1. Renal bone disease Professor Mike Stone University Hospital Llandough

2. CKD Affects 5 – 10 % of population Increasingly common
Ageing, diabetes, undetected hypertension
Associated with:
Cardiovascular disease
Premature death
Disorders of bone and mineral metabolism

3. Revised classification CKD
KDIGO 2013

4. CKD-MBD CKD mineral bone disorder
Systemic disorder of mineral and bone metabolism including one or more of:
Abnormalities of Ca2+, PO4, PTH, or Vit D
Abnormalities of bone turnover, mineralization, volume, strength
Vascular or other soft tissue calcification
KDIGO Kidney International 2009; 76 (Suppl 113): S1–S130

5. Renal osteodystrophy
Skeletal pathology component of the CKD-MBD syndrome
Histomorphometry
KDIGO 2009

6. CKD-MBD Normal serum levels of Ca2+ and PO4 maintained by 3 hormones
PTH
1,25(OH)2D
calcitriol
Phosphatonins
FGF23
Act on kidney, bone and intestine
CKD-MBD

7. CKD-MBD Kidneys responsible for:
PTH mediated PO4 excretion and Ca2+ reabsorption
Increased PO4 excretion mediated by FGF23
Conversion of 25(OH)D to 1,25(OH)2D

8. CKD-MBD
Disturbances in mineral metabolism are common occurring early in CKD
Begins in CKD 3:
Unable to fully excrete PO4 causing in FGF23
Compensatory 2o hyperparathyroidism
production of 1,25(OH)2D
Changes in FGF23 and PTH occur first
Isakova T 2011 Kidney Int 79

10. As CKD progresses … PO4 will tend to Ca2+ will at first tend to
In more advanced disease especially for patients on dialysis, hypercalcaemia may occur
Hyperplasia of PTh glands
Iatrogenic
Calcitriol, calcium containing PO4 binders

11. Renal osteodystrophy (ROD)
Seen universally in those on dialysis
Majority of patients with CKD 3b – 5
High bone turnover - predominant hyperPTH
Low bone turnover – adynamic (aluminium induced) and/or osteomalacia
Mixed - hyperPTH and mineralisation defect
Histology may transform from one category to another

12. CKD-MBD Osteoporosis may coexist with ROD
hyperPTH
Vitamin D deficiency
Acidosis
sclerostin
Fracture rates are about 4 fold higher and to a certain extent independent of BMD
Cortical bone loss may outstrip trabecular
Jamal S Osteopor Int 2012; 23

13. CKD-MBD Clinical manifestations
Fracture risk higher
Vascular calcification
Systolic hypertension, cardiovascular disease
Heterotopic mineralisation
Skin: calciphylaxis – skin necrosis
Lung: restrictive lung disease
Heart – arrhythmias, CCF
Tumoral calcinosis: periarticular
Bone pain

14. Medical management of CKD-MBD
“Conspicuous lack of robust evidence esp in context of clinically relevant outcomes”
Cunningham J The spectrum of bone and mineral disorders in CKD. OUP, 2010

15. Diagnosis of CKD-MBD To define and monitor CKD-MBD:
Measure PTH, 25(OH)D, calcium and phosphate
Base decisions on serial measurements and consider results together
Serum FGF23 not routinely measured
Bone markers + bone biopsies not commonly used
Renal Association Guidelines 2015

16. Diagnosis of CKD-MBD
No test other than bone biopsy identifies subtypes of bone disease in CKD
BUT
Not clear that bone biopsy result:
is clinically important or
can be used to direct treatment
Alshayeb and Quarles. Primer on the Metabolic Bone Diseases and disorders of Mineral Metabolism Ch 78 p

17. Treatment of CKD-MBD
Clinical practice guidelines by National Kidney Foundation:
Kidney disease: Outcomes Quality Initiative
KDOQI 2003
Kidney Disease: Improving Global outcomes
KDIGO 2009
Clinical Practice Guideline Update
KDIGO 2017
Renal Association (UK) Guidelines 2015

18. Treatment of CKD-MBD KDIGO 2017 - More emphasis on lack of evidence!
Treatment Goals
Aim to avoid hypercalcaemia
Mild hypocalcaemia may be acceptable
calcimimetics
Lower elevated PO4 into normal range

19. Treatment of CKD-MBD Treatment Goals
PTH optimum level “unknown” except CKD 5D where aim for 2 to 9 x ULN
Aim for normal PTH in CKD 3
As CKD advances aim for PTH no lower than 2.5 to 3 x ULN
Modest increases in PTH may be appropriate adaptive response
Look for trends eg progressively rising
KDIGO 2017

20. Treatment Goals CKD-MBD Rationale for PTH
PTH too high
leads to progressive PTh bone disease, fractures, tertiary hyperparathyroidism, parathyroidectomy
Association with cardiovascular events and death
PTH too low
Increases risk of low bone turnover
? relevance

21. Treatment of CKD-MBD Phosphate binders
Ca2+ salts (acetate binds more PO4 than carbonate)
Risk of hypercalcaemia
Non Ca2+
Avoid hypercalcaemia
Generally preferred
KDIGO 2017

22. Treatment of CKD-MBD Controlling PTH levels
CKD 4 to 5
Calcitriol and vitamin D analogues no longer recommended for routine use
Reserve for progressive and severe hyperparathyroidism
KDIGO 2017

23. Treatment of CKD-MBD Controlling PTH levels
Calcitriol or alfacalcidol and/or calcimimetics
Titrate against PTH levels
Look for trends in PTH levels
Take into account calcium and PO4 levels
Calcimimetics lower Ca2+ and PO4 (CKD5)
Vitamin D analogues increase Ca2+ and PO4

24. Treatment of CKD-MBD Controlling PTH levels
Vitamin D3/D2 supplements
Worth correcting vitamin D deficiency/insufficiency in all
Peripheral hydroxylation in cardiovascular and immune system
Association with better clinical outcomes
Vitamin D supplements can modestly suppress PTH in CKD 3 - 4
KDIGO 2009

25. Treatment of CKD-MBD Controlling PTH levels
Parathyroidectomy
Most severe forms of hyperparathyroidism
Medical management has failed
Usually ESRD
Indications
Severe hypercalcaemia or hyperphosphataemia
Symptomatic bone disease
Calciphylaxis
KDIGO 2009

26. CKD-MBD 62 y/o man Haemodialysis Calciphylaxis Vertebral fractures
Peripheral vascular disease
Skin necrosis
R BKA
Vertebral fractures
Parathyroid bone disease
Refused surgery
PTH = 270 (ULN 5)

27. CKD-MBD 62 y/o man

28. CKD-MBD 62 y/o man Treated with Cinacalcet
Serum calcium lower limit of normal
started on calcitriol
PO4 normal
PTH decreased to 130
Died from multiorgan failure 6 months later

30. Osteoporosis and renal disease
24% CrCl <35
50% CrCl < 35 if >80 y/o
The current analysis has shown that women and men with osteoporosis, who are typically in the older age range, are concentrated in the low range of creatinine clearance. BMD and CrCl decrease with age
Klawansky OI 2003

31. Osteoporosis and renal disease
Fractures in CKD could be due to osteoporosis, CKD-MBD or both
CKD 1-3
RCTs include patients with CKD 1 to 3 so OK to diagnose and treat as usual
Preferably correct any biochemical abnormalities of CKD-MBD

32. Osteoporosis and renal disease
CKD 4-5
DXA less reliable but is now recommended
We do measure BMD in patients with fractures
Vertebral imaging can be useful
Not sure if antiresorptives effective
Antiresorptives may be harmful if
Adynamic bone disease or osteomalacia
Low PTH and/or low bALP
KDIGO 2017
My own opinion

33. Osteoporosis and renal disease
Data for antiresorptives CKD 4
Post hoc analyses
Risedronate
Denosumab
Limited vertebral fracture data
Safety looked alright

34. Consistent risk reduction in vertebral fracture at 36 months by baseline CrCl in FREEDOM
Placebo (N=3906)
DMAb (N=3902) 10
9.1
Percent Incidence at Month 36 9
8.1 8
7.2
7.0
7.0 7 6 5 4 * *
3.2
3.1 *
2.9 3
2.3 * 2
1.8
Jamal ASBMR 2010 1 N1
3691
3702 33 31
1309
1332
1952
1924
394
413
All
15 – 29
mL/min
30 – 59
mL/min
60 – 89
mL/min
≥ 90
mL/min
N = number of randomized subjects. N1 = number of randomized subjects with an evaluation during the time period of interest. There were no subjects with a CrCl < 15 mL/min. *P < 0.05
The interaction terms were NOT statistically significant, indicating no difference in effect of DMAb by level of renal function
SA Jamal Oral Abstract ASBMR 2010 34

35. Osteoporosis and renal disease
Denosumab
Be very careful if GFR < 30
Risk of hypocalcaemia
Can be profound and prolonged if CKD 5
Do not use it if PTH very high
Suggest : do not use in CKD 5
MHRA safety update 2012 and my own opinion

36. Osteoporosis and renal disease
Practical message
In patient with severe renal disease having low trauma fractures with low BMD and no clear evidence of low bone turnover
Reasonable to consider oral risedronate
IV ibandronate once per 3 to 6 months
Otherwise treat CKD-MBD and preferably have patient on calcitriol/alfacalcidol

37. Renal transplantation
Practical message
Most things get better!
CKD-MBD
Bone strength
Sometimes best to wait for transplant rather than try and tackle their bone disease with unproven treatments
Harding KA et al ASBMR Annual Meeting 2000

38. Summary CKD-MBD Monitor serum Ca2+, PO4 , PTH, 25(OH)D
Modestly raised PTH acceptable
Evidence base for treatment poor
Osteoporosis often coexists
CKD 4/5 – cautious use of antiresorptives
CKD 5 – best to avoid denosumab

39. Further reading KDIGO guidelines for CKD-MBD
Kidney International 2009; 76 (Suppl 113): S1–S130
Clinical Update 2017 Kidney International Supplements 7: 1–59
Primer on the Metabolic Bone Diseases and disorders of Mineral Metabolism, 8th Edition, Rosen CJ (Ed) Wiley-Blackwell , Chapters 77 and 78

40. Further reading

41. Further reading
The spectrum of Mineral and Bone Disorders in Chronic Kidney Disease, Second edition, Olgaard K, Salusky S, Silver J (Eds) OUP, 2010