Metabolic Bone Diseases in Kidney Patients

Metabolic Bone Diseases in Kidney Patients Rubin Zhang, MD, PhD, FASN Section of Nephrology Department of Medicine LSU Health Sciences Center Objectives     High turnover bone disease: osteitis fibrosa cystica due to secondary hyperparathyroidism in CKD patients Low turnover bone disease: adynamic bone disease, osteomalacia Mixed bone disease, bone disease transformation Osteoporosis, avascular necrosis after kidney transplantation Normal Bone Metabolic Unit Normal Bone -Calcification -CVD / PVD -nervous system -immunologic -cutaneous Osteitis fibrosa cystica (OFC)    Cause: secondary hyperparathyroidism (SHPT) Increased bone resorption, extensive osteoclastic activity and endosteal fibrosis Biochemical profile: high Phos, low active vitamin D, relative low Ca, high PTH, elevated AP and osteocalcin (secreted by osteoblasts, marker of bone turnover) Osteitis Fibrosis Cystica Treatment of SHPT   Diet phosphorus restriction to 1,000 mg per day Calcium-containing phosphorus binders: Ca -carbonate (Tums), Ca –acetate (PhosLo), for patients have low calcium level Non-calcium containing binder, Sevalamer (Renagel), Lanthanum-carbonate (Fosrenol): for hypercalcemia (>10.5) or high CaxPhos product (>60)    Vitamin D analogs: three generations Calcimimetics: cinacalcet (Sensipar), binds to CaSR of parathyroid glands. Surgical parathyroidectomy  Change in Vascular Calcification Score By EBCT from Week 26 - Week 52 Coronary Artery Calcification 30 Median Percent Change 25 20 14% Sevalamer Calcium binders 25% 24% Aortic Calcification 28%* 15 10 6% 5% 1% 5 0 0 Week 26 Week 52 Week 26 Week 52 Chertow et al: Treat to Goal Study, KI, June 2002 EBCT Scan: Tubular Right Coronary Artery Vitamin D analogs       Regular Vit D (calciferol, ergocalciferol): from food, sun exposure 1st generation: calcitriol (1, 25-dihydroxy-vit D3), in 1971, 5060% hypercalcemia 2nd generation: alfacalcidol (1-alpha hydroxy-vit D3), in 1974, a prohormone of calcitriol, 15% hypercalcemia Doxercalciferol (Hectorol, 1-alpha hydroxy-vit D2), in 1974, a prohormone, much less hypercalcemia (5%) 3rd generation: paricalcitol (Zemplar, 19-Nor-1-alpha-25 dihydroxy-vit D2), in 1985, more potent PTH suppression, less Ca, Phos absorption, hypercalcemia -2% Zemplar has a survival benefit over calcitriol in ESRD patients Mean Percentage Changes in Ca, Phos, and PTH after Vitamin D Therapy in ESRD patients Teng, M. et al. N Engl J Med 2003;349:446-456 Teng, M. et al. N Engl J Med 2003;349:446-456 Kaplan-Meier Analysis of Survival According to the Type of Vitamin D Therapy Teng, M. et al. N Engl J Med 2003;349:446-456 Block, G. A. et al. N Engl J Med 2004;350:1516-1525 Summary  As kidney function diminishing, iPTH secretion increases and SHPT progresses, which causes osteitis fibrosa cystica    Treatment goal is to maintain iPTH at target level according the CKD stage Diet phosphorus restriction and phos binders Sevalamer (Renagel), Lanthanum carbonate (Fosrenol) and Al hydroxide (Amphogel) are non-calcium containing phos binder, decreases the risk of vascular and systemic calcification Vitamin D analogs can directly suppress iPTH, but they vary in Ca, Phos absorption. Paricalcitol has the least GI effects Cinacalcet (Sensipar) provides “chemical parathyroidectomy” Surgical parathyroidectomy    Aplastic bone disease       Causes: over suppression of PTH, low gonadal hormones, GH and IKGH-1 Low bone formation rate or remodeling: thin or no osteoid seams; little or no evidence of cellular activity (paucity of osteoblasts and osteoclasts) Biochemical Profile: high Ca, low PTH, AP and osteocalcin Treatment: decrease the suppression of PTH by reducing vitamin D and Ca supplements, using lower Ca bath PTH 1-84, PTH 1-34 (Teriparatide) supplement: stimulate bone formation Associated with high rate of fracture and hypercalcemia, high risk of vascular calcification and CVD/PVD Diagnosis of Aplastic bone disease     Tetracycline labeling: assess the kinetics of bone turnover rate Fluorescence-labeled tetracycline binds to newly formed bone at the bone / osteoid interface Two doses are given 2 weeks apart The distance between the two fluorescent labels tells the amount of new bone formed during that interval Double Tetracycline Labeling of Bone First label: tetracycline 250 mg tid po for 3 days Wait 2 weeks Second label: tetracycline 250 mg tid for 3 days Wait 3 to 5 days, then biopsy the bone NKF K/DOQI clinical practice guideline New PTH Assay     iPTH measured by “Nichols intact PTH Assay” (2nd generation) recognize 1-84 PTH and a truncated fragment 784 PTH 7-84 PTH lowers bone turnover; 1-84 PTH raises bone turnover The 3rd generation “ Nichols Biointact PTH” or “Scantibodies Whole PTH” assay measures only the full-length 1-84 PTH Scandibodies PTH Accuratio (1-84 PTH / 7-84 PTH) may better reflect bone turnover: ratio >2 high turn over; <1 low turn over; a cut point of 1 or 1.6 was also suggested Osteomalacia     Causes: vitamin D deficient, malnutrition, hypophosphatemia, aluminum toxicity A deficit in bone mineralization: wide osteoid seams, low bone formation, absence of osteoblasts, osteoclasts and endosteal fibrosis Biochemical profile: low Ca and Phos; PTH and AP may WNL or slightly high Treatment: address the causes; Ca and Vitamin D supplements Osteomalacia Aluminum Stain Desferoxamine Stimulation Test     Draw a baseline Al level (predialysis) Give DFO: 15 mg/kg (total <2g) DFO in 250 cc NS, IV drip slowly (in last hr of HD) Draw Al level 2 days later (at the following HD) Positive if the increment of serum Al > 50 ug/L Mixed bone Diseases and Transformation  Combination of different type of bone diseases can also exist: High turnover osteitis fibrosa mixed with low turnover osteomalacia due to Al toxicity Each type of bone lesion may evolve into another, depending on the clinical setting – reflecting the dynamic nature High turnover osteitis fibrosa transforming into a low turnover aplastic bone disease after aggressive suppression of hyperparathyroidism  Bone diseases after kidney transplantation 1. 2. 3. Pre-transplant uremic osteodystrophy: - its nature and evolution after KT remain unknown, largely due to lack of serial histological study by bone biopsy Avascular necrosis or osteonecrosis Osteopenia / osteoporosis from continuing bone loss (bone resorption > bone formation), increase bone fragility and fracture. Post-transplant Avascular Necrosis        Incidence: 3 to 16%; usually appears in first 1 to 2 years after KT Site: femoral head, knee, shoulder, elbow Joint pain, worsening by weight bearing Cause: mainly steroid, cumulative doses Risk: pre-existing bone disease, DM, SLE Diagnosis: MRI Treatment: resting, core decompression, joint replacement Post-transplant Osteoporosis - bone fracture      Fracture rate increases to 3% to 4 % per year in first 2 to 3 years after KT; then decreases Total fractures rate 15 -17%; symptomatic fractures 8% (4 to 11 %) Common sites: legs, vertebral bodies, hips and ribs BMD correlates to fracture rate in KT patients Prevention of BMD loss decreases bone fracture DEXA – dual energy X-ray absorptiometry T Score - compares the individual patient’s BMD with that of a race and gender matched young person at the peak of BMD. It is expressed as a standard deviation from the control. Osteoporosis Post-transplant Bone Loss possible causes          Pre-existing uremic osteodystrophy Steroid and CI induced bone loss Ongoing hyperparathyroidism Hyperphosphaturia, hypophosphatemia Poor allograft function, loop diuretics Acidosis / RTA Smoking, alcohol abuse Hypogonadism, Aging Chronic diseases, physical inactivity, poor nutrition, et al Post-transplant Osteoporosis: BMD loss     Primarily trabecular bone loss Rapid decline in BMD during first 6 to12 m: 3 to 7% at lumbar spine, 3 to 9% at femoral neck Then, either continue loss, stabilize or improve – depends on individual patient’s clinical setting (renal function, PTH, preventive measures, et al) Low BMD remains common in long term Julian BA et al: NEJM 1991; 325:544 Cayco AV et al: Transplantation 2000; 70:1722 Post-transplant Osteoporosis - role of steroid    It suppresses bone formation rate by inhibiting transformation of osteoblast from preosteoblast Also decreases intestinal Ca absorption; increases renal Ca excretion; inhibits sex hormones, ILGF-1 and other GHs The main cause of the early rapid bone loss after KT Post-transplant Osteoporosis – role of CIs     Animal studies: CI increases bone resorption Clinical studies: a significant correlation between BMD and CsA dose Tacrolimus may be less osteotoxic than CsA Cellcept and Rapamycin: effects on bone remodeling remain unknown Post-transplant Osteoporosis - HPT     Elevated PTH level usually declines after KT 30% patients have elevated PTH beyond 1 year in the presence of normal renal function and vitamin D metabolism, - tertiary HPT Biochemical profile: high Ca, low Phos; elevated AP and osteocalcin HPT causes continuing bone loss, should be treated Prevention & Treatment of Posttransplant Osteoporosis -1    Vitamin D (800 IU / d cholecalciferol) and Calcium (1200 mg / d) supplements are recommended to prevent steroid-induced osteoporosis BMD increases in treated Pt and decreases in untreated Pt, a difference of 6 -7% can be seen in 1 year after KT Calcitriol should be used when GFR < 30 cc/min, or secondary HPT Prevention and Treatment -2: control HPT      HPT: 70% spontaneous regression, or response to vitamin D suppression 30% pts have persistent high PTH BMD increases after surgical correction of HPT Surgical indications: persistant HPT after 1 year of KT, symptomatic / severe hypercalcemia (>11.5 mg/dl), symptomatic bone disease / fracture, vascular calcification / calciphylaxis, Cinacalcet Prevention and Treatment -3: HRT    Anti-resorptive effects, reduce bone turnover and prevent bone loss Estrogen, or selective estrogen -receptor modulator (raloxifene) should be used for postmenopausal recipients after KT, if not contraindicated Testosterone may be considered for men with documented hypogonadism and osteoporosis Prevention and Treatment -4: lowering steroid     Rapidly taper steroid to 5 -7.5mg / day Steroid-sparing protocols should be considered for those have pre-transplant osteoporosis Steroid withdrawal at 6 months improved BMD at 1 year after KT - in highly selected patients Few data support later steroid withdrawal (after 1 year) in stable patients – should not be advertised Prevention and Treatment -5: bisphosphonate      Anti-resorptive agents: increase osteoclast apoptosis, reduce active osteoclasts and bone resorption BMD difference of 6 to 9% after 1 year’s treatment in KT Alendronate 10mg/d, Risedronate 5mg/d, or Pamidronate 0.5mg/kg IV at the time of KT, and at 3 months after KT Esophageal erosion, hypocalcemia; not used if GFR < 30 mL/min or in pregnant women May worsen secondary HPT and osteomalacia Alendronate versus Calcitriol for the Prevention of Bone Loss after Cardiac Transplantation Shane, E. et al. N Engl J Med 2004;350:767 A total of 149 patients were randomly assigned to receive either alendronate (10 mg per day) or calcitriol (0.5 µg per day) a mean (±SD) of 21±11 days after transplantation. Hypercalciuria developed in 27 percent of the patients in the calcitriol group and 7 percent of those in the alendronate group (P=0.01). Intention-to-Treat Analysis of the Mean Percent Change in BMD from Base Line Shane, E. et al. N Engl J Med 2004;350:767 Prevention and treatment -6: others     Anti-resorptive agent calcitonin: inhibits osteoclast action, used for osteoporosis, hypercalcemia, pain from compression fracture, few side effects, less effective than bisphosphonate Anabolic agent strontium ranelate: stimulates bone formation and decreases bone resorption Anabolic agent PTH1-34 (periparatide) and PTH 1-84: stimulate bone formation AMG 162 monoclonal antibody against RANKL (receptor activator of nuclear factor kappa B ligand) - a key mediator of bone resorption