Relationship Between Intact l-84 Parathyroid Hormone and Bone Histomorphometric Parameters in Dialysis Patients Without

Aluminum Toxicity Mei Wang, MD, Gavril Hertz, MD, Donald J. Sherrard, MD, Norma A. Maloney, PhD,

Gino V. Segre, MD, and York Pei, MD

0 Wii ths markedly reduced usage of aluminum salts in renal failure, parathyroid hormone (PTH) has become the major determinant of currently seen bone disease. Clinicians now must consider what PTH level should be sought Too low a level may lead to the aplastic bone lesion (low turnover bone), and too high a level may cause osteltls flbrosa. Furthermore, conventional normal PTH levels may not be a suitable target because of the well- known resistance to PTH In uremic patients. In this report, we derive the PTH levels that best distinguish patis& wfth low and hiih bone formation states from those wlth normal bone formation in a group of 175 dialysll patients without aluminum toxicity. Using bone histological parameters, we propose that ideally PTH levels should bs maintained between 10 pmol/L (100 pg/mL) and 20 to 30 pmol/L (200 to 300 pg/mL) in chronic dialysis patients, levels two to four times the upper limit of values found in normal subjects. 0 19% by the National Kidney Foundation, Inc.

INDEX WORDS: Osteodystmphy; bone; parathyroid hormone; renal failure.

A BNORMALITIES in mineral and bone me- tabolism are among the most important

complications increasing morbidity and im- pairing quality of life in chronic renal failure patients treated with hemodialysis or peritoneal dialysis. These disorders begin early in the course of renal insufficiency and vary in severity. Histo- morphometric analysis, including aluminum staining and tetracycline labeling, is the most re- liable technique for detecting these bone abnor- malities and establishes a basis for treatment, especially because previous reports have high- lighted the histological diversity of bone in dialysis patients.‘” Because even a single bone biopsy pre- sents practical difficulties, however, noninvasive assays, if reliable, would be extraordinarily useful for diagnosing and managing uremic bone disease. Recent studies have demonstrated that serum bone Gla-protein (S-BGP), parathyroid hormone @TH), and alkaline phosphatase (ALP) arc useful markers

From the Department of Medicine, Veterans Administra- tion Hospital and University of Washington, Seattle, WA; the Department of Medicine, Universiv of Toronto, Toronto, Ontario, Canada; and the Endocrine Unit, Massachusetts General Hospital, Boston, MA.

Received March 2, 1995; accepted in revised form May 16, 1995.

Supported by the Research Services of the Department of Veterans Affairs, Seattle, WA; the Ontario Ministry of Health (grant no. 02175), Toronto, Ontario, Canada; and Nichols Institute, San Juan Capistrano, CA.

Address reprint requests to Donald J. Sherrard, MD, VA Medical Center (IIIA), Seattle, WA 98108.

0 1995 by the National Kidney Foundation, Inc. 0272-63&S/95/2605-0022$3.00/O

of bone mmodeling.4~7~‘~‘8 Measurement of colla- gen crosslinks in the urine have also been of value in assessing bone resorption, but such urine mea- surements arc not possible in dialysis patients. We have recently defined criteria for accurately pm- dieting aluminum bone disease without bone bi- opsy, using a combination of plasma aluminum and PTH measurements.7~‘8

We report the relationship between serum lev- els of PTH, BGP, and ALP and histomorphome- tric parameters in 175 dialysis patients who do not have aluminum bone disease (bone surface aluminum [BSA] less than 25%). These data allow identification of the appropriate PTH level for dialysis patients without aluminum toxicity.

METHODS

Patients Between January 1987 and June 1988,445 dialysis patients

were endld in a study designed to characterize renal osteodys- trophy in three hospitals in Toronto. A mom complete descrip- tion of the design, patient management and selection, and data collection for the study was previously reported.’ Among the 445 patients, 269 underwent transihac bone biopsy and were followed for at least 1 year. Only 258 of the 269 patients who had adequate bone biopsy samples and complete biochemical data were included in the study. Patient demographics am shown in Table 1. Bone biopsy was performed after double labeling with tetracycline and declomycin.‘9

Bone Histology Bone specimens were fixed in 10% neutral phosphate-buf-

fered formalin, dehydrated in ethanol, and embedded in methyl methacrylate/glycol methacrylate medium according to methods previously mported.‘~20 Five-micron thick unde- calcified serial sections were stained with a modified Gold-

836 American Jouma/ of Kidney Diseases, Vol26, No 5 (November), 1995: pp 836-844

l-84 PTH AND BONE HlSTOMORPHOMER?lC PARAMETERS 837

Table 1. Demographics of Dialysis Patients et the Time of Bone Biopsy

sex Age (Yrs) Dialysis Modality

Male Female Mean + SD Range HD CAPDIIPD

AL<25%(n=175) 108 67 56 + 16 19-82 66 109 AL 2 25% (n = 83) 48 35 56 5 13 24-78 51 32

ner’s trichrome stain,*’ with aurin tricarboxylic acid ammo- nium salt for ahnninum,2z and a simultaneous coupling azo dye method, using substituted naphthol phosphate and hexa- zotized pararosaniline for acid phosphatase.*’ The unstained section was analyzed under fluorescent illumination for the dynamic measurements.

The patients were assigned to the following groups using criteria previously published’: (1) mild lesion: an increase in osteoid-covered bone surface and bone formation rate (BFW TAr) 2 108 ~mz/mm*/day; (2) aplastic lesion: similar to the mild lesion but BPR < 108 ~mz/mrnZ/day; (3) osteomalacia: an increase in osteoid area (~15%) and BPR < 108 pm*/ mm’/day; (4) osteitis fibrosa: an increase in area of peritra- becular fibrosis (~0.5%) and BPR 2 108/~m*/mmz/day; and (5) mixed uremic osteodystrophy: an increase in both osteoid area (~15%) and fibrosis (~0.5%). Rates of bone formation as defined in this report are considered low if under 108 urn*! mm*/day, normal if 108 to 576, and high if over 576.8 Normal values were obtained from 48 subjects aged 21 to 69 years.

Bone data for static and dynamic parameters are reported using standardized nomenclature and definitions.24 A sum- mary of the abbreviations and definitions of these parameters is presented in Table 2.

In an earlier report’ involving the same patient population used in this study, patients with osteomalacia and aplastic lesions with bone formation < 108 ~mz/mmZ/day and with BSA 2 25% were designated as aluminum bone disease (ABD). Patients were also assigned to this category with low normal BPR (108 to 250 ~m*/mn?/day) and BSA 2 25%. Of the original 258 patients, 65 (25%) were classified as having ABD. There were in addition 18 patients with BSA z 25% but with BPR of 258 to 1,106.

The remaining 175 patients (68%) who had BSA < 25% and low to high BPR exhibited all five histologic types of osteodystrophy. A cutoff of BSA < 25% was chosen because

many previous observations of dialysis patients showed that symptoms related to ABD did not appear until BSA was >25% to 30%.25~z6

Table 2. Summary of Histomorphometric Parameters: Abbreviations and Definitions of Terms

Parameters Definitions

Static parameters Osteoid area (O.Ar%B.Ar) Percentage of total bone that is unmineralized Osteoid surface (OS%BS) Percentage of trabecular bone surface that is covered by osteoid Osteoblast surface (Ob.S%BS) Percentage of tralxcular bone surface that is lined by osteoblasts Osteoblast osteoid (Ob.S%OS) Percentage of osteoid surface that is covered by osteoblasts Eroded surface (ES%BS) Percentage of trabecular bone surface where past destruction occurred

(crenated and no osteoid) or is occurring (with osteoclasts) Osteoclast number (N.Oc/mmBS) Number of osteoclasts lining actively resorbing trabecular bone surface

per millimeter bone surface Fibrosis area (Fb.Ar%T.Ar) Percentage of tissue area (marrow and bone) that is occupied by

fibrosis tissue around the trabecular bone Dynamic parameters

Bone formation rate (BFR/T.Ar) Area of mineral in pm2 deposited per mm2 of tissue area per day; (Tissue referrent) calculated from double and first single tetracycline labels

Bone formation rate (BFWOS) The average amount in pm” of newly mineralized bone made per day (Surface referent) per micrometer of osteoid-covered surface. It was calculated using

double tetracycline labels Mineral apposition rate (MAR) The mean width of mineral in micrometer per day laid down at actively

forming sites of bone Total labeled surface (Tt.LS%BS) The percentage of the total trabecular surface showing double and

single labels Double labeled surface (dLS%BS) The percentage of the total trabecular surface showing double labels Double labeled osteoid (dLS%OS) The percentage of the osteoid surface showing double labels

NOTE. Terns and abbreviations are from Parfitt et aIT

838 WANG ET AL

Table 3. Correlation Coefficients (r values) Between Bone Histological Parameters and Intact Parathyroid Hormone, Bone Gla-protein, and Alkaline Phosphatase in 175 Dialysis Patients

with Bone Aluminum Surface c 25%

Static parameters Osteoid area (O.Ar%B.Ar) Osteoid surface (OS%BS) Osteoblast surface (Ob.S%BS) Osteoblast osteoid (Ob.S%OS) Eroded surface (ES%BS) Osteoclast number (N.Oc/mmBS) Fibrosis area (Fb.Ar%T.Ar)

Dynamic parameters Bone formation rate ~m’?lmm*/day) Bone formation rate bm’/pm/day) Mineral apposition rate @m/day) Total labeled surface (%BS) Double labeled surface (%BS) Double labeled osteoid (%OS)

iPTH (pmol/L) BGP (ng/mL) ALP (NJ/L)

0.298 0.087 0.404 0.252 0.077 0.206t 0.663 0.407 0.646 0.634 0.427 0.586 0.578 0.341 0.446 0.594 0.422 0.463 0.685 0.169$ 0.776

0.709 0.315 0.617 0.648 0.408 0.456 0.415 0.2195 0.318 0.703 0.396 0.575 0.851 0.380 0.502 0.609 0.394 0.406

NOTE. See Table 2 for definition of terms. Unless otherwise noted, all values are significant at P < 0.001. The use of multicomparisons may invalidate the significance of P values > 0.001 in this setting.’

l Not significant. tP<0.006. $ P < 0.025. 5 P < 0.004.

Assays Serum samples for biochemical analysis were collected at

the time of biopsy. Serum intact parathyroid hormone (iPTH) was measured using an immunoradiometric assay with a nor- mal range of 1 to 5.5 pmol/L (10 to 55 pg/mL). PTH values for each patient represent a mean of three to four determina- tions in the year before the bone biopsy. S-BGP level was determined with a sensitive radioimmunoassay, using a rabbit antiserum that cross-reacts with human BGP (Nichols lnsti- tute, San Juan Capistrano, CA) with a normal range of 1.6 to 9.2 ng/mL. ALP analysis was measured by spectrophotom- etry according to Tietz’s modification of the original Bessey, Lowry, and Brock method with p-nitrophenyl phosphate as substrate. Normal values are 25 to 100 IV/L.

Statistical Evaluation Data were analyzed with the SigmaStat software system

(Jandel Scientific, San Rafael, CA) using linear regression, Rruska-Wallis one-way analysis of variance, Dunn’s multiple comparison procedure, and a nonparametric Mann-Whitney rank-sum test.

RESULTS

Table 1 shows that gender and mean age distri- bution are similar in the two groups of patients classified according to BSA < 25% or ~25%. Of 175 patients with BSA < 25%, 62.3% were on continuous ambulatory peritoneal dialysis/

intermittent peritoneal dialysis. In contrast 61.4% of the 83 patients with BSA 2 25% were on hemodialysis.

The aplastic lesion was the most common (5 1%) histological type found in the 175 patients with BSA < 25%, followed by osteitis fibrosa (24%), mild lesion (17%), mixed osteodystrophy (7%), and osteomalacia (1%).

The correlation coefficients between PTH, BGP, and ALP measurements and bone histol- ogy are shown in Table 3. PTH exhibited highly significant correlations (P < 0.001) with the histomorphometric indices, including static parameters (osteoid area, osteoid surface, os- teoblast surface, eroded surface, osteoclast number and fibrosis) and dynamic parameters (bone formation, mineral apposition, total la- beled surface, double-labeled surface, and dou- ble-labeled osteoid). Fig 1 depicts the relation- ship between iPTH and bone formation rate in these 175 patients. There also were highly significant correlations between ALP and bone histology. Although similarly significant corre- lations were found between BGP and most dy- namic and static parameters of bone, there was no correlation between BGP and O.Ar/B.Ar or

l-84 PTH AND BONE HISTOMORPHOMETRIC PARAMETERS 839

OS/BS. Though all these correlations are statis- tically significant, only those with PTH are strong enough to be useful clinically.

To analyze thoroughly the relationship be- tween the biochemical markers and the bone re- modeling process, these 175 patients were grouped according to their BFRs. Low bone for- mation was found in 92 (52%) of the 175 patients (90 patients with the aplastic lesion and one each with osteomalacia and mixed osteodystrophy). Of the 50 patients (29%) with normal BFR, 29 (58%) had a mild lesion, 19 (38%) had osteitis fibrosa, and 2 (4%) had a mixed lesion. Thirty- three patients (19%) had high bone formation, and 23 (70%) of these showed osteitis fibrosa as the predominant lesion, 9 (27%) had mixed osteodystrophy, and 1 (3%) had a mild lesion. Distribution of the different histological types according to BFR is summarized in Table 4.

Analysis of variance showed highly significant differences between these three BFR groups for all static and dynamic parameters except for OS/ BS, which showed no significant difference be- tween the normal and high turnover groups. Ta- ble 5 summarizes the mean (+SD) values of the histomorphometric parameters of the three groups of high, normal, and low turnover. Pa- tients with high BFR had strikingly higher PTH and ALP (P < 0.001) than those with normal or low BFR, but they did not differ in their BGP

250

200 I .

i-=0.7 11 pt0.001

4

I 0 500 1000 1500 2000

BFR (mcm ‘/nun ‘/day)

Fig 1. Correlation between iPTH and bone forma- tion rate in 175 dialysis patients with bone surface aluminum < 25%.

Table 4. Disbibution of Histologic Qroups According to Rate of Bone Formation in 175 Diiiysis Patients

With Bone Surface Aluminum < 25%

High BFR Normal BFR Low BFR (X76) (108-576) ww

(n = 33) (n = 50) (n = 92)

Aplastic 0 0 90 Mild 1 29 0 OF 23 19 0 Mx 9 2 1

OM 0 0 1

Abbreviations: OF, osteitis fibrosa; Mx, mixed uremic osteodystrophy; OM, osteomalacia.

* Bone formation rate ~m2/mm2 tissue area/day) from 48 normal subjects aged 21 to 69 years.

levels. There were highly significant differences (P < 0.001) between normal and low BFR groups in PIT-I and BGP but none for ALP (Table 6).

To evaluate iPTH values for discriminating between the different bone turnover groups, the cumulative frequency of iPTH was plotted for each group. A comparison of patients with low BFR (n = 92) with those having normal BFR (n = 50) showed the curves of the plot intersected at a value of 10 pmol/L; at that point 75% of patients with low BFR had lower PTH and 75% of the normal BFR patients had higher values (Fig 2).

To determine how closely PTH values would predict the aplastic lesion, a receiver operating characteristic curve was constructed (Fig 3).“*** Six decision threshold values for PTH were in- cluded in the plot. For each threshold point below the PTH level, the true positive fraction (sensitiv- ity) or percentage of patients with below-normal bone formation (shown on the ordinate) is plotted against the false-positive fraction (1 - specific- ity) or percentage of the patients with osteitis fibrosa, mixed or mild lesions, and with normal to high BFR. For example, with a PTH threshold of 9 pmol/L, approximately 67% of the aplastic patients would be below the value (true positive), and 10% of the patients with normal to high BFR would be below this value and would be defined as false positives (90% true-negative rate). At 15 pmol/L the true-positive fraction is 91%, the true-negative fraction 82% and the false-positive fraction is 18%. Thus, the true-negative rate (specificity) decreases with an increase in the

840 WANG ET AL

Table 5. Values of Static and Dynamic Parameters in 175 Dialysis Patients Wii Bone Surface Aluminum < 25% Subdivided According to Bone Formation and Their Differences

High BFR (>576) (n = 33)

Dialysis Patients

Normal BFR (108-576) (n = 50)

Low BFR (<108) (n = 92)

Normal Subjects* (n = 84)

Static parameters O.Ar%B.Ar OS%BS Ob.S%BS Ob.S%OS ES%BS Oc.N/mmBS Fb.Ar%T.Ar

Dynamic parameters+ BFR/T.Ar BFFUOS MAR Tt.LS%BS dLS%BS dLS%OS

12.6 + 8.5 58.8 t 14.lT

8.9 2 5.2 15.5 k 8.8 17.8 2 6.3

2.2 ? 1.0 3.35 2 3.21

1,031 k 327 0.424 t 0.164

0.91 ” 0.20 31.8 2 8.9 26.8 5 9.4 47.0 + 16.3

7.4 2 5.3 50.8 + 17.3T

3.3 2 4.1 6.6 2 7.4

12.2 2 6.8 0.9 k 0.6

0.54 2 0.58

309 k 148 0.172 5 0.093

0.80 2 0.16 12.5 t 6.4 10.3 + 5.5 22.1 2 13.5

5.0 -+ 5.2 41.2 2 21.1

0.4 -+- 0.5 1.3 2 2.0 8.3 2 3.1 0.2 2 0.3

0.02 +- 0.10

25.446 2 28.7 303 k 108 0.024 2 0.042 0.393 + 0.130

0.43 2 0.38 0.68 2 0.13 2.2 5 2.7 16.1 k 0.1 1.0 2 1.4 11.5 + 0.1 3.6 2 7.1 57.3 ? 15.0

3.4 2 1.7 19.9 + 7.1

2.3 + 1.8

5.5 2 2.7 0.6 ” 0.2

0

NOTE. Values given as mean 2 SD. See Table 2 for definition of abbreviated terms. Unless otherwise noted, histomorphometric parameters are significantly different (P < 0.001) between the three groups

(Dunn’s multiple comparison test). l Dynamic parameter values are from 48 subjects aged 21-69 years. T No significant difference. * Selection criteria.

true-positive rate (sensitivity). At the low ranges dialysis groups were similar, there appeared to of BFR, discrimination between different types be differences in response to FTH. In Fig 4 and of dialysis was not important because peritoneal Table 7 we present the predictive values, sensi- dialysis and hemodialysis groups had the same tivity, and specificity of various F’TH levels for PTIWBFR correlations. high-turnover disease. In hemodialysis patients,

At higher BFR levels, however, although the the best discrimination is at a PTI-I of 20 pmolk

Table 6. Biochemical Parameters in 175 Dialysis Patients With Bone Surface Aluminum < 25%

Dialysis Patients

High BFR (~576) (n = 33)

Normal BFR (108-576) (n = 50)

Low BFR (<108) (n = 92) Normal Subjects*

iPTH (PM) Mean k SD Range

BGP (@ml) Mean ? SD Range

ALP (IU/L) Mean 2 SD Range

70.12T + 48.47 25.66$ 2 20.36 7.58 k 6.27 20.5-250 1.7-l 00 0.9-36 1 .o-5.5

65.09 + 116.94 40.33$ t 95.19 6.19 5 7.56 - 1 .O-587 - 1 .O-586 -1 .O-32.7 1.6-9.2

206.91T + 156.79 93.24 2 60.39 75.59 ? 41.77 35-809 1.4-293 20-315 25-l 00

* No evidence of metabolic bone disease. t High BFR greater than normal BFR & low BFR (P < 0.001). * Normal BFR greater than low BFR (f < 0.001).

l-84 PTH AND BONE HISTOMORPHOMETRIC PARAMETERS 841

0 Low BFR <Value l Normal BFR >Value

0 IL -JLL,i -----b-L- O 20 40 60 80 100 120

iPTH (PM)

Fig 2. Cumulative frequency plot of IPTH for 92 low-BFR and 50 normal-BFR patients. The plot shows the pmcentage of low-BFR patients with IPTH less than the value shown on the abscissa and ths percent- age of normal-BFR patients whose iPlH were greater than the value on the abscissa.

True Negative Fraction (Specificity) 0.8 0.6 0.4 0.2 0

1 .oo I ’ I

2 0.95 5

2 2 0.90 .

01 z 0.85 0 . iPTH (PM)

0” 5 2 0.80 -

2

$! 0.75 . .A 5 $ a 0.70 .

z 9 & 0.65

0.60 L. 0.0 0.2 0.4 0.6 0.8 1 .o

False Positive Fraction

TPR (%)

60

60

A

l PTH(pm): (A > 10) (B > 20) (C > 30)

4 (D > 40) - E (E > 50)

20 tl

00 0 20 40

FPR (if; 80 100

TPR (%)

tt

D (D > 4oj 40 (E > 50)

20 E

tt

00 0 20 40 60 80 100

FPR (%)

Fig 4. ROC curves for iPTH showing five decision threshold values in (A) 33 hemodiaiysis and (B) 109 peritoneal patients. The true-positive fraction (% of patients with high bone turnover) is plotted against the false-positive fraction (% of patients with low bone turnover).

with a positive predictive value of 82%, a nega- tive predictive value of 91%, and a sensitivity of 88%. In peritoneal dialysis patients, 30 pmol/L would appear to be a better discriminator, with a positive predictive value of 87, a negative pre- dictive value of 95%, and a sensitivity of 68%.

Fig 5 depicts the information as a histogram of the different bone groups as they relate to the PTH levels. Only one osteitis fibrosa patient with normal bone formation had a PTH < 10 pmoY L, whereas only one patient with a low BFR (of 92) had a PTH > 25 pmol/L.

Fig 3. ROC curve for iF+TH showing six decision threshold values in 175 dialysis patients with bone sur- face aluminum < 25%. The true positive fraction (% patients with aplastic lesion -90, osteomalacia -1, and mixed osteodystrophy-1 below the value) is plotted against the false-positive fraction (% patients with os- teitis fibrosa. mixed osteodvstroohv. and mild lesion). - .-_

DISCUSSION

Bone is seriously impacted by the loss of renal function. Despite significant skeletal disease, symptoms do not develop predictably in uremic

842 WANG ET AL

Table 7. Positive Predictive Value, Negative Predictive Value, and Sensitivity of Various iPTH Values in the Prediction of High-Turnover Bone Disease in Dialysis Patients

PTH (pm) PPV (%)

Hemodialysis Patients (n = 66)

NPV (%) Sens (%)

Peritoneal Dialysis Patients (n = 109)

PPV (%) NPV (46) Sens (%)

>I0 62 97 98 30 99 95 >20 82 91 88 55 97 84 >30 83 80 66 87 95 68 >40 93 72 50 100 92 47 >50 100 70.5 44 100 89 21

Abbreviations: PPV, positive predictive value; NPV, negative predictive value; Sens, sensitivity.

patients. In addition, when symptoms do de- toring of calcium metabolism in dialysis patients. velop, they do not closely parallel the severity Although not as specific in delineating what is nor the duration of renal failure, and there are going on, the serum assays described in this and no clinical features distinguishing the various previous reports’.““’ will suffice for most pa- types of bone disease. Bone histology remains tients most of the time. In a previous study, we the gold standard for distinguishing these lesions, described the use of the deferoxamine challenge which may require different approaches to ther- test and intact PTH measurements to reliably pre- apy. dict ABD.’

Although bone biopsy remains of importance for absolute confirmation of specific lesions and clarification of contradictory data, less invasive approaches are important for day-to-day moni-

Using a similar strategy, we report the correla- tions between PTH and other biochemical param- eters with bone histology in dialysis patients who do not have ABD. We have found it useful to divide the patients according to bone turnover status, as reflected by bone formation. Static his- tomorphometric measurements largely reflected the bone formation categories (Table 5), support- ing the concept that these are different lesions. In this categorization, high turnover lesions (high bone formation) include a majority of patients (69.7%) with hyperparathyroid bone disease (os- teitis fibrosa), a significant minority with mixed uremic osteodystrophy (27.3%), and a small group (3%) with the mild lesion. To distinguish these lesions, an iPTH of 20 pmol/L (200 pg/mL) is best in hemodialysis patients, and 30 pmoY L (300 pg/rnL) is superior in peritoneal dialysis patients.

50

1

0 <5 5-<lO lo-<20 20-<30 230 iPTH (pm)

Fig 5. Frequency distribution of 174 dialysis pa- tients with bone surface aluminum < 25% based on histologic classification and PTH. There were 90 aplastic patients (m), 30 mild (B), and 54 OWMX (a) (single osteomalacic patient not included).

At the other extreme, the patients with low turnover conditions (mostly aplastic, with the oc- casional osteomalacic and mixed) are unlikely to benefit from FTH suppression. Conceivably, further PTH suppression could even be harmful. These low-turnover patients generally have low intact PTH levels. Indeed, 91% have a value be- low 15 pmol/L (150 pg/mL), and 99% are below 25 pmovL (250 pg/mL) (Fig 2). A PTH value of 10 pmol/L, however, best distinguishes low-

l-84 PTH AND BONE HISTOMORPHOMETRIC PARAMETERS 843

turnover from normal-turnover lesions (75% of low turnover falling below that value and 75% of normal turnover being above it [Fig 21). At the lower levels of bone formation, dialysis mo- dality did not appear to influence the PTH utility.

From a practical point of view, it appears that with a PTH level below 10 pmol/L, there is no need to consider aggressive action to suppress PTH levels further. Indeed, one might consider decreasing calcitriol and calcium therapy to allow the PTH to increase somewhat, a study in which we are currently engaged. A recent prelim- inary report suggesting that aplastic disorder may be associated with higher long-term morbidity and mortality29 further supports the concept that PTH levels < 10 pmol/L may be harmful in these patients.

Table 7 and Fig 4 offer the clinician the oppor- tunity to use other cutoff values if he or she wishes to improve sensitivity, specificity, or pre- dictive value. For example, if the physician wishes a number that would predict high turnover 100% of the time (positive predictive value), he or she would use a PTH of 40 pmol/L in perito- neal dialysis patients and 50 in hemodialysis pa- tients.

Therapeutic approaches can be guided to some extent by these data. Almost everyone would agree that there is no need to lower PTH below 10 pmol/L. Many would argue that patients who have values < 10 pmol/L should have therapy adjusted to permit the PTH to rise.

At higher values, recommendations are not so clear-cut. Certainly, few would argue with at- tempting to keep the PTH level below 50 pmoY L, but where should the line be drawn? The data define the best discriminators, but clinical care is not so clear-cut. There is no convincing evi- dence that patients with PTH levels between 10 and 20 pmol/L are any better off than patients with levels between 20 and 30 pmol/L. Certainly there will be more patients with high turnover disease in the latter group (Fig 5), but the severity of disease in this group will not be inordinate.“’

Plasma BGP and ALP measurements may also provide a means for evaluating bone homeostasis in some dialysis patients. These biochemical markers, in addition to PTH, showed significant correlations with the bone histomorphometric pa- rameters, especially those involving BFP. BGP and ALP, however, are much less useful to the

clinician and are helpful only as adjuncts to PTH, or in some research studies.

The data reported here are similar to those reported previously by Quarles, Lobaugh, and Murphy.7’ Their study differs somewhat from ours in that they excluded patients with any histo- logical evidence of aluminum, and as a result, they evaluated somewhat fewer patients. We were unable to identify sufficient numbers of pa- tients with absolutely no stainable bone alumi- num and so chose to select patients we had pre- viously identified as not having aluminum bone disease.7-9 Salusky et al also report compatible findings, though their study’* was in a pediatric age-group. In addition, they noted that calcium levels improved the discriminatory value of PTH, a finding we could not confirm. Given these dif- ferences, we still come up with quite similar rec- ommendations.

In this report, we have assessed the use of noninvasive assays in managing renal osteodys- trophy. Of currently available assays, those that measure intact PTH are the most useful. We have identified PTH ranges that are appropriate targets for patient management that will sustain the most normal bone, as assessed histologically. Until the advent of newer therapies that may impact on bone or PTH metabolism or further evolution of renal osteodystrophy,’ these recommendations seem reasonable.

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844 WANG ET AL

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