management of hyperparathyroidism and bone …...ckd 2 ckd 3 ckd 4 & 5 prevalence of abnormal...
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Management of hyperparathyroidism and bone
disease in CKD and DM
Dr Helen Eddington
Consultant Nephrologist
University Hospital Birmingham NHS Trust
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Aims
• Why bone disease develops in CKD
• Adynamic bone disorder
• Hyperparathyroidism
• Osteoporosis in CKD
• Treatment of osteoporosis
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CKD- Mineral Bone Disorder
A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:
• Abnormalities of Ca,PO4, PTH or vitamin D metabolism
• Abnormalities in bone turnover, mineralisation, volume, linear growth or strength
• Vascular or other soft tissue calcification
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Levels decrease as GFR worsens
Levin A et al KI 2007: 71; 31-38 (latitude 49o)
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0
25
50
75
100
> 80 79–70 69–60 59–50 49–40 39–30 29–20 < 20
Pati
en
ts (
%)
GFR (mL/min)(n = 61) (n = 117) (n = 230) (n = 396) (n = 355) (n = 358) (n = 204) (n = 93)
CKD 4 & 5CKD 3CKD 2
Prevalence of Abnormal PTH, Calcium and Phosphorous
Levels With Decline in Kidney Function
Adapted from Levin A, et al. Kidney Int. 2007;71:31-38.
N = 1,814
Calcium < 2.1 mmol/LPhosphorous > 1.48 mmol/LIntact PTH > 65 pmol/L
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25-34 35-44 45-54 55-64 65-74 75-84 >85
An
nu
al m
ort
alit
y (%
)
Age
Adapted from Levey AS et al. Am J Kidney Dis 1998; 32: 853-906.
Cardiovascular Mortality Rates are
Higher among Dialysis Patients
General population: male
General population: female
Dialysis: male
Dialysis: female
10
100
1
0.01
0.1
0.001
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Medial vascular calcification
All cause mortality in patients
with no calcification compared
to those with medial
calcification
London, G. M. et al. Nephrol. Dial. Transplant. 2003
18:1731-1740
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Case 1:
• 32 year old female
• Type 1 diabetes mellitus
• Haemodialysis patient
• Low impact rib fractures
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Diabetes and bone disease
• Decreased bone formation (precedes
CKD)
• More profound vitamin D deficiency
• Improving diabetes control should
improve bone formation
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Case 1: rib fractures
• KDIGO:
• PTH: 2-9 x
upper limit
of normal
• 13-
62pmol/L
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Adynamic bone disorder
• Low bone turnover / fragile bone
• Diabetes
• Aging
• Malnutrition
• Prevalence higher in peritoneal dialysis compared to haemodialysis
• Increased vascular calcification
• Not always related to low PTH
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Case 2: 68yr old woman
• Haemodialysis patient
• Unknown cause of renal disease
• Spinal surgery in India after a fall
• DXA 2016: osteopenia
• PTH, Alk Phos, calcium and phosphate
well controlled
• 2018 low impact fracture of pubic ramus
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Fracture risk
• Increased risk of fragility with CKD
• 4x higher rate of fracture compared to
general population1
• Increasing fracture related mortality as
CKD progresses
• Exact mechanism underdetermined but
potential mechanisms (that could be
independent or collectively impact are)….
1. KI 2006; &0:1358-1366
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Potential mechanisms
• Phosphate retention
• SHPT
• Chronic acid loads
• High FGF23
• Sclerostin overproduction,
• Increased risk of falls,
• Steroid use
• Hypogonadism
• Hyperprolactinaemia
• Poor nutrition
• Vitamin D deficiency
• Inactivity
• Other medical
conditions - IBD,
malabsorption, liver dx)
• Diabetes
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Case 2: 68 yr old woman
• PTH now increasing
• Alk Phos now high
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Secondary hyperparathyroidism
• KDIGO guidelines: CKD 5D
• PTH: 2-9 x upper limit of normal
13-62pmol/L
monitor change
• Manage secondary
hyperparathyroidism
• Alfacalcidol increased
• Ensure phosphate
controlled
• Cinacalcet?
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Fracture free survival in haemodialysis population in PTH
rangesPTH target 150-
300pg/mL
(15-31pmol/L)
NDT 2012 27 (1):345-351
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KDIGO guidelines CKDMBD 2017
• 3.2.1: In patients with CKD G3a–G5D
with evidence of CKD-MBD and/or risk
factors for osteoporosis, we suggest
BMD testing to assess fracture risk if
results will impact treatment
decisions (2B).
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Case 2: 68 yr old woman
• DXA scan
• FRAX Major osteoporotic fracture 33%
Lumbar spine Total Hip
T score -2.1 -3.5
Z score -0.5 -2.2
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From: Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting
fracture in CKD stage 5D patients—a single-center cohort studyNephrol Dial Transplant. 2011;27(1):345-351. doi:10.1093/ndt/gfr317
Nephrol Dial Transplant | © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]
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Differences between CKD-MBD and postmenopausal osteoporosis
Clinical factor CKD-MBD Post-menopausal Osteoporosis
PTH levels Increased Usually normal
Alkaline Phosphatase Increased Usually normal
Bone Mineral Density Weakly related to fracture risk
Predicts risk of fracture
Bone loss Mostly in cortical bone Trabecular and cortical bone
Bone formation rate Either very low (ABD) or very high
Generally normal or slightly increased
Vascular calcification Strongly associated Weakly associated
Laboratory findings Abnormal Normal or mildy abnormal
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• CKD-MBD and osteoporosis co-exist
frequently
• Very difficult to diagnose osteoporosis in
setting of CKD
• The WHO classification may not apply to
CKD
• Need to exclude adynamic bone disorder
(ABD)
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Management
• Lifestyle measures
• (Adequate calcium and Vit D, exercise,
cessation of smoking, alcohol intake, fall
prevention)
• GFR <30 – effects of Ca and Vit D
supplements on fracture risk not studied
• Repleting vitamin D in severe CKD may be
beneficial (J clin endocrinol metab 2011)
• Hypogonadism – specialist advice
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Osteoporosis management in CKD?
• Bisphosphonate
• Denosumab
• Teriparatide
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Bisphosphonate
• GFR >30 ml/min
• Suppress bone turnover
• Renal excretion
• Retained in bones / long half life
• Drug ‘holidays’
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Denosumab
• Monoclonal antibody blocks RANKL to
inhibit osteoclasts leading to less bone loss.
• 6 monthly injections
• Increased risk of hypocalcaemia in CKD
• Unknown length of treatment
• No drug holidays
• Rebound spinal fractures if stop treatment
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Denosumab in CKDcauses significant drop in calcium
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Denosumab
• Monoclonal antibody blocks RANKL to
inhibit osteoclasts leading to less bone loss.
• 6 monthly injections
• Increased risk of hypocalcaemia in CKD
• Unknown length of treatment
• No drug holidays
• Rebound spinal fractures if stop treatment
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Treatment of osteoporosis
• Teriparatide
• Stimulates bone formation
• Little data in poor renal function
• ? Beneficial in ABD
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Do we really know what is happening in these
patient’s bones?
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KDIGO guidelines CKD-MBD 2017
• .
• 3.2.2: In patients with CKD G3a–G5D, it is reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will impact treatment decisions (Not Graded).
• 4.3.3: In patients with CKD G3a–G5D with biochemical abnormalities of CKD-MBD and low BMD and/or fragility fractures, we suggest that treatment choices take into account the magnitude and reversibility of the biochemical abnormalities and the progression of CKD, with consideration of a bone biopsy (2D).
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Birmingham
• Specialist Renal and Endocrine meeting
to discuss complex patients
• Try and do no harm
• No bone biopsy service (yet?)
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How can we prevent fractures?
• Lack of accurate and non-invasive diagnostic tools.
• Metabolic abnormallities associated with CKD-MBD are poor markers for bone disease and cannot discriminate between turnover types and abnormal mineralisation.
• Bone turnover markers are not validated in CKD and ESRD and are used infrequently.
• Transiliac crest bone biopsy remains the gold standard tool; however, bone biopsy is invasive, expensive, painful, and is available at only a few centres worldwide.
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Summary:
• CKD MBD complex
process
• No easy, non-invasive
test to diagnose bone
disease in CKD
• Osteoporosis in CKD
should only be treated
with specialist advice
• We don’t have many
answers