Bone Disease in Renal Failure
Dr Anne Kleinitz and
Dr Cherelle Fitzclarence
renalgp@kamsc.org.au
Overview
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Pathogenesis
Normal Bone Remodeling
Hyperparathyroidism
Classifications of bone disease
Diagnosis of bone disease
Treatment of bone disease in CKD
Case Studies
Pathogenesis
• Kidney failure disrupts systemic calcium and phosphate
homeostasis and affects the bone, GIT and parathyroid
glands.
• In kidney failure there is decreased renal excretion of
phosphate and diminished production of calcitriol (1,25dihydroxyvitamin D)
– Calitriol increases serum calcium levels
• The increased phosphate and reduced calcium, feedback
and lead to secondary hyperparathyroidism, metabolic
bone disease, soft tissue calcifications and other metabolic
abnormalities
PO4
Ca
GFR
1,25 DHCC
Calcitriol
PTH
• Although bone disease and abnormal PTH
are a major feature, CVD and excess
calcification (extra-skeletal) are important
causes of morbidity and mortality
• Pathogenesis
• Normal Bone Remodeling
Normal Bone
Remodelling Cycle
Resorption
osteoclasts
Quiescence
Formation
osteoblasts 
matrix
Mineralisation
• Pathogenesis
• Normal Bone Remodeling
• Hyperparathyroidism
Hyperparathyroidism
• Increase PTH is hallmark of secondary
hyperparathyroidism
• The major factors leading to it’s increase
are;
– Decreased production of Vit D3 (calcitriol)
– Decreased serum calcium
– Increased serum phosphorous
PO4
Ca
GFR
1,25 DHCC
Calcitriol
PTH
• 4 or more small glands on
the posterior surface of the
thyroid gland.
• Can function without
neural control so can
transplant to another part
of the body
• 2 types of cells
– Chief cells – produce
parathyroid hormone
– Oxyntic cells – function
unknown
Role of PTH
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Responsible for maintaining serum
calcium in a narrow range (2.15-2.6)
Does this by;
1. acting directly on the distal tubule of the
kidney to increase calcium reabsorption
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Increases calcitriol production (D3)
D3 increases GIT absorption of Ca and Phos and
promotes osteoclast formation.
2. Acting on bone to increase calcium and
phosphate efflux
• The net effect of PTH is to create positive
calcium balance necessary to maintain
homeostasis.
• To balance out the increased phos from
skeletal effects, and GIT effects of
calcitriol, PTH acts secondarily to increase
renal phos excretion
– By decreasing activity of sodium phosphate cotransporter in prox renal tubule.
Uraemic Secondary
Hyperparathyroidism
Cause
PO4 retention
Low 1,25 Vit D synthesis
Effects
Proximal weakness, Bone pain (late)
Alk Phos, bone erosions
Rx
Diet, PO4 binders
Calcitriol, PTHx (usually for 3o)
Secondary hyperparathyroidism
• In renal failure driven by
– Hypocalcaemia
– Decreased vitamin D
– hyperphosphataemia
PO4
Ca
GFR
1,25 DHCC
Calcitriol
PTH
hyperPTH in CKD
• In CKD is a progressive disorder.
• Involves both increased secretion PTH &
hyperplasia
• Can occur once eGFR < 60
• PTH levels increase progressively as renal
function declines and by CKD stage 5(<15) most
pt’s expected to have this.
• Usually the 1st sign and occurs before lab tests
pick up 
phosphatemia, ↓ Vit D3 and ↓ calcium
– Presumably as PTH is maintaining homeostasis.
• Unless treated, progresses and frequency of
parathyroidectomy proportional to yrs on dialysis
Overview
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Pathogenesis
Normal Bone Remodeling
Hyperparathyroidism
Classifications of bone disease in CKD
Classification of
Bone Disease in CKD
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The circulating level of PTH is primary
determinant of bone turnover in CKD
Type of bone disease depends upon
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Age of pt
Duration of kidney failure
Severity of hyperPTH
Type of dialysis
PTH & Vit D receptors, as well as calcium
sensors are present on osteoblasts
Types of Renal Bone Disease
• Traditionally classified according to degree of
abnormal bone turnover
High Turnover (osteitis fibrosa)
– Hyperparathyroidism
Low turnover
– Adynamic
- Osteomalacia
Beta 2 MG amyloidosis
Osteoporosis
– Post-menopausal
- Post-transplant
Uraemic Bone
Remodelling
Cycle
Resorption
osteoclasts
Quiescence
Retards:
Vit D3, Age,
Diabetes, Al3+, PTHx
Accelerates:
High PO4 or
Low Ca2+, Vit D3,
Formation
osteoblasts 
matrix
Mineralisation
Uraemic Bone
Remodelling
Cycle
Accelerates:
High PO4 or
Low Ca2+, calcitriol,
HCO3, oestrogen
Via PTH*, IL-1,6 & TNF
Resorption
osteoclasts
Quiescence
Retards:
Calcitriol*, Age,
Diabetes, Al3+, PTHx
Formation
osteoblasts 
matrix
Mineralisation
*Acts via
osteoblasts
High turn over bone disease
• Due to excess PTH
• Increased bone turnover activity (greater
number of osteoclasts and osteoblasts) and
defective mineralization.
• Associated with bone pain and increased
risk of fractures.
• Severe symptomatic disease is currently
uncommon with modern therapy.
Mixed uraemic bone disease
• Mixture of high turn over bone disease and
osteomalacia
Osteomalacia
• Formally linked to aluminium toxicity
– From aluminium based phosphate binders
– From contamination of water in diasylate
solutions
Adynamic bone disease
• Characterized by low osteoblastic activity and bone
formation rates
• Seen in up to 40% HD and 50% PD
• May be due to excess suppression of the parathyroid gland
with therapies, particularly calcium-containing phosphate
binders and vitamin D analogues.
• Typically maintain a low serum intact PTH concentration,
which is frequently accompanied by an elevated serum
calcium level.
• Felt to represent a state of relative hypoparathyroidism
Clinical manifestations of bone
disease
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Most with CKD and mildly elevated PTH
are asymptomatic
When present classified as either
1. Musculoskeletal
2. Extra-skeletal
Musculoskeletal
• Fractures, tendon rupture and bone pain
from metabolic bone disease, muscular pain
and weakness.
• Most clinically significant is hip fracture,
seen in CKD 5 (and is associated with
increase risk of death)
– NB. In dialysis pts there is already a 4.4 x
increase risk of hip fracture.
Extra-skeletal
• Important to recognise disordered bone and
mineral metabolism is a systemic disorder
affecting soft tissues, particularly vessels,
heart valves and skin.
• CVD accounts for around half of all deaths
of dialysis patients.
• Coronary artery and vascular calcifications
occur frequently in CKD 5 (and increase
each year on dialysis)
Types of calcification
1. Focal calcification associated with lipid laden
atherosclerotic plaques
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Increases fragility and risk of plaque rupture
2. Diffuse calcification
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not in atherosclerotic plaques and occurs in media of
vessels
Called “Monckeberg’s sclerosis”
Increases blood vessel stiffness and reduces vascular
compliance
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Results in widened pulse pressure
Increased afterload
LVH
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Contributing to CVD morbidity
• As per Cherelle “If we X-Ray most of our
patients, they’ve got “tram tracks” – we
hardly need an angiogram!”
Types of calcification
• Calciphylaxis or calcemic uremic
arteriopathy
– Seen primarily in CKD 5
– Occurs in 1-4% of dialysis patients
– Presents with extensive calcification of the
skin, muscles and SC tissues.
• Extensive medial calcification of small arteries,
arterioles, capillaries and venules.
• Clinically they may have skin nodules, skin
firmness, eschars, livedo reticularis and painful
hyperaesthesia of the skin.
• May lead to non healing ulcers and gangrene
calciphylaxis
• A, Confluent calf plaques
(borders shown with arrows).
Parts of the skin are
erythematous, which is easily
confused with simple cellulitis.
B, Gross ulceration in the same
patient 3 months later. The black
eschar has been surgically
débrided. C, Calciphylactic
plaques, a few of which are
beginning to ulcerate.
(Photographs courtesy of Dr.
Adrian Fine. Up To Date)
Angulated black eschar with surrounding livedo.
Note the bullous change at the inferior edge of the eschar.
(courtesy Up To Date)
Amyloidosis
• Pts on dialysis for 7- 10 years can develop
osteoarticular amyloid deposits.
• May present with carpel tunnel syndrome
and arthritis
Overview
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•
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Pathogenesis
Normal Bone Remodeling
Hyperparathyroidism
Classifications of bone disease
Diagnosis of bone disease
Diagnosis of CKD bone disease
• Blood
– PTH
• Random circulating PTH (1/2 life 2-4 mins)
• Excreted renally so present for longer in RF
– Calcium
– Phosphate
• Bone biopsy
– no longer frequently performed
• Imaging
– In general not indicated
PTH levels
• Normal (Pathwest) 0.7 – 7.0 pmol/L
• In CKD there is end-organ resistance
• Hence, recommended levels are 2 – 3 x
normal.
Overview
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•
•
•
•
•
Pathogenesis
Normal Bone Remodeling
Hyperparathyroidism
Classifications of bone disease
Diagnosis of bone disease
Treatment of bone disease in CKD
Treatment of CKD bone disease
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Directed towards normalising serum
calcium, phosphate and PTH, while
minimizing the risks associated with Rx
Treatment of CKD bone disease
• Various Rx for secondary hyperPTH and
hyperphosphataemia include;
1. Dietary phosphorous restriction
2. Calcium and non-Ca phosphate binders
3. Calcitriol or other Vit D analogues
4. Calcimimetics
5. Parathyroidectomy
Coke &
dairy food
PO4
CaCO3 with meals
Ca
GFR
1,25 DHCC
Calcitriol
PTH
Phosphorus (oxidized form is phosphate)
• 80% in the bone
• Food products include; nuts, beer, chocolate,
coca-cola
• Normal level 0.8 – 1.5mmol/L (Pathwest)
• Passes into glomerular filtrate and 90%
reabsorbed
• Reabsorption decreased by PTH and by calcitonin
and increased if PTH is absent
• Low levels if hyperparathyroidism with excessive
losses in urine
• High levels in hypoparathyroidism or renal failure
Phosphate binders
• Calcium-based phosphate binders
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Calcium carbonate (Cal-Sup/Caltrate)
Only Cal-Sup i PBS/S100
Varies, eg. 1 BD, 1-4 TDS
Must be chewed with food to maximize
binding of ingested phosphorous.
Phosphate binders
• Non-calcium phos binder
• Sevelamer (available for 12 months)
– Often used in conjunction with Cal-sup
– Used when phos still high despite max Cal-Sup
(2 TDS)
– More costly
Phosphate binders
• Aluminium-containing phos binders
– Alu-tabs/aluminium hydroxide
– Most effective, but ceaesd use around 12
months ago when sevelamer and cinacalcet
available.
– Systemic absorption with subsequent
neurological, haematological and bone toxicity.
Calcitriol
• 1,25-(OH)2 Vitamin D3 or other analogues
bind to receptor on PT tissue and suppress
PTH production
PO4
Ca
GFR
1,25 DHCC
Calcitriol
PTH
Calcitonin
• Produced by parafollicular or C cells of the
thyroid gland
• Secreted when plasma calcium level rises
• Main action is the lowering of plasma calcium by
limiting bone resorption and it increases
phosphate excretion in the urine
Calcimimetics
• Calcium receptor-sensing agonists
• Act on PT gland and increase sensitivity of
receptor to calcium
• Cinacalcet (Sensipar)
– Significant decrease PTH, w/o Ca or phos
– Avoids calcification
PO4
Ca
GFR
1,25 DHCC
Calcitriol
PTH
Parathyroidectomy
• Last option
• Considered when other methods fail to ↓
PTH
• Either total or sub-total
– Used to re-implant in forearm.
Summary of Rx
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Dietary phosphate restriction
Phosphate binders
Calcitriol or other Vit D analogues
Calcium supplementation/calcimimetics
Parathyroidectomy
Prevention of osteodystrophy
Coke &
dairy food
PO4
CaCO3 with meals
Ca
GFR
1,25 DHCC
Calcitriol
PTH
Transplant
• Bony changes improve post Tx, but if
severe increased PTH, levels can persist for
up top 10 years.
• Although Tx corrects many conditions
leading to disordered mineral metabolism,
• Steroids may lead to bone fragility,
osteoporosis and increased fractures.
Case Studies
Case 1
MC
• Diabetic nephropathy – Haemodialysis
• Hypothyroidism
• Pancreatic pseudocyst
• Epilepsy
• Anaemia
• Hypertension
Case 1
• Currently PTH 104
• Ca corrected 2.04
• Po4 1.77
• Medications
– Calcium carbonate 2 three times with meals
– Calcitriol 1mic 3 times a week
Case 1
• What do we do?
• Thoughts?
Case 1
• This lady is non compliant!
• No point changing her regime if she is not
taking what you have written up
• Encourage compliance
• Explain the essential nature of compliance
with this therapy
Case 2
RJ
• Diabetes
• Anaemia
• Dementia
• Alcoholism
• End stage kidney disease – CAPD
• IHD/cardiomyopathy – recent massive AMI
• Syphilis
Case 2
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PO4 3.77
Ca 1.82
Product 6.86
PTH 166
• Thoughts?
Case 2
• Again non compliance
• Recent finding of around 20 webster packs
in his room
Case 3
DB
• Diabetes
• End stage kidney disease – HD
• Hypothyroidism
• Hypertension
• Anaemia
• Recurrent laryngeal palsy
• IHD
• Constipation
• Depression
• Cerebrovasvcular disease
Case 3
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Ca 2.72
PO4 1.39
PTH 20.1
Product 3.7
• Thoughts?
Case 3
• Has had parathyroidectomy (hence the
recurrent laryngeal palsy) and parameters
are exactly where we want them
• Meds
– Calsup 2 tds with food
– Calcitriol 6 (1.5mics) twice a week at dialysis
Case 4
ID
• Usual litany of problems
• HD
• Po4 1.0
• Ca 2.6
• PTH 3.1
• Thoughts?
Case 4
• Oversuppressed
• Need the PTH to be 2-3 times normal or patient
will likely get adynamic bone disease
• Back off Vit D and Calcium
• In this case pt was on Calsup 2 tds and Calcitriol 6
(1.5mics) twice a week. Decrease Calcitriol eg
1.5mics once a week and decrease Calsup to 1 tds
• Monitor
Thank you!
renalgp@kamsc.org.au
Calcium and Phosphorus Homeostasis
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References
• Dr Mark Thomas, Nephrologist, Royal
Perth Hospital
• Primer on Kidney Diseases, 5th Edition.
Greenberg, National Kidney Foundation.
2009