Arizona Chapter AACE Paul D. Miller, M.D.

Transcription

1 Arizona Chapter AACE Paul D. Miller, M.D. Management of fractures in CKD and atypical subtrochanteric femur fractures September 2018

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

3 Fracture Risk is Very High In Stage 5 KD ~ 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: 15% female 30% male Leinau L and Perazella MA. Sem Dialysis 19: 75-79, Bliue D, et al. JAMA 301: , 2009

5 It s Just Not ESRD All stages of CKD have 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 agematched 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 Elevated PTH Phosphorus and pyrophosphate retention Elevated FGF 23 Chronic metabolic acidosis Sarcopenia

8 Regulation of Serum Phosphorus The Interactions Between the Parathyroid Glands, Kidneys, Bone and Systemic Vasculature: Miller PD, Sprague S and Shane E Am J Kid Dis 2014 PTH Serum P Ca Absorption P Absorption 1,25 D GFR PTH 1,25 D PTH P Reabsorption SCLEROSTIN Ca and P Osteoclast FGF 23 1,25 D FGF 23 P Reabsorption FGF 23 Osteocyt e Osteoblast FGF 23 PTH PTH Osteoblast Activity

9 Fractures In Chronic Kidney Disease 1. Hyperparathyroidism 2. Adynamic bone disease 3. Osteomalacia 4. Post-transplantation 5. Osteoporosis 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):

10 2 Bone Diseases to Avoid turning bone turnover down Osteomalacia Adynamic bone disease

11 Von Kossa, H&E Stain for Calcium and Osteoid: 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

12 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)

13 Biochemical Tests to Screen for Etiologies of Osteomalacia 25D 1,25D Serum and urine phosphorus Electrolytes, arterial blood gases, urine ph FGF 23 Elevated BSAP

14 Elevated BSAP Excludes adynamic bone disease (unless there has been a recent fracture)

15 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) 10. Treatment with strontium ranelate (Europe) 11. Future: treatment with PTHrp analogues, anti-sclerostin 12. High bone turnover osteoporosis

16 Adynamic Bone Disease Absence of single tetracycline labels

17 Renal Adynamic Bone Disease

18 Normal Double Tetracycline Labels

19 PTH and BSAP combining the best of both worlds 1. PTH extremes ( < 100 pg/ml) or (> 600pg/ml) high specificity for adynamic/ofc. 2. Bone specific alkaline phosphatase ( < 20 IU/L) has a high PPV (80%) for low bone turnover. 3.BSAP correlate with PTH values in stage 5D CKD: both are 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

20 Bone Biopsy in CKD 1. Is the gold standard for diagnosis of renal bone disease and for defining the bone turnover activity. 2. Require double tetracycline labeling for quantitative bone histomorphometry 3. Is safe and has very low morbidity (including post-op pain) in experienced operators 4. Is especially important before bone turnover is turned down

21 Courtesy of Dr. Elliott Schwartz

22 Renal Adynamic Bone Disease Courtesy of Dr. Paul Miller

23 Therapies for osteoporosis: USA Hormone therapy Raloxifene Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Calcitonin Teriparatide Denosumab (anti-rank ligand antibody) Abaloparatide

24 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: Post-hoc analysis show efficacy and safety through 3 years of risedronate, alendronate and raloxifene and denosumab down to egfr of 15 ml/min for 2-3 years. 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):

25 Bisphosphonates in CKD

26 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

27 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):

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

29 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

30 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 56% (11,78%) P=0.021 Miller PD et al JBMR 2005

31 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 Jamal S et at JBMR 2007

32 Percent Incidence at Month 36 Incidence of New Vertebral Fracture Through Month 36 by Baseline CrCl * 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 * * * Jamal S et JBMR 2012

33 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 P, et al. Osteopor Int 2007

34 Active Trial

35 BTM s of TPTD and Abaloparatide

36 Time to Event of Non-vertebral Fractures

37 Adverse Events

38 X-rays of Stress Fractures Later mid-shaft Femur Stress fracture with beaking Courtesy of Dr. Paul Miller

39 X-ray 3 Days later after Diagnosis of Stress Fractures Completed sub-trochanteric femur fracture Courtesy of Dr. Paul Miller

40 Case 24 yo healthy recent Colorado College graduate, healthy, pre-menopausal woman. No Hx of eating disorder, weight change in past 5 years Runs ~2 miles/day Jogging in Denver City Park had sharp pain right thigh. Went to a local Denver hospital and had x-rays that showed a stress fracture and sent home. 3 days later while walking at work heard a snap and fell to the ground with right femur at ~30 degree angle

41 Atypical Subtrochanteric Femur Fracture ASSOCIATIONS 1. Long term bisphosphonate exposure 2. Chronic glucocorticoids 3. Chronic protein pump inhibitors 4. Hypophosphatasia 5. Cathepsin K inhibitior defeciency 6. Young healthy premenopausal women (? Elevated sclerostin) 7. Diabetes Mellitus Shane E et al. ASBMR Working Group JBMR 2015

42 Teriparatide in Atypical Subtrochanteric Femur Fractures The BAFFETT Study Responses to Treatment With Teriparatide in Patients With Atypical Femur Fractures Previously Treated With Bisphosphonates Nelson B Watts, Deborah Aggers, Edward F McCarthy, Tina Savage, Stephanie Martinez, Rachel Patterson, Erin Carrithers, and Paul D Miller Mercy Health Osteoporosis and Bone Health Services, Cincinnati, OH, USA 2Colorado Center for Bone Research at Centura Health, Lakewood, CO, USA 3Department of Orthopedic Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, Watts N et al. JBMR 2016

43 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 therapeutic approaches. The 2 most important renal related metabolic bone diseases that must be R/O before turning bone turnover down are adynamic and osteomalacia bone disease ASFF have heterogeneous conditions associated with their presentation-not all due to bisphosphonates

44 Thank You Arizona AACE For the invitation Paul D. Miller, M.D.