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BONE IN RENAL TRANSPLANTATION

M. COURBEBAISSE,Service de Néphrologie et Dialyses, Hôpital Tenon

NECKER SEMINARS IN NEPHROLOGY, 2011

• Introduction : Epidemiology and Physiopathology of bone loss and fracture after renal transplantation

• Corticosteroid-induced osteoporosis and steroid avoidance or withdrawal

• Bisphosphonates after renal transplantation

• Active and native vitamin D after renal transplantation

• Conclusions and Perspectives

BONE STORY OF A RENAL TRANSPLANT RECIPIENT…

Avascular necrosis

BONE STORY OF A RENAL TRANSPLANT RECIPIENT…

Avascular necrosis

Bilateral arthroplasty

BONE STORY OF THE RENAL TRANSPLANT RECIPIENTS…Incidence of low BMD : 50%

• Immedialtely after transplantation- High dosage of steroid- Persistent abnormalities of

phosphocalcic metabolism

Leidig-Bruckner G. et al. Lancet 2001;357:342

• Stabilization-↓Immunosuppressive treatment- Improvement of phosphocalcic metabolism

• Worsening with chronic renal graft dysfunction….

• Before transplantation : renal osteodystrophy : 50 % Osteitis fibrosa, 30 % : Adynamic renal bone disease, 20 % : Mixed uremic osteodystrophy +/- OsteomalaciaCoco M et al. JASN 2003;14:2669.

CsACsA

M. Bia, Transplantations reviews, 2008; 22 : 52-61

Poor muscle mass

Specific and non specific risk factors

Diuretic treatment :Increased urinaryCa excretion

CsACsA

M. Bia, Transplantations reviews, 2008; 22 : 52-61

Poor muscle mass

Specific and non specific risk factors

Diuretic treatment :Increased urinaryCa excretion

Classical risk factors of low BMD- Age- Low BMI- Menopause- Smoking- Familial history (hip fracture++)

FRACTURE : HIGH RISK AFTER RENAL TRANSPLANTATION

FRACTURE : HIGH RISK AFTER RENAL TRANSPLANTATION

- Most fractures occur during the first 3 years after transplantation (Nisbeth, U., Transplantation, 1999) but the risk remains increased on the long-term (Vautour, L.M., Osteoporos Int, 2004)

→ After renal transplantation: Bad correlation between BMD and fracture risk(Grotz, W.H., Transplantation, 1994; Vautour, L.M., Osteoporos Int, 2004; Durieux, S., Transplantation, 2002)

Bone biopsy after renaltransplantation5.4 ± 0.8 [6 mo-27 year](n= 57)

37% 45%

OsteomalaciaAdynamic renal bone disease

BONE DISEASE AFTER KIDNEY TRANSPLANTATION

-Severe 25OHD deficiency-hypophosphataemia

– Pain

– Invalidity

– Skeletal deformation

– Poor quality of life

– Hospitalizations

– High cost

SEVERE CONSEQUENCES…..

CORTICOSTEROID-INDUCED OSTEOPOROSIS

Maalouf NM, JCEM, 2005

Monier-Faugere et al, JASN 2000

53 renal transplant recipientsBone biopsy after renal transplantation

5.4 ± 0.8 [6 mo‐27 year]

Relationship between cumulative dose of prednisone and bone volume

SteroidNo Steroid

Fracture risk Fracture risk

SteroidNo Steroid

Fracture risk Fracture risk

STEROIDTscore < -1,5 : Increased fracture risk

A dose dependence of fracture risk is observed even forlow doses of oral cortocosteroids

< 2.5 mg/day 2.5‐7,5 mg/day > 7.5 mg/day

RR of Hip fracture

0.99 1.77 2.27

RR of Vertebral fracture

1.55 2.59 5.18

Van Staa TP, JBMR, 2000

Early corticosteroid withdrawal

Withdrawal at 7days

posttransplant(n=191)

5 mg/d after 6months

posttransplant(n=195)

p

OSTEONECROSIS 0 % 2,6 % 0.06

FRACTURE 5.2 % 9.7 % 0.12

OSTEONECROSIS + FRACTURE

5.2 % 11.3 % 0.041

Woodle ES, Ann Surg 2008;248:564.

5 years of follow up

Late low-dose steroid withdrawal increases BMD

Control group Withdrawal group

Time post transplantation (yr) 7.3 (1.0–13.1) 6.5 (1.0–14.7)

Start of the study : Prednisolone dose (mg)

5.9 (0.2) 6.0 (0.3)

Farmer CTK, Am J Transplant 2006(6):2929.

92 RTR, > 1 year post transplant, randomized

One year follow-up

Steroid avoidance or withdrawal and graft survival

Knight SR, Transplantation. 2010 Jan 15;89(1):1-14. Review

• cardiovascular riskHypertension (RR 0.90, p<0.0001) New onset diabetes (RR 0.64, P=0.0006),Hypercholesterolemia (RR 0.76, p<0.0001)

• risk of Acute Rejection (RR 1.56, p<0.0001)•No significant differences in -patient survival-graft survival

META-ANALYSIS: 34 RTCs, including 5,637 patients

Effects of Bisphosphonates

Gennari L et al, Lancet, 2009

37% 45%


Bisphosphonates treatment should be used with caution…

37% 45%


Bisphosphonates treatment should be used with caution…

!! Bisphosphonate treatment

Fan et al, Kidney International, 2000

Femoral neck

Controln = 13

Pamidronaten = 13

Lumbar spine

Bisphosphonates : IV Pamidronate prevents bone loss during the first year after renal transplantation

26 male RTR : randomized to receive either placebo or IV pamidronate (0.5 mg/kg) at thetime of transplantation and again one month later, BMD T0, M3 and M12

- 6.4%- 9%

stable stable

Femoral Neck

Lumbar spine

Fan et al, Kidney International, 2003

-12.3%

-4.64%

stable

stable

4-year data from 17 of the 26 original cohort

Bisphosphonates : pamidronate (T0 and M1) protects femoral neck from significant bone loss over the 4 years after transplantation.

80 RTR, Randomization– Ibandronate : 1 mg IV immediately

before, and 2 mg 3, 6, and 9 mo after transplantation

– Placebo

Grotz W et al. J Am Soc Nephrol 2001;12:1530-7.

Bisphosphonates : Ibandronate (T0 ,M3, M6, M9) protects from significant bone loss, spinal deformation and loss of body height

During the first year after kidneytransplantation Ibandronate also prevents- Spinal deformation - Loss of body height

Lumbar spine

Femoral Neck

Ibandronate

Placebo

Reid DM, Lancet, 2009;373:1253

A single 5 mg IV infusion of zoledronic acid is non-inferior, possibly more effective,and more acceptable than is 5 mg of oral risedronate daily for prevention and

treatment of corticosteroid-associated bone loss

TreatmentSteroid>3 months

PreventionSteroid<3 months

Femoral neck

Lumbar spine

Bisphosphonates and the kidney….

Palmer SC, Cochrane Databse Syt Rev 2007;CD005015.

Pamidronate and Alendronate : collapsing HSFZolendronate : acute tubular necrosisPerazella MA, Kidney Int, 2008

European Best Practice Guidelines :Bisphosphonates Ok if GFR stable and > 50-60 ml/min

Maalouf NM, JCEM, 2005

Calcitriol

?

Influence of calcitriol on corticosteroid-induced osteporosis

Impaired calcitriol production after successful renal transplantationFleseriu M, Osteoporos Int, 2007

+

_

• 40 RTR• Randomization

– Alfacalcidol 0,5 µg/D + 500mg Ca– Placebo + 500 mg Ca

• % change in BMD at 1 year :

El-Agroudy AE. JASN 2003

Preventive treatment : Active vitamin D

Placebo (n = 20)

Alfacalcidol(n = 20)

p

Lumbar spine ‐ 3,2 % + 2,1% p<0,05

Femoral neck ‐ 3,8% + 1,8% p<0,05

Forearm ‐ 1,8 % + 3,2% p<0,05

- Decreased PTH in the treated group

- Similar urinary calcium excretion in both groups

- Similar rate of acute rejection in both groups

2

Courbebaisse M, Transplantation. 2010, 89(2):131-137.

1α-hydroxylase

25-hydroxylase

24-hydroxylase

NATIVE VITAMINE D

25(OH)vit D (ng/ml)

Post-transplant 25OHD insufficiency (< 30 ng/ml)

PREVALENCE• Day 0 : 88% • One year : 89 % • 7 years : 75.5 %

Sadlier, D.M. Clin Transplant, 2007Boudville, N.C. Nephrol Dial Transplant, 2006

CAUSES

• Insufficient intake

• Reduced sun exposure

• Increased 25OHD catabolism

due to 24-hydroxylase activation

(steroid and FGF23)

Prié D, non published data

Bhan, I., Kidney Int, 2006

Wissing, K.M., Transplantation, 2005

Inverse correlation between[25OHD] and [PTH]

Consequences of 25OHD deficiency and insufficiency

(n = 90 RTR, Month 9 post-transplant)

• 250HD insufficiency (<30 ng/ml) causes secondary hyperparathyroidism.

•Severe 25OHD (<10 ng/ml) deficiency causes osteomalacia.

M3 M12transplantation

Exploration 1 GFR (iohexol)25(OH)D, PTH,CaT, P, urinary Ca/creat

M6

25(OH)D, PTHCaT, P, urinaryCa/creat

Exploration 2 GFR (iohexol)25(OH)D, PTH,CaT, P, ,urinaryCa/creat

M4

INTENSIVE TREATMENTCholecalciferol100 000 IU/15 days

MAINTENANCE TREATMENTCholecalciferol100 000 IU/2 months

TREATED GROUP2006

CONTROL GROUP2005

No vitamin D treatment

TREATED AND CONTROL GROUPS TREATED AND CONTROL GROUPSTREATED GROUP

47 adult RTR-[25OHD] < 30 ng/ml-[Ca] < 2.70 mmol/l

49 adult RTR-[25OHD] < 30 ng/ml-[Ca] < 2.70 mmol/l

Courbebaisse M, Kidney Int 2009; 75:646-51.

-25OHD deficiency does not spontaneously normalize in RTR.

- 100 000 UI of CLF every two weeks during 2 months correct 25OHDinsufficiency.

- Maintenance treatment (100 000 UI of CLF every two months) cannot maintain 25OHD ≥ 30 ng/ml in half of patients and should be 100 000 UIevery month.

- In RTR, increasing 25OHD ≥ 30 ng/ml decreases serum PTH level.

- Doses used to correct 25OHD deficiency are safe : no hypercalcaemia, nohyperphosphataemia, no induced hypercalciuria, stable mesured GFR

Treatment of 25OHD insufficiency after renal transplantation

Courbebaisse M, Kidney Int 2009; 75:646-51.

After transplantation : General preventive rules- Steroid avoidance or withdrawal ++++

- Control of hypercalciuria : NaCl and protein intake/avoidance of furosemide- Adequate calcium intake (≥ 1200 mg/jour)

- Replete vitamin D status (25OHD≥30 ng/mL)- Encourage weight-bearing physical activity

First year post transplantation (KDIGO)- BMD

-Serum calcium, Serum phosphate, Serum PTH, Total Alkaline Phosphatases

Before transplantation : Prevention of renal osteodystrophy

BMD> -1.5No fracture history

No osteoporosis risk factorNo hypogonadism

No specific treatment

Other Cases Oral or IV Bisphosphonates-CI : osteomalacia, low bone turn over-GFR<30/ml/min??-Dental care BEFORE initiation

Active form of vitamin D

Treatment of symptomatic hypogonadism

Other Cases

P. Ebeling, J Clin Endocrinol Metab 94: 1483–1490, 2009; KDIGO: Am J Transplant 2009;9(S3):S93-S96; AFSSAPS

Perspective : Anti RANK ligand antibody = DENOSUMAB

Pre osteoclastPre osteoclast

RANKRANK

OsteoblastOsteoblaststromal cellstromal cell

RANKLRANKL

osteoclastosteoclast

OPGOPG



RANKRANK


RANKLRANKL


OPGOPG AntiAnti RANKL AbRANKL Abdenosumabdenosumab



RANKRANK


RANKLRANKL



- Phase 3 clinical trial (FREEDOM) : fractures



RANKRANK


RANKLRANKL




- Sub cutaneous injection every 6 months



RANKRANK


RANKLRANKL




- Sub cutaneous injection every 6 months- Pharmocokinetic and pharmocodynamic

not influenced by GFR++



RANKRANK


RANKLRANKL




- Sub cutaneous injection every 6 months- Pharmocokinetic and pharmocodynamic

not influenced by GFR++- Safety OK

‐RTR, 12‐48 months post‐transplant ‐25OHD< 30 ng/ml

RANDOMIZATION

CLC : 100 000 IU every other week

= intensive treatment(Eq 6600 IU/D)

CLC : 100 000 IU/month= maintenance treatment

(Eq 3300 IU/D)

M2 M24M0

CLC : 12000 IU every other week(Eq 800 IU/D)

CLC 12000 IU/month(Eq 400 IU/D)

Follow‐up= 2 years

Statistical analysis

Inclusion = 1 year

Treated groupn = 320

Control groupn = 320

VITALE : « Etude prospective, multicentrique, randomisée, en double aveugle, évaluant le bénéfice d’un traitement par vitamine D3 chez des patients transplantés

rénaux », Pr. Thervet, Dr. Courbebaisse, PHRC 2010

composite criteria : NODAT Cardiovascular events de novo cancerDeath

‐RTR, 12‐48 months post‐transplant ‐25OHD< 30 ng/ml

RANDOMIZATION

CLC : 100 000 IU every other week

= intensive treatment(Eq 6600 IU/D)

CLC : 100 000 IU/month= maintenance treatment

(Eq 3300 IU/D)

M2 M24M0

CLC : 12000 IU every other week(Eq 800 IU/D)

CLC 12000 IU/month(Eq 400 IU/D)

Follow‐up= 2 years

Statistical analysis

Inclusion = 1 year

Treated groupn = 320

Control groupn = 320

VITALE : « Etude prospective, multicentrique, randomisée, en double aveugle, évaluant le bénéfice d’un traitement par vitamine D3 chez des patients transplantés

rénaux », Pr. Thervet, Dr. Courbebaisse, PHRC 2010

composite criteria : NODAT Cardiovascular events de novo cancerDeath

Among secondary criteria : BMDFractureSerum PTH

THANK YOU FOR YOUR ATTENTION

bone in renal transplantation - nephro … · bone in renal transplantation m. courbebaisse,...

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