CKD Renal bone disease Dr Mike Stone University Hospital Llandough Affects 5 10 % of population Increasingly common Ageing, diabetes, undetected hypertension Associated with: Cardiovascular disease Premature death Disorders of bone and mineral metabolism Revised classification CKD CKD mineral bone disorder Systemic disorder of mineral and bone metabolism including one or more of: Abnormalities of Ca 2+, PO 4, PTH, or Vit D Abnormalities of bone turnover, mineralization, volume, strength Vascular or other soft tissue calcification KDIGO 2013 KDIGO Kidney International 2009; 76 (Suppl 113): S1 S130 Renal osteodystrophy Skeletal pathology component of the syndrome Histomorphometry Normal serum levels of Ca 2+ and PO 4 maintained by 3 hormones PTH 1,25(OH) 2 D calcitriol Phosphatonins FGF23 KDIGO 2009 Act on kidney, bone and intestine 1
Kidneys responsible for: PTH mediated PO 4 excretion and Ca 2+ reabsorption Increased PO 4 excretion mediated by FGF23 Conversion of 25(OH)D to 1,25(OH) 2 D Disturbances in mineral metabolism are common occurring early in CKD Begins in CKD 3: Unable to fully excrete PO 4 causing in FGF23 Compensatory 2 o hyperparathyroidism production of 1,25(OH) 2 D Changes in FGF23 and PTH occur first Isakova T 2011 Kidney Int 79 As CKD progresses PO 4 will tend to Ca 2+ 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 PO 4 binders 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) osteomalacia Mixed - hyperpth and mineralisation defect Histology may transform from one category to another 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 Osteosclerosis may include woven bone Cortical bone loss may outstrip trabecular Jamal S Osteopor Int 2012; 23 2
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 Esp low bone turnover Medical management of Treatments have evolved from better understanding of pathophysiology 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 Diagnosis of To define and monitor : Measure PTH, 25(OH)D, calcium and phosphate Serum FGF23 not routinely measured Bone markers, radiographs, bone biopsies not commonly used BUT Bone specific alkaline phosphatase (balp) probably is useful Diagnosis of 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 p640-650 Clinical practice guidelines by National Kidney Foundation: Kidney disease: Outcomes Quality Initiative KDOQI 2003 Kidney Disease: Improving Global outcomes KDIGO 2009 KDIGO 2009 - More emphasis on lack of evidence! Treatment Goals Aim for calcium and PO 4 in normal range 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 times the ULN Avoid adynamic bone disease Esp ESRD, elderly, diabetes 3
Treatment Goals 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 Phosphate binders Ca 2+ salts (acetate binds more PO 4 than carbonate) Risk of hypercalcaemia Sevalamer Avoids hypercalcaemia GI side effects Binds tacrolimus, frusemide Lanthanum Avoids hypercalcaemia Better tolerated Controlling PTH levels Calcitriol or alfacalcidol and/or calcimimetics Titrate against PTH levels Look for trends in PTH levels Take into account calcium and PO 4 levels Calcimimetics lower Ca 2+ and PO 4 Vitamin D analogues increase Ca 2+ and PO 4 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 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 Osteoporosis 24% CrCl <35 50% CrCl < 35 if >80 y/o Klawansky OI 2003 4
Percent Incidence at Month 36 Fractures in CKD could be due to osteoporosis, 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 4-5 DXA less reliable We do measure BMD in patients with fractures Vertebral imaging can be useful Not sure if antiresorptives effective Antiresorptives may well be harmful if Adynamic bone disease or osteomalacia Low PTH and/or low balp My own opinion Data for antiresorptives CKD 4 Post hoc analyses Risedronate Denosumab Limited vertebral fracture data Safety looked alright Consistent risk reduction in vertebral fracture at 36 months by baseline CrCl in FREEDOM 10 9 8 7 6 5 4 3 2 1 0 N1 7.2 2.3 Placebo (N=3906) 9.1 3.2 DMAb (N=3902) 3691 3702 33 31 1309 1332 1952 1924 394 413 All 15 29 7.0 2.9 30 59 7.0 1.8 60 89 8.1 3.1 90 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. 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 28 Denosumab Be very careful if GFR < 30 Risk of hypocalcaemia Can be profound and prolonged if CKD 5 Do not use it if adynamic bone disease Suggest : do not use in CKD 5 MHRA safety update 2012 and my own opinion 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 once per fortnight IV ibandronate once per 3 to 6 months Otherwise treat and preferably have patient on calcitriol/alfacalcidol 5
Renal transplantation Practical message Most things get better! Bone strength Sometimes best to wait for transplant rather than try and tackle their bone disease with unproven treatments Further reading KDIGO guidelines for Kidney International 2009; 76 (Suppl 113): S1 S130 Primer on the Metabolic Bone Diseases and disorders of Mineral Metabolism, 8 th Edition, Rosen CJ (Ed) Wiley-Blackwell, 2013. Chapters 77 and 78 Harding KA et al ASBMR Annual Meeting 2000 Further reading The spectrum of Mineral and Bone Disorders in Chronic Kidney Disease, Second edition, Olgaard K, Salusky S, Silver J (Eds) OUP, 2010 6