Kidney International, Vol. 64, Supplement 87 (2003), pp. S120–S124

New assays for parathyroid hormone (PTH) and the relevanceof PTH fragments in renal failure

WILLIAM G. GOODMAN

Department of Medicine, Division of Nephrology, UCLA School of Medicine, Los Angeles, California

New assays for parathyroid hormone (PTH) and the relevanceof PTH fragments in renal failure.

Background. Immunometric assays for parathyroid hor-mone (PTH) are used extensively to assess bone and mineralmetabolism in patients with end-stage renal disease (ESRD)who are treated with dialysis. Results generally correspond tobone histology as documented by bone biopsy, and they areuseful in monitoring disease progression. Recent work hasshown, however, that older, first-generation immunometricPTH assays detect not only full-length PTH(1-84), but alsoother amino-terminally-truncated PTH fragments (ntPTH)that may have inhibitory effects on bone cell metabolism and/orcontribute to the development of adynamic renal osteodystro-phy. New second-generation immunometric PTH assays, bycontrast, detect PTH(1-84) exclusively. The diagnostic valueof plasma PTH determinations using second-generation immu-nometric PTH assays and the utility of estimates of the concen-tration of ntPTH in plasma in patients with ESRD has beenassessed only recently.

Methods. Results were reviewed from three published stud-ies that examined the relationship between bone histology andplasma PTH levels as measured both by first- and by second-generation immunometric PTH assays in patients with ESRD.In all three studies, the concentration of ntPTH was estimatedfrom the numerical difference between the results obtainedwith each assay and a ratio of PTH(1-84)/ntPTH was calculated.

Results. In one report, all patients with adynamic renal os-teodystrophy had PTH(1-84)/ntPTH ratio values �1.0, al-though some patients with high-turnover skeletal lesions alsohad values �1.0. Estimates of the ratio of PTH(1-84)/ntPTHwere found to be a better predictor of adynamic bone thanPTH values measured by either assay. By contrast, two otherstudies failed to confirm these observations. One made use ofthe same second-generation immunometric PTH assay em-ployed in the original report, whereas the other used a differentassay with similar specificity for PTH(1-84). Plasma PTH levelsobtained by first- and second-generation assays were highlycorrelated in these two independent reports.

Conclusion. Plasma PTH levels, as determined by first-gener-ation and second-generation immunometric assays, are highlycorrelated and have similar diagnostic value for the non-inva-sive assessment of renal osteodystrophy. The contention thatntPTH estimates and values for the PTH(1-84)/ntPTH ratio

Key words: parathroid hormone, end-stage renal disease, renal osteo-dystrophy.

2003 by the International Society of Nephrology

S-120

are useful in the diagnostic assessment of renal osteodystrophyhas yet to be confirmed.

Immunometric assays for parathyroid hormone (PTH)have been used extensively for the past 15 to 20 yearsto assess bone and mineral metabolism in patients withchronic kidney disease [1]. These double antibody sand-wich-type assays circumvent many of the shortcomingsof single-antibody radioimmunoassays (RIAs) used pre-viously, thus making it possible to obtain reliable andreproducible measurements of the concentration of PTHin serum or plasma in those with end-stage renal disease.Several studies of large numbers of patients using quanti-tative bone histomorphometry and tetracycline-basedmeasurements of bone formation have demonstratedthat plasma PTH levels, as determined by immunometricassays, are generally reliable predictors of bone histologyand the underlying type of renal osteodystrophy in pa-tients undergoing either hemodialysis or peritoneal dial-ysis [2–7]. Accordingly, plasma PTH measurements areemployed extensively not only for the initial diagnosisof renal bone disease but also to monitor its evolutionbecause bone biopsy is not used commonly in routineclinical practice.

Despite these findings, certain therapeutic interven-tions such as the use of large intermittent doses ofcalcitriol or other active vitamin D sterols to treat sec-ondary hyperparathyroidism and the use of large oraldoses of calcium as a phosphate-binding agent can dis-rupt the relationship between plasma PTH levels andthe rates of bone formation and turnover in patients withend-stage renal disease [8, 9]. Moreover, recent reportshave led to considerable uncertainty among cliniciansabout the overall validity of plasma PTH measurementsfor the diagnosis and management of renal osteodystro-phy [10, 11]. In part, some of these difficulties are relatedto the introduction of new immunometric PTH assays,which differ fundamentally from those utilized pre-viously, providing substantially different numerical re-sults [12]. Controversy persists, however, about the bio-

Goodman: New assays for PTH and PTH fragments in renal failure S-121

logical significance of several large peptide fragments ofPTH that are present in the circulation both in normalsubjects and in those with renal failure. Some of thesepeptides have been shown to influence bone cell functionand may thus affect skeletal metabolism, but their impor-tance as modifiers of bone formation and turnover inpatients with renal bone disease remains uncertain [11].

Technical details about new immunometric assays forPTH and their use in the clinical management of patientswith chronic renal failure are the primary focus of thecurrent discussion. The role of PTH fragments as poten-tial modifiers of bone metabolism in chronic renal failureis also addressed.

EVOLUTION OF PTH ASSAYS

RIA methods were used almost exclusively in earlyPTH assays [13, 14]. These systems employed single anti-bodies directed at epitopes located in the mid- or car-boxy-terminal regions of the hormone in competitivedisplacement assays with isotopically labeled peptides,usually highly purified full-length PTH or synthetic PTHfragments. Because the portions of the molecule targetedby these antibodies were some distance from the amino-terminal end, most RIAs for PTH cross-reacted with, andthus detected a variety of amino-terminally-truncatedPTH-derived peptides, or carboxy-terminal fragments,as well as the full-length hormone comprised of 84 aminoacids, or PTH(1-84).

Most, if not all, amino-terminally-truncated PTH frag-ments have generally been thought to lack biologicalactivity because they do not contain the amino-terminalportion of the hormone responsible for binding to andactivating the type 1 PTH receptor, or PTH1R. Some ofthese peptide fragments arise from the degradation ofPTH(1-84) within parathyroid cells, whereas others aregenerated by the metabolism of PTH(1-84) in peripheraltissues, most notably liver [15, 16]. They are removedfrom the circulation predominantly by glomerular filtra-tion and thus accumulate in the plasma of patients withrenal failure [16–18]. Because these peptide fragmentswere detected by conventional RIAs for PTH, plasmaPTH values were commonly elevated, frequently mark-edly so, in patients with end-stage renal disease. Mea-surements often were not reproducible, and values failedto consistently predict the underlying type of renal bonedisease [19, 20].

The subsequent development of immunometric PTHassays made it possible to reliably and reproducibly mea-sure the concentration of PTH in serum or plasma inpatients with end-stage renal disease [1, 21]. These assaysutilize two antibodies directed toward distinct epitopesin different portions of the PTH molecule. One antibody,which is tagged with 125I or a chemiluminescent agent,serves to label peptides that are immobilized for quanti-

tation by a second capture antibody attached to a solidphase such as a plastic bead. Only large peptides capableof interacting with both antibodies, presumably PTH(1-84), are measured in immunometric PTH assays. Smallpeptides that lack one or both targeted epitopes are notdetected.

Until recently, immunometric PTH assays were thoughtto detect predominantly full-length, biologically activePTH(1-84). It is now apparent, however, that severalwidely utilized immunometric PTH assays detect one ormore peptides distinct from PTH(1-84) [12, 22, 23]. Someof these run on high-performance liquid chromatographyat the same position as synthetic PTH(7-84) [22, 24, 25].Thus, first-generation immunometric PTH assays overes-timate the concentration of PTH(1-84) in serum or plasma.In contrast, recently developed second-generation im-munometric PTH assays measure PTH(1-84) exclusivelyand do not detect large amino terminally truncated pep-tides such as synthetic PTH(7-84). The specificity of sec-ond-generation immunometric PTH assays for PTH(1-84) is determined by labeling antibodies that are directedtoward epitopes located in the most amino-terminal por-tion of the molecule [12]. Indeed, the capacity for de-tecting synthetic human PTH(1-34) by the labeling anti-body used in one second-generation immunometric PTHassay is eliminated almost completely by deleting thefirst amino acid residue.

The ability to measure PTH(1-84) specifically and ex-clusively represents an important technical advance. Sec-ond-generation immunometric PTH assays should thusprove to be useful in studies designed to better character-ize the physiology of PTH secretion and hormone metab-olism. Ultimately, they may also provide better diagnos-tic discrimination in certain clinical disorders of boneand mineral metabolism, but sufficient data to addressthese issues are not yet available.

The impact of recent advances in PTH assay methodson the diagnosis and management of patients with renalosteodystrophy remains to be determined. It is not yetknown whether second-generation immunometric PTHassays provide additional diagnostic information com-pared to first-generation assays in the biochemical assess-ment of patients with renal osteodystrophy. Consider-able additional work will be required to address thisissue.

Despite the limitations of currently available data, sev-eral reports indicate that plasma PTH values obtainedusing second-generation immunometric assays are highlycorrelated with values determined by first-generationassays [12, 23, 26]. Although there is some variationamong assays from different commercial sources, avail-able results indicate that plasma PTH levels measuredby second-generation immunometric PTH assays are ap-proximately 40% to 50% lower than those determinedusing first-generation assays across a wide range of

Goodman: New assays for PTH and PTH fragments in renal failureS-122

plasma PTH concentrations [11, 12, 23, 26]. Such findingssuggest that PTH(1-84) represents slightly more thanhalf of the immunoreactivity detected by first-generationimmunometric PTH assays. The remainder of the immu-noreactivity detected in first-generation PTH assays re-flects the presence of a variety of amino terminally trun-cated peptide fragments.

PTH MEASUREMENTS AND BONEMETABOLISM IN RENAL FAILURE

The utility of PTH measurements for the diagnosisand management of bone disease in patients with end-stage renal disease depends largely on the extent towhich results have been validated by bone histomorpho-metry. Abundant quantitative histologic data are avail-able from clinical studies of renal osteodystrophy usingfirst-generation immunometric PTH assays, but rela-tively little information is available using second-genera-tion immunometric assays that measure PTH(1-84) ex-clusively. As such, the diagnostic value of recentlyintroduced immunometric PTH assays has yet to be de-termined.

When measured by first generation immunometricassays, plasma PTH levels generally predict the underly-ing type of renal bone disease in patients with end-stagerenal disease who have not been treated with vitamin Dsterols or who are receiving small daily oral doses ofvitamin D, specifically calcitriol [2–7]. Values two- tofour-fold above the upper limit of normal correspond torelatively normal rates of bone formation as documentedby the technique of double tetracycline labeling in bonebiopsy specimens. For the most widely utilized first-gen-eration immunometric assays, plasma PTH levels in pa-tients with normal rates of bone formation usually rangefrom 150 to 250 pg/mL, or 15 to 25 pmol/L. Higher levelsare seen in those with bone biopsy evidence of secondaryhyperparathyroidism, whereas plasma PTH concentra-tions below 150 pg/mL, or 15 pmol/L, suggest the presenceof adynamic renal osteodystrophy. Plasma PTH levels lessthan 100 pg/mL, or 10 pmol/L, provide even strongerbiochemical evidence of adynamic bone, particularly ifserum calcium concentrations are also elevated [3].

It should be recognized, however, that most reportsdescribing the relationship between plasma PTH levelsand bone histology in patients with end-stage renal dis-ease antedate the use of large, intermittent intravenousdoses of vitamin D to treat secondary hyperparathyroid-ism [2–7]. As such, these somewhat dated results maynot accurately reflect the consequences of current thera-peutic strategies on bone formation and turnover in pa-tients with secondary hyperparathyroidism. Large, inter-mittent doses of calcitriol and the use of large oral dosesof calcium to manage phosphorus retention have eachbeen implicated as causes of adynamic renal osteodystro-

phy. Both therapeutic interventions reduce osteoblasticactivity and diminish bone formation in patients under-going long-term dialysis [8, 9, 27, 28]. Indeed, bone for-mation may decrease substantially in some patients withsecondary hyperparathyroidism who are treated withlarge intermittent doses of calcitriol even though plasmaPTH levels remain as high as 400 or 500 pg/mL, or 40or 50 pmol/L [8].

The mechanisms responsible for the disparity betweenplasma PTH levels and bone formation during intermit-tent calcitriol therapy remain uncertain. It may, however,reflect direct inhibitory actions of vitamin D, either aloneor together with vitamin D–associated changes in cal-cium metabolism, on osteoblastic function [8, 9, 27, 28].Such observations underscore the importance of moreprecisely defining the relationship between plasma PTHlevels and bone formation within specific therapeuticcontexts. Although PTH is the predominant regulatorof bone formation and turnover in patients with end-stage renal disease, other factors also affect osteoblasticactivity through PTH-independent pathways [8, 9, 27–29]. Thus, diabetes mellitus, corticosteroid therapy, os-teoporosis, bone aluminum toxicity, and growth hor-mone therapy each directly affect osteoblastic activityand bone formation. Failure to adequately consider theseissues may partially account for results from studies thatchallenge the diagnostic value of first-generation immu-nometric PTH assays as predictors of bone histology inpatients with end-stage renal disease [10].

Three reports have examined the relationship betweenbone histology and plasma PTH levels as determined byfirst-generation and second-generation PTH assays inpatients with renal osteodystrophy [11, 30, 31]. Althoughneither PTH assay was shown to be superior as a pre-dictor of bone histology and bone turnover, technicaldifferences between first- and second-generation PTHassays were used in all three studies to estimate theconcentration of amino terminally truncated PTH pep-tides in plasma. Several reports indicate that amino ter-minally truncated PTH peptides exert inhibitory effectson osteoblasts and other bone cells [32, 33]. Moreover,the accumulation of excess amounts of these peptides hasbeen suggested to contribute to the skeletal resistance toPTH that characterizes end-stage renal disease, possiblyby interacting with a putative C-PTH receptor, distinctfrom PTH1R, which is capable of high-affinity bindingto mid- and/or carboxyterminal regions of the PTH mole-cule [11, 26].

To examine the potential clinical relevance of theseobservations, the concentration of amino terminallytruncated PTH fragments (ntPTH) in plasma was esti-mated by subtracting PTH values obtained using a sec-ond-generation immunometric PTH assay, which detectsPTH(1-84) exclusively, from those determined by a first-generation immunometric PTH assay that detects both

Goodman: New assays for PTH and PTH fragments in renal failure S-123

PTH(1-84) and other relatively large amino terminallytruncated PTH-derived fragments. A ratio depicting therelative abundance of biologically active PTH(1-84) andPTH fragments was also calculated and expressed asPTH(1-84)/ntPTH [11].

In a study of 51 patients with end-stage renal disease,Monier-Faugere et al [11] reported that the PTH(1-84)/ntPTH ratio was a better predictor of adynamic renalosteodystrophy than plasma PTH values measured byeither first-generation or second-generation PTH assays.All patients with adynamic bone had PTH(1-84)/ntPTHvalues �1, although some individuals with high-turnoverskeletal lesions of secondary hyperparathyroidism alsohad PTH(1-84)/ntPTH ratio values that were �1. In con-trast, Coen et al [30] found no relationship betweenvalues for the PTH(1-84)/ntPTH ratio and bone histol-ogy among 35 patients undergoing regular hemodialysis.Values for the PTH(1-84)/ntPTH ratio did not differamong patients with various histologic subtypes of renalosteodystrophy, and the results failed to selectively iden-tify patients with adynamic renal osteodystrophy [30].Similar results were reported by Salusky et al [31] usinga different second-generation immunometric PTH assay.As such, the contention that values for the PTH(1-84)/ntPTH ratio and/or estimates of the abundance of ntPTHin plasma affect bone metabolism in patients with renalosteodystrophy remain unsubstantiated.

Overall, currently available data indicate that second-generation immunometric PTH are similar to first-gen-eration PTH assays in their capacity to discriminatebetween patients with high-turnover or low-turnoverskeletal lesions of renal osteodystrophy. The diagnosticprecision of new PTH assays has not yet been shownto be greater than previously employed immunometricassays in patients with renal bone disease. Results ob-tained using first- and second-generation immunometricPTH assays are highly correlated, and the slope of thisrelationship ranges from approximately 0.5 to 0.6. Thus,values determined by second-generation immunometricPTH assays are usually 50% to 60% of those measuredby first-generation assays. It is possible, therefore, toestimate plasma PTH values that would be expectedusing second-generation immunometric assays in pa-tients with various subtypes of renal osteodystrophybased upon available data using first-generation immu-nometric PTH assays.

The recommended therapeutic target range of 150 to250 pg/mL, or 15 to 25 pmol/L, in patients with end-stage renal disease and relatively normal rates of boneformation as determined by first-generation immunome-tric PTH assays should correspond to values of approxi-mately 75 to 125 pg/mL as measured by second-genera-tion assays. Slightly higher values would be expected ifthe slope of the linear correlation between first- andsecond-generation PTH assays were somewhat greater

[30]. Values above 125 to 150 pg/mL using second-gener-ation PTH assays are likely to be associated with skeletalchanges of secondary hyperparathyroidism, whereas lev-els below 50 to 75 pg/mL would be expected in patientswith adynamic renal osteodystrophy. More definitivestatements about the relationship between plasma PTHlevels as determined by second-generation immunome-tric PTH assays and bone histology in patients with end-stage renal disease must await the results of additionalstudies.

CONCLUSION

New second-generation immunometric PTH assayshave been developed. The assays measure full-lengthbiologically active PTH(1-84) exclusively and do not de-tect amino terminally truncated PTH fragments, a fea-ture that distinguishes them from first-generation immu-nometric PTH assays. Although only a few studies havebeen done, second-generation immunometric PTH assayshave not been shown to be superior to first-generationassays for the diagnostic assessment of patients with re-nal osteodystrophy. Plasma PTH levels obtained usingfirst-generation immunometric PTH assays thus providethe most definitive guide to the management of renalbone disease because they are supported by abundantbone histology data. Additional work is needed to fur-ther characterize the utility of second-generation immu-nometric PTH assays as predictors of bone histology inpatients with end-stage renal disease.

ACKNOWLEDGMENTS

This work was supported in part by the USPHS grants DK-60107 andDK-35423. The author is an Academic Associate of Nichols InstituteDiagnostics.

Reprint requests to William G. Goodman, M.D., Division of Nephrol-ogy, 7-155 Factor Bldg., UCLA Medical Center, 10833 Le Conte Ave.,Los Angeles, California 90095.E-mail: wgoodman@ucla.edu

REFERENCES

1. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al: Highly sensitivetwo-site immunoradiometric assay of parathyrin, and its clinicalutility in evaluating patients with hypercalcemia. Clin Chem33:1364–1367, 1987

2. Sherrard DJ, Hercz G, Pei Y, et al: The spectrum of bone diseasein end-stage renal failure—An evolving disorder. Kidney Int43:436–442, 1993

3. Salusky IB, Ramirez JA, Oppenheim WL, et al: Biochemical mark-ers of renal osteodystrophy in pediatric patients undergoingCAPD/CCPD. Kidney Int 45:253–258, 1994

4. Quarles LD, Lobaugh B, Murphy G: Intact parathyroid hormoneoverestimates the presence and severity of parathyroid-mediatedosseous abnormalities in uremia. J Clin Endocrinol Metab 75:145–150, 1992

5. Cohen-Solal ME, Sebert JL, Boudailliez B, et al: Comparisonof intact, midregion, and carboxy-terminal assays of parathyroidhormone for the diagnosis of bone disease in hemodialyzed pa-tients. J Clin Endocrinol Metab 73:516–524, 1991

6. Torres A, Lorenzo V, Hernandez D, et al: Bone disease in

Goodman: New assays for PTH and PTH fragments in renal failureS-124

predialysis, hemodialysis, and CAPD patients: Evidence of a betterbone response to PTH. Kidney Int 47:1434–1442, 1995

7. Hutchison AJ, Whitehouse RW, Boulton HF, et al: Correlationof bone histology with parathyroid hormone, vitamin D3, and radi-ology in end-stage renal disease. Kidney Int 44:1071–1077, 1993

8. Goodman WG, Ramirez JA, Belin TR, et al: Development ofadynamic bone in patients with secondary hyperparathyroidismafter intermittent calcitriol therapy. Kidney Int 46:1160–1166, 1994

9. Salusky IB, Foley J, Nelson P, Goodman WG: Aluminum accu-mulation during treatment with aluminum hydroxide and dialysisin children and young adults with chronic renal disease. N Engl JMed 324:527–531, 1991

10. Qi Q, Monier-Faugere MC, Geng Z, Malluche HH: Predictivevalue of serum parathyroid hormone levels for bone turnover inpatients on chronic maintenance dialysis. Am J Kidney Dis 26:622–631, 1995

11. Monier-Faugere MC, Geng Z, Mawad H, et al: Improved assess-ment of bone turnover by the PTH-(1–84)/large C-PTH fragmentsratio in ESRD patients. Kidney Int 60:1460–1468, 2001

12. John MR, Goodman WG, Gao P, et al: A novel immunoradiome-tric assay detects full-length human PTH but not amino-terminallytruncated fragments: Implications for PTH measurements in renalfailure. J Clin Endocrinol Metab 84:4287–4290, 1999

13. Berson SA, Yalow RS, Aurbach G, Potts JT, Jr: Immunassayof bovine and human parathyroid hormone. Proc Natl Acad SciUSA 49:613–617, 1963

14. Berson SA, Yalow RS: Immunochemical heterogeneity of para-thyroid hormone in plasma. J Clin Endocrinol Metab 28:1037–1047,1968

15. Segre GV, D’Amour P, Hultman A, Potts JT, Jr: Effects ofhepatectomy, nephrectomy, and nephrectomy/uremia on the me-tabolism of parathyroid hormone in the rat. J Clin Invest 67:439–448, 1981

16. Habener JF, Kemper B, Potts JT, Jr: Calcium-dependent intracel-lular degradation of parathyroid hormone: A possible mechanismfor the regulation of hormone stores. Endocrinology 97:431–441,1975

17. Segre GV, D’Amour P, Potts JT: Metabolism of radioiodinatedbovine parathyroid hormone in the rat. Endocrinology 99:1645–1652, 1976

18. Freitag J, Martin KJ, Hruska KA, et al: Impaired parathyroidhormone metabolism in patients with chronic renal failure. N EnglJ Med 298:29–32, 1978

19. Andress DL, Endres DB, Maloney NA, et al: Comparison ofparathyroid hormone assays with bone histomorphometry in renalosteodystrophy. J Clin Endocrinol Metab 63:1163–1169, 1986

20. Salusky IB, Coburn JW, Brill J, et al: Bone disease in pediatricpatients undergoing dialysis with CAPD or CCPD. Kidney Int33:975–982, 1988

21. Addison J, Hales C, Woodhead J, O’Riordan J: Immunoradio-metric assay of parathyroid hormone. J Endocrinol 49:521–530,1971

22. Lepage R, Roy L, Brossard JH, et al: A non-(1–84) circulatingparathyroid hormone (PTH) fragment interferes significantly withintact PTH commercial assay measurements in uremic samples.Clin Chem 44:805–809, 1998

23. Gao P, Scheibel S, D’Amour P, et al: Development of a novelimmunoradiometric assay exclusively for biologically active wholeparathyroid hormone 1–84: Implications for improvement of accu-rate assessment of parathyroid function. J Bone Miner Res 16:605–614, 2001

24. Brossard JH, Cloutier M, Roy L, et al: Accumulation of a non-(1–84) molecular form of parathyroid hormone (PTH) detectedby intact PTH assay in renal failure: Importance in the interpreta-tion of PTH values. J Clin Endocrinol Metab 81:3923–3929, 1996

25. Brossard JH, Lepage R, Cardinal H, et al: Influence of glomerularfiltration rate on non-(1–84) parathyroid hormone (PTH) detectedby intact PTH assays. Clin Chem 46:697–703, 2000

26. Slatopolsky E, Finch J, Clay P, et al: A novel mechanism forskeletal resistance in uremia. Kidney Int 58:753–761, 2000

27. Andress DL, Norris KC, Coburn JW, et al: Intravenous calcitriolin the treatment of refractory osteitis fibrosa of chronic renal fail-ure. N Engl J Med 321:274–279, 1989

28. Salusky IB, Kuizon BD, Belin T, et al: Intermittent calcitrioltherapy in secondary hyperparathyroidism: A comparison betweenoral and intraperitoneal administration. Kidney Int 54:907–914,1998

29. Salusky IB, Goodman WG: Growth hormone and calcitriol asmodifiers of bone formation in renal osteodystrophy. Kidney Int48:657–665, 1995

30. Coen G, Bonucci E, Ballanti P, et al: PTH 1–84 and PTH “7–84”in the noninvasive diagnosis of renal bone disease. Am J KidneyDis 40:348–354, 2002

31. Salusky IB, Goodman WG, Kuizon BD, et al: Similar predictivevalue of bone turnover using first and second generation immuno-metric PTH assays in dialyzed children. Kidney Int 63:1801–1808,2003

32. Divieti P, John MR, Juppner H, Bringhurst FR: Human PTH-(7–84) inhibits bone resorption in vitro via actions independent ofthe type 1 PTH/PTHrP receptor. Endocrinology 143:171–176, 2002

33. Divieti P, Inomata N, Chapin K, et al: Receptors for the carboxyl-terminal region of pth(1–84) are highly expressed in osteocyticcells. Endocrinology 142:916–925, 2001