495

61 Transplantation Osteoporosis

Peter R. Ebeling

ABSTRACT

Transplantation is an established therapy for end-stage diseases of the kidney, endocrine pancreas, heart, liver and lung, intestines, and for many hematological disor-ders. Current immunosuppressive regimens with gluco-corticoids and calcineurin inhibitors produce excellent patient and graft survival rates. This has resulted in both increases in transplant numbers and an increased recog-nition of previously neglected long-term complications of transplantation such as fractures and osteoporosis. Both pre-transplantation bone disease and immunosup-pressive therapy result in high bone turnover, rapid bone loss, and increased fracture rates, particularly early after transplantation. The bone health of candidates for organ transplantation should be assessed with bone densitom-etry of the hip and spine. Spinal X-rays should be per-formed to diagnose prevalent fractures. Secondary causes of osteoporosis should be identifi ed and treated. Vitamin D defi ciency should be corrected to achieve a serum 25(OH)D concentration 30 ng/mL or higher. Patients with kidney failure should be evaluated and treated for chronic kidney disease–mineral and bone disorder (CKD–MBD), including renal osteodystrophy. Secondary hyper-parathyroidism, in particular, should be treated.

Treatment is indicated in the immediate post-transplantation period irrespective of bone mineral density, since further rapid bone loss will occur in the fi rst several months after transplantation. The duration of therapy will depend on the type of transplant. Long-

term organ transplant recipients should also have bone mass measurement and treatment of osteoporosis.

Oral and intravenous bisphosphonates are the most promising approach for the management of transplanta-tion osteoporosis and reduction of the number of patients with vertebral fractures following transplantation. Active vitamin D metabolites may have additional benefi ts in reducing hyperparathyroidism, particularly after kidney transplantation.

INTRODUCTION

Transplantation is an established therapy for end-stage diseases of the kidney, endocrine pancreas, heart, liver and lung, intestines, and for many hematological disor-ders. Improved survival rates, due to the addition of cal-cineurin inhibitors, cyclosporine A, and tacrolimus to immunosuppressive treatment, have been accompanied by a greater awareness of the long-term complications of transplantation such as fractures and osteoporosis [1, 2] .

PREEXISTING BONE DISEASE

Chronic k idney d isease Renal osteodystrophy or chronic kidney disease–bone and mineral disorder (CKD-MBD) is the most complex

Abstract 495 Introduction 495 Preexisting Bone Disease 495 Skeletal Effects of Immunosuppressive Drugs 496

Management of Transplantation Osteoporosis 497 Summary and Conclusion 503 Acknowledgments 504 References 504

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. Edited by Clifford J. Rosen.© 2013 American Society for Bone and Mineral Research. Published 2013 by John Wiley & Sons, Inc.

496 Osteoporosis

mass index (BMI) prior to lung transplantation (LT), cho-lestatic liver disease, and older age are important risk factors [11, 12] for osteoporosis.

Chronic r espiratory f ailure Osteoporosis may be most common in patients awaiting lung transplantation. Hypoxia, hypercapnia, smoking, and glucocorticoids all contribute. Fragility fractures are extremely common in cystic fi brosis (CF) because addi-tional risk factors (pancreatic insuffi ciency, vitamin D defi ciency, calcium malabsorption, hypogonadism, genetic factors, and inactivity) exist . Up to 61% of patients with end-stage pulmonary disease have osteoporosis. Chronic glucocorticoid use, low BMI, and decreased pulmonary function are all associated with low BMD [13] .

Candidates for b one m arrow t ransplantation Bone loss in bone marrow transplantation (BMT) recipi-ents is related both to the underlying diseases and to chemotherapeutic drugs. These include glucocorticoid (GC)-induced decreases in bone formation and serum 1,25-(OH) 2 D 3 , as well as hypogonadism secondary to the effects of high-dose chemotherapy, total body irradiation (TBI), and GCs. Women are particularly sensitive to the adverse effects of TBI and chemotherapy on gonadal func-tion. Ovarian insuffi ciency occurs in the majority [14, 15] , although some young, premenarchal women may recover ovarian function. Testosterone levels decline acutely after BMT related to a reduction in luteinizing hormone, then return to normal in most men [16–18] . There may be long-term impairment of spermatogenesis with elevated follicle stimulating hormone (FSH) occur-ring in 47% of men [14, 15] . In patients studied after chemotherapy but before BMT, osteopenia was present in 24% and osteoporosis in 4% [18] .

Candidates for i ntestinal t ransplantation Osteoporosis occurs in 36% of candidates for intestinal transplantation, with age and duration of parenteral nutri-tion being signifi cant risk factors. Bone density at the spine and hip is reduced by about 1.5 standard deviations below normal age- and sex-matched mean levels [19] .

SKELETAL EFFECTS OF IMMUNOSUPPRESSIVE DRUGS

Glucocorticoids Exposure to glucocorticoids (GCs) varies with the organ transplanted and the number of rejection episodes. High doses are commonly prescribed immediately after trans-

form of pre-transplant bone disease. One or more types of bone disease may be present, including osteitis fi brosa cystica as a result of secondary hyperparathyroidism (SHPT), low turnover bone disease (osteomalacia, ady-namic bone disease, or aluminum bone disease), osteo-porosis, mixed bone disease, and β 2 -microglobulin amyloidosis. In addition, hypogonadism, both in men and women, metabolic acidosis, and certain medications (loop diuretics, heparin, warfarin, glucocorticoids, or immunosuppressive agents) also adversely affect bone health. Patients with chronic kidney disease (CKD) who have low bone mineral density (BMD) and bone turnover markers in the upper half of the normal premenopausal range are at the highest risk of fracture [3] .

Adynamic bone disease needs exclusion prior to treat-ment with bisphosphonates, which reduce bone turnover further. It is commonly associated with osteoporosis and occurs early in CKD. On bone histomorphometry, there is a scarcity of bone cells, reduced osteoid thickness, and a low bone formation rate [4] . The factors reducing bone turnover are a low vitamin D system, high phosphate, and FGF-23, which override the stimulatory effect of parathyroid hormone (PTH) in early CKD. The use of cinacalcet, calcium, and calcitriol may also reduce bone turnover. The perturbation in bone turnover in CKD therefore needs careful evaluation before treatment is initiated. Bone histomorphometry is the best method. The combination of a low bone formation marker and a slightly increased or normal PTH level is less specifi c.

In hemodialysis patients, the prevalence of both low BMD and fractures is increased. All skeletal sites are affected, including the spine, hip, and distal radius. Ver-tebral fracture prevalence is as high as 21%, and the rela-tive risk of hip fracture is increased 2-fold to 14-fold. Fracture risk is increased with older age, female gender, Caucasian race [5] , duration of hemodialysis [6] , diabetic nephropathy, peripheral vascular disease [7] , low spine BMD, and low bone turnover states.

Congestive h eart f ailure Osteoporotic BMD affects up to 40% of patients with congestive heart failure (CHF), with a 2.45-fold increase in fracture risk in one study [8] . In another study of patients awaiting heart transplantation, lumbar spine (LS) osteopenia was found in 43%, and osteoporosis in 7% [9] . Mild renal insuffi ciency, vitamin D defi ciency, SHPT, and increased bone resorption markers, and use of loop diuretics may contribute.

End- s tage l iver d isease Osteoporosis and fractures commonly accompany chronic liver disease and low BMD is seen in the majority of patients undergoing liver transplantation. Osteoporosis at the spine or hip has been reported in 11–52% of patients awaiting liver transplantation [1, 10] . Low body

Transplantation Osteoporosis 497

suggest rapamycim inhibits osteoblast proliferation and differentiation [29] , but more clinical data are required.

MANAGEMENT OF TRANSPLANTATION OSTEOPOROSIS

Diagnostic s trategies

Before o rgan t ransplantation All candidates going onto the waiting list for organ trans-plantation should have bone densitometry by dual energy X-ray absorptiometry (DXA) of the hip and spine. Spinal X-rays should be performed to diagnose prevalent frac-tures. Any secondary causes of osteoporosis should be identifi ed and treated. Common secondary causes include hyperparathyroidism, hypogonadism, smoking, use of loop diuretics, low dietary calcium intake, and vitamin D defi ciency (less than 20 ng/mL).

Vitamin D defi ciency may be related to disease-related factors, decreased sunlight exposure and low dietary intakes [30] . Vitamin D defi ciency should be corrected and all patients should receive adequate calcium and vitamin D (1,000–1,300 mg of calcium and at least 800 IU of vitamin D per day). Replacement doses of vitamin D may need to be higher (2,000 IU of vitamin D per day), but should be selected to achieve a 25(OH)D con-centration of 20–30 ng/mL or greater. Patients with kidney failure should be evaluated and treated for renal osteodystrophy and secondary hyperparathyroidism, in particular.

Individuals with osteoporosis awaiting solid organ transplants should be evaluated and treated similarly to others with this condition, with the exception of patients awaiting kidney transplantation, in whom CKD–MBD is more complex. In this group, it is important to diagnose and treat secondary hyperparathyroidism and to exclude adynamic bone disease.

After o rgan t ransplantation Risk factors for post-transplant bone loss and fractures are shown in Table 61.1 . Bone loss is most rapid imme-diately after transplantation. Fractures often occur in the fi rst year after transplantation and may affect patients with either low or normal pre-transplant BMD. There-fore, the majority of patients may benefi t from treatment instituted immediately after transplantation, with excep-tion of patients with CKD–MBD and adynamic bone disease. Patients who present after being transplanted months or years before should also be assessed for treatment.

Vitamin D defi ciency is common post transplantation and in long-term graft recipients. Vitamin D status is partly determined by demographic and lifestyle factors and defi ciency is associated with poorer general health, lower serum albumin levels, and even decreased survival in these groups [30] .

plantation and are weaned rapidly. Doses are increased at the time of rejection episodes. The highest GC-associated rates of bone loss are in the fi rst 3 to 12 months post transplant. Trabecular sites are predominantly affected. The use of calcineurin inhibitors and more recent immu-nosuppressive regimens both have limited GC use. As a result, more recent studies show lower rates of post-transplant bone loss.

However, even small doses of glucocorticoids are asso-ciated with marked increases in fracture risk in epide-miological studies [20] . Glucocorticoids reduce bone formation by decreasing osteoblast replication and dif-ferentiation, and increasing apoptosis. Osteoblast genes including type I collagen, osteocalin, insulin-like growth factors, bone matrix proteins, transforming growth factor β (TGF β ) are downregulated, whereas receptor activator for nuclear factor- κ B ligand (RANKL), is upregulated. Direct and indirect effects of GCs to increase bone resorp-tion also contribute to the rapid increase in fracture risk post transplant. The immediate post-transplant period is characterized by high bone remodeling and increased bone resorption. Hyperparathyroidism may result from GC-induced reductions of intestinal and renal calcium absorption.

More recently, data from the United States Renal Data System have shown the use of early steroid withdrawal after kidney transplantation has been associated with a 31% fracture risk reduction [21] . Fractures associated with hospitalization were also signifi cantly lower with regimens that withdraw corticosteroids. As this study likely underestimated overall fracture incidence, pro-spective studies are needed to determine the differences in overall fracture risk in patients managed with and without corticosteroids after kidney transplantation.

Calcineurin i nhibitors Cyclosporine (CsA) has independent adverse effects to increase bone turnover [22] . Although CsA treatment could result in high bone turnover after transplantation, it is reassuring that kidney transplant patients receiving CsA without GCs [23, 24] do not lose bone, and fractures are also reduced [21] .

Tacrolimus (FK506), another calcineurin inhibitor (CI), also causes trabecular bone loss in the rat [22] . Both cardiac [25] and liver [26] transplant recipients sustained rapid bone loss with tacrolimus. However, tacrolimus may cause less bone loss in humans than CsA [27, 28] and may also protect the skeleton by reducing GC use.

Other i mmunosuppressive a gents Limited information is available regarding the effects of other immunosuppressive drugs on BMD and bone metabolism. However, azathioprine, sirolimus (rapamy-cin), mycophenelate mofetil, and daclizumab may also protect the skeleton by reducing GC use. In vitro studies

498 Osteoporosis

tion have reported osteoporosis in 17–49% at the spine, 11–56% at the femoral neck, and 22–52% at the radius [1] . There is a correlation between cumulative GC dose and BMD. Rates of bone loss are greatest in the fi rst 6–18 months after transplantation, and range from 4% to 9% at the spine and 5% to 8% at the hip. Bone loss has not been consistently related to gender, patient age, cumula-tive GC dose, rejection episodes, activity level, or PTH levels. Although increasing time since transplantation is considered to be a risk factor for low BMD, studies exam-ining BMD after the fi rst year or two do not consistently show ongoing bone loss; however, BMD remains low up to 20 years after transplantation. Secondary HPT and low 1,25(OH) 2 D levels also often persist [3, 33] .

Fractures affect appendicular sites (hips, long bones, ankles, feet) more commonly than axial sites (spine and ribs) [33] . Women and patients transplanted for diabetic nephropathy are at particularly increased risk of frac-tures. The majority of fractures occur within the fi rst 3 years; however, fractures continue to increase the longer the post-transplant period [34] .

Prevention and t reatment Calcium and vitamin D supplementation alone does not prevent bone loss in renal transplant patients [35] . Bisphosphonates reduce bone loss after kidney trans-plantation (KT) [36] . In a small study, the combination of alendronate (10 mg/day), calcium carbonate (2 g/day), and calcitriol (0.25 μ g/day) resulted in a 6.3% increase in spinal BMD in the fi rst 6 months after KT, compared with a 5.8% decrease with calcium and calcitriol alone [37] . Alendronate, calcitriol, and calcium treatment was also superior to calcitriol and calcium treatment alone, beginning 5 years post KT [38] . Intermittent cal-citriol (0.5 μ g/48 hours) during the fi rst 3 months after renal transplantation, preserved total hip BMD more than calcium (500 mg/day) supplementation alone over 1 year [39] .

Renal safety issues and dosing schedules are different for intravenous bisphosphonates. Zoledronic acid (ZA) may cause acute renal failure, with the induction of acute tubular necrosis related to the rate of its infusion rather than the dose. The risk of renal failure is also increased by preexisting renal impairment, so the infu-sion rate should be reduced to half the recommended rate in patients with a glomerular fi ltration rate (GFR) less than 30 mls/min or baseline serum creatinine concentra-tion greater than 2 mg/dL [40] . The former measurement is the more accurate.

Intravenous ibandronate was effective at preventing spinal and hip bone loss post KT [41] . There were also fewer spinal deformities in the ibandronate group after 12 months. A small, randomized study compared the long-term effects of two infusions of 4 mg of ZA or placebo at 2 weeks and 3 months after KT. Although early bone loss was prevented by ZA, both treatment groups had signifi cant and similar later increases in femoral neck (FN) BMD [42] .

Most therapeutic trials have focused on the use of active vitamin D metabolites and antiresorptive drugs, particularly oral and intravenous bisphosphonates. Hormone therapy with estrogen ± progestin helps protect the skeleton in women receiving liver, lung, and bone marrow transplantation. Because amenorrhea is a common sequela of BMT in premenopausal women, they should receive hormone replacement therapy (HRT). However, it does not prevent bone loss after BMT. Hypo-gonadism is common in male cardiac and bone marrow transplant recipients, due to chronic illness and hypothalamic-pituitary-adrenal suppression by GCs and CsA. Testosterone levels fall immediately after trans-plantation and normalize 6 to 12 months later. However, testosterone treatment alone does not prevent bone loss after cardiac transplantation or BMT in men.

Recent studies examined prevention of bone loss after transplantation (Table 61.2 ).

Kidney t ransplantation Renal osteodystrophy improves after transplantation; however, hyperparathyroidism (HPT) may persist. Bone resorption remains elevated in a substantial proportion of kidney transplant recipients, and there is GC-induced osteoblast dysfunction [31, 32] . Cross-sectional studies of patients evaluated several years after kidney transplanta-

Table 61.1. Risk Factors for Post-Transplant Bone Loss and Fractures

Contributing Factors Mechanisms

Aging Low pre-transplant BMD Low body mass indexHypogonadismCalcium and vitamin D defi ciency

TobaccoAlcohol abuseCholestasis (liver disease)Organ failure (heart, lung, liver, kidney)

Pancreatic insuffi ciency (cystic fi brosis)

Physical inactivityHigh dose prednisone Decreased bone formation

Direct effect Decreased gonadal function Reduced intestinal and renal calcium transport

Calcineurin inhibitors Cyclosporine or FK506

Increased bone resorption Decreased renal function and 1,25(OH) 2 D

Increased PTH secretion Possible direct effect

Calcineurin inhibitor Sirolimus

Decreased bone formation Possible direct effect

499

Tab

le

61.2

. R

ando

miz

ed

Con

trol

led

Tri

als

Usi

ng

Vit

amin

D

A

nal

ogu

es

or

Bis

phos

phon

ates

fo

r P

reve

nti

on

of

Bon

e L

oss

Aft

er

Hea

rt,

Lu

ng,

L

iver

, an

d B

one

Mar

row

Tra

nsp

lan

tati

on

Tra

nsp

lan

t ty

peFi

rst

auth

or,

yrn

Du

rati

on T

reat

men

t re

gim

en

Con

trol

re

gim

en

Fin

din

gs/

Sum

mar

y

Hea

rt a

nd

Lung

Sa

mbr

ook

(2

000)

(R

ef.

51 )

6524

mon

ths

Cal

citr

iol

0.5–

0.75

μ g

for

12

mon

ths

or 2

4 m

onth

s C

alci

um

600

mg/

day

Pla

cebo

C

alci

um

600

mg/

day

BM

D:

FN (

but

not

LS)

bon

e lo

ss

was

att

enu

ated

in

th

e ca

lcit

riol

gr

oups

at

12 m

onth

s. L

S bo

ne

loss

w

as s

imil

ar a

mon

g al

l 3

grou

ps.

Frac

ture

: N

ot p

ower

ed.

Lung

(CF)

A

ris

(200

0)

(Ref

. 47

)37

24 m

onth

s Pa

mid

rona

te 3

0 m

g IV

q 3

m

onth

s C

alci

um

100

0 m

g/da

y V

itam

in D

800

IU/d

ay

Cal

ciu

m 1

,000

mg/

day

Vit

amin

D 8

00 IU

/day

B

MD

: L

S an

d T

H B

MD

in

crea

sed

sign

ifi c

antl

y m

ore

in t

he

pam

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nat

e gr

oup

vs c

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ols.

Fr

actu

re:

No

diff

eren

ce.

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rt

Shan

e (2

004)

(R

ef.

58 )

149 a

12

mon

ths

Ale

ndro

nate

10

mg/

day

or

Cal

citr

iol

0.5

μ g/d

ay

Cal

ciu

m 9

45 m

g/da

y V

itam

in D

1,0

00 IU

/day

Non

-ran

dom

ized

re

fere

nce

gro

up

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D:

Sim

ilar

sm

all

loss

es a

t L

S an

d T

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oth

gro

ups

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gnifi

can

tly

less

bon

e lo

ss a

t L

S an

d T

H t

han

ref

eren

ce g

rou

p.

Frac

ture

: N

o di

ffer

ence

. H

eart

G

il-F

ragu

as

(200

5) (

Ref

. 56

) 87

12 m

onth

s A

lend

rona

te

10 m

g/da

y C

alci

toni

n 20

0 IU

/day

BM

D:

Les

s bo

ne

loss

fro

m F

N i

n

the

alen

dron

ate

grou

p.

Frac

ture

: Fe

wer

ver

tebr

al f

ract

ure

s th

an i

n c

alci

ton

in g

rou

p (6

vs

15).

Hea

rt

Fah

rlei

tner

-P

amm

er (

2009

) (R

ef.

57 )

3512

mon

ths

Iban

dron

ate

2mg

IV q

3 m

onth

s ca

lciu

m 1

000

mg/

day

Vit

amin

D 4

00 IU

/day

Pla

cebo

ca

lciu

m 1

,000

mg/

day

Vit

amin

D 4

00 IU

/day

BM

D:

Bon

e lo

ss f

rom

LS

and

FN

prev

ente

d in

iba

ndr

onat

e gr

oup.

Fr

actu

re:

Few

er v

erte

bral

fra

ctu

res

than

in

con

trol

gro

up

(2 v

s 17

). Li

ver

and

mul

tivi

scer

al

Hom

man

n

(200

2) (

Ref

. 63

)36

12 m

onth

s Ib

andr

onat

e 2

mg

IV q

3

mon

ths

Cal

ciu

m 1

,000

mg/

day

Vit

amin

D 1

,000

IU/d

ay

Cal

ciu

m 1

,000

mg/

day

Vit

amin

D 1

,000

IU/d

ay

BM

D:

LS,

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an

d fo

rear

m B

MD

de

crea

sed

init

iall

y in

bot

h g

rou

ps.

Rev

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l of

bon

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ss w

ith

ib

andr

onat

e se

en a

fter

12

mon

ths.

Live

r N

ink

ovic

(20

00)

(Ref

. 62

)99

12 m

onth

s Pa

mid

rona

te 6

0 m

g IV

giv

en

once

pri

or t

o tr

ansp

lan

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onN

o tr

eatm

ent

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D:

Sign

ifi c

ant,

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ble

bon

e lo

ss a

t FN

in

pam

idro

nat

e an

d co

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ol g

rou

ps

Frac

ture

: N

o di

ffer

ence

. Li

ver

Cra

wfo

rd (

2006

) (R

ef.

64 )

6212

mon

ths

Zol

edro

nic

acid

4 m

g IV

ad

min

iste

red

wit

hin

7 d

ays

of t

ran

spla

nta

tion

an

d at

1,

3, 6

, an

d 9

mon

ths

afte

r tr

ansp

lan

t C

alci

um

600

mg/

day

Vit

amin

D 1

,000

IU/d

ay

Pla

cebo

C

alci

um

600

mg/

day

Vit

amin

D 1

,000

IU/d

ay

BM

D:

At

3 m

onth

s, d

iffe

ren

ce i

n

bon

e lo

ss f

rom

bas

elin

e w

as

decr

ease

d in

ZA

gro

up

vs p

lace

bo.

At

12 m

onth

s, t

he

diff

eren

ces

in

% b

one

loss

was

les

s.

Frac

ture

: N

ot p

ower

ed.

Live

r B

odin

gbau

er

(200

7) (

Ref

. 65

)69

12 m

onth

s Z

oled

roni

c ac

id 4

mg

IV 1

–6,

9, a

nd

12 m

onth

s C

alci

um

60

0 m

g/da

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itam

in D

1,0

00 IU

/day

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m 6

00 m

g/da

y V

itam

in D

1,0

00 IU

/day

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: L

ess

bon

e lo

ss f

rom

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(bu

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N)

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ic a

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grou

p.

Frac

ture

: Fe

wer

ver

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al f

actu

re

than

in

con

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s 11

). (C

onti

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lan

t ty

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rst

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reat

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d 3

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n b

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gr

oups

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actu

re:

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e fr

actu

res

in

pam

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nat

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(15

vs 3

). Li

ver

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erer

(2

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ef.

67 )

7412

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mon

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m 1

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0 IU

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D:

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at

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and

less

bon

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in

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actu

re:

few

er f

ract

ure

s in

ib

andr

onat

e gr

oup

(2 v

s 8)

. B

MT

T

auch

man

ova

(200

3) (

Ref

. 78

)34

12 m

onth

s R

ised

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te 5

mg/

day

Cal

ciu

m 1

g/d

ay

Vit

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/day

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m 1

g/d

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: L

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sig

nifi

can

tly

incr

ease

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ris

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at 6

an

d 12

mon

ths

and

decr

ease

d in

th

e co

ntr

ol g

rou

p at

6 m

onth

s. F

N

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D d

ecre

ased

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nifi

can

tly

in

con

trol

gro

up

at 6

mon

ths

only

. B

MT

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500

Transplantation Osteoporosis 501

A large, recent systematic review of 24 trials with 1,299 patients showed any treatment for bone disease reduced the risk of fracture by 49% (95%; CI 0.27–0.99) compared with placebo [43] . Bisphosphonates and active vitamin D analogues had benefi cial effects on the BMD at the spine and FN. Bisphosphonates were better at pre-venting bone loss compared with vitamin D analogues. An unexpected fi nding was a reduction in the risk of graft rejection associated with bisphosphonate therapy. A trial using fractures as a primary end point is now required to compare treatment with oral or parenteral bisphospho-nates with calcitriol after KT.

Kidney- p ancreas t ransplantation Severe osteoporosis complicates kidney-pancreas trans-plants in recipients with type 1 diabetes, occurring in 23% and 58% at the LS and FN, respectively. Vertebral or nonvertebral fractures were documented in 45% [1] . Other retrospective studies have documented a fracture prevalence of 26–49% up to 8.3 years after transplanta-tion [44] .

A prospective study addressed osteoporosis and second-ary hyperparathyroidism in simultaneous pancreas-kidney transplantation (SPK) recipients before transplant and 4 years after. Prior to transplantation, 68% had hyper-parathyroidism. After 6 months, bone loss of 6.0% and 6.9% occurred at both LS and FN sites, respectively, and fractures were related to low pre-transplant FN BMD [45] .

Lung t ransplantation The prevalence of osteoporosis is as high as 73% in lung transplantation (LT) recipients. During the fi rst year after lung transplantation, rates of bone loss at the LS and FN range from 2% to 5% [1] . Fracture rates are also high during the fi rst year, ranging from 18% to 37%. Bone turnover is also increased [46] . Repeated doses of intra-venous pamidronate prevented LS and FN bone loss in LT recipients [47, 48] .

Cardiac t ransplantation The most rapid rate of bone loss occurs in the fi rst year post transplant. Spinal BMD declines by 6–10% during the fi rst 6 months, while FN BMD falls by 6–11% in the fi rst year and stabilizes thereafter in most cases. BMD declines at the largely cortical proximal radius site over the second and third years, perhaps refl ecting post-transplant SHPT. Vitamin D defi ciency and testosterone defi ciency (in men) are associated with more severe bone loss. Testosterone levels fall immediately after cardiac transplantation (CT) and normalize after 6–12 months. Some studies have found correlations between GC dose and bone loss. Vertebral fracture incidence ranges from 33% to 36% during the fi rst 1 to 3 years after CT [49, 50] .

Prevention and t reatment Vitamin D and calcitriol. Calcium and vitamin D alone do not prevent bone loss after CT [1] . Early studies

showed calcitriol was effective at reducing bone loss, particularly at the FN, after CT [51] . Another study com-pared rates of bone loss in patients randomized to receive calcitriol (0.5 μ g/day) or two cycles of etidronate during the fi rst 6 months after CT or LT [52] . Signifi cant and similar bone loss (3–8%) occurred at the spine and FN in both treatment groups, but was less than in historical controls [51, 52] .

Other studies observed that CT recipients randomized to either alphacalcidol or cyclic etidronate sustained con-siderable bone loss at the spine and FN during the fi rst year after transplantation [1] , while another study of cal-citriol [53] found no protective benefi t. Thus, data regard-ing calcitriol and prevention of post-CT bone loss are inconsistent. Monitoring of serum and urine calcium levels is also required.

Intranasal calcitonin. One small study showed spinal BMD was higher 1–3 years, but not 7 years after CT in those treated with intranasal salmon calcitonin [54] .

Testosterone. Because low post-transplant testosterone concentrations are often transient, only hypogonadal men should receive testosterone therapy.

Bisphosphonates. An open-label study of a single intra-venous dose of pamidronate (60 mg) followed by four cycles of etidronate (400 mg every 3 months) and daily low-dose calcitriol (0.25 μ g), prevented spinal and FN bone loss and reduced fracture rates in CT recipients compared with historical controls [55] . Compared with calcitonin (200 IU/day), alendronate (10 mg/day) treat-ment reduced hip bone loss and resulted in fewer verte-bral fractures [56] . In a small study of 35 men post CT, intravenous ibandronate (2 mg every 3 months) prevented spine and hip bone loss and resulted in fewer morpho-metric vertebral fractures [57] .

In the largest study, where 149 patients were random-ized immediately after CT to receive either alendronate (10 mg/day) or calcitriol (0.25 μ g twice daily) for 1 year, bone loss at the spine and hip was prevented by both regimens compared with a prospectively recruited, non-randomized reference group who received only calcium and vitamin D [58] . After 1 year of treatment withdrawal, BMD did not change in either the former alendronate or calcitriol group, but bone resorption increased in the calcitriol group [59] . This suggests that antiresorptive therapy may be discontinued 1 year post transplant in CT recipients without inducing rapid bone loss. However, these patients still require observation to ensure that BMD remains stable in the long-term.

Exercise. Resistance exercise signifi cantly improved lumbar spine BMD after lung [60] and heart [61] trans-plantation when used alone and in combination with alendronate. However, these small studies utilized highly variable lateral BMD measurements.

Liver t ransplantation Bone loss and fracture rates after liver transplantation (LIT) are highest in the fi rst 6–12 months. Spine BMD declines by 2–24% during the fi rst year in earlier studies.

502 Osteoporosis

age- and sex-matched controls with similar small bowel diseases. Long-term SBT recipients are at risk of both osteoporosis (44%) and fractures (20%) [19] . In a small longitudinal study of nine patients, signifi cant bone loss occurred at both the spine (2.6%) and the total hip and FN (by about 15%) 1.3 years after SBT [69] . A larger longitudinal study (n = 24) documented acceleration (p = 0.025) of bone loss after SBT with a decline of 13.4% (FN), 12.7% (total hip), and 2.1% (spine) over 2.5 years. Alendronate reduced (p < 0.05), but did not prevent bone loss [19] .

Bone m arrow t ransplantation Bone marrow or stem cell transplantation (BMT) is the treatment of choice for patients with many hematologi-cal malignancies, the majority of whom will survive for many years. However, up to 29% and 52% of survivors have osteopenia at the spine or FN, respectively [1] . Osteoporosis is more common at proximal femur sites. The pathogenesis of post-BMT osteoporosis is complex, relating both to effects of treatment and effects on the bone marrow stromal cell (MSC) compartment [70, 71] . Bone resorption increases while bone formation decreases [1, 16] , resulting in early, rapid bone loss. In addition to osteoporosis, osteomalacia, and avascular necrosis may occur.

Dramatic bone loss from the proximal femur occurs within the fi rst 12 months of allogeneic BMT [1, 72, 73] . Spinal bone loss is less. Most studies suggest that little additional bone loss occurs after this time. Studies of long-term survivors of BMT have shown that losses from the proximal femur are not regained [74] . After autolo-gous BMT, bone loss from the proximal femur is less (about 4%), occurs as early as 3 months and persists at 2 years, while spine BMD returns to baseline [75] .

Bone loss after BMT is related to both cumulative GC exposure and duration of CsA exposure [72] . There may also be a direct effect of graft versus host disease (GVHD) itself on bone cells. Abnormal cellular or cytokine-mediated bone marrow function may affect bone turnover and BMD after BMT [1] . Both myeloablative treatment and BMT stimulate the early release of cytokines. BMT also has adverse effects on bone marrow osteoprogenitors. Osteocyte viability is decreased after BMT and bone marrow stromal cells are damaged by high-dose chemo-therapy, TBI, GCs, and CsA, thereby reducing osteoblas-tic differentiation from osteoprogenitor cells [76] . In this regard, colony forming units-fi broblasts (CFU-f) are reduced for up to 12 years after BMT [1] .

Avascular necrosis develops in 10% to 20% of allo-BMT survivors, a median of 12 months after BMT [71, 77] . Glucocorticoid treatment of chronic GVHD-inducing osteoblast apoptosis is the most important risk factor. Avascular necrosis appears to be related to decreased numbers of bone marrow CFU-f colonies in vitro , but not to BMD [77] . Avascular necrosis may thus be facilitated by a defi cit in bone marrow stromal stem cell regenera-tion with low osteoblast numbers post BMT [76] .

In more recent studies, rates of bone loss have been lower or absent. Fracture rates range from 24–65%, and the ribs and vertebrae are the most common sites. Women with primary biliary cirrhosis and the most severe preexisting bone disease appear to be at greatest risk. Older age and pre-LIT spinal and FN BMD predicted post-LIT fractures in one recent prospective study, while the presence of pre-LIT vertebral fractures also predicted post-LIT verte-bral fractures [1, 62] . Post LIT, bone turnover is increased compared with low bone turnover pre-LIT.

Prevention and t reatment Both oral and intravenous bisphosphonates are effective in reducing post-LIT bone loss, although one early study of intravenous pamidronate was ineffective due to insuf-fi cient dosing [62] . A randomized trial of intravenous ibandronate in liver [63] transplant recipients found a signifi cant protective effect on BMD at 1 year. In a ran-domized, double-blind trial, 62 LIT recipients received treatment with either infusions of 4 mg ZA or saline within 7 days of transplantation and again at 1, 3, 6, and 9 months post LIT [64] . All patients also received calcium and vitamin D. ZA signifi cantly prevented bone loss from the LS, FN, and total hip by 3.8–4.7%, with differ-ences being greatest 3 months post LIT. At 12 months post LIT, differences only remained signifi cant at the total hip. Similar fi ndings were identifi ed in another study using 4 mg intravenous ZA at 1–6, 9, and 12 months post LIT. Bone loss from the spine (but not hip) was pre-vented and fewer vertebral fractures occurred in the ZA group [65] . Vitamin D defi ciency should be corrected before giving bisphosphonates post LIT to prevent hypocalcemia.

One study using two intravenous doses of pamidronate (90 mg) at baseline and 3 months post LIT showed an increase in spinal BMD in the pamidronate group, but more fractures in the pamidronate group [66] . Intrave-nous ibandronate given every 3 months post LIT resulted in increases in spinal BMD and less bone loss from the FN, and fewer fractures in the ibandronate group [67] .

Two studies examined effects of alendronate on bone after LIT. An uncontrolled, prospective study of 136 LIT patients showed alendronate prevented bone loss in patients with osteopenia and led to an increase in BMD at the spine and FN in patients with osteoporosis over 4 years [9] . Another study of 59 LIT patients used historical controls to examine effects of alendronate combined with calcium and calcitriol 0.5 μ g daily [68] . Increases in spinal, FN, and total hip BMD at 12 months were higher than in historical controls.

Small b owel t ransplantation Small bowel transplantation (SBT) is being increasingly used for severe infl ammatory bowel disease. It may also include concomitant liver, pancreas, and stomach trans-plantation. In a cross-sectional study of 81 patients who had SBT 2.2 years previously, BMD at the spine, total hip, and FN was reduced by about 0.8 SD compared with

Transplantation Osteoporosis 503

A small uncontrolled, prospective study of a single 4 mg ZA infusion in allogeneic BMT patients with either osteoporosis or rapid bone loss post-allogeneic BMT [81] showed reduced bone loss at the spine and FN.

SUMMARY AND CONCLUSION

Pre-transplantation bone disease and immunosuppres-sive therapy result in a severe form of osteoporosis characterized by rapid bone loss and increased fracture rates, early after transplantation. There is increased bone resorption and decreased bone formation, sugges-tive of uncoupling of bone turnover. In the late post-transplant period, with weaning of glucocorticoid doses, bone formation begins to increase and underlying high bone turnover resulting in osteoporosis. Although rates of bone loss and fractures reported in recent studies are lower than those of 10 years ago, they remain too high. Transplant candidates should be assessed, and pre-transplantation bone disease should be treated. Preventive therapy initiated in the immediate post-transplantation period is indicated in patients with osteopenia or osteopo-rosis, since further bone loss will occur immediately after transplantation. All organ transplant recipients should be considered at risk for post-transplantation bone loss and fractures, as it is impossible to identify patients with the highest fracture risk. Long-term organ transplant recipi-ents should also have bone mass measurement and treat-ment of osteoporosis.

A recent meta-analysis showed treatment with a bisphosphonate or active vitamin D metabolite during the fi rst year after solid organ transplantation is associ-ated with a 50% reduction in the number of subjects with fractures and 76% fewer vertebral fractures [Fig. 61.1 (A)] [82] . Bisphosphonate treatment was associated with a 47% reduction in the number of subjects with fractures [Fig. 61.1 (B)], but no signifi cant reduction in vertebral

Prevention and t reatment Risedronate or intravenous ZA given 12 months after BMT prevents spinal and proximal femoral bone loss [78, 79] . ZA effects may be related to improved osteoblast recovery and increased osteoblast numbers post BMT as increases in ex vivo growth of bone marrow CFU-f have been shown.

Two randomized trials recently assessed the effective-ness of intravenous pamidronate in preventing bone loss after BMT. The fi rst studied 99 allogeneic BMT recipi-ents, who were randomized to receive calcium and vitamin D daily, hormone therapy with estrogen in females or testosterone in men, or the same treatments plus intravenous 60 mg pamidronate infusions before and 1, 2, 3, 6, and 9 months after BMT [16] . In the pamidro-nate group, LS BMD remained stable but decreased sig-nifi cantly in the control group. Total hip BMD and FN BMD decreased by 5.1% and 4.2%, respectively, in the pamidronate group, and by 7.8% and 6.2%, respectively, in the control group at 12 months. Thus, pamidronate reduced bone loss more than in those treated with calcium, vitamin D, and sex steroid replacement alone.

A larger randomized, multicenter open-label 12-month prospective study compared intravenous pamidronate (90 mg/month) beginning prior to conditioning versus no pamidronate [80] . All 116 patients also received calcitriol (0.25 μ g/day) and calcium, which were continued for a further year. Pamidronate signifi cantly reduced bone loss at the spine, FN, and total hip at 12 months. However, BMD of the FN and total hip was still 2.8% and 3.5% lower than baseline, respectively, following pamidronate. Only the BMD benefi t at the total hip remained signifi -cant between the two groups at 24 months. This study also showed the benefi ts of pamidronate therapy were restricted to patients receiving an average daily predniso-lone dose greater than 10 mg and cyclosporin therapy for more than 5 months within the fi rst 6 months of alloSCT (stem cell transplantation). Importantly, most BMD ben-efi ts were lost 12 months after stopping pamidronate.

(A)

−4

−3 −2 −1 0 1 2

−2 0

Vertebral FracturesSubjects with Fractures

2

(B)

BodingbauerCrawfordDe SavauxFahrleitnerGilfraguasGrotzKaemmererMonegalSambrookSchwarzWalshFixed-effect Random-effect

BodingbauerCrawfordFahrleitnerGilfraguasGrotzKaemmererMonegalSchwarzWalshFixed-effectRandom-effect

Fig. 61.1. (A) Log odds ratios (OR) and 95% confi dence intervals for the effect of treatment with bisphosphonates or vitamin D analogues after organ transplantation on the number of vertebral fractures (OR 0.24, 95% CI 0.07, 0.78 by random effects model). (B) Log odds ratios (OR) and 95% confi dence intervals for the effect of treat-ment with bisphosphonates after organ transplantation on the number of subjects with vertebral fractures (OR 0.53, 95% CI 0.30, 0.91 by fi xed effect model). Repro-duced with permission from Ref. 82 .

504 Osteoporosis

5. Stehman-Breen CO , Sherrard DJ , Alem AM , Gillen DL , Heckbert SR , Wong CS , Ball A , Weiss NS . 2000 . Risk factors for hip fracture among patients with end-stage renal disease . Kidney Int 58 ( 5 ): 2200 – 5 .

6. Alem AM , Sherrard DJ , Gillen DL , Weiss NS , Beresford SA , Heckbert SR , Wong C , Stehman-Breen C . 2000 . Increased risk of hip fracture among patients with end-stage renal disease . Kidney Int 58 ( 1 ): 396 – 9 .

7. Ball AM , Gillen DL , Sherrard D , Weiss NS , Emerson SS , Seliger SL , Kestenbaum BR , Stehman-Breen C . 2002 . Risk of hip fracture among dialysis and renal transplant recipients . JAMA 288 ( 23 ): 3014 – 8 .

8. Majumdar S , Ezekowitz JA , Lix LM , Leslie W . 2012 . Heart failure is a clinically and densitometrically inde-pendent and novel risk factor for major osteoporotic fractures: Population-based cohort study of 45,509 sub-jects . J Clin Endocrinol Metab 97 ( 4 ): 1179 – 86 .

9. Shane E , Mancini D , Aaronson K , Silverberg SJ , Seibel MJ , Addesso V , McMahon DJ . 1997 . Bone mass, vitamin D defi ciency and hyperparathyroidism in congestive heart failure . Am J Med 103 : 197 – 207 .

10. Monegal A , Navasa M , Guanabens N , Peris P , Pons F , Martinez de Osaba MJ , Ordi J , Rimola A , Rodes J , Munoz-Gomez J . 2001 . Bone disease after liver transplantation: A long-term prospective study of bone mass changes, hormonal status and histo-morphometric characteristics . Osteoporos Int 12 ( 6 ): 484 – 92 .

11. Millonig G , Graziadei IW , Eichler D , Pfeiffer KP , Finken-stedt G , Muehllechner P , Koenigsrainer A , Margreiter R , Vogel W . 2005 . Alendronate in combination with calcium and vitamin D prevents bone loss after ortho-topic liver transplantation: A prospective single-center study . Liver Transpl 11 : 960 – 6 .

12. Ninkovic M , Love SA , Tom B , Alexander GJ , Compston JE . 2001 . High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation . Calcif Tissue Int 69 ( 6 ): 321 – 6 .

13. Tschopp O , Boehler A , Speich R , Weder W , Seifert B , Russi EW , Schmid C . 2002 . Osteoporosis before lung transplantation: Association with low body mass index, but not with underlying disease . Am J Transplant 2 ( 2 ): 167 – 72 .

14. Keilholz U , Max R , Scheibenbogen C , Wuster C , Kor-bling M , Haas R . 1997 . Endocrine function and bone metabolism 5 years after autologous bone marrow/blood-derived progenitor cell transplantation . Cancer 79 ( 8 ): 1617 – 22 .

15. Tauchmanova L , Selleri C , Rosa GD , Pagano L , Orio F , Lombardi G , Rotoli B , Colao A . 2002 . High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases . Cancer 95 ( 5 ): 1076 – 84 .

16. Valimaki M , Kinnunen K , Volin L , Tahtela R , Loyttni-emi E , Laitinen K , Makela P , Keto P , Ruutu T . 1999 . A prospective study of bone loss and turnover after alloge-neic bone marrow transplantation: Effect of calcium supplementation with or without calcitonin . Bone Marrow Transplant 23 : 355 – 61 .

fractures. Overall, bisphosphonates are the most promis-ing approach for the prevention and treatment of trans-plantation osteoporosis. Active vitamin D metabolites may have additional benefi ts in reducing hyperparathy-roidism, particularly after kidney transplantation. Poten-tial new agents for transplantation osteoporosis include anabolic agents that stimulate bone formation, namely PTH(1-34) or teriparatide, and the anticatabolic drugs, human antibodies to RANKL (denosumab), and cathepsin K inhibitors. PTH(1-34) and other PTH1 receptor agonists may have a specifi c role after BMT in stimulating MSC cell differentiation into the osteoblast lineage and reduc-ing adipogenesis [83, 84] .

Several issues remain regarding the administration of bisphosphonates for transplantation bone disease, including the optimal route of administration and dura-tion of therapy. Treatment may only need to be given for 1 year following cardiac transplantation, but its optimal duration is less clear following other transplants. It is also uncertain at what level of renal impairment oral bisphosphonates should be avoided and whether this level is the same for intravenous bisphosphonates. Another special consideration in using bisphosphonates in kidney transplant recipients is adynamic bone disease (see above). Large multicenter trials comparing treatment with oral or parenteral bisphosphonates and calcitriol, and commencing at the time of transplantation that are powered to detect differences in fracture rates are recom-mended here.

Despite some continuing uncertainties, much has been learned about transplantation osteoporosis. Armed with this information, it is now critical to act to prevent and treat this disabling disease.

ACKNOWLEDGMENTS

I thank Dr. Elizabeth Shane for her mentorship in this area.

REFERENCES

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Transplantation Osteoporosis 505

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43. Palmer SC , McGregor DO , Strippoli GFM . 2007 . Inter-ventions for preventing bone disease in kidney trans-plant recipients . Cochrane Database Syst Rev ( 3 ): CD005015 .

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