SKELETAL FRAGILITY AND FRACTURE RISK IN PATIENTS WITH DIABETES

Transcription

1 SKELETAL FRAGILITY AND FRACTURE RISK IN PATIENTS WITH DIABETES Nelson B. Watts, MD OSTEOPOROSIS AND BONE HEALTH SERVICES CINCINNATI, OHIO

2 DISCLOSURES Stock options/holdings, company owner, official role: OsteoDynamics co-founder, shareholder Honoraria in the past year: Amgen, Merck, Shire Consulting fees in the past year: AbbVie, Amgen, Merck, Radius

3 DIABETES MELLITUS AND FRACTURE RISK... Any reduction of bone mass in diabetics that is revealed by sophisticated analysis is of no medical or economic importance... Further extensive studies of bone metabolism in diabetics are unlikely to yield results of practical importance... Heath HH III et al N Engl J Med 1980;303:

4 Scientific Committee of the First International Symposium on Diabetes and Bone Rome, Italy, November 2014

5 DIABETES MELLITUS AND BONE Type 1 diabetes and fracture risk Type 2 diabetes and fracture risk Prediction of fracture risk Predisposing factors What to do

6 BMD AND FRACTURES IN TYPE 1 DIABETES MELLITUS Lower body weight and lower BMI If DM onset is before growth spurt, lower peak bone mass Modest reduction in BMD Higher hip fracture risk RR expected from lower BMD = 1.4 Meta-analysis: RR = 6.3* (2.6, 15.1) Clearly, fracture risk is increased, but something more than reduced BMD is going on *Risk increased 12-fold in type 1 patients with nephropathy Vestergaard P et al Osteoporos Int 2007;18:

7 TYPE 1 DM AND FRACTURE RISK In patients with type 1 DM, fractures are more likely in the distal radius, proximal humerus, hip and spine (OR 2.4) Mechanisms include Deficiency of insulin and IGF-1 Low peak bone mass Increased risk of falling (sarcopenia, retinopathy, cataracts, neuropathy, gait disturbance, hypoglycemia) Decreased bone formation (AGEs, glucose toxicity), amylin, IFG-1, IAPP, osteocalcin, increased resorption (uncoupling) Renal calcium leak, CKD, secondary/tertiary HPTH Inflammatory cytokines Altered collagen structure and cross linking (AGEs, pentosidine) Medications that increase fall risk (sedatives, opiates, anti-epilepsy drugs, anti-parkinson s), also SSRIs, PPIs Other autoimmune diseases: celiac disease with calcium malabsorption, hyperthyroidism, supraphysiologic T4 Rx Hough FS et al Europ J Endocrinol 2016;174:R127-R138

8 Relative risk of fracture DUAL ENERGY X-RAY ABSORPTIOMETRY (DXA) BMD by DXA is a powerful predictor of fracture risk x -1 SD Z-score or T-score

9 BMD (g/cm 2 ) BMD IS HIGHER IN PATIENTS WITH T2DM Study of Osteoporotic Fractures Adjusted for age, BMI All p <0.01 for non-ins tx vs. not DM All NS for insulin tx vs. non-insulin-tx 0.3 Femoral Neck Calcaneal Distal Radius Insulin Tx Non-insulin Tx Non-diabetic Schwartz AV et al J Clin Endocrinol Metab 2001:86:32-38

10 FRACTURE RISK IN T2DM BASED ON BONE MINERAL DENSITY BMD is higher in T2DM therefore fracture risk should be lower than age-matched controls

11 FRACTURES ARE MORE COMMON IN PATIENTS WITH DIABETES Major osteoporosis-related fracture Hip fracture Giangregorio LM et al J Bone Miner Res 2012;27:

12 META-ANALYSIS HIP FRACTURE RISK IN T2DM 12 studies RR 1.7 (1.3, 2.2) Janghorbani M et al Am J Epidemiol 2007;166:

13 META-ANALYSIS HIP FRACTURE RISK IN DM 21 studies 42 subgroups Both type 1 and type 2 T1DM RR 5.76 (3.66, 9.07) T2DM RR 1.34 (1.01, 1.51) RR 2.07 (1.83, 2.33) Fan Y et al Osteoporos Int 2016;27:

14 HIP FRACTURE INCIDENCE IN RECENT ONSET T2DM 58,438 newly-diagnosed T2DM 113,448 controls Hip fx 2.7 vs 2.1 per 1,000 pt-yrs HR 1.20 (1.06, 1.35) Martinez-Laguna D et al Osteoporos Int 2015;26:

15 NOT JUST HIP FRACTURES T2DM AND FRACTURE RISK WHI-OS RR (95% CI) Proximal humerus 1.30 (1.07, 1.56) Foot 1.44 (1.21, 1.71) Ankle 1.34 (1.16, 1.55) Clinical spine 1.28 (1.04, 1.56) Forearm 0.98 (0.84, 1.15) 30-40% increased risk for any clinical fracture Bonds DE et al J Clin Endocrinol Metab 2006;91:

16 WHY IS FRACTURE RISK INCREASED IN PATIENTS WITH TYPE 2 DIABETES? Napoli N et al Nature Rev Endocrinol 2016; epub ahead of print

17 RISK OF MORE FREQUENT FALLS Health, Aging and Body Composition Study OR* (95% CI) Normal 1.00 Reference Impaired glucose metabolism 0.95 (0.82, 1.11) T2DM 1.42 (1.20, 1.68) Falls: 0, 1, 2-3, 4-5, 6+ in past year *Adjusted for age, race, gender Schwartz AV et al Diab Care 2008:31:

18 FALL RISK: A1c AND INSULIN USE

19 FALL PREVENTION IN TYPE 2 DIABETES Standard fall prevention measures Reducing complications through glycemic control likely to prevent falls Intensive control safer with oral meds, but caution with insulin use and low A1c

20 WHAT OTHER FACTORS COULD CONTRIBUTE TO FRACTURE RISK IN DIABETES? Falls Biochemical abnormalities Renal calcium loss 1 Abnormal PTH levels (high or low) 2 Vitamin D deficiency 3 Decreasing Sirt1 4,5 1. Gregorio F et al Diabetes Res Clin Pract 23: McNair P et al Dan Med Bull 1988;35: Pittas AG et al Diab Care 2006;29: Iyer S et al J Biol Chem 2014;289; Artsi H et al Endocrinol 2014:155:

21 WHAT FACTORS COULD CONTRIBUTE TO FRACTURE RISK IN DIABETES? Falls Biochemical abnormalities Renal calcium loss Abnormal PTH levels (high or low) Vitamin D deficiency Decreasing Sirt1 Reduced bone quality Collagen glycosylation Reduced bone formation Microarchitectural deterioration

22 ADVANCED GLYCATION END PRODUCTS MIGHT DECREASE BONE STRENGTH Pentosidine AGE can reduce pyridinium crosslinks 1 AGE accumulation could impair mechanical properties of bone 2 In cadaver bone, higher pentosidine is associated with reduced strength 3 1. Dominguez LJ et al Biochem Biophys Res Commun 2005;330: Saito M et al Osteoporos Int 2006;17: Viguet-Carrin S et al Bone 2006;39:

23 OSTEOBLAST DYSFUNCTION MIGHT INCREASE FRACTURE RISK Glucose can be toxic to osteoblasts 1 Histomorphometry: low bone formation 2 Osteocalcin, a marker of bone formation, is low in diabetes (inverse correlation with blood glucose) 3 1. Inaba M et al J Bone Miner Res 1995;10: Krakauer JC et al Diabetes 1995;44: Kanazawa et al J Clin Endocrinol Metab 2009;94:

24 BONE STRUCTURE IN TYPE 2 DIABETES NORMAL Melton LJ III et al J Clin Endocrinol Metab 2008;93:

25 BUT.

26 HIGH RESOLUTION pqct (Xtreme CT, Scanco Medical AG) 3-D stack of 116 high resolution CT slices acquired at nondominant distal radius and tibia ~ 82 µm 3 voxel size ~ 3 min scan time, < 4 µsv Reproducibility: density: 0.7 to 1.8% structure: %

27 CORTICAL POROSITY IS INCREASED IN T2DM, WITH AND W/O FRACTURE HR pqct Distal Proximal Mineralized Cortical Tibia Tibia Bone Porosity Control T2DM No fx T2 DM w fracture Images from Burghardt AJ et al J Clin Endocrinol Metab 2010;95: Similar findings by Patsch JM et al J Bone Miner Res 2013;28:

28 TYPE 2 DIABETES AND HIP FRACTURE RISK META-ANALYSIS Compared with subjects without diabetes, for patients with T2DM, based on BMD alone, the age-adjusted RR for hip would be expected to be lower, ~0.8 But RR for hip fracture is higher, Janghorbani M et al Am J Epidemiol 2007;166: Fan Y et al Osteoporos Int 2016;27:

29 BONE DENSITOMETRY, T2DM AND FRACTURE RISK Given that in diabetes mellitus, fractures occur at higher BMD, compared with ageand weight-matched controls Is BMD still predictive? In patients with diabetes, is lower BMD associated with a higher fracture risk?

30 Total hip BMD (g/cm 2 ) LOWER BMD PREDICTS FRACTURE IN T2DM Health, Aging and Body Composition Study Baseline BMD among participants with diabetes in the Health ABC Study * *P< Incident fracture No fracture Strotmeyer ES et al Arch Intern Med 2005;165:

31 What if any effect do treatments for diabetes have on fracture risk?

32 PIOGLITAZONE: INCREASED FRACTURE RISK IN WOMEN Meta-analysis of fracture AEs for clinical trials of pioglitazone PIO N=8,100 Comparison N=7,400 12,000 person-years per group Increased risk in women but not men Rx Fx per 100 person-yrs RR Pioglitazone Placebo or active comp 1.1 Periscope, April 2008: 543 SUBJECTS FX 3% PIOGLITAZONE GROUP 0% GLIMEPERIDE Takeda Letter to Health Care Providers 2007

33 % with Fracture ADOPT: ROSIGLITAZONE INCREASED FRACTURE RISK IN WOMEN Rosiglitazone Metformin * 30 * * 18 * 8 22 * Glyburide All Fractures All Fx Lower limb Upper limb Spine Men Women *P<0.05 vs rosiglitazone (unadjusted, contingency chi-square test) Kahn SE et al Diabetes Care 2008;31:

34 TZDs AND FRACTURE RISK UK GPRD Observational study, Patients with type 2 diabetes (N=66,696) Cases: First low trauma fracture (N=1,020) Controls: Matched for age, sex, general practice attended, index date (N=3,728) 58% were 70 years or older at index date 68% were women 6% of cases used a TZD (PIO and ROSI) Meier C et al Arch Intern Med 2008;168:

35 NO EVIDENCE OF INTERACTION WITH GENDER OR AGE Fracture Risk: Current TZD 8+ Rxs vs Non Use OR 95% CI Women 2.56 ( ) Men 2.50 ( ) <70 y.o ( ) 70+ y.o ( ) Meier C et al Arch Intern Med 2008;168:

36 TZDS AND FRACTURE RISK BY SKELETAL SITES All Fx Sites Hip / Femur Humerus Wrist / Forearm No Rx 1-7 Rx 8-14 > >8 1-7 >8 1-7 > Too few vertebral or rib fractures to include Adjusted RR Meier C et al Arch Intern Med 2008;168:

37 TZDs AND THE DECISION PATHWAYS FOR OSTEOBLAST AND ADIPOCYTE DEVELOPMENT GOOD FOR BONE Mesenchymal progenitor cells in bone marrow TZDs Runx2 PPARg BAD FOR BONE Adipocytes (fat cells) Osteoblasts (bone-forming cells) Rzonca SO et al Endocrinology 2004;145: Akune T et al J Clin Invest 2004;113: Pei L, Tontonoz P J Clin Invest 2004;113: Lecka-Czernik B et al Endocrinology 2007;148:

38 MICRO-COMPUTED TOMOGRAPHY (MICROCT) OF PROXIMAL TIBIA Mouse Model vehicle rosiglitazone % difference rosiglitazone vs. control Bone volume * Trabecular thickness * Trabecular number * Trabecular spacing 17.4 * Connectivity * p < 0.05 rosiglitazone vs. control Rzonca SO et al Endocrinology 2004;145:

39 SGLT2 INHIBITION SGLT1 found in kidney, intestine SGLT2 mainly in the kidney Neither are expressed in bone In rats, treatment with canagliflozin leads to carbohydrate malabsorption, skeletal hyperostosis, absorptive hypercalciuria, decreased PTH and 1,25 D Not seen in mice, dogs or humans

40 EFFECT OF CANAGLIFLOZIN ON BONE TURNOVER MARKERS AND BMD Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51

41 BTM CHANGE WITH CANAGLIFLOZIN C-telopeptide Osteocalcin Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51

42 CHANGE IN WEIGHT AND CHANGE IN CTX Week 26 Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51

43 BMD CHANGE WITH CANAGLIFLOZIN Total hip Lumbar spine Distal radius Femoral neck Bilezikian JP et al J Clin Endocrinol Metab 2016:101:44-51

44 FRACTURES WITH CANAGLIFLOZIN Watts NB et al J Clin Endocrinol Metab 2016:101:

45 FRACTURES WITH CANAGLIFLOZIN Watts NB et al J Clin Endocrinol Metab 2016:101:

46 FRACTURES IN CANVAS 4.0% 2.6% Watts NB et al J Clin Endocrinol Metab 2016:101:

47 FRACTURES IN CANVAS Watts NB et al J Clin Endocrinol Metab 2016:101:

48 FRACTURES IN CANVAS PBO CANA Total 2.6% 4.0% Upper limb 1.2% 1.7% Lower limb 1.1% 1.6% Watts NB et al J Clin Endocrinol Metab 2016:101:

49 FRACTURES IN CANVAS Rate per 1000 patient years Site Placebo All CANA Upper limb Hand Wrist Humerus Lower limb Foot Ankle Watts NB et al J Clin Endocrinol Metab 2016:101:

50 CLINICAL IMPLICATIONS Fracture risk is increased in patients with diabetes, both type 1 and type 2 Peripheral fractures are increased; hip and spine fractures appear to be increased as well TZDs appear to increase the risk for hip and other fractures further, especially in postmenopausal women, more risk with longer treatment Canagliflozin slightly increases the risk of upper and lower limb fractures in older, higher-risk subjects. The increased risk is seen early, too soon to be due to changes in BMD or bone turnover; possibly related to increased risk of falling

51 DIABETES MELLITUS AND FRACTURE RISK... Any reduction of bone mass in diabetics that is revealed by sophisticated analysis is of no medical or economic importance... Further extensive studies of bone metabolism in diabetics are unlikely to yield results of practical importance... Heath HH III et al, N Engl J Med 1980;303: Until more is known, it is not unreasonable to consider diabetes as a risk factor for fracture; patients with type 2 diabetes are certainly not protected from fracture and deserve at least the same screening for osteoporosis that is recommended for nondiabetic subjects. Watts NB and D Alessio DA J Clin Endocrinol Metab 2006:91;

52 FRAX UNDERESTIMATES FRACTURE RISK IN PATIENTS WITH DIABETES Schcter GI and Leslie WD, Calcif Tiss Int 2016; epub ahead of print

53 USING FRAX WITHOUT BMD NO ADJUSTMENT FOR DIABETES

54 USING FRAX WITHOUT BMD TYPE 2 DM RR 1.7 FOR HIP FX, 1.4 FOR MAJOR FX CHECK OFF SECONDARY OSTEOPOROSIS x 1.4 x 1.7

55 USING FRAX WITH BMD NO ADJUSTMENT FOR DIABETES

56 USING FRAX WITH BMD NO ADJUSTMENT FOR DIABETES

57 USING FRAX WITH BMD TYPE 2 DM RR 1.7 FOR HIP FX, 1.4 FOR MAJOR FX REDUCE T-SCORE BY -0.5 x x 1.7

58 TYPE 2 DM INCREASES FRACTURE RISK RR ~1.4 for clinical fractures RR ~1.7 for hip fracture FRAX without BMD Secondary osteoporosis = DM risk FRAX with BMD Reduce T-score by 0.5 Glucocorticoid Rx = TZD risk

59 TRABECULAR BONE SCORE (TBS) Silva et al. JBMR 2014; Epub.

60 TRABECULAR BONE SCORE (TBS) TBS is a texture analysis parameter which correlates with micro-architecture parameters Roux JP et al. ASBMR 2012 Hans et al. JCD 2012 Resch et al. ASBMR 2012 Bilezikian JCEM 2013

61 BMD OR TRABECULAR BONE SCORE (TBS) TO PREDICT FRACTURE IN T2DM? 29,407 women age 50 and older 2356 with DM, median f/u 4.7 yr Leslie WD et al J Clin Endocrinol Metab 2013:98:

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64 ANTI-RESORPTIVE DRUGS DO NOT AFFECT THE RISK FOR GETTING DIABETES Risk of incident diabetes Schwartz AV et al J Bone Miner Res 2013;28;

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66 Bonnet N Calcif Tiss Int 2017;100:

67 Bonnet N Calcif Tiss Int 2017; 100:

68 SKELETAL FRAGILITY AND FRACTURE RISK IN PATIENTS WITH DIABETES Fracture risk is increased in patients with diabetes The causes are multiple: increased skeletal fragility and increased risk of falling TZDs increase fracture risk further; effects of canagliflozin are minor Fracture risk should be assessed in patients with T2DM Adjustments are needed for accurate use of FRAX For patients at high risk of fracture, pharmacologic and other measures to reduce fracture risk should be considered but no agents have proven efficacy

69 Thank you for your attention