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 Santos ESPN – Lyon 2008

Control of hyperparathyroidism and growth F Santos ESPN – 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 Guideline 1. Evaluation of Calcium and Phosphorus Metabolism F Santos ESPN – Lyon 2008 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 F Santos ESPN – Lyon 2008

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 Ekim Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol :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. F Santos ESPN – Lyon 2008 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, vant 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 Ekim Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol :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 ) F Santos ESPN – Lyon 2008

Calcitriol (ng/kg/day) 3 times per wk Kuizon B, Goodman WG, Jüppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD Kidney Int 1998; 53: Sixteen prepubertal children 15.1± ± patients PTH = 660±120 Calcitriol: 39.2±7.2 4 patients PTH = 100±30 Calcitriol: 34.5±2.9 Average monthly intact PTH (pg/l) 553± ±109 GROWTH F Santos ESPN – Lyon 2008 Bone biopsy: adynamic disease

Kuizon B, Goodman WG, Jüppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD Kidney Int 1998; 53: r=0.71, p<001 Intermittent calcitriol therapy Daily calcitriol therapy: r = -0.38, p = NS F Santos ESPN – Lyon 2008

Waller SC, Ridout D, Cantor T, Rees L Parathyroid hormone and growth in children with chronic renal failure Kidney Int 2005; 67: patients, 69% males, age (median = 9.9 years; range = years), GFR < 60 ml/min/1.73m 2, no GH per year F Santos ESPN – Lyon 2008 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 Failure Growth in children with chronic renal failure on intermittent versus daily calcitriol Pediatr Nephrol 2003; 18: prepubertal children with GFR 70 pg/ml, 1 year of follow-up, no GH Daily calcitriol Intermittent calcitriol Daily calcitriol Intermittent calcitriol F Santos ESPN – Lyon 2008

Schmitt CP, Ardissino G, Testa S, Appiani AC, Mehls O, The European Study Group on Vitamin D in Children with Renal Failure Growth in children with chronic renal failure on intermittent versus daily calcitriol Pediatr 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 F Santos ESPN – Lyon 2008

NAPRTCS CHRONIC RENAL INSUFFICIENCY 1848 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 922: Unknown 566: < 2 X UNL 360: > 2 X UNL F Santos ESPN – Lyon 2008

Control of hyperparathyroidism and growth F Santos ESPN – Lyon 2008 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

Control of hyperparathyroidism and growth F Santos ESPN – Lyon 2008 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 MatrixMatrix STRUCTURE SYSTEMIC AND LOCAL REGULATION: hormones, growth factors, … Cartilage formation and progression Bone aposition DYNAMICS F Santos ESPN – Lyon 2008

F Santos ESPN – Lyon 2008 PTH Vitamin D – Ca – P metabolism Other hormonal systems UNLIKELY! Direct effects Indirect effects PTH & ENDOCHONDRAL GROWTH

F Santos ESPN – Lyon 2008 Goltzman D, Arch Biochem Biophys 2008 PTH & ENDOCHONDRAL GROWTH

F Santos ESPN – Lyon 2008 BONE REMODELING UNITS Goltzman D, Arch Biochem Biophys 2008 PTH & ENDOCHONDRAL GROWTH BONE RESORPTION BONE FORMATION = BODY STATUS (calcium, vitamin D, IGF-1) FORM OF PTH ADMINISTRATION ?