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Correlation of Bone Histology with Parathyroid Hormone, Vitamin D3, and Radiology in End-Stage Renal Disease

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Correlation of Bone Histology with Parathyroid Hormone, Vitamin D3, and Radiology in End-Stage Renal Disease Kidney International, Vol. 44 (1993), PP. 1071—1077 Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease ALASTAIR J. HUTCHISON, RIcK W. WHITEHOUSE, HELEN F. BOULTON, JUDY E. ADAMS, E. BARBARA MAWER, TONY J. FREEMONT, and RAM GOKAL Renal Dialysis Unit, Manchester Royal Infirmary, Departments of Diagnostic Radiology, Medicine, and Osteoarticular Pathology, University of Manchester, Oxford Road, Manchester, England, United Kingdom Correlation of bone histology with parathyroid hormone, vitamin D3, times in conjuction with a desfemoxamine mesylate infusion and radiology in end-stage renal disease. We analyzed transiliac bone test), and plain skeletal X-rays (the so-called "skeletal sur- biopsy specimens from 30 end-stage renal failure patients, taken at the time of admission for CAPD training. Results were compared withvey"). However, as pointed out by Malluche and Faugere, values of iPTH, bone alkaline phosphatase, I ,25-dihydroxyvitamin D3, serum biochemical parameters are relatively poor predictors of skeletal survey, quantitative computed tomography (QCT) and singlethe type and severity of bone disease, while information ob- photon absorptiometry (SPA) bone density measurements. Osteitistained from skeletal X-rays is limited and often misleading. In fibrosa was the most common histological diagnosis, present in 15 of the addition most radiologic signs considered to be pathognomonic 30 patients (50%), with eight classified as "severe" and seven as "mild." Eight patients (27%) had adynamic bone lesion, four mixed of severe osteitis fibrosa can be found in any of the three renal osteodystrophy (13%), and two (7%) osteomalacia. The mean age histological types of renal osteodystrophy [1]. of the adynamic group was higher than the osteitis fibrosa group (41 In recent years, other techniques have been developed for 12.1vs. 56 10.2years; P <0.01), and than the mixed group (397.5examining bone disease including measurement of the intact vs. 56 10.2years; P <0.02).Levels of iPTH enabled discrimination between groups, but not between individual patients, and valuesparathyroid hormone molecule by radioimmunoassay [6], se- correlated with bone alkaline phosphatase (r =0.62;P <0.001). rum bone alkaline phosphatase, and measurement of bone Erosion of the terminal phalanges was seen on the plain X-rays of 7 of density and mineral content by single or dual photon densitom- 15 patients with mild or severe OF, and in three patients with another etry, plus quantitative CT scan [7, 8]. We used these non- diagnosis. The majority of patients (>90%) had bone density measure- invasive techniques to measure the above parameters in a group ments within the normal range. No significant correlation existed between QCT or SPA scores and any of the histomorphometricof patients with end-stage renal disease, prior to the start of parameters, or iPTH. We conclude that iP'l'H is the most helpfuldialysis, and compared them with bone histomorphometry, non-invasive investigation in this group of patients. Plain X-ray of the accepted as the 'gold standard' for assessing renal osteodystro- hands is the most useful radiological investigation, but single measure-phy. ments of bone density are not diagnostic. Since hyperparathyroidism, osteomalacia and the adynamic bone lesion might all be expected to lead to a low bone mass, our hypothesis was that patients with these diagnoses may be Abnormalities of mineral metabolism and bone impart signif-readily identifiable by measurements of bone density, and that icant morbidity and mortality to patients with end-stage renalbiochemical markers could then allow differentiation between disease [1]. Renal bone disease has its origins early in thethe groups. Therefore, the aim of our study was to determine course of renal failure [2, 31, so that by the time GFR has fallenthe presence and type of renal osteodystrophy by bone biopsy, to 50% of normal, at least 50% of the patients exhibit abnormaland to correlate the histomorphometric findings with a variety bone histology [1, 4]. In a study of 16 patients with creatinineof non-invasive techniques. clearances between 20 and 59ml/min,Baker et a! found all of them to have abnormal bone histology [5]. Since few of these Methods patients are symptomatic, diagnosis of bone disease has de- Patients pended on routine examination of various biochemical param- eters, and skeletal radiology. Generally available techniques Thirty patients in end-stage renal failure (creatinine clearance include measurement of serum 25-hydroxy-, and 1 ,25-dihy-5mllmin)were enrolled in the study (7 females, 23 males). droxy-vitamin D3, serum parathyroid hormone fragments, totalTheir mean age was 47 (range 25 to 71) years, and the etiology serum alkaline phosphatase, serum aluminum levels (some-of their renal failure was chronic glomerulonephritis six, adult polycystic kidney disease five, hypertension four, chronic py- elonephritis two, diabetes mellitus three, others three, and Received for publication September 21, 1992 unknown seven. Three of the seven female patients were and in revised form July 1, 1993 post-menopausal (aged 52, 54 and 57 years); however, all seven Accepted for publication July 1, 1993 had developed amenorrhea during the course of their chronic © 1993 by the International Society of Nephrology renal failure. Patients had not previously received any renal 1071 1072 Hutchison et a!: Bone histology with PTH, vitamin D3, and radiology replacement therapy, and none had clinical signs or symptomsperformed by single photon absorptiometry (SPA) in the non- of overt bone disease, nor undergone parathyroidectomy. Theirdominant forearm using a Nuclear Data scanner with an 1125 treatment comprised calcium carbonate (2 to 10 g/day) takenradionuclide source [14]. The forearm was placed into a water with meals as a phosphate binder, supplements of iron, vitaminbath and preliminary rectilinear scanning determined the posi- B complex, ascorbic acid, and antihypertensive drugs. Nonetion of the 8 mm gap between the medial cortices of the distal was taking aluminum-containing phosphate binders at the timeradius and ulna, When this site was identified, six rectilinear of starting dialysis, but five had previously taken them forscans were performed distally and six proximally to obtain bone variable periods during the course of their renal failure. mineral density in these two sites. The bone mineral measure- Bone biopsy and radiological examinations were performedment in the proximal site was principally cortical bone and that during the time of admission to the hospital for commencementin the distal site was integral (cortical + trabecular) bone, but of dialysis. With the exceptions of serum iPTH and aluminum,predominantly trabecular. The precision of the SPA measure- quoted results represent means of two samples taken in thement in a general patient population within the department had month before admission. Serum IPTH and aluminum results arebeen previously measured at 1% for the proximal cortical site from single assays of blood taken immediately prior to begin-and 2.8% for the distal integral site. ning peritoneal dialysis. All radiological investigations were reported by one radiolo- The study was approved by the Central Manchester Healthgist (JEA) without prior knowledge of biochemical or histolog- Authority Ethical Committee. ical results. Biochemistry Bone histomorphometry Ionized calcium was determined using a Radiometer ICA2 electrode. An American Monitor parallel analyzer was used to Each patient received a double label with one gram of oral measure serum levels of phosphate (polyvinylpyrrolidone cat-tetracycline on day 1 and day 10. Transiiac bone biopsy was alysed phosphate-molybdate reaction). Serum concentration ofperformed two days after the last tetracycline dose. Eight immunoreactive intact-molecule parathyroid hormone wasmillimeter bone trephines were split longitudinally using a fine measured by immunoradiometric whole molecule "sandwich"jeweler's saw. Each half was embedded in methyl methacry- assay (Nichols Allegro). Aluminum levels were determined bylate. Seven micrometer serial sections were taken from the cut face of each block and three sets of ten step serial sections electro-thermal atomic-absorption spectrometry (Perkin-Elmer Zeeman 3030 with an HGA-600 furnace). The bone isoenzymetaken at 50 pm intervals were stained with von Kossa's stain, of alkaline phosphatase, 25-hydroxy and 1 ,25-dihydroxyvitamintoluidine blue and solachrome azurine. In addition 20 pm D3 were measured by methods already described [9—11]. unstained sections were cut for examination of tetracycline fluorescence in ultraviolet light. Radiology The sections were analyzed histomorphometrically using a Each patient underwent: (1) skeletal survey comprising plainVIDS II image analyzer for the following parameters, which are radiographs of hands, chest/clavicles, lateral lumbar and tho-expressed according to the standardized nomenclature [15]: racic spine, and pelvis. All radiographs were taken by the same(1) Static radiographer. trabecular bone volume (TBV%) BY/TV (2) Measurement of vertebral trabecular bone mineral density osteoid surfaces (OsS%) OS/BY relative osteoid volume (ROV%) OV/BV was performed by quantitative computed tomography (QCT) on mean osteoid thickness (MOT sm) a General Electric 9800 general purpose scanner, using both osteoblastic surfaces (ObS%) ObS/BS single-energy and dual-energy low dose scanning techniques mineralizing surfaces
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