9/5/2016. Faculty. Cardiometabolic Risk and Impact on Bone Health. Learning Objectives. Disclosures. Osteoporosis

Transcription

1 Faculty Cardiometabolic Risk and Impact on Bone Health Cheryl L. Lambing, MD, FAAFP Clinical Professor Department of Family Medicine University of Calinia, Los Angeles Medical Director, Ventura County Health Care Agency Professional and Community Education and Outreach, Ventura, Calinia Disclosures Learning Objectives Dr. Lambing has disclosed no relevant financial relationships with any commercial interests. Discuss the pathophysiology and factors that contribute to higher fracture risk in cardiometabolic conditions Review the benefits and limitations of fracture risk prediction tools individuals with cardiometabolic risk Implement a patient-centered approach to managing patients with cardiometabolic conditions to reduce risk of fractures Osteoporosis Systemic skeletal disorder of compromised bone strength increased risk of fracture 43 million Americans: Low bone mass 10 million Americans: Osteoporosis Underdiagnosed and undertreated 1 in 2 women and 1 in 4 men aged >50 years will have an -related fracture in their lifetime By the year 2020, 1 in 2 Americans aged >50 years will be at risk of fractures from or low bone mass 61 million Americans with low bone mass Prediction, Diagnostic Tools, Treatment Prediction and diagnostic tools Bone densitometry with : Noninvasive test Fracture risk assessment tools to help with management decisions in patients with (eg,, Garvan Fracture Risk Calculator, QFracture ) Effective and safe s Strong evidence exercise, calcium, vitamin D sufficiency fractures and falls US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; Available at: Accessed July 31, International Osteoporosis Foundation Facts & Statics = dual-energy X-ray absorptiometry; = bone mineral density. National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; Accessed July 31, Marques A, et al. Ann Rheum Dis. 2015;74(11):

2 Strong Relationship Between Bone Density and Bone Strength Relative Risk of Hip Fracture T-score Bone density accounts 60% to 80% of bone strength in untreated patients Best early predictor of fracture risk Permits diagnosis bee fractures Kushida K. Clin Calcium. 2004;14: Fogelman J, et al. J Nucl Med. 2000;41: Example: Statistically robust fracture risk prediction tool developed by the WHO worldwide use Combines + clinical risk factors to predict fracture risk better than either alone Predicts the 10-year probability of major osteoporotic fracture Hip, spine, wrist, or humerus Use when the decision to treat is uncertain >20% major -related fracture >3% hip fracture WHO = World Health Organization. Accessed September 5, When Clinical Judgment Is Needed may underestimate fracture risk Some risk factors (eg, glucocorticoids, smoking, alcohol, fractures) are dose dependent, but cannot consider dose Some risk factors that increase the risk of fractures independently of their effect on are not included in Falls Frailty Some s and medications (eg, immobilization, diabetes, hyperthyroidism, hyperparathyroidism, human immunodeficiency virus, anticonvulsants, selective serotonin receptor inhibitors, proton pump inhibitors, thiazolidinediones) Does Not Fully Predict the Increase in Fracture Risk In patients with diabetes (cardiometabolic risk): Observations and assumptions Osteoporosis, an underappreciated complication of diabetes Why? Fracture Plateau Except High-Rate Fracture Persists in Mellitus Risk Factors and Pathophysiology Frequently overweight/load bearing = Assumed protective In general, preserved, normal = Assumed protective Data demonstrate diabetes is a significant risk factor osteoporotic fractures (two-fold increase in fractures) Increase risk additional two-fold Oei L, et al. Curr Osteoporosis. 2015;13(2): Vestergaard P, et al. Osteoporos Int. 2007;18(4): Less Likely to be on National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; Accessed July 31, Gnudi S, et al. J Bone Miner Res. 2001;16: Nguyen TV, et al. J Bone Miner Res. 2005;20: Sornay-Rendu E, et al. J Bone Miner Res. 2005;20: Agent Mellitus, Osteoporosis, and Obesity The relationship between diabetes and is under intense investigation worldwide due to prevalence of both conditions and evidence of increased fragility fractures compared with the general population (ie, non-diabetics) given any -specific level Recent developments in obesity research show that increased adiposity is characterized by greater systemic inflammation, a well-known risk factor CV, diabetes, and Fracture Prediction Tools Underestimate Fracture Risk in with Mellitus CV = cardiovascular. Oei L, et al. Curr Osteoporosis. 2015;13(2): Vestergaard P, et al. Osteoporos Int. 2007;18(4):

3 Mellitus and Osteoporosis Increased prevalence with aging Type 1 diabetes and T2DM increased risk of fractures Current diagnostic () and assessment () tools estimating are discordant Growing evidence that diabetes impacts skeletal metabolism Increased fracture risk despite higher in T2DM (eg, 69% increased risk non-vertebral fracture and fall risk) T2DM = type 2 diabetes. Oei L, et al. Curr Osteoporosis. 2015;13(2): Khazai NB, et al. Curr Opin Endocrin Care. 2009;16(6): Vestergaard P, et al. Osteoporos Int. 2007;18(4): Giangregorio LM, et al. J Bone Miner Res. 2012;27(2): Cardiometabolic Risk and Fractures with T2DM show significant and independent increased risk of fractures CV, including atherosclerosis, is more common in patients with T2DM Obesity CV Osteoporosis Atherosclerosis Risk in Communities (ARIC) Study. Oei L, et al. Curr Osteoporosis. 2015;13(2): Khazai NB, et al. Curr Opin Endocrin Care. 2009;16(6): Schneider AL, et al. Care. 2013;36(5): Pathophysiology Mellitus Advanced glycation end-products accumulate in tissue: bone, kidney, coronary arteries (impact of hyperglycemia on bone quality) Adipokines cell signaling proteins stimulate chronic inflammatory state related to development of insulin resistance T2DM Release of proinflammatory cytokines More likely to be vitamin D deficient than the general population More likely to exhibit renal insufficiency; primary/secondary hyperparathyroidism Associated with higher risk of falls (hypoglycemia, neuropathy, neuromuscular impairment, retinopathy/vision, renal impairment, stroke, medications) Pollock NK, et al. Molecul Cell Endocrinol. 2015;410: Wang C. J Res. 2013;2013: Mozos I, et al. BioMed Res Int (2015) Article ID , 12 pages. Schwartz AV, et al. JAMA. 2011;305(21): Wang C, et al. J Pediatr. 2014;90(1):4-6. Mozos I, et al. BioMed Res Int (2015) Article ID , 12 pages. Fracture Prediction Tools Underestimate Fracture Risk in with Mellitus Tools use 4-31 factors Decision making based on fracture risk, not simply T-score (10-year prediction) Most validated; most studied, best with Available online, no cost Good choice patients without fall history Garvan Fracture Risk Calculator (functional residual capacity; 5-year/10-year prediction) Requires Available on-line, no cost Better choice patients with fall history QFracture-2013 (10-year prediction) For electronic health record, most accurate Larger number and variety of risk factors Adherence/application may be limited in clinical setting due to time and length of tool Giangregorio LM, et al. J Bone Miner Res. 2012;27(2): Patient Case: Maria 65-year-old woman 5 2 ; 180 lb, BMI years post-menopause T2DM 25 years HgbA1c: 8.0% Vitamin D sufficiency 25 OH vitamin D level: 30 HgbA1c = hemoglobin A1c. 3

4 Personal History: Maria Both her mother and father as well as two siblings and two children diagnosed with T2DM Family history and personal history negative fracture Does not exercise Non-smoker Does not consume alcohol, consumes 1 tablet calcium plus vitamin D daily Takes oral medication diabetes Calcium Intake Recommendations from the Institute of Medicine Estimated Requirement Recommended Dietary Upper Level Intake Life Stage Group (mg/d) Allowance (mg/d) (mg/d) Infants 0 to 6 months * * 1000 Infants 6 to 12 months * * years old years old years old years old years old years old year-old male year-old female >70 years old years old, years old, *For infants, adequate intake is 400 IU/d 0 to 6 months of age and 400 IU/d 6 to 12 months of age. Institute of Medicine. Dietary Reference Intakes Calcium and Vitamin D: Report Brief. Washington, DC: IOM; Available at Intakes--Calcium-and-Vitamin-D.aspx. Accessed September 12, Vitamin D Intake Recommendations from the Institute of Medicine Estimated Avg Recommended Upper Level Intake Requirement Dietary Allowance (IU/d) Life Stage Group (IU/d) (IU/d) Infants 0 to 6 months * * 1000 Infants 6 to 12 months * * years old years old years old years old years old years old year-old male year-old female >70 years old years old, years old, *For infants, adequate intake is 400 IU/d 0 to 6 months of age and 400 IU/d 6 to 12 months of age. Institute of Medicine. Dietary Reference Intakes Calcium and Vitamin D: Report Brief. Washington, DC: IOM; Available at Intakes--Calcium-and-Vitamin-D.aspx. Accessed September 12, Maria ordered routinely at aged 65 years based on standard evidence Recommendation preventive health US Preventive Services Task Force. USPSTF: Ann Intern Med Jan Accessed September 5, Maria with : Aged 65 Years Clinical Practice Annals of the Rheumatic Diseases: The EULAR Journal. June vol 75, 5(2). Schwartz AV, et al. JAMA. 2011;305(21): Presented at American Society Bone and Mineral Research (ASBMR) 2015 Annual Meeting Oct 9-12, 2015, Seattle USA. Leslie W et al., Obesity and Fracture Risk Assessment: Paradox and Progress. 4

5 Maria with Personal Fracture Clinical Practice Personal fracture 20% 4.2% high risk EULAR J. June 2016;75, 5(2). Schwartz AV, et al. JAMA. 2011;305(21): Leslie W, et al., Obesity and Fracture Risk Assessment: Paradox and Progress. Presented at American Society Bone and Mineral Research (ASBMR) 2015 Annual Meeting Oct 9-12, 2015, Seattle, WA. Clinical Practice (cont) Maria with DM Surrogate Risk Personal fracture 20% 4.2% high risk Re T2DM (five-fold increased risk of fracture) Surrogate risk EULAR J. June 2016;75, 5(2). Schwartz AV, et al. JAMA. 2011;305(21): Leslie W, et al., Obesity and Fracture Risk Assessment: Paradox and Progress. Presented at American Society Bone and Mineral Research (ASBMR) 2015 Annual Meeting Oct 9-12, 2015, Seattle, WA. Clinical Practice Maria with Surrogate Risk + Fracture Personal fracture 20% 4.2% high risk Re T2DM (five-fold increased risk of fracture) Major fracture: 16% Hip fracture: 3.6% EULAR J. June 2016;75, 5(2). Leslie W, et al., Obesity and Fracture Risk Assessment: Paradox and Progress. Presented at American Society Bone and Mineral Research (ASBMR) 2015 Annual Meeting Oct 9-12, 2015, Seattle, WA. 5

6 Underestimates Fracture Risk in with Mellitus does not explain fracture risk Women with T2DM have increased cortical porosity; increased trabecular volumetric density changes not captured with Factors stimulate adipogenesis; inhibit osteoblast differentiation Falls are not captured in (peripheral neuropathy, vision impairment) Medication (thiazolidinediones) Hyperglycemia (advanced glycation end-products); hyperinsulinemia -specific factors increase fracture risk (retinopathy, cataracts, renal impairment, insulin, hypoglycemia, duration of diabetes ) Cellular signaling pathways (abnormal cytokines and adipokines) Giangregorio LM, et al. J Bone Miner Res. 2012;27(2): Mellitus is an Independent Risk Factor Fracture 10-Year Probability of Symptomatic Fracture (%) Age 65 Surrogate % Fx Risk 3.6% Hip Fx Risk Age 65 T-score % Fx Risk 2.5% Hip Fx Risk Black DM, et al. J Bone Mineral Res. 2012;27(2): EULAR J. June 2016;75, 5(2). Leslie W, et al., Obesity and Fracture Risk Assessment: Paradox and Progress. Presented at American Society Bone and Mineral Research (ASBMR) 2015 Annual Meeting Oct 9-12, 2015, Seattle, WA. Pathophysiologic Defects in Hyperglycemia and Obesity increased appetite incretin effect gut carbohydrate delivery and absorption pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA stress hormones leptin Additional Risks - hepatic glucose production osteocalcin - Proinflammatory Cytokines peripheral glucose uptake Goldman's Cecil Medicine. 24th ed. New York, NY: Elsevier Saunders; Osteoporosis: What Are the Risk Factors? Non-Modifiable Risk Factors Age Female gender Family history of Previous fracture Ethnicity Menopause/hysterectomy Long-term glucocorticoid therapy Rheumatoid arthritis Primary/secondary/hypogonadism in men International Osteoporosis Foundation. Who s at Risk? http// Modifiable Risk Factors Alcohol Smoking Low BMI Poor nutrition Vitamin D deficiency Low dietary calcium intake Eating disorders Insufficient exercise Frequent falls Variance gene and response to DNA binding Role of Vitamin D Activated Vitamin D Binds Vitamin D Receptor (VDR) Cellular nucleus Activators/Suppressors binds DNA Impact gene expression >200 genes directly/indirectly Wang C, et al. J Pediatr. 2014;90 (1):4-6. Vacek JL, et al. Am J Cardiol. 2010;106:798. Wang C. J Res. 2013;2013: Mozos I, et al. BioMed Res Int (2015) Article ID , 12 pages. Gene polymorphisms 6

7 Receptors Vitamin D Vitamin D Gastrointestinal (enterocytes) Bone (osteoblasts) Parathyroid gland Kidney (renal tubule cells) Liver (hepatocytes) Immune system Skeletal muscle Cardiac muscle (cardiomyocytes) Vascular endothelial cells (vascular smooth muscle cells) Central nervous system (neurons) Pancreas (B cells) Epithelial cells Wang C, et al. J Pediatr. 2014;90 (1):4-6. Vacek JL, et al. Am J Cardiol. 2010;106:798. Wang C. J Res. 2013;2013: Mozos I, et al. BioMed Res Int (2015) Article ID , 12 pages. Marenzi G, et al. Medicine. 2015;94 (1):1-8. CV Lower systolic blood pressure Lower vascular resistance Lower arterial intima thickness Increased insulin secretion/sensitivity Lower very lowdensity lipoprotein and triglycerides Effect on myocardial contractility Decreased inflammatory cytokines References Vacek JL, et al. Am J Cardiol. 2010;106: Activated Bone-related health VitaD binds in cells to VDR Calcium - phosphate (Vitamin D Receptor) Homeostasis regulation Deficiency associated with variety of s: Hypertension, diabetes, autoimmune, colon cancer To Improve Clinical Outcomes, Clinical Considerations Assess dietary intakes calcium and vitamin D Ensure vitamin D sufficiency Avoid calcium supplementation without vitamin D In patients with a CV event, screen underlying (altered bone quality risk) In patients with fractures assess CV risk Assess patients with diabetes adequate bone health and fall risk; maintain HgbA1c at goal Address overlapping CV risks (eg, age, smoking, inflammation, activity) Avoid under of patients with diabetes who are at increased risk Khazai NB, et al. Curr Opin Endocrinol Obes Dec;16(6): Vestergaard P, et al. BMJ. 2016:1-9. American Association. Care. 2016;39(9):1653. Best Evidence Vitamin D sufficiency appears to be of benefit improved bone health, fall risk, and a variety of cardiometabolic effects No guidelines; mounting evidence; clinical recommendations based on current evidence Vitamin D deficiency may be considered a CV risk marker Wang C, et al. J Pediatr. 2014;90 (1):4-6. Vacek JL, et al. Am J Cardiol. 2010;106:798. Wang C. J Res. 2013;2013: Mozos I, et al. BioMed Res Int (2015) Article ID , 12 pages. Marenzi G, et al. Medicine. 2015;94 (1):1-8. Take-Home Points is considered an independent risk factor fracture The hazard ratio is comparable to or even greater than many of the current tool factors and other prediction tools Questions? Modeling to ensure future fracture prediction tool(s) accurate across populations Maintain low index of suspicion increased fracture risk Assess dietary intakes, ensure vitamin D sufficiency, and avoid calcium without vitamin D 7