SYMPOSIUM. Novel aspects of renal bone disease Control of hyperparathyroidism and growth Fernando...

SYMPOSIUM.

Novel aspects of renal bone disease

Control of hyperparathyroidism and growth

Fernando Santos

Hospital Universitario Central de Asturias

University of Oviedo

Oviedo, Spain

F SantosESPN – Lyon 2008



Clinical information

Basic science data on the effect of PTH on longitudinal growth

K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. 2005.

Guideline 1. Evaluation of Calcium and Phosphorus Metabolism


“The relationship among iPTH, PTH fragments, vitamin D therapies, and linear growth needs to be established in children with CKD”

Guideline 14A. Hyperparathyroid (High-Turnover) Bone Disease

“adynamic bone disease appears to be associated with further impairment

in longitudinal growth in children with CKD Stage 5 after treatment with

calcium-containing binders and intermittent calcitriol therapy” (Kuizon BD,

Goodman WG, Juppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth

during intermittent calcitriol therapy in children undergoing CCPD. Kidney Int 1998; 53:205–211)

Guideline 14C. Adynamic Bone Disease

In CKD Stage 5, adynamic bone disease not related to aluminum (as

determined either by bone biopsy or suggested by PTH <150 pg/mL)

should be treated by allowing serum levels of PTH to rise in order to

increase bone turnover. (OPINION)

K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. 2005.


G Klaus, A Watson, A Edefonti, M Fischbach, K Rönnholm, F Schaefer, E Simkova, CJ Stefanidis, V Strazdins, J Vande Walle, C Schröder, A Zurowska · M EkimPrevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 2006 21:151-9

Abstract

The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2–3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.


Recommendation 8

Marked hyperparathyroidism should be prevented in children with CRF prior to dialysis (evidence).

“In children with moderate renal failure (GFR >30 ml/min/1.73 m2) … slight catch-up growth with PTH levels at the upper limit of normal was reported (Waller S, Ledermann S, Trompeter R, van’t Hoff W, Ridout D, Rees L Catch-up growth with normal parathyroid

hormone levels in chronic renal failure. Pediatr Nephrol 2003; 18:1236–1241). In a sub-group analysis, improved growth was restricted to patients with enteral feeding tubes”

G Klaus, A Watson, A Edefonti, M Fischbach, K Rönnholm, F Schaefer, E Simkova, CJ Stefanidis, V Strazdins, J Vande Walle, C Schröder, A Zurowska · M EkimPrevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 2006 21:151-9

Recommendation 9

PTH levels should be kept at two to three times the upper limit of the normal range in end-stage renal disease (evidence)

Low turnover bone disease “may adversely affect growth in dialysed children” (Kuizon BD, Goodman WG, Juppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD. Kidney Int 1998; 53:205–211)


Calcitriol (ng/kg/day)

3 times per wk

Kuizon B, Goodman WG, Jüppner H, Boechat I, Nelson P, Gales B, Salusky IBDiminished linear growth during intermittent calcitriol therapy in children undergoing CCPDKidney Int 1998; 53:205-211

Sixteen prepubertal children

15.1±3.5 38.1±5.4

12 patientsPTH = 660±120Calcitriol: 39.2±7.2

4 patients PTH = 100±30Calcitriol: 34.5±2.9

Average monthly intact PTH (pg/l)

553±101 520±109

GROWTH


Bone biopsy: adynamic disease

Kuizon B, Goodman WG, Jüppner H, Boechat I, Nelson P, Gales B, Salusky IBDiminished linear growth during intermittent calcitriol therapy in children undergoing CCPDKidney Int 1998; 53:205-211

r=0.71, p<001

Intermittent calcitriol therapy

Daily calcitriol therapy: r = -0.38, p = NS


Waller SC, Ridout D, Cantor T, Rees LParathyroid hormone and growth in children with chronic renal failureKidney Int 2005; 67:2338-45

162 patients, 69% males, age (median = 9.9 years; range = 0.3-17.1 years), GFR < 60 ml/min/1.73m2, no GH

per year


Patients with “the highest 1-84 PTH:C-PTH ratio (a marker of bone turnover) grew better than those with the lowest ratio

Schmitt CP, Ardissino G, Testa S, Appiani AC, Mehls O, The European Study Group on Vitamin D in Children with Renal FailureGrowth in children with chronic renal failure on intermittent versus daily calcitriolPediatr Nephrol 2003; 18:440-4

29 prepubertal children with GFR < 40 ml/min/1.73m2 and PTH > 70 pg/ml, 1 year of follow-up, no GH

Daily calcitriolIntermittent calcitriol

Daily calcitriolIntermittent calcitriol


Schmitt CP, Ardissino G, Testa S, Appiani AC, Mehls O, The European Study Group on Vitamin D in Children with Renal FailureGrowth in children with chronic renal failure on intermittent versus daily calcitriolPediatr Nephrol 2003; 18:440-4

“The correlation between PTH and growth was weak for the entire patient group, indicating a relatively small effect of PTH on growth”

“The correlation was only significant in the intermittent group (r=0.73, P<0.01), if both groups were analyzed separately … the correlation was mainly dependent on the 2 patients with the highest PTH. These were the youngest patients with an age below 2 years”

“The correlation between PTH and growth velocity SDS was not significant”


NAPRTCS 2007. CHRONIC RENAL INSUFFICIENCY1848 patients with height Z score <-1.88 and Tanner stage I, II, III at the baseline

“GH utilization was highest at baseline among patients PTH greater

than twice the upper normal limit”

PTH VALUES

922: Unknown

566: < 2 X UNL

360: > 2 X UNL




Some clinical data indicate that oversuppression of PTH

(which means normal values in CKD stage 5) may adversely affect growth

Convincing evidence to sustain the previous statement is still missing



Clinical information

Basic science data on the effect of PTH on longitudinal growth

- Epiphyseal bone

- Stem cells

- Proliferating chondrocytes

- Prehypertrophic chondrocytes

- Hypertrophic chondrocytes

- Metaphyseal bone

GROWTH PLATE

Matrix

STRUCTURE

SYSTEMIC AND LOCAL REGULATION: hormones, growth factors, …

Cartilage formation and progression

Bone aposition

DYNAMICS



PTH

Vitamin D – Ca – P metabolismOther hormonal systems

UNLIKELY!

Direct effectsIndirect effects

PTH & ENDOCHONDRAL GROWTH


Goltzman D, Arch Biochem Biophys 2008



BONE REMODELING UNITSGoltzman D, Arch Biochem Biophys 2008


BONE RESORPTION BONE FORMATION

= ≠

BODY STATUS (calcium, vitamin D, IGF-1)FORM OF PTH ADMINISTRATION

?

SYMPOSIUM. Novel aspects of renal bone disease Control of hyperparathyroidism and growth Fernando...

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