effect of cinacalcet on bone markers in a maintenance haemodialysis patient solenn pelletier, md and...

Effect of cinacalcet on bone markers in a maintenance haemodialysis patient

Solenn Pelletier, MD and Denis Fouque, MD, PhD

Hôpital E. Herriot

Lyon, France

© Springer Healthcare, a part of Springer Science+Business Media; 2010.

Objectives

• To discuss:— the clinical value of bone markers in the diagnosis of

CKD-MBD

— the effect of cinacalcet treatment on bone markers and metabolism

CKD-MBD: chronic kidney disease – mineral bone disorder© Springer Healthcare, a part of Springer Science+Business Media; 2010.

Effect of sHPT on bone metabolism

• The reduction in renal function in CKD patients results in disturbed Ca2+ and PO4

2- metabolism, impaired vitamin D action and increased PTH levels (secondary HPT)

• Secondary HPT stimulates bone demineralisation, leading to high bone turnover and the formation of osteitis fibrosa— Characterised by fragile bone structure, increased risk of

fracture and bone pain

• The increased bone turnover also results in increased turnover of Ca2+ and PO4

2- that can increase the risk of vascular calcification and CV events

CKD: chronic kidney disease; CV: cardiovascular; HPT: hyperparathyroidism; PTH: parathyroid hormone

Spasovski. Int Urol Nephrol 2007;39:1209–1216© Springer Healthcare, a part of Springer Science+Business Media; 2010.

Bone markers in CKD-MBD

• Several biochemical markers have been shown to be correlated with bone turnover including:— Bone alkaline phosphatase (b-ALP)

— Tartrate-resistant acid phosphatase (TRAP)

— Telopeptides of type I collagen (beta-crosslaps, CTx)

• Cinacalcet has been shown to reduce PTH levels and correct abnormalities in these bone markers in patients with CKD

CKD-MBD: chronic kidney disease – mineral bone disorder; PTH: parathyroid hormone

Shigematsu, et al. Am J Nephrol 2009;29:230–236, Yano, et al. J Bone Miner Metab 2010;28:49–54


Patient presentation

• A 42-year-old male patient— Diagnosed with ERSD secondary to Berger’s disease in

1989

— Began HD and then received a kidney transplant in 1996

— In 2005 he started HD again because of chronic rejection

• At the start of HD, secondary HPT was diagnosed with a serum PTH level of 1000 ng/mL despite active therapy with:— Vitamin D analogue (alfacalcidol 0.25 g/day)

— Calcium carbonate (4.5 g elemental calcium/day)

ESRD: end-stage renal disease; HD: haemodialysis; HPT: hyperparathyroidism; PTH: parathyroid hormone


Baseline laboratory parameters

Parameter Value KDOQI 2003 range (stage 5)

Parathyroid hormone 1000 ng/mL 150–300 ng/mL

Serum phosphate 1.43 mmol/L 1.13–1.78 mmol/L

Serum calcium 2.48 mmol/L 2.10–2.37 mmol/L

Serum 25(OH)D3 52 nmol/L Normal range: 75–300 nmol/L

Serum bone alkaline phosphatase

26.5 g/L Normal range: 4–21 g/L

Serum beta-crosslaps 3.0 g/L Normal range: <0.45 g/L

KDOQI: Kidney Disease Outcomes Quality Initiative

KDOQI 2003 Guidelines. Am J Kidney Dis 2003;42(Suppl 3): S1–S201© Springer Healthcare, a part of Springer Science+Business Media; 2010.

Multiple choice question 1

What does a higher than normal level of serum bone alkaline phosphatase indicate?

A. Increased serum calcium

B. Increased serum phosphate

C. Increased bone turnover

D. Decreased bone turnover

E. None of the above


Initial therapy

• Cinacalcet therapy (30 mg/day) and cholecalciferol (100,000 IU/month for 3 months) were initiated

• The patient’s serum PTH declined sharply to200 ng/L

PTH: parathyroid hormone



According to the KDIGO guidelines, which of the following is NOT a recommendation for a bone biopsy?

A. Unexplained fractures

B. Persistent bone pain

C. Elevated phosphate levels

D. Possible aluminium toxicity

E. Unexplained hypercalcaemia

KDIGO: Kidney Disease Improving Global Outcomes


Increase in PTH

• Five months later serum PTH rapidly increased to1200 ng/L due to patient spontaneously stopping cinacalcet

• Serum calcium decreased to 1.98 mmol/L , serumb-ALP rose to 71.2 g/L and serum beta-crosslaps were >6 µg/L

• Patient suffered thigh and knee pains and so a bone biopsy was performed – severe osteitis fibrosa was diagnosed

B-ALP: bone alkaline phosphatase; PTH: parathyroid hormone



What are the classical histological findings for osteitis fibrosa?

A. Extended resorption surfaces

B. Multi-nucleated osteoclasts

C. Osteoid surfaces covered by osteoblasts

D. Presence of fibrosis in the bone marrow

E. All of the above


Bone section showing high bone turnover

Bone histology provided by Pascale Chavassieux, Faculty of Medicine Lyon-Est, Lyon, France

Osteoid surfaces Woven bone Resorption surfaces with osteoclasts© Springer Healthcare, a part of Springer Science+Business Media; 2010.

Subsequent therapy

• Following therapy with cinacalcet (up to 120 mg/day) and alfacalcidol (1 µg/day) a sustained decrease in serum PTH was observed (to 270 ng/L)

• Following an additional couple of months, serum calcium, phosphate and PTH were corrected to within KDOQI guidelines, cinacalcet was tapered to 30 mg/day

• Serum 25(OH)D3 increased to 76 nmol/L, serum b-ALP decreased to 21 g/L, and serum beta-crosslaps decreased to 1.2 µg/L

B-ALP: bone alkaline phosphatase; KDOQI: Kidney Disease Outcomes Quality Initiative; PTH: parathyroid hormone

KDOQI 2003 Guidelines. Am J Kidney Dis 2003;42(Suppl 3): S1–S201© Springer Healthcare, a part of Springer Science+Business Media; 2010.

PTH level and cinacalcet therapy

0

500

1000

1500

2000

2500

3000

0 2 4 6 8 10 12 14 16 18 20 22Time (months)

PT

H (

ng

/L)

0

30

60

90

120

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alc

et

(mg

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PTH Cinacalcet

120

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30 30

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Figure reprinted with permission from Dr. Fouque

PTH: parathyroid hormone© Springer Healthcare, a part of Springer Science+Business Media; 2010.

Key learning points

• The monitoring of bone markers is a useful tool for monitoring bone health in patients with CKD-MBD

• Cinacalcet, in addition to effectively lowering PTH levels, can improve bone health, as suggested by normalisation of bone markers

CKD-MBD: chronic kidney disease – mineral bone disorder; PTH: parathyroid hormone


Conclusion

• In this 42-year-old patient with severe secondary hyperparathyroidism, treatment with cinacalcet effectively returned PTH levels to normal, and returned calcium and phosphate to levels within KDOQI guidelines

• In addition, cinacalcet normalised levels of bone markers, including bone alkaline phosphatase, indicating that calcimimetics, through their action on PTH, may have additional benefits for CKD-MBD patients

CKD-MBD: chronic kidney disease – mineral bone disorder; KDOQI: Kidney Disease Outcomes Quality Initiative, 2003; PTH: parathyroid hormone


effect of cinacalcet on bone markers in a maintenance haemodialysis patient solenn pelletier, md and...

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