AACE ANNUAL MEETING. Osteoporois and Fractures across the 5 stages of Chronic Kidney Disease. Boston, Mass Paul D. Miller, M.

Transcription

1 AACE ANNUAL MEETING Osteoporois and Fractures across the 5 stages of Chronic Kidney Disease Boston, Mass 2018 Paul D. Miller, M.D Medical Director

2 Paul D. Miller, M.D. Disclosures: Amgen (Consultant, Advisory Board, grants) Radius Health (Advisory Board, grants) Alexion (consultant, grants) Regeneron (consultant, grants) Merck and Co (consultant, grants) Eli Lilly and Co (Advisory board, grants, consultant) National Bone Health Alliance (scientific advisory board and research grants) EQUITY : NONE Speakers Bureaus: NONE

3 Fracture Risk is Very High In Stage 5 CKD ~ 50 % prevalence of fractures ~ 50% excess mortality as compared to age matched controls without stage 5 CKD Fractures occur ~ 10 years earlier than age matched, BMD matched patients without CKD Hip fractures risk 17X higher than age matched patients without stage 5 CKD Leinau L and Perazella MA. Sem Dialysis 19: 75 79, 2006 Bliue D, et al. JAMA 301: , 2009

4 Mortality is Much Higher Following Hip Fracture in ESRD Patients than Age Matched Controls 1 year mortality after hip fracture in stage 5D CKD: 60% 1 year mortality after hip fracture in age matched controls: 20% female 30% male 4 Leinau L and Perazella MA. Sem Dialysis 19: 75 79, 2006 Bliue D, et al. JAMA 301: , 2009

5 It s Just Not ESRD CKD stage 3 (GFR ml/min) also has a higher fracture risk than aged matched persons without CKD

6 Studies of Fracture Risk Associated with Age Related Reductions in GFR Author N Kidney Function Dukas 1 5,481 GFR: <65 ml/min Hip 1.57* ( ) Ensrud 2 9,704 Tiered GFR 60 ml/min ml/min <45 ml/min OR for Fracture (95% Confidence Interval) Vertebral 1.31* ( ) Hip ( ) 2.32 ( ) Radial 1.79* ( ) Fried 3 4,699 Tiered Cystatin-C <0.92 mg/l mg/l mg/l 1.22 mg/l Men at Hip ( ) 0.80 ( ) 1.25 ( ) Women at Hip ( ) 1.49 ( ) 1.66 ( ) Nickolas 4 6,270 GFR: <60 ml/min Hip 2.12 ( ) *P<0.01; P for trend <0.05 Mild to moderate kidney impairment is associated with an approximate doubling in OR of all fractures as compared to age matched people with normal kidney function 1.Dukas L et al. Osteoporos Int. 2005;16: Ensrud KE et al. Arch Intern Med. 2007;167: Fried LF et al. J Am Soc Nephrol. 2007;18: Nickolas TL et al. J Am Soc Nephrol. 2006;17:3223.

7 Fractures In Chronic Kidney Disease 1. Hyperparathyroidism 2. Adynamic bone disease 3. Osteomalacia 4. Post transplantation bone disease 5. Osteoporosis And all can have low T scores and altered bone quality Atsumi K, et al Am J Kidney Dis 1999; 33(2): Gupta A, et al. Journal of Bone and Mineral Research 12(Suppl. 1):S274. Stehman Breen CO, et al. Kidney Int 2000; 58(5): Fried LF et al J Am Soc Nephrol 2007; 18: Coco M and Rush H. Am J Kid Dis 2000; 36 (6): Nickolas TL et al. Kid Internat 2008; 74(6): Miller PD Bone Key 2014; 3: Paranhos-Neto FP, et al. HRpQCT and microstructure in stage 3-4 CKD Clin Nephrol Jan;89 (2018)

8 Fractures in CKD Renal Bone Disease Osteoporosis

9 Osteoporosis: Identifying the Problem A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength is a composite of bone density and bone quality Osteoporotic bone NIH Consensus Development Conference on Osteoporosis, Healthy bone 9

10 Osteoporosis Compromises Bone Strength Increases Risk of Fracture Bone Strength Bone Quality + 1. Architecture 2. Turnover 3. Damage Accumulation 4. Mineralization 5. Collagen quality Bone Density abmd = g/cm 2 vbmd = g/cm 3 Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 2001

11 Normal Moderate Osteoporosis Severe Osteoporosis Courtesy Dr. A. Boyde

12 How Do We Measure bone quality?

13 HRCT vs HRpQCT vs Bone Bx HRCT microns HRpQCT 82 microns MicroCT microns

14 The Office Based Bone Quality Measurement Tool

15 Dr. P. Miller s Patented Bone Quality Meter $14.95

16 Discriminating Among The Renal Bone Diseases Bone Biopsy Biochemical Markers of Bone Turnover

17 2 Renal Bone Diseases to potentially avoid turning bone turnover down Osteomalacia Adynamic bone disease

18 Bone Biopsy in CKD 1. Is the gold standard for diagnosis of renal bone disease and for defining the bone turnover activity. 2. Is the ONLY means for measuring nonmineralized surfaces; osteoid thickness; BFR/BS; MS/BS; and tetracycline labels. 3. Require double tetracycline labeling for quantitative bone histomorphometry 4. Is safe and has very low morbidity (including post op pain) in experienced operators 5. May be needed before bone turnover is turned down

19 Courtesy of Dr. Elliott Schwartz

20 How can we avoid needing a bone biopsy to discriminate among the renal bone diseases? Biomarkers MAY OFFER HOPE

21 PTH and BSAP combining the best of both worlds 1. PTH extremes ( < 100 pg/ml) or (> 600pg/ml) high specificity for adynamic or OFC (hyperparathyroid bone disease). 2. TNSAP or Bone specific alkaline phosphatase ( lower quartile) has a high PPV (80%) for low bone turnover. 3.TNSAP or BSAP correlate with PTH values in stage 5D CKD: both may be increased on bone biopsy in established high bone turnover. 4. Combining the lower quartile BSAP and PTH < have a high PPV (90%) for adynamic bone disease. Garrett G et al CJASN 2013 Couttenye C et al Nephrol Dialysis Transpl 2009 Sprague S et al Am J Kid Dis 2016

22 The serum biomarkers ipth, whole PTH, and balp were able to discriminate low from non-low BFR/BS, whereas ipth and balp were able to discriminate high from nonhigh BFR/BS. The best PTH cutoff to discriminate low from non-low BFR/BS was <103.8 pg/ml, and to discriminate high from non-high BFR/BS was >323.0 pg/ml. The best cutoff for balp to discriminate low from non-low BFR/BS was <33.1 U/L, and for high from non-high BFR/BS, 42.1U/L. Sprague SM, et al. Diagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis Am J Kidney Dis. 2016;67(4):559-66

23 Bone Turnover Markers and HR pqct The biomarkers balp, intact PINP, and TRAP5b and radius HR-pQCT parameters can discriminate low from non-low bone turnover. Despite poor diagnostic accuracy for low bone turnover, ipth can discriminate high bone turnover with good accuracy. Salam S, Gallagher O, Gossiel F, Paggiosi M, Khwaja A, Eastell R. J Am Soc Nephrol Diagnostic Accuracy of Biomarkers and Imaging for Bone Turnover in Renal Osteodystrophy.

24 Correlation between bone turnover on histomorphometry and BTMs Formation Resorption Correlation between ipth and BFR/BS, rho=0.42 (p<0.01) Salam et al. J Am Soc Nephrol Mar 19.

25 Elevated BSAP Excludes adynamic bone disease (unless there has been a recent fracture) Could indicate osteomlacia

26 Elevated BSAP (DDX) 1.Severe primary hyperparathyroidism 2. Hyperthyroidism 3. Metastatic cancer in bone 4. Paget s disease of bone 5. Recent large bone fracture 6. Osteomalacia 7. Severe (< 8 10 ng/ml) vitamin D deficiency 7. Space travel 8. Immobilization 9. Treatment with anabolics (teriparatide or abaloparatide) 10. Treatment with strontium ranelate (Europe) 11. Future: treatment with anti sclerostin antibody 12. High bone turnover osteoporosis

27 Osteomalacia Thick Trabeculae Increased Osteoid A 25X B 100X Unstained, Fluorescent for Tetracycline Von Kossa, H&E Stain, Fluorescent for Osteoid Peri-osteocytic Osteoid No label Osteoid Diffuse label Single label C 100X D 100X Courtesy of PD Miller

28 Osteomalacia: always has a cause Severe 25 OHD deficiency (< 8 ng/ml). Chronic hypophosphatemia Vitamin D resistant rickets Renal tubular acidosis Oncogenic osteomalacia TIO: (low serum PO⁴, elevated FGF 23, low, 1, 25 D, phosphaturia) X linked hypophosphatemia (XLH)

29 Biochemical Tests to Screen for Etiologies of Osteomalacia 25D 1,25D ipth Serum and urine phosphorus Electrolytes, arterial blood gases, urine ph (looking for RTA). FGF 23 BSAP PHEX gene

30 Low BSAP HPP Renal adynamic bone disease Treatment with anti resorptive agents Hypoparathyroidism Vitamin D intoxication (perhaps via hypercalcemia and PTH suppression) Celiac disease Cardiac bypass Clofibrate Cushings Disease Massive transfusions Milk alkali syndrome Vitamin C deficiency Wilson s disease

31 Adynamic Bone Disease Absence of single tetracycline labels

32 Normal Double Tetracycline Labels

33 Renal Adynamic Bone Disease

34 Renal Adynamic Bone Disease 1. Seen more in diabetics with stage 5 or 5D CKD 2. Seen more often in chronic peritoneal dialysis 3. Iatrogenic is due to over suppression of PTH 4. Biochemistries can be helpful 5. Bone Biopsy is the Gold Standard HIGH total serum calcium concentration may be seen despite (PTH suppressed )

35 Therapies for osteoporosis: USA Hormone therapy Raloxifene Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Calcitonin Denosumab (anti rank ligand antibody) Teriparatide Abaloparatide (Romosozumab Registration under FDA review)

36 Treatment of Osteoporosis in CKD 1. Stage 1 3 CKD: Treatment does not differ as in patients with PMO since clinical trials randomized patients down to GFR of 30 ml/min 2. Stage 4 CKD: Management dependent on considerations for off label use for BP s; no GFR cut off for denosumab. Post hoc analysis show efficacy and safety through 3 years of risedronate, alendronate and raloxifene and denosumab down to egfr of 15 ml/min ; Teriparatide to egfr of Stage 5/5D CKD: No data off label consideration for fracturing patients, e.g. very high risk with established osteoporosis. Miller PD. Chronic kidney disease and the skeleton. Bone Res (2):

37 The Anabolics teriparatide and abaloparatide and, hopefully romosozumab

38 Anabolic Agents Improve Bone Quality Teriparatide (1 34 hpth) Abaloparatide (PTHrp analogue) Romosozumab (monoclonal antibody to sclerostin)

39 Healed Microfracture with Anabolics Provided by D. Dempster, Ph.D., Helen Hayes Hospital, NY

40 Anabolics for Idiopathic Adynamic Bone Disease? Single case study with paired bone biopsies Palcu P et al. Am J Kid Dis 2015

41 Effect of Teriparatide on Idiopathic Renal (5D) Adynamic Bone Disease Palcu P et al. Am J Kid Dis 2015

42 Effect of Teriparatide to Improve Mineralization in Stage 5D CKD Palcu P et al Am J Kid Dis 2015

43 Abaloparatide Abaloparatide is a novel synthetic peptide analog of hpthrp(1 34) Enhanced PTH1 Receptor RG/RO selectivity as compared to PTH or PTHrP Preclinical demonstration of significant BMD increases, restoration of bone microarchitecture, and increased bone strength ENDO 2014 Hattersley et al ENDO 2015 Bahar et al

44 SN2 TC2 Risk Reduction of New Vertebral Fractures Modified ITT Population* N= Proportion of Patients with New Vertebral Fractures, % % (n=30) Placebo n=711 86% 80% 0.6% (n=4) Abaloparatide SC n= % (n=6) Teriparatide n=717 *Includes all ITT patients who had pretreatment and postbaseline evaluable radiologic assessments. P < vs placebo. Adapted from Miller et al. JAMA. 2016;316:

45 Slide 44 SN2 Shari Noble, 12/20/2016 TC2 Per Ted's recommendation, added Adapted from in front of Miller et al, etc. Rationale is that all of the data are in Miller et al, and the figure was generated for this deck. Thomas, Camille, 1/20/2017

46 Risk Reduction of Nonvertebral Fractures 5 ITT Population N= %* Proportion of Patients with Nonvertebral Fractures, % % (n=33) Placebo n=821 *P = vs placebo; NS vs placebo. Based on cumulative Kaplan Meier estimates ITT at 19 months. 2.7% (n=18) Abaloparatide SC n=824 NS 3.3% (n=24) Teriparatide n=818 Miller et al. JAMA. 2016;316:

47 Abaloparatide Registration Trial (ACTIVE) Renal Impairment Subgroups Pre specified by Baseline egfr Bilezikian JP et al ASBMR 2016

48

49 Effect of Renal Function on Changes in PINP Concentrations with Teriparatide PINP (3 months) Median Change from Baseline [ng/ml] ((25th, 75th percentiles) * * * * * * Placebo TPTD20 TPTD40 * P<0.05 from Placebo Normal (> 80 ml/min) Mild Impairment (50-79 ml/min) Moderate Impairment (30-49 ml/min) Miller PD, et al. Osteopor Int 2007

50 Serum sclerostin as a function of CKD stage based on GFR measured by inulin clearance CJSAN May 2013

51 Romo Effects of Lumbar Spine and Total Hip BMD Through Month 12 Placebo (N = 61) Romosozumab (N = 65) Placebo (N = 62) Romosozumab (N = 66) Lumbar Spine Total Hip %* %* 12 Percent Change From Baseline Percent Change From Baseline %* 6.8%* 2 0.4% 0.0% 2 0.4% 0.0% BL 6 12 Study Month 2 BL 6 12 Study Month *p < compared with placebo. Data are least square means (95% CI) adjusted for relevant baseline covariates Cosman F et al NEJM September 19, 2016 (on line); October 2016 (print)

52 New Vertebral Fracture Incidence Through Month 12 (Co Primary Endpoint) Placebo (N = 3,591) Romosozumab (N = 3,589) 2.0% RRR = 73% p = < % Subject Incidence (%) 1.5% 1.0% 0.5% 0.8% RRR = 46% p = % 0.5% 0.0% Through Month 6 Through Month 12 n/n1 = 26/ / / /3321 n/n1 = number of subjects with fractures/number of subjects in the primary analysis set for vertebral fractures p-value based on logistic regression model adjusted for age (< 75, 75) and prevalent vertebral fracture Cosman F et al NEJM September 19, 2016 (on line); October 2016 (print)

53 Bisphosphonates in CKD

54 US/European Labeling States: Oral bisphosphonates are not recommended in patients with creatinine clearance < 30 (35) ml/min: (Stage 4 5 CKD) Zoledronic acid contraindicated at GFR < 35 ml/min

55 FDA Label 1. Randomization excluded patients with elevated baseline serum creatinine (< 1.5/<2.4). 2. egfr exclusion criteria added by HORIZON and FREEDOM. 2. Renal (glomerulosclerosis or ATN) seen in case reports with IV bisphosphonates. 3. Bone retention probably greater with reduced GFR since bisphosphonates are cleared by the kidney (both filtration and tubular secretion) Miller PD, Jamal SA, Evenepoel P, Eastell R, Boonen S. Renal safety in patients treated with bisphosphonates for osteoporosis: a review. J Bone Miner Res. 2013;28(10):

56 Mean Changes in Calculated Creatinine Clearance From Baseline Over Time Horizon: Zoledronate 5mg/yr vs Placebo Placebo ZOL 5 mg Mean (±SE) Change From Baseline in Calculated Creatinine Clearance (ml/min) Last Visit ZOL n = PBO n = Black D et al NEJM 2007

57 Managing Renal Risk with ZOL 1. Faster infusion time and greater risk of ARF suggests renal damage might be due to the Cmax rather than the AUC. 2. Slower infusion rate (30 minutes) suggested (opinion) in Stage 3 CKD (egfr ml/min). 3. Patients should be well hydrated, off diuretics for several days, and avoid NSAIDs for several days before infusion. 4. Off label use in stage 4 5 CKD in established osteoporosis suggest even slower infusion rate (60 minutes). Miller PD. Cleve Clin J Med. 2009;76: ; Miller PD. Semin Dial. 2007;20: Miller PD. Semin Nephrol. 2009;29: Miller PD. BONE 2011 Miller PD et al JBMR 2013

58 Percent (%) of Patients Vertebral Fracture Risk Reduction With Risedronate 32% (14,46%) P=0.001 Control 45% (31,57% P<0.001 Mild Moderate Severe Baseline Renal Impairment Risedronate 56% (11,78%) P=0.021 Miller PD et al JBMR 2005 No change in serum creatinine concentration

59 Fracture Risk with Alendronate by Estimated GFR (egfr) Site egfr All Women (n=6459) Clinical Fractures Severely reduced Moderately reduced or normal Odds Ratio (95% Confidence Interval) 0.78 (0.51 to 1.2) 0.81 (0.70 to 0.94) P-value for Interaction 0.90 Spine Fractures Severely Reduced Moderately reduced or normal 0.72 (0.31 to 1.7) 0.50 (0.32 to 0.76) 0.44 No change in egfr Jamal S et at JBMR 2007

60 Denosumab (FREEDOM TRIAL) Incidence of New Vertebral Fracture Through Month 36 by Baseline CrCl Percent Incidence at Month * 2.3 Placebo (N=3906) DMAb (N=3902) N All ml/min ml/min ml/min ml/min 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 ml/min. *P < 0.05 No change in egfr * * * Jamal S et JBMR 2012

61 Conclusions Patients with Stage 1 3 CKD should be diagnosed and managed as patients with normal GFR In stage 4 5 CKD the DDX in patients that fracture could be one or more of a heterogeneous group of metabolic bone disease that requires different diagnostic and therapeutic approach. The 2 most important renal related metabolic bone diseases that should be R/O before turning bone turnover down are adynamic and osteomalacia bone disease If in doubt (alklaline phosphatase in lower quartile; and PTH in lower range (<150 pg/ml); or, PTH not 6X ULN or alkaline phosphatase not high also use anabolic first line (initial therapy).

62 Thank You Dr. Dan Hurley and the Program Committee of AACE For the invitation Paul D. Miller, M.D.