Annual Rheumatology & Therapeutics Review for Organizations & Societies

Transcription

1 Annual Rheumatology & Therapeutics Review for Organizations & Societies

2 Osteoporosis in Men: An Update on the Epidemiology, Clinical Evaluation Current Treatments and Treatments in Development

3 Learning Objectives Discuss the epidemiology of osteoporosis in men Describe the pathophysiology of osteoporosis in men. Understand the evaluation of a man for osteoporosis Review approved treatments for the treatment of osteporosis in men

4 OSTEOPOROSIS IN MEN The New Yorker, 2006

5 Bone Mass CHANGES IN BONE MASS WITH AGE Men Women Age (in years)

6 Incidence per population Males Females Age group (years) Figure 1 Average annual fracture incidence rate per 10,000 population in Leicester, UK, by age, group, and sex American Society for Bone and Mineral Research From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition.

7 Women Have Lower Bone Mineral Density (BMD) than Men BMD from DXA scans used to diagnose osteoporosis T-score: number of standard deviations different a BMD is from a young reference value A negative t-score indicates the BMD value is below that mean T-score Diagnosis -2.5 or worse Osteoporosis -1.0 to -2.5 Low bone mass > -1.0 Normal

8 Lifetime Risk of Fracture is Higher in Women than in Men Lifetime risk of fracture from age 60 Women: 44% Men: 25% In those with osteoporosis: Women: 65% Men: 42% Nguyen N. JBMR 2007

9 Fracture Incidence in Men Compared to Other Disease Lung Cancer Prostate Cancer Alzheimer's Disease Stroke Heart Attack Fracture Adapted from Binkley N 2009

10 Men Have Worse Outcomes After Fracture Excess mortality after hip fracture at age 80 for men and women Women Men 1 year 8% 18% 2 year 11% 22% 5 year 18% 26% 10 year 22% 20% Haentjens P. Annals of Internal Medicine 2010

11 Cost Effectiveness of Screening DXA screening followed by oral bisphosphonates Cost effective if bisphosphonates are <$500/year in men aged 70 years Alendronate is generic Schousboe JT JAMA 2010

12 Alendronate Costs $2/pill =$104/year Accessed May 3, 2010

13 Under-treatment of Osteoporosis Problem in both genders; large proportion of those at high risk (>30%) are not receiving recommended drug therapies Bisphosphonates, hormone replacement therapy, SERMs, calcitonin, and teriparatide Drugs reduce fracture risk by up to 50% Men with a prevalent fracture are 30-60% less likely to receive drug therapy than women Vik SA. Journals of Geronology: Medical Sciences 2007

14 Under-treatment of Osteoporosis Treatment after hip fracture assessed in men and women after discharge from Texas hospital Percent Receiving Treatment At discharge At 1-year Women 27% 71% Men 4.5% 27% Kiebzak GM. Arch Intern Med 2002

15 Conclusions Women have more fractures and lower BMD than men Fractures in men are important and common health events Under-treatment of osteoporosis is more common in men than in women Even though fractures are less common in men, outcomes after fracture are worse for men than for women

16 Risk Factors for Osteoporosis in Men: Medications and Co-Morbidities

17 Causes of Osteoporosis and Bone Loss in Men From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition American Society for Bone and Mineral Research

18 MAJOR CAUSES OF OSTEOPOROSIS IN MEN Alcohol 35-40% Primary Glucocorticoids Hypogonadism ~45% Other ~15-20%

19 Age-adjusted fractures per 1,000 person years SSRI Use is Associated with Increased Risk of Fracture Among Older Men Medication Use and Fracture Rate Multivariate Analyses for SSRI Use and Fracture SSRI users Non-users Adjusted model Non-spine fracture HR (95% CI) 40 Age, hip BMD 2.3 ( ) Age, hip BMD, fall history and SF-12 mental score 2.1 ( ) 10 0 Non-spine fracture 95% CI: SSRI users: Non-users: Final adjusted model 1.9 ( ) Included adjustment for age, hip BMD, BMI, non-traumatic fracture after age 50, falls in past 12 months, height change since age 25, SF-12 mental summary score, IADL impairment, SF-12 physical summary score Selective serotonin reuptake inhibitors (SSRI) use is associated with increased risk of fracture in elderly men ASBMR 2007 From Haney EM et al., Portland, USA, abstract 1159, updated La Lettre du Rhumatologue

20 Determinants of Bone Strength BMD Bone Mass Distribution Micro- Architecture Previous FX Skeletal Fragility Mineralization Bone Turnover Damage Collagen ML Bouxsein 2003

21 Women Men Perforation Thinning

22 Osteocyte Network: Sclerostin, Which is Secreted by Osteocytes, Negatively Regulates Bone Formation Mature Osteoblasts New bone X Sclerostin Pre-osteoblast lining cells X Mesenchymal stem cells Osteocyte Bone Ott SM. J Clin Endocrinol Metab. 2005;90: Semenov M, et al. J Biol Chem. 2005;280: Semenov MV, et al. J Biol Chem. 2006;281: Li X, et al. J Biol Chem. 2005;280:

23 FGF23 Released from Osteocytes to Control Serum Phosphorus secondary hyperparathyroidism PTH Bone Disease And Systemic Toxicity Ca 2+ FGF-23 Both FGF-23 and PTH are phosphaturic 1,25(OH) 2 D 3 P Chronic Kidney Disease

24 Table 1. HR (95% Cl): Association of Incident FX Status With FGF-23 Quartiles HR (95% Cl) OR (95% Cl) FGF-23 Quartiles Nonspine fx N=386 Hip Fractures N=73 Major Osteoporotic Fractures N=109 Prevalent Fractures N = 167 Q1 (ref) Q2 1.2 ( ) 1.6 ( ) 0.6 ( ) 0.7 ( ) Q3 1.1 ( ) 1.6 ( ) 0.8 ( ) 0.9 ( ) Q4 1.2 ( ) 1.6 ( ) 0.7 ( ) 0.7 ( ) P trend Lane JBMR 2013

25 HAZARD RATIO (HR) (95%CI) STRATIFIED ANALYSIS OF ASSOCIATION OF NONSPINE FX PER 50% INCREASE IN FGF-23 BY egfr<60 vs egfr <60 egfr >= Age Base Base+BMD hip MV Base models adjusted for age, race, clinic and BMI MV models adjusted for age, race, clinic, BMI, hip BMD, vitamin D and PTH. No significant interactions of egfr and FGF-23 with the other fracture types (vertebral, hip and major osteoporotic fx) Lane JBMR 2013

26 Background Serum UA has the highest concentration of any blood antioxidant and provides over half of the total antioxidant capacity of human serum. At serum UA Concentrations of umol/L UA may protect against the age and disease associated oxidative stress. Recently UA was reported to be associated with increased BMD and lower prevalent fractures in older men (Nabipour, JBMR 2011)

27 Hazard Ratio on the Log Scale Association Between Baseline Serum Uric Acid and Non-spine Fracture P for Trend= Q1 (ref) Q2 Q3 Q4 Quartiles of Uric Acid mg/dl Models adjusted for age, clinic site, BMI, race, vitamin D and PTH and frailty and egfr using CDK-EPI formula with standardized creatinine.

28 Total Hip BMD (g/cm 2 ) Association Between Serum Uric Acid and Total Hip Bone Mineral Density in the Random Cohort P for Trend= Q1 Q2 Q3 Q4 Quartiles of Uric Acid ng/ml Models adjusted for age, clinic site, race, BMI, total hip BMD, 25 vitamin D, PTH, frailty and egfr

29 Conclusions There is a significant association between serum Uric Acid and non-vertebral fractures and hip BMD in Elderly men. The mean serum uric acid level was an average of /- 1.3 mg/dl The relation of serum uric acid, antioxidant abilities and bone mass and strength requires further investigation.

30 Kyphosis is Common in Elderly Men, But Not always from Vertebral Fractures Cohort of elderly ethnically diverse group, mean age 74 yrs., Reviewed lateral T and L spine QCT scans and determined presence of DISH 3% of subjects with and without DISH had vertebral fractures, hip BMD was > with no DISH than DISH Primary Endpoint: Association of Cobb Angle with DISH DISH was highly associated with kyphosis in elderly men and women

31 Example of Diffuse Idiopathic Skeletal Hyperostosis (DISH) Example of DISH and Kyphosis Does the DISH stiffen the spine and increase the kyphotic curve? Or Does Kyhosis change the loading of the spine and activate ostification of the anterior longitudinal Ligament?

32 % Mortality Mortality One Year After Hip Fracture One year after fracture, mortality is much higher in men than in women Men Women Katelaris AG, et al. Am J Public Health 1996;86: Orwoll ES, et al. Endocrinol Metab Clin 1998;72: Forsen L, et al. Osteoporos Int 1999;10:73-8. Hannan EL, et al. JAMA 2001;285:

33 When Should Men Have A Bone Density Test? Women 1,2 Men 3, 4 Age >65 >70 3 Fragility fracture YES YES Starting steroids YES YES Other risk factors <65 if Weight <127 lbs (58 kg) Early menopause Smoking FH of fracture Medical causes present < 70 if Low weight? Low T Smoking FH of fracture Medical causes present 1 National Osteoporosis Foundation 2 AACE 3 ISCD, Watts et al, 2012

34 Other Causes of Osteoporosis in Men Gastrointestinal disorders Hypercalciuria Anticonvulsants Thyrotoxicosis Primary Hyperparathyroidism Neoplastic disease Rheumatoid arthritis Cushing s disease Immobilization Osteogenesis imperfecta Homocystinuria Mastocytosis

35 TES Recommendations (JCEM, 2012) for Standard Evaluation for Male Osteoporosis (BMD <-2.5) FOR ALL Serum calcium, phosphate, creatinine (egfr) Alkaline phosphatase and LFTs 25-OH D Total Testosterone CBC 24-hour urine for calcium and creatinine TO BE CONSIDERED Free or Bioavailable T PEP and/or Urine PEP Celiac screen TFTs PTH VFA Cortisol not mentioned The Endocrine Society

36 How to Deal with the Man Whose Bone Density is in the Osteopenic Range T-score -2.5 or below -1.5 to -2.5 Therapy Decision High risk Treat Intermediate risk Treatment is needed if other risk factors are present Fractures Weight < 127 F. Hx of hip fx FRAX Smoking Age (>70) CAN BE USED IN MEN! Steroids Secondary Causes Above -1.5 Low risk General preventive measures

37 FDA-Approved Medications and Indications For Men PMO GIO in men/women Men Drug Prevention Treatment Prevention Treatment Estrogen Calcitonin (Miacalcin ) Raloxifene (Evista ) Denosumab (Prolia ) (ON ADT RX) Ibandronate (Boniva ) Alendronate (Fosamax ) Risedronate (Actonel ) Zoledronic acid (Reclast ) Teriparatide (Forteo )

38 Proportion of Patients (%) Morphometric Vertebral Fracture Results % p= Zoledronic acid (N=588) Placebo (N=611) RR:0.32 (95% CI: 0.12, 0.88) 67% (95% CI: 30%, 84%) p= RR: 0.33 (95% CI: 0.16, 0.70) 4.9 (28/574) (16/574) (5/553) 1.6 (9/553) 0 Boonen et al, N Eng J Med, 2012 RR, relative risk 12 months 24 months Primary Endpoint

39 Major Change in Bone Architecture in Female is Trabecular Dropout and Form Men it is Trabecular Thinning. Women Men Perforation Thinning

40 Bone Loss in Aging Men is Attributed to Change in Osteoblast Number and Activity More Than Osteoclast Activity

41 PERCENT CHANGE (MEAN±SE) The Effect of Teriparatide [Human Parathyroid Hormone (1 34)] Therapy on Bone Density in Men With Osteoporosis PLACEBO TPTD20 TPTD MONTHS P<0.001 VS PLACEBO P TPTD20 vs 40 AT ALL TIMEPOINTS AFTER BASELINE Journal of Bone and Mineral Research Volume 18, Issue 1, pages 9-17, 1 JAN 2003 DOI: /jbmr

42 MEDIAN PERCENT CHANGE MEDIAN PERCENT CHANGE The Effect of Teriparatide [Human Parathyroid Hormone (1 34)] Therapy on Bone Density in Men With Osteoporosis 80 BONE ALP 100 PICP P<0.001 VS PLACEBO NTX/CR P<0.001 VS PLACEBO MONTHS P<0.04 VS PLACEBO fdpd/cr PLACEBO TPTD20 TPTD40 P<0.001 VS PLACEBO P<0.06 VS PLACEBO MONTHS P<0.001 VS PLACEBO P<0.021 VS PLACEBO P TPTD20 VS 40 (BONE, AUP,PCP, NTX, CTX): P<.01 (DPD) AT ALL TIMEPOINTS AFTER BASELINE Journal of Bone and Mineral Research Volume 18, Issue 1, pages 9-17, 1 JAN 2003 DOI: /jbmr

43 Wnt Signaling Pathway Induces Bone Formation TNFα Dickkopf-1 (DKK-1) and sclerostin (Scl) inhibit Wnt Scl Wnt Wnt sfrp Dkk-1 Wnt Frizzled Β-Catenin Β-Catenin Nucleus Β-Catenin Β-Catenin Adapted from Krishnan V, et al. J Clin Invest 2006; 116: Pre-osteoblast

44 Sclerostin Antibody Inhibits Sclerostin, A Naturally Occurring Inhibitor of the Bone Forming Cell Pathway WITHOUT Sclerostin Antibody Mesenchymal Stem Cell (MSC) WITH Sclerostin Antibody Mesenchymal Stem Cell (MSC) Osteoprogenitor Cell Osteoprogenitor Cell Pre-Osteoblast Pre-Osteoblast Scl-MAb Sclerostin Osteocyte Bone Osteocyte This depiction is believed to be the mechanism of action for the sclerostin antibody: this compound is investigational. Scl-MAb=Sclerostin antibody

45 Original Article Romosozumab in Postmenopausal Women with Low Bone Mineral Density Michael R. McClung, M.D., Andreas Grauer, M.D., Steven Boonen, M.D., Ph.D., Michael A. Bolognese, M.D., Jacques P. Brown, M.D., Adolfo Diez-Perez, M.D., Ph.D., Bente L. Langdahl, Ph.D., D.M.Sc., Jean-Yves Reginster, M.D., Ph.D., Jose R. Zanchetta, M.D., Scott M. Wasserman, M.D., Leonid Katz, M.D., Judy Maddox, D.O., Yu-Ching Yang, Ph.D., Cesar Libanati, M.D., and Henry G. Bone, M.D. N Engl J Med Volume 370(5): January 30, 2014

46 Group Study Schema to 12 Months. Placebo (N=52 [every 3 mo, N=22; monthly, N=30]) Romosozumab 140 mg every 3 mo (N=54) Romosozumab 210 mg every 3 mo (N=53) Romosozumab 70 mg monthly (N=51) Romosozumab 140 mg monthly (N=51) Romosozumab 210 mg monthly (N=52) Alendronate 70 mg weekly (N=51) Teriparatide 20 µg daily (N=55) Screening Day 1 Month 12 McClung MR et al. N Engl J Med 2014;370:

47 Percentage Change from Baseline in Bone Mineral Density McClung MR et al. N Engl J Med 2014;370:

48 Percentage Change from Baseline in Bone-Turnover Markers. McClung MR et al. N Engl J Med 2014;370:

49 Recommendations for Evaluation Evaluation of BMD at age 70 years including Lumbar spine and hip Measure the forearm DXA (1/3 or 33% radius) when spine or hip BMD cannot be interperted and for men with hyperpth or receiving androgen deprivation therapy (ADT) for prostate cancer BMD evaluation between if delayed puberty, hypogonadism, hyperpth, or COPD, or medications: GCs, GnRH agonists, ETOH or smoking or history of a fracture

50 Recommendations for Treatment All men History of hip or vertebral fracture BMD of spine, hip or femoral neck is T score of below the mean for white males US T score between -1.0 and -2.5 of spine, femoral neck or total hip with a 10 year risk of hip fracture >= 3% and an fracture of >=2-% Receiving long term glucocorticoid therapy in doses of > 7.5mg per day according to the 2010 guidelines of American College of Rheumatology JCEM June 2012:

51 Lifestyle Recommendations Men with or at risk for osteoporosis consume mg of calcium daily ideally from dietary sources ( diet and supplement Men with low vitamin D (<30ng/ml or 75nmol/liter) receive vitamin D supplements to achieve 25 vitamin D of 30ng/ml

52 Recommendation for the Selection of Therapeutic Agent Alendronate 70mg once a week Risedronate 35mg once a week Zoledronic acid 5mg each year Teriparatide 20ug/day for 2 years subcutaneously Denosumab 60mg sq every 6 months Hypogonadal men at high risk for fracture on testosterone + agent for anti-fracture efficacy any approved treatment. Men with testosterone < 200ng/dl and low risk for fracture be treated with testosterone therapy if symptoms of androgen deficiency (low libido, fatigue, loss of body hair, hot flushes, or organic hypogonadism secondary to a medical problem.

53 Monitoring Therapy Clinicians monitor BMD by DXA at the spine and hip every 1 to 2 years to assess response to treatment. Once BMD reaches a plateau the frequency of BMD measures can be reduced Monitor bone turnover markers such as serum CTX or urine NTX for anti-resorptive therapies and a bone formation marker PINP for anabolic therapy. Use concept of least significant change in a BTM can 40% for urine NTX after 3 months of treatment. Lack of change in BTM man mean non-compliance, secondary osteoporosis, change in therapy or route of administration