BONE IN RENAL TRANSPLANTATION - nephro … · BONE IN RENAL TRANSPLANTATION M. COURBEBAISSE, Service de Néphrologie et Dialyses, Hôpital Tenon NECKER SEMINARS IN NEPHROLOGY, 2011

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


Avascular necrosis

Bilateral arthroplasty


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.

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

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





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

Documents

BONE IN RENAL TRANSPLANTATION - nephro … · BONE IN RENAL TRANSPLANTATION M. COURBEBAISSE, Service de Néphrologie et Dialyses, Hôpital Tenon NECKER SEMINARS IN NEPHROLOGY, 2011