seminar 09-04-2014 osteoporose en cni

Osteoporosebehandeling bij CKD

Joop van den Bergh, internist-‐endocrinoloog VieCuri MC Noord-‐Limburg

Maastricht UMC+ UHasselt, België

CBO guideline 2011 Osteoporose en fractuurprevenIe

1.  PaIents at increased risk for fracture 2.  EvaluaIon of skeletal status (DEXA/VFA) 3.  AnI-‐osteoporosis therapy:

•  BMD T-‐score ≤ -‐2.5 •  Vertebral fracture(s)

Studies of fracture risk associated with CKD

Kidney InternaIonal 2008: 721–731

•  High risk of fracture because of low bone mineral density •  Resembles or is higher than in postmenopausal osteoporosis

However

•  The mineral and bone disorder associated with CKD (CKD–MBD) is more complex than osteoporosis and the same treatments might not be appropriate.

Renal osteodystrophy: a complex interplay of geneIc, growth and cellular factors, some of which inhibit bone formaIon,

whereas others sImulate bone resorpIon

Prevalence of low, normal, and high bone turnover in black and white CKD paIents on maintenance dialysis

JBMR 2011: 1368–1376

Review of 630 bone biopsies

JBMR 2011: 1368–1376

EvaluaIons and limitaIons in clinical pracIce

•  Laboratory parameters •  Bone turnover markers •  BMD / DEXA

•  HRpQCT •  Bone biopsy

Laboratory parameters

Bone turnover markers: levels dependent on eGFR

Moorthi et al. Kidney InternaIonal 2013:886–894

Studies of imaging modaliIes to assess fracture status in paIents with CKD that report test diagnosIc characterisIcs

Kidney InternaIonal 2008: 721–731

HR-‐pQCT= High resoluIon periferal quanItaIve computer tomography

HR-‐pQCT radius (lei) and Ibia (right) B healthy, post-‐ menopausal C predialysis with CKD and without fracture D predialysis with CKD with prevalent fracture

J Am Soc Nephrol 21: 1371–1380, 2010

BMD and HR-‐pQCT vs fracture predicIon •  while both tests were able to discriminate fracture status, the addiIon of

HR pQCT measures to BMD by DXA did not improve fracture discriminaIon ability

Osteoporos Int 2012:2805–2813

LimitaIons in clinical pracIce

•  Overlap in laboratory parameters •  Bone turnover markers influenced by eGFR •  BMD / DEXA provides ‘only’ 2D density parameters

•  PotenIal role of HRpQCT needs to be further studied •  LimitaIons for bone biopsies (as gold standard) in clinical pracIce

•  UlImately: combinaIon of mulIple imaging techniques and biomarkers that are specific to each gender and race in CKD to predict fracture risk

Considered together

•  Fracture risk appears to be higher than in age-‐ and BMD-‐matched paIents without CKD

•  In predialysis CKD without substanIal derangements in markers of mineral metabolism BMD by DXA can be used to diagnose osteoporosis

Jamal et al. Curr Rheumatol Rep (2012) 14:217–223

CBO guideline 2011 Osteoporose en fractuurprevenIe

1.  PaIents at increased risk for fracture 2.  EvaluaIon of skeletal status (DEXA/VFA) 3.  AnI-‐osteoporosis therapy:

•  BMD T-‐score ≤ -‐2.5 •  Vertebral fracture(s)

Therapy should depend on the underlying pathophysiology

Resorption Formation

Teriparatide/ rec PTH Bisphosphonates SERMs

Denosumab

% Change vs. baseline

Bone turnover and anI-‐osteoporosis medicaIon

Strontium Ranelate

Nat. Rev. Nephrol. Online October 2013

Bone Biopsies with tetracycline double labelling

J Bone Miner Res 1997;12:191–199



Normal bone turnover

hop://courses.washington.edu/bonephys

Adynamic bone


OsteiIs fibrosa cysIca


J Bone Miner Res 1997;12:191–199



Fracture outcomes in paIents with CKD–MBD

•  No clinical studies to assess fracture outcomes in paIents with CKD–MBD

Risedronate in PaIents With Age-‐Related Reduced Renal FuncIon : A Pooled Analysis of Nine Clinical Trials

n=301 vs 271

J Bone Miner Res 2005;20:2105–2115.

new vertebral fractures

Bisphosphonate use in paIents with CKD

•  Mainly confined to those with early stages of the disease

•  Post hoc analyses from osteoporosis clinical trials: –  paIents with mild CKD (but normal Ca, AF and PTH) have a similar

reducIon in fractures to that observed in paIents without CKD

•  Histological findings: in only one single-‐centre, observaIonal study –  in all 13 paIents with CKD stage 2–4 who had taken bisphosphonates,

bone biopsies revealed adynamic bone disease*.

•  The KDIGO commioee could not idenIfy any clinical trial that met their minimum criteria for incorporaIon into their consensus guidelines: inclusion of at least 50 paIents and a duraIon of at least 6 months.

*Blood Purif. 2010:293-‐99

jnephrol 2013; 26 (3): 450-‐455 35% administered dose cleared by hemodialysis

Acute Kidney Injury and Bisphosphonate Use

•  Preclinical and clinical observaIons reveal that all BPs can potenIally cause acute tubular necrosis

•  Decline in GFR, coupled with decreased renal blood flow, leads to reduced drug clearance and increased concentraIon of drugs in the renal medulla

•  Mainly aier iv dosing

•  In cancer paIents (high dose and co-‐morbidity)

J Oncology PracIce 2013:101-‐106

Raloxifene (SERM)

•  Raloxifene is excreted via hepaIc metabolism, and serum drug concentraIons are about 1.4 Imes higher in paIents with CKD than in individuals with normal renal funcIon

•  Aier 1 year raloxifene, lumbar spine BMD (trabecular bone) significantly improved, femoral neck BMD (corIcal bone) did not change significantly

•  Incidence of breast cancer is lowered by 70% •  However, raloxifene, like oestrogen, increases the risk of

thromboembolism

Kidney InternaIonal 2003:2269–2274

Denosumab

•  MAB that targets the osteoclast-‐differenIaIon cytokine RANKL –  Reducing the number of osteoclasts and bone formaIon rates

•  Is not excreted by the kidney

JBMR 2012: 1471

GFR at baseline by Cockcroi-‐Gault esImaIon: •  normal renal funcIon (GFR >80 mL/min/1.73m2) •  mild CKD (GFR 50–80 mL/min/1.73m2) •  moderate CKD (GFR 30–49 mL/min/1.73m2) •  severe CKD (GFR <30 mL/min/1.73m2) •  kidney failure requiring hemodialysis

Denosumab in paIents with CKD

•  None had stage 5 CKD •  Fracture risk reducIon and changes in BMD at all sites were in favour of DMAb •  The test for treatment by subgroup interacIon was not staIsIcally significant,

indicaIng that treatment efficacy did not differ by kidney funcIon

JBMR 2011;1829

•  Denosumab has not been available long enough to assess its long-‐term safety in paIents with CKD–MBD

•  Problems related to suppression of bone formaIon are likely to be seen

Denosumab in paIents with CKD

Hypocalcemia aier denosumab in severe CKD

JBMR 2012: 1471

Calcium and vitamin D supplementaIon was not iniIally required by the study protocol, but was added during the trial No subject who received adequate calcium and vitamin D supplementaIon became hypocalcemic.

Hypocalcemia

•  Increased risk of post-‐denosumab and iv bisphophonate hypocalcaemia in renal impairment may result from sudden inhibiIon of the high bone turnover that occurs in secondary hyperparathyroidism

•  Is preventable with adequate calcium and vitamin D supplementaIon

•  Measurement of serum calcium levels at 8–14 days post-‐denosumab may be useful to allow Imely detecIon of hypocalcaemia and insItuIon of early treatment

Intern Med J. 2013 Nov;43(11):1243-‐6

Bone turnover and BMD aier disconInuaIon of Denosumab

JCEM 2011:972–980

Am J Nephrol 2012;36:238–244

HD paIents

HD paIents

•  TeriparaIde improved BMD with adynamic bone disease, although no staIsIcal significance

•  PaIents with osteiIs fibrosa, ibandronate did not improve BMD while cinacalcet reduced BMD

Am J Nephrol 2012;36:238–244

Cinacalcet Effect on Risk of Fractures

Cunningham J, et al. Kidney Int. 2005;68:1793-1800.

Week

Even

t-Fre

e Pr

obab

ility

0 4 8 12 16 20 24 28 32 36 40 44 48 52

0.75

0.95

1.00

n = 487 Placebo n = 697 Cinacalcet

Placebo

Cinacalcet

0.90

0.85

0.80

470 445 419 404 367 314 136 132 120 117 112 109 383 656 614 574 554 485 392 132 131 125 115 110 106 513

P = 0.04

Pooled analysis of safety data from 4 similarly designed randomized, double-blind, placebo-controlled trials

All patients received standard care with phosphate binders and vitamin D, if prescribed.

Risk of Hip Fracture May be Greater Aier Parathyroidectomy

1,0

1,7

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

No Parathyroidectomy Parathyroidectomy

Adjusted Odd

s Ra

;o for Hip Fracture

Jadoul M, et al. Kidney Int. 2006;70:1358-‐1366.

Dialysis Outcomes Prac;ce PaBerns Study analysis of 8,978 pa;ents on hemodialysis with and without a history of parathyroidectomy (2002-‐2004)

P = 0.02

TeriparaIde

•  Recombinant PTH (1-‐34) –  Anabolic effect

•  Small observaIonal studies suggest that teriparaIde might be beneficial in paIents with CKD–MBD –  who have adynamic bone disease

–  who have undergone parathyroidectomy

Conclusions

•  PaIents with CKD –  Have a high risk of fracture owing to their low BMD

–  ConvenIonal medicaIons for osteoporosis are effecIve at reducing fracture rates in stage 3 CKD and normal PTH, Ca and phosphate measurements

–  In stage 4–5 CKD, or those with abnormal PTH and mineral values, the available data are insufficient to determine whether these commonly used medicaIons are effecIve against fractures

Conclusions

•  Alendronate, risedronate

•  Zoledronate (iv)

•  Denosumab

•  Raloxifene

•  TeriparaIde

•  Cinacalcet

•  Not recommended CrCl < 30 (some data for risedronate if CrCl 15-‐30)

•  Contra-‐indicated CrCl < 35

•  Might be useful in hypercalcemia •  Risk of hypocalcemia CrCl < 30, risky for

low bone turnover,

•  No concerns, in HD beneficial effects; the best current choice in women with CKD without VTE problems

•  Benefit in low PTH en low BMD

•  Possible effect on fractures in SHPT

seminar 09-04-2014 osteoporose en cni

Health & Medicine

normalboneturnover hop

adynamicbone hop

osteiisbrosacysica hop

growth andcellularfactors

301vs271 jboneminerres200520

73m2 mildckdgfr5080mlmin1