Osteoporosis Review UNM Family Community Medicine April 18

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Osteoporosis Review UNM Family & Community Medicine April 18, 2018 Albuquerque, NM E. Michael

Osteoporosis Review UNM Family & Community Medicine April 18, 2018 Albuquerque, NM E. Michael Lewiecki, MD, FACP, FACE Director, New Mexico Clinical Research & Osteoporosis Center Director, Bone Health Tele. ECHO University of New Mexico Health Sciences Center Albuquerque, NM

Disclosure Institutional Grant / Research Support Amgen, Radius Consulting Amgen, Radius, Shire, Alexion, Ultragenyx

Disclosure Institutional Grant / Research Support Amgen, Radius Consulting Amgen, Radius, Shire, Alexion, Ultragenyx Speaking Radius, Shire, Alexion

Objectives • Define the pathophysiology of postmenopausal osteoporosis • Recognize osteoporosis treatment guidelines •

Objectives • Define the pathophysiology of postmenopausal osteoporosis • Recognize osteoporosis treatment guidelines • Discuss balance of benefits and risk with treatment

Osteoporosis • A skeletal disorder characterized by compromised bone strength predisposing to an increased

Osteoporosis • A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture • Bone strength reflects the integration of two main features: bone density and bone quality NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. March 27 -29, 2000. Published in JAMA. 2001; 285: 785 -795. Images by David Dempster, Ph. D.

Major Public Health Concern • • 54 million Americans with osteoporosis or low BMD

Major Public Health Concern • • 54 million Americans with osteoporosis or low BMD 2 million osteoporotic fractures each year Direct healthcare costs about $19 billion per year Increase is mortality, disability, loss of independence 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; 2004. www. surgeongeneral. gov/library/bonehealth/. National Osteoporosis Foundation. www. nof. org. Accessed 01 -01 -2018.

Maura’s Aunt Edna

Maura’s Aunt Edna

Who gets osteoporosis? • 1 of every 2 women will have an osteoporotic fracture

Who gets osteoporosis? • 1 of every 2 women will have an osteoporotic fracture • 1 of every 5 men will have an osteoporotic fracture • It could be you (or me)

Fracture Risk Assessment Will I end up like my mother? Intervention Thresholds Treatment Follow-up

Fracture Risk Assessment Will I end up like my mother? Intervention Thresholds Treatment Follow-up

Ann is a healthy 65 year-old woman is physically active with healthy lifestyle and

Ann is a healthy 65 year-old woman is physically active with healthy lifestyle and good nutrition. She has had no fracture and has no family history of osteoporosis. She asks you if she should have a bone density test. Your answer is … A. B. C. D. Yes No Maybe You need more information

Indications for Bone Density Testing ISCD 2015 Women and Men NOF 2016 Women and

Indications for Bone Density Testing ISCD 2015 Women and Men NOF 2016 Women and Men AACE 2016 Women Only NAMS 2010 Women Only ACOG 2012 Women Only USPSTF 2011 Screening Only Women age ≥ 65 ✔ ✔ ✔ Younger postmenopausal women with risk factors ✔ ✔ ✔* Perimenopausal women with risk factors ✔ ✔ Men age ≥ 70 ✔ ✔ Younger men with risk factors ✔ ✔ Adults with fragility fracture ✔ ✔ Adults with med, disease, or condition, causing low BMD ✔ ✔ Monitor treatment ✔ ✔ ✔ * FRAX MOF risk ≥ 9. 3%

DXA

DXA

T-score Patients BMD – Young-Adult Mean BMD SD of Young-Adult BMD in g/cm 2

T-score Patients BMD – Young-Adult Mean BMD SD of Young-Adult BMD in g/cm 2 Example: T-score = 0. 700 g/cm 2 - 1. 000 g/cm 2 0. 100 g/cm 2 = - 3. 0

WHO Classification of BMD T-score Normal Osteopenia -1. 0 or higher Between -1. 0

WHO Classification of BMD T-score Normal Osteopenia -1. 0 or higher Between -1. 0 and -2. 5 Osteoporosis Severe Osteoporosis -2. 5 or lower + fragility fracture Applies to peri- and postmenopausal women, and men age 50 and older. Cannot be used in premenopausal women and men under age 50. Should never be used in children (under age 20). T-score ≤ -2. 5 is not always osteoporosis. A patient may have osteoporosis with a T-score > -2. 5. WHO Study Group 1994. ISCD Official Positions. 2015.

More About T-scores • T-score ≤ -2. 5 is not always osteoporosis – Osteomalacia

More About T-scores • T-score ≤ -2. 5 is not always osteoporosis – Osteomalacia – Invalid measurement (e. g. , laminectomy) • T-score > -2. 5 may be osteoporosis – Fracture – High fracture probability (FRAX) • Many risk factures for fracture other than T-score – Especially advancing age and previous fracture – Also family history, smoking, glucocorticoids, RA, etc. • Correlation between T-score and fracture risk is a gradient

Age is an Independent Risk Factor for Osteoporotic Fractures Age 80 70 60 Ten

Age is an Independent Risk Factor for Osteoporotic Fractures Age 80 70 60 Ten Year Fracture Probability (%) Probability of first fracture of hip, distal forearm, proximal humerus, and symptomatic vertebral fracture in women of Malmö, Sweden. 50 Adapted from Kanis JA et al. Osteoporosis Int. 2001; 12: 989 -995.

You order a DXA for Ann. The report states: Lumbar spine T-score = -2.

You order a DXA for Ann. The report states: Lumbar spine T-score = -2. 8, fracture risk is high Femoral neck T-score = -2. 1, fracture risk is moderate Total hip T-score = -1. 7, fracture risk is moderate 33% radius T-score = - 0. 9, fracture risk is low The diagnosis is … A. B. C. D. Osteoporosis Osteopenia Normal All of the above Fracture risk is … A. B. C. D. High Moderate Low All of the above

Most Women with Hip Fracture have T-score > -2. 5 Wainwright SA et al.

Most Women with Hip Fracture have T-score > -2. 5 Wainwright SA et al. J Clin Endocrinol Metab. 2005; 90: 2787 -2793.

3 Ways to Diagnose Osteoporosis • BMD testing (WHO, ISCD) – T-score ≤ -2.

3 Ways to Diagnose Osteoporosis • BMD testing (WHO, ISCD) – T-score ≤ -2. 5 at LS, TH, FN, or 33%R • Fragility fracture (NBHA) – Low trauma hip fracture regardless of BMD – Low trauma vertebral, proximal humerus, pelvis or some distal forearm fractures with T-score between 1. 0 and -2. 5 • FRAX (NBHA, USA only) – MOF risk ≥ 20% or HF risk ≥ 3% WHO Technical Report. 1994; ISCD Official Positions. 2015. Siris ES et al. Osteoporos Int. 2014; 25: 1439 -1443.

You tell Ann that she has osteoporosis and fracture risk is high. Now she

You tell Ann that she has osteoporosis and fracture risk is high. Now she is very worried. She is upset that she has done everything right and still got osteoporosis. What do you do next? A. B. C. D. Tell her not to worry since she feels fine Prescribe alendronate Refer for physical therapy You need more information

NOF Treatment Guidelines For postmenopausal women and men age 50 and older, after appropriate

NOF Treatment Guidelines For postmenopausal women and men age 50 and older, after appropriate evaluation for secondary causes Osteoporosis by T-score • T-score -2. 5 or less at FN, TH, or LS, or. . . Clinical Osteoporosis • Hip or vertebral (clinical or morphometric) fracture, or. . . Low BMD + High Fx Risk • T-score between -1. 0 and -2. 5 at FN, TH, or LS, and. . . • FRAX 10 -year probability of hip fracture ≥ 3% or major osteoporotic fracture ≥ 20% National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2014.

Many Causes of Low BMD Lewiecki EM. Evaluation of Osteoporosis. Chapter 63 in Osteoporosis.

Many Causes of Low BMD Lewiecki EM. Evaluation of Osteoporosis. Chapter 63 in Osteoporosis. Marcus R et al, eds. 2013.

In the Office Focused history Physical exam • • • • • • Prior

In the Office Focused history Physical exam • • • • • • Prior fractures Family history of fractures Childhood development Falls Medications, supplements Osteoporosis treatments Historical max. height Lifestyle Surgery Diet Review of systems More Height (stadiometer) Falls risk assessment Gait Sclerae Kyphosis Rib-pelvis space Skeletal deformity Rash Tremor Hepatomegaly Flexibilty More

Laboratory Evaluation Almost everyone • CBC • Blood chemistries – – – Creatinine Calcium

Laboratory Evaluation Almost everyone • CBC • Blood chemistries – – – Creatinine Calcium Phosphorus Albumin Alkaline phosphatase Liver enzymes • 25 -OH-vitamin D • 24 -hour urine for calcium, sodium Selected patients • TSH • Celiac antibodies • Bone turnover markers • Urinalysis • s. IFE, kappa/lambda light chain ratio • Intact PTH • Overnight dexamethasone suppression Lewiecki EM. Evaluation of Osteoporosis. Chapter 63 in Osteoporosis. Marcus R et al, eds. 2013.

Rare Bone Diseases You Should Never Miss • Tumor Induced Osteomalacia – Suspect: low

Rare Bone Diseases You Should Never Miss • Tumor Induced Osteomalacia – Suspect: low P; confirm with renal P wasting, high FGF 23 – Manage: P, calcitriol – Cure: resection of tumor; monoclonal antibody to FGF 23? • Hypophosphatasia – Suspect: low alk phos; confirm with high B 6 – Manage: avoid bisphonates – Cure: asfotase alfa for severe forms • Hypoparathyroidism – Suspect: low albumin-corrected Ca; confirm with low PTH – Manage: Ca, calcitriol – Cure: PTH(1 -84) when poorly controlled

Other Guidelines Endorsed by American Academy of Family Physicians Qaseem A et al. Ann

Other Guidelines Endorsed by American Academy of Family Physicians Qaseem A et al. Ann Intern Med. 2017; 166: 818 -839. Lagari V et al. Clin Ther. 2018; 40: 168 -176.

ACP Guideline 2017 Update # 1 Recommendation Offer ALN, RIS, ZOL, or Dmab to

ACP Guideline 2017 Update # 1 Recommendation Offer ALN, RIS, ZOL, or Dmab to reduce risk of hip and VFs in women with osteoporosis Strength Strong 2 Treat osteoporotic women for 5 years Weak 3 Offer BPs to reduce VF risk in men with osteoporosis Weak 4 No BMD monitoring during 5 years of treatment in women Weak 5 No E, E+P, or RLX for treatment of PMO Strong Decision to treat women age ≥ 65 with osteopenia and high fracture risk should be based on discussion of patient 6 preferences, fracture risk profile, benefits, harms, and cost of medication Weak Commentaries from ASBMR, AACE, ISCD, NOF, NBHA, and many letters to the editor Qaseem A et al. Ann Intern Med. 2017; 166: 818 -839.

The work-up for Ann is unrevealing except serum 25 OH-D = 18 ng/m. L,

The work-up for Ann is unrevealing except serum 25 OH-D = 18 ng/m. L, PTH = 87 pg/m. L, and 24 -hour urinary calcium = 42 mg What do you do now? A. B. C. D. E. Refer for primary hyperparathyroidism Tell her to take OTC calcium/vitamin D Nonpharmacological therapy Pharmacological therapy Order more lab tests

Nonpharmacological Therapy • Calcium – about 1200 mg per day • Vitamin D –

Nonpharmacological Therapy • Calcium – about 1200 mg per day • Vitamin D – about 1000 IU per day • Regular weight-bearing and muscle strengthening physical activity • Fall prevention • Don’t smoke • Moderate alcohol (if at all) • Avoid bone toxic drugs when possible National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2014.

“Calcium with or without vitamin D intake from food or supplements has no relationship

“Calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time. ” Kopecky SL et al. Ann Intern Med. 2016; 165(12): 867 -668.

Ann has more lab tests. Celiac panel results: Ig. A normal Tissue transglutaminase Ig.

Ann has more lab tests. Celiac panel results: Ig. A normal Tissue transglutaminase Ig. A Ab = 341 (0 -14. 9) Gliadin Ig. A Ab = 87 (0 -14. 9) What is next? A. B. C. D. Refer to GI for small bowel biopsy Start gluten free diet now Gluten free diet + alendronate Gluten free diet + zoledronate

Pharmacological Therapy Inhibit Bone Resorption (Antiresorptive) Stimulate Bone Formation (Anabolic) Alendronate (Fosamax, generic) Teriparatide

Pharmacological Therapy Inhibit Bone Resorption (Antiresorptive) Stimulate Bone Formation (Anabolic) Alendronate (Fosamax, generic) Teriparatide (Forteo) Risedronate (Actonel, Atelvia, generic) Abaloparatide (Tymlos) Ibandronate (Boniva, generic) Zoledronate (Reclast, generic) Denosumab (Prolia) Raloxifene (Evista, generic) Salmon Calcitonin (Miacalcin, generic) Estrogen (various) CE/Baxedoxifene (Duavee)

Drug PMO Prevention GIO (Women, Men) Treatment Estrogen Alendronate PO (Fosamax, generic) Risedronate PO

Drug PMO Prevention GIO (Women, Men) Treatment Estrogen Alendronate PO (Fosamax, generic) Risedronate PO (Actonel, generic) Teriparatide SC (Forteo) Abaloparatide SC (Tymlos) Romosozumab SC (Evenity) Denosumab SC (Prolia) CE/Bazedoxifene PO (Duavee) Calcitonin IN (Miacalcin, generic) Raloxifene PO (Evista, generic) Ibandronate IV (Boniva, generic) Zoledronate IV (Reclast, generic) Treatment Risedronate DR PO (Atelvia) Ibandronate PO (Boniva, generic) Prevention Men

Basic Multicellular Unit (BMU) Martin TJ. J Bone Metab. 2014; 21: 8 -20.

Basic Multicellular Unit (BMU) Martin TJ. J Bone Metab. 2014; 21: 8 -20.

Individualizing Initial Treatment Agent Comments Oral BPs Pro: inexpensive, work well in many patients

Individualizing Initial Treatment Agent Comments Oral BPs Pro: inexpensive, work well in many patients Con: GI distress, avoid with low GFR, bad rep in lay press ZOL Pro: very long dosing interval, post-hip fracture data Con: acute phase reaction, avoid with low GFR, IV Dmab Pro: long dosing interval, greatest BMD increase, SC Con: FDA list of “side effects” (back pain, high cholesterol, etc. ) RLX Pro: not a BP, decreases breast cancer risk Con: VTE, hot flashes, no proven hip fracture decrease TPT Pro: anabolic [SEQUENCE MATTERS] Con: high cost, daily injection, refrigeration, rat osteosarcoma Abalo Pro: anabolic [SEQUENCE MATTERS] Con: high cost, daily injection, rat osteosarcoma Personal opinion.

Osteoporosis Wheel of Fear Atrial Fib Jaw Rot Brittle Bones Joint Pain Muscles Ache

Osteoporosis Wheel of Fear Atrial Fib Jaw Rot Brittle Bones Joint Pain Muscles Ache Femur Snaps Back Pain Heartburn Fatal Stroke Blood Clots

Bisphonate Safety Issues Side Effects “Side Benefits” • Short-term • • • – –

Bisphonate Safety Issues Side Effects “Side Benefits” • Short-term • • • – – GI distress Acute phase reaction Hypocalcemia Renal toxicity • Long-term – Osteonecrosis of the jaw – Atypical femur fractures • Questionable – – Chronic musculo-skeletal pain Atrial fibrillation Esophageal cancer Impaired fracture healing Improved implant survival �risk of breast cancer �risk of endometrial cancer �risk of colorectal cancer �risk of stroke �risk of gastric cancer �risk of MI in RA patients �risk of type 2 DM �mortality Prieto-Alhambra D et al. Arthritis Rheum. 2014; 66: 3233 -3240. Chlebowski RT et al. J Clin Oncol. 2010; 28: 3582 -3590. Newcomb PA et al. J Clin Oncol. 2015; 33: 1186 -1190. Dreyfuss JH. CA Cancer J Clin. 2010; 60: 343 -344. Newcomb PA et al. Br J Cancer. 2010; 102: 799 -802. Rennert G et al. J Clin Oncol. 2010; 28: 3577 -3581. Vestergaard P et al. Calcif Tissue Int. 2011; 88: 255 -262. Rennert G et al. J Clin Oncol. 2011; 9: 1146 -1150. Kang JH et al. Osteoporos Int. 2012; 23: 2551 -2557. Abrahamsen B et al. J Bone Miner Res. 2012; 27: 679 -686. Center JR et al. J Clin Endocrinol Metab. 2011; 96: 1006 -1014. Wolfe F et al. J Bone Miner Res. 2013; 28: 984 -991. Konstantinos A et al. J Clin Endocrinol Metab. 2015; 100: 1933 -1940. Sambrook PN et al. Osteoporos Int. 2011; 22: 2551 -2556. Lee P et al. J Clin Endocrinol Metab. 2016; 101: 1945 -1953.

Denosumab Safety Message to patients: “The most common side effects of Prolia® include back

Denosumab Safety Message to patients: “The most common side effects of Prolia® include back pain, pain in the arms and legs, high cholesterol, muscle pain, and bladder infections. ” Adverse reactions in ≥ 2% of Patients with Osteoporosis and More Frequent Than with PBO Term Prolia (N=3886) PBO (N=3876) Back Pain 1347 (34. 7%) 1340 (34. 6%) Pain in extremity 453 (11. 7%) 430 (11. 1%) Hypercholesterolemia 280 (7. 2%) 236 (6. 1%) Myalgia 114 (2. 9%) 94 (2. 4%) Cystitis 228 (5. 9%) 225 (5. 8%) https: //www. prolia. com/about/safety/ and package insert May 2017.

10 -Year Probabilities 80 year-old woman with FN T-score = -3. 3 Includes 0.

10 -Year Probabilities 80 year-old woman with FN T-score = -3. 3 Includes 0. 01% Atypical Femur Fracture Risk Includes 0. 5% Atypical Femur Fracture Risk Untreated probability of major osteoporotic fracture calculated by FRAX. ONJ estimate is ~1/100, 000 patienttreatment-years from ASBMR Task Force by Khosla S et al. J Bone Miner Res 2007; 22: 1479– 149. AFF estimate untreated is ~0. 01/10, 000 and treated is ~5/10, 000 patient-years from Schilcher J et al. N Engl J Med. 2011; 364: 17281737. Risk estimates assume long-term bisphonate therapy resulting in 50% reduction in fracture risk. MVA and murder data from the CDC at http: //www. cdc. gov/nchs/data/nvsr 56/nvsr 56_10. pdf. Image copyright © 2011 Lewiecki EM. Slide version.

Postmenopausal Women Treated with Oral BP ≥ 5 Years or IV BP ≥ 3

Postmenopausal Women Treated with Oral BP ≥ 5 Years or IV BP ≥ 3 Years • Low fracture risk: hip T-score > -2. 5 and no hip, spine, or multiple osteoporotic fracture before or during therapy – Consider drug holiday of 2 -3 years • High fracture risk: hip T-score ≤ -2. 5 or hip, spine, or multiple osteoporotic fracture before or during therapy – Consider continuing oral BP up to 10 years and IV BP up to 6 years Adler RA et al. J Bone Miner Res. 2016; 31: 16– 35.

No Holiday with Other Osteoporosis Medications

No Holiday with Other Osteoporosis Medications

Bone Health Register at www. ofnm. org

Bone Health Register at www. ofnm. org

Bone Health USA Participants: 21 Months 263 registered, 221 attended at least once, 35

Bone Health USA Participants: 21 Months 263 registered, 221 attended at least once, 35 -50 attendees each week Other countries Canada Mexico Chile Brazil Trinidad and Tobago Ireland UK Russia Lewiecki EM et al. ASBMR. 2017.

Summary • Osteoporosis is a common disease with serious consequences due to fractures •

Summary • Osteoporosis is a common disease with serious consequences due to fractures • Effective and safe medications to reduce fracture risk are available • Treatment decisions should be based on all available clinical information by a knowledgeable physician and wellinformed patient

58 year-old woman with PMO. L 1 -L 4 T-score = -2. 6. Takes

58 year-old woman with PMO. L 1 -L 4 T-score = -2. 6. Takes calcium, vitamin D, and a bisphonate.