1. 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.Springer HealthcareSpringer Science+Business Media

2. 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.Springer HealthcareSpringer Science+Business Media

3. Effect of sHPT on bone metabolism The reduction in renal function in CKD patients results in disturbed Ca 2+ and PO 4 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 Ca 2+ and PO 4 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.Springer HealthcareSpringer Science+Business Media

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

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

6. Baseline laboratory parameters ParameterValueKDOQI 2003 range (stage 5) Parathyroid hormone1000 ng/mL150–300 ng/mL Serum phosphate1.43 mmol/L1.13–1.78 mmol/L Serum calcium2.48 mmol/L2.10–2.37 mmol/L Serum 25(OH)D352 nmol/LNormal range: 75–300 nmol/L Serum bone alkaline phosphatase 26.5  g/LNormal range: 4–21  g/L Serum beta-crosslaps 3.0  g/LNormal range: <0.45  g/L KDOQI: Kidney Disease Outcomes Quality Initiative K DOQI 2003 Guidelines. Am J Kidney Dis 2003;42(Suppl 3): S1–S201 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

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

8. 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 to 200 ng/L PTH: parathyroid hormone © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

9. Multiple choice question 2 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 KD IGO: Kidney Disease Improving Global Outcomes © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

10. Increase in PTH Five months later serum PTH rapidly increased to 1200 ng/L due to patient spontaneously stopping cinacalcet Serum calcium decreased to 1.98 mmol/L, serum b-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 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

11. Multiple choice question 3 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 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

12. Bone section showing high bone turnover Bone histology provided by Pascale Chavassieux, Faculty of Medicine Lyon-Est, Lyon, France Osteoid surfacesWoven boneResorption surfaces with osteoclasts © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

13. 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.Springer HealthcareSpringer Science+Business Media

14. PTH level and cinacalcet therapy 0 500 1000 1500 2000 2500 3000 0246810121416182022 Time (months) PTH (ng/L) 0 30 60 90 120 150 180 Cinacalcet (mg) PTHCinacalcet 12 0 90 30 60 Figure reprinted with permission from Dr. Fouque PTH: parathyroid hormone © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

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

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