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 Sevalamer Calcium binders 25% Aortic Calcification 28%* 24% 20 14% 15 10 6% 5% 5 0 1% 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