry in children on long-term dialysis

Bone mineral density (BMD) at the lumbar vertebrae (L(1)-L(4)) was assessed by dual-energy X-ray absorptiometry (DXA) in 20 children with chronic kidney disease (CKD) on dialysis, and its results were compared with bone biopsy and biochemical parameters. Biopsy specimens provided evidence of hyperparathyroid bone disease in eight cases (40%), and low bone turnover in 12 (60%). For BMD, expressed as Z-scores relative to normal, median Z-scores were -1.05 (range -2.36 to 1.06) for hyperparathyroid patients and -1.05 (range -4.40 to -0.03) for low bone turnover patients, with no statistical differences between groups (P = 0.512). In relation to BMD, of the whole sample, five (25%) had a Z-score under -2.0. When it was corrected for height, BMD was in the normal range. Additionally, there were no significant differences in single samples of serum calcium, alkaline phosphatase, phosphorus and intact parathyroid hormone (PTH) between groups with high or low bone turnover. Assessment of nutritional status, through height/age, showed that ten patients had Z-scores below -2.0 (median -2.12, range -7.13 to 0.73). In conclusion, renal osteodystrophy (ROD) seems to have a high prevalence among CKD pediatric patients, although only approximately a quarter of them developed changes in BMD. In children with CKD, measurements of bone mineral density may not be used for classification of various forms of ROD.

Bone Health in Chronic Kidney Disease–Mineral and Bone Disease

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis that play an important role in the pathophysiology of renal bone disease. The increased cardiovascular morbidity and mortality observed among patients with CKD has recently been recognized to be associated with these disturbances in mineral metabolism. Thus, disturbances in mineral metabolism observed in renal failure results in a multisystem disorder, making the development of a standardized definition of these disorders a top priority. Therefore, the Board of Directors of Kidney Disease: Improving Global Outcomes proposed to define the broader category of mineral disorders associated with CKD as CKD-mineral and bone disorder (CKD-MBD). This newly proposed definition will include the disorders of mineral metabolism, bone histology (renal osteodystrophy), and the extraskeletal manifestations such as vascular calcification. This new definition and stratification of disease should result in improvement not only in the clinical management of patients but also will facilitate the interpretation and translation of clinical research. Renal osteodystrophy is now considered as 1 component of this disorder and will be defined as a morphologic alteration only, based on unification of the histomorphometric definitions that will include parameters of turnover, mineralization, and volume. An internationally accepted classification system will enable the consensus for bone biopsy evaluation as well as for the role of biomarkers. This article will focus on the newly proposed definitions of bone disease as part of CKD-MBD, based on the complex pathophysiologic process underlying bone disease in CKD stages 2 to 5.

Variant of Adynamic Bone Disease in Hemodialysis Patients: Fact or Fiction?

Adynamic bone disease is a type of renal osteodystrophy characterized by low bone turnover and paucity of bone cells. It was proposed that a new type of this disease featuring high osteoclastic resorption without parathyroid hormone stimulus and designated adynamic bone disease variant occurs in hemodialysis patients. The present study is designed to evaluate the frequency and characteristics of both diseases in a large series of bone biopsy specimens. We reviewed 1,160 bone biopsy specimens from hemodialysis patients. Specimens in which adynamic bone disease was diagnosed were selected and categorized as classic or variant based on osteoclastic surface. In 218 bone biopsy specimens (18.8%), adynamic bone disease was identified, whereas the variant form was identified in 35 specimens (38.8%). Biopsy specimens categorized as the variant form were from patients who were younger and had greater phosphorus and parathyroid hormone levels. Histologically, the variant form presented greater osteoid volume, fibrosis volume, osteoid surface, osteoblast surface, and eroded surface. Similarly, values for all dynamic parameters were greater in the variant group. Osteoclastic surface correlated with phosphorus level, parathyroid hormone level, and osteoblast surface. Age and osteoblast surface were identified as independent determinants of the variant form. Adynamic bone disease variant seems to occur in younger hemodialysis patients with greater levels of parathyroid hormone, which acts on cell-covered bone surfaces. It probably is a transitional phase from low- to high-turnover status, rather than a true entity within the spectrum of renal osteodystrophy.

Inter-method variability in PTH measurement: Implication for the care of CKD patients

The National Kidney Foundation/Kidney-Dialysis Outcome Quality Initiative guidelines recommend to maintain the serum intact parathyroid hormone (PTH) concentration between 150 and 300 ng/l in chronic kidney disease (CKD) stage 5 patients. As these limits were derived from studies that used the Allegro intact PTH assay, we aimed to evaluate whether they were applicable to other PTH assays. We compared the PTH concentrations measured with 15 commercial immunoassays in 47 serum pools from dialysis patients, using the Allegro intact PTH assay as the reference. We also evaluated the recovery of graded amounts of synthetic 1-84 and 7-84 PTH added separately to a serum pool. Although the assays were highly correlated, the concentrations differed from one assay to another. The median bias between the tested assays and the Allegro intact PTH assay ranged from -44.9 to 123.0%. When the PTH concentrations were 150 or 300 ng/l with the Allegro intact PTH assay, they ranged with other assays from 83 to 323 ng/l and from 160 to 638 ng/l, respectively. The tested assays recognized 7-84 PTH with various cross-reactivities, whereas a given amount of 1-84 PTH was recovered differently by these assays. We found important inter-method variability in PTH results owing to both antibody specificity and standardization reasons. The unacceptable consequence is that opposite therapeutic attitudes may be reached in a single patient depending on the PTH assay used. We propose to use assay-specific decision limits for CKD patients, or to apply a correcting factor to the PTH results obtained with a given assay.

La Osteodistrofia Renal y la Paratohormona supresora de la remodelación ósea

Hyperparatiroidism plays a central role in renal osteodystrophy (ROD) in patients with chronic renal failure (CRF). The first plasmatic paratohormone (PTH) determinations back in 1960 were based in radioinmunoanalysis (RIA), using one antibody against the carboxiterminal or middle region of the hormone. In 1987, an inmunometric method (IMA) based on two antibodies, denominated or sandwich assay was introduced, and it is used until today in clinical treatment, guideliness, and investigation of ROD. In the late 1990s, authors detected two inmunoreactive peaks using the traditional method; one of them moved with intact PTH 1-84 and the second peak migrated with the fraction 7-84, which suggested that an important inactive segment was included in the IMA quantifications, increasing the real value of PTH, therefore, exposing the patient to high doses of active vitamin D. This method allowed the separation of a biologically active fraction (CAP-PTH) from a bone-metabolism suppressor fraction (CIP-PTH), maybe associated to the lack of correlation between bone histomorphometry and intact PTH 1-84. The increase of the adynamic form of ROD and the presence of vascular calcifications in uremic adults have been related to high dosis of vitamin D, along with calcium and phosphorus therapies, that were orientated by plasmatic PTH levels until nowadays. The current treatment of ROD must be re-evaluated according to new knowledge, and future laboratory research will allow a better control of this CRF complication.

Race and sex: Predictors of the severity of hyperparathyroidism in peritoneal dialysis patients

Uraemic hyperparathyroidism remains a common clinical problem. Conversely, oversuppression of parathyroid hormone (PTH), particularly in diabetic patients on peritoneal dialysis, has been implicated in low bone turnover disease. Race may also be an important factor determining susceptibility to hyperparathyroidism and the different forms of renal osteodystrophy. These compounding factors that might influence the severity of hyperparathyroidism have been studied in US dialysis and predialysis populations. Dialysis-dependant Africans and Afro-Caribbeans (AC) are known to have higher circulating PTH concentrations than comparable Caucasians (C) but Indo-Asians (IA) living in temperate climates have not been studied. We performed a cross-sectional study of all patients undergoing peritoneal dialysis at St Bartholomew's and The Royal London Hospital on 1 May 2000. The highest historical recorded PTH was recorded with concurrent biochemical and demographic details. Regression models were used for the analysis of covariance and separate manova was performed incorporating the factors that were shown on univariate analysis to be significant. The current study confirmed that in 50 AC patients on peritoneal dialysis, the mean (+/- SEM) peak PTH concentration (93.9 +/- 9.3 pmol/L) was higher than in 148 C (56.7 +/- 4.3 pmol/L) and 67 IA (60.2 +/- 5.7 pmol/L), P < 0.0001 and P < 0.002, respectively. This is despite there being no significant difference in serum calcium concentrations and AC having a lower serum phosphate concentration at the time of peak hyperparathyroidism. There was no significant difference in mean peak PTH concentration between C and IA. Females were also found to have higher peak PTH concentrations, but the presence of diabetes did not influence the peak PTH concentration in this study. Although we have demonstrated that patients of African (but not Asian) descent undergoing peritoneal dialysis have more severe hyperparathyroidism than Caucasians, other studies suggest that Afro-Americans develop low bone turnover at higher PTH. This would suggest that PTH values should be interpreted with care and that bone biopsies to determine histology remain important. It may emerge that there are different optimal PTH concentrations according to race.

Non Invasive Diagnosis to Predict Adynamic Bone Disease in Haemodialysed Patients

Precise evaluation of the underlying type of bone disease in hemodialysed patients frequently requires bone histomorphometry (including static and kinetic variables after double tetracycline labeling) which is an invasive and costly method. Due to the prevalence of adynamic bone disease in hemodialysis patients, different biochemical non invasive markers such as (serum intact osteocalcin, serum intact parathyroid hormone (iPTH) and bone specific alkaline phospha- tase (bAP) have been shown to be helpful in differentiation between low and high bone turnover. Our study was conducted to detect the usefulness of measuring serum intact osteocalcin and its correlation with serum iPTH and bAP to distinguish adynamic bone disease from other forms of renal osteodystrophy in hemodialysed patients. The study included 60 patients and 20 normal control subjects, presented at renal dialysis units, Ain Shams University hospitals. The hemodialysed patients were classified according to the results serum iPTH and bAP into two groups :  Group I : Included 18 patients (30%) with serum iPTH level 150 pg/ml and serum bAP  27 ng/ml.  Group II : Included 42 patients (70%) with serum iPTH level > 150 pg/ml and serum bAP > 27 ng/ml. The serum level of intact osteocalcin was measured for the control group and for all hemodialysed patients. The results revealed highly significant stastical differences in serum level of intact osteocalcin between all patients group and the control subjects being lower in control group. Also, the results revelaed that 30% of all patients group had adynamic bone disease and comparison between serum level of intact osteocalcin in adynamic bone disease group versus other patients group was highly significant, being higher in other patients group. There was no significant difference between adynamic bone disease patients and other patients as regard serum phosphorus, and serum calcium but there was a sigificant difference as regard age, while highly significant difference as regard sex, duration of hemodialysis, serum intact osteocalin, iPTH and bAP. These results suggest that combined estimation of serum iPTH, serum intact osteocalcin, and bAP can provide a useful information on the bone status in uremic patients and repesent reliable non invasive diagnostic tools for the prediction of adynamic bone disease.

Specific measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry

Parathyroid hormone (PTH) measurements serve as a noninvasive, diagnostic tool for the assessment of renal osteodystrophy (ROD). Their value has been questioned following reports indicating that all commercially available intact PTH (I-PTH) assays cross-react with amino terminally truncated PTH fragments. Because these fragments can account for 50% of total PTH, their detection will overestimate the true PTH concentration and may lead to diagnostic inaccuracies. The aim of this study was to evaluate the specific Bio-Intact PTH (1-84) Assay (BI-PTH) in patients with various types of ROD confirmed by bone biopsy. Bone biopsies were taken from 132 patients with chronic kidney disease (CKD) stages 3 to 5, and quantitative bone histomorphometry was done. Plasma PTH levels were measured using both the BI-PTH and I-PTH assays on an automated analyzer. Patients with CKD stages 3/4 and low turnover skeletal lesions had BI-PTH values (pg/mL, mean +/- SD) of 35 (+/-34) and I-PTH values of 59 (+/- 63). Corresponding values for BI-PTH and I-PTH in those with high turnover lesions were 141 (+/-60) and 221 (+/-106). Patients with CKD stage 5 and low turnover skeletal lesions had BI-PTH and I-PTH levels of 51 (+/-38) and 90 (+/-60), respectively, whereas the corresponding results for BI-PTH and I-PTH in those with high turnover lesions were 237 (+/-214) and 461 (+/-437). The areas under the receiver operating characteristic (ROC) curves for distinguishing low turnover from high turnover lesions were 0.94 for BI-PTH and 0.91 for I-PTH in CKD stages 3/4 and 0.86 for BI-PTH and 0.85 for I-PTH in CKD stage 5. Among all patients, BI-PTH levels are approximately 50% lower than I-PTH levels, but the results of the two assays are correlated highly (R2 = 0.92). Plasma PTH measurements using either the BI-PTH or I-PTH assay effectively identify patients with reduced bone turnover and serve to distinguish this subgroup from those with high turnover lesions of renal bone disease. Both assays provide better diagnostic discrimination for this purpose than calculated values for the ratio of PTH (1-84)/amino terminally truncated PTH fragments.

Treatment of osteoporosis in chronic kidney disease and end-stage renal disease

As glomerular filtration rate (GFR) declines from age-related bone loss or disease that specifically induces a decline in GFR, there are a number of metabolic bone conditions that may accompany the decline in GFR. These metabolic bone conditions span a spectrum from mild-to-severe secondary hyperparathyroidism in early stages of chronic kidney disease (CKD) to the development of additional heterogeneous forms of bone diseases each with its distinctly quantitative bone histomorphometric characteristics. Osteoporosis can also develop in patients with CKD and ESRD for many reasons beyond age-related bone loss and postmenopausal bone loss. The diagnosis of osteoporosis in patients with severe CKD or end-stage renal disease (ESRD) is not as easy to do as it is in patients with postmenopausal osteoporosis (PMO)--neither fragility fractures nor The World Health Organization bone mineral density criteria can be used to diagnose osteoporosis in this population since all forms of renal bone disease may fracture or have low "T scores". The diagnosis of osteoporosis in patients with CKD/ESRD must be done by first the exclusion of the other forms of renal osteodystrophy, by biochemical profiling or by double tetracycline-labeled bone biopsy; and the finding of low trabecular bone volume. In such patients, preliminary data would suggest that oral bisphosphonates seem to be safe and effective down to GFR levels of 15 mL/min. In patients with stage 5 CKD who are fracturing because of osteoporosis or who are on chronic glucocorticoids, reducing the oral bisphosphonate dosage to half of its usual prescribed dosing for PMO seems reasonable from known bisphosphonate pharmacokinetics, though we do need better scientific data to fully understand bisphosphonate usage in this population.

Treatment of metabolic bone disease in patients with chronic renal disease: A perspective for rheumatologists

As glomerular filtration rate (GFR) declines from age-related bone loss or disease that specifically induces a decline in GFR, there are a number of metabolic bone conditions that may accompany the decline in GFR. These metabolic bone conditions span a spectrum from mild-to-severe secondary hyperparathyroidism in early stages of chronic kidney disease (CKD) to the development of additional heterogeneous forms of bone diseases each with distinctly quantitative bone histomorphometric characteristics. Osteoporosis can also develop in patients with CKD and end-stage renal disease (ESRD) for many reasons beyond age-related bone loss and postmenopausal (PMO) bone loss. Diagnosing osteoporosis in patients with severe CKD or ESRD is not as easy to do as it is in patients with PMO. The diagnosis of osteoporosis in patients with CKD/ESRD must be done by first excluding other forms of renal osteodystrophy, through biochemical profiling or by double tetracycline-labeled bone biopsy and the finding of low trabecular bone volume. In such patients oral bisphosphonates seem to be safe and effective down to GFR levels of 15 mL/min. In patients with stage 5 CKD, who are fracturing because of osteoporosis or who are on chronic glucocorticoids, reducing the oral bisphosphonate dosage to half of its usual prescribed dosing for PMO seems reasonable from known bisphosphonate pharmacokinetics. However, we need better scientific data to fully understand bisphosphonate usage in this population. This paper deals with the evidence available to understand management of patients with CKD and opinions on what might be a reasonable clinical approach where evidence is currently lacking.

In Memoriam Tribute to Jack W Coburn, MD: 1932–2004

Jack W. Coburn, M.D., one of the leading nephrologists devoted to research in divalent cation and bone metabolism, died suddenly on April 4, 2004. Dr. Coburn was Professor of Medicine at the David Geffen School of Medicine at UCLA and staff nephrologist at the VA Greater Los Angeles Health-Care System-Wadsworth, where he had been chief of nephrology for many years. Dr. Coburn was an important individual in the history of the American Society of Bone and Mineral Research. He began participation at the second Annual Meeting in Washington, D.C. in 1980. In 1981 he was elected to the ASBMR Council and served for three years. He chaired a workshop on Renal Osteodystrophy in 1984 at the sixth Annual Meeting in Hartford, Connecticut. The brilliance of his work in the field of renal osteodystrophy led him to be the first investigator to be presented with the Frederic C. Bartter Award for Research by the Society in 1986. Dr. Coburn was born in Fresno, California on August 6, 1932 and grew up in Sacramento. He graduated from UCLA School of Medicine in 1957 and began his post-graduate training as an intern at UCLA Medical Center. He then spent two years as a medical resident in Seattle at the University of Washington and returned to finish his residency at UCLA. His interest in nephrology led to a research fellowship at the Wadsworth VA Medical Center, a hospital affiliated with UCLA. In 1964 he began his military service and was stationed at Walter Reed Hospital in Washington, D.C. Upon completion, he joined the faculty at UCLA and established a base of clinical and research activity at the Wadsworth VA Medical Center. Except for a sabbatical year, the rest of his academic career was spent at this institution. I met Jack during my internship at the Wadsworth VA Medical Center in 1963. Little did I know what an important role he would play in my future. He was obviously highly intelligent, soft spoken and kind. I had contact with him only while rotating on the nephrology service. You can imagine my surprise and pleasure when he asked me eight years later if I would like him to sponsor me as a VA Clinical Investigator. This allowed me to spend an extra year at the Endocrine Unit of the Massachusetts General Hospital after which I returned to Los Angeles to work with him on renal osteodystrophy. I am sure that my experience was similar to that of the more than 100 trainees that were fortunate to have Jack Coburn as a mentor. Jack Coburn's contributions to the field of renal physiology, renal osteodystrophy and nutrition were broad and truly outstanding. His early research with Charles Kleeman, Shaul Massry and colleagues helped define the complex relationships between calcium, magnesium, phosphate, parathyroid hormone and the kidneys. His collaboration with Anthony Norman produced the first studies to demonstrate the benefits of calcitriol in patients with uremia. Another major interest was in the classification of renal osteodystrophy. This led to the important discovery that aluminum excess was a major factor in the pathogenesis of one form of renal osteodystrophy as well as in the bone disease associated with total parenteral nutrition. Collaborations with Donald Sherrard, Susan Ott, Marvin Ament and Gordon Klein were key to the success of this research. Jack's scientific achievements brought him numerous awards in addition to the Bartter Award. Most recently, he was presented with the Belding H. Scribner Award of the American Society of Nephrology (2003). He particularly enjoyed traveling throughout the world to give invited lectures at universities and meetings. During the past 20 years, Jack devoted considerable time to private practice. He was a consummate and compassionate clinician whose advice was sought by numerous colleagues. Despite the long hours he devoted to patient care, he was able to maintain a strong research activity, and, remarkably, was co-author of more than 80 publications during this time. His most recent efforts were directed towards suppressing secondary hyperparathyroidism by the use of a calcimimetic agent or a vitamin D analog. As recently as May of this year, he was the first author of a study documenting the suppression of parathyroid hormone by doxercalciferol in uremic patients. I am certain that Jack derived great satisfaction from his professional life but I believe equally satisfying was his family life. His wonderful wife Kathy, his lovely daughters, Elizabeth, Laurel and Rachel, his son-in-laws, his nine grandchildren, his mother Eula and sister Sally were a source of great pride and pleasure to him. His family, colleagues and friends feel a great void in his absence. Hopefully, the wonderful memories of this remarkable man will reduce the sadness of his departure.

Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy

HE ABNORMALITIES of the skeleton in chronic kidney disease (CKD), collectively known as renal osteodystrophy, are an important cause of morbidity and decreased quality of life. In the management of patients with kidney disease, it is necessary to have a rational approach to the diagnosis and assessment of renal osteodystrophy in order to devise a treatment plan that hopefully will lead to an improved outcome. In the past, the term renal osteodystrophy was mainly equated only with abnormalities of bone turnover, but as described in the article by Cunningham and Sprague 1 in this same issue, renal osteodystrophy is a complex disorder of compromised bone strength in CKD patients. While osteoporosis is a term used to describe fragile bones prone to fracture in the general population and is most often assessed by dual x-ray absorptiometry (DEXA), renal osteodystrophy should be the principal term to describe fragile bones prone to fracture and other morbidities in CKD. Renal osteodystrophy is a function of bone turnover (assessed by bone biopsy), bone density (assessed by DEXA or quantitative CT [qCT]), and bone architecture, but the principal determinant of bone fragility in CKD is abnormal bone turnover. However, diagnosing and treating bone turnover abnormalities remains challenging. Our discussion group met to assess the current state of knowledge, understand the basis of our current therapy, and identify the information that needs to be gathered to improve the therapy of bone turnover and thereby improve the disorder of renal osteodystrophy. A number of important questions, listed in Table 1, were considered.