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Update on Treatment of Osteoporosis

E. Michael Lewiecki, MD, FACP, FACE Director, New Mexico Clinical Research & Osteoporosis Center

Director, Bone Health TeleECHOUniversity of New Mexico Health Sciences Center

Albuquerque, NM

Disclosure• No direct compensation from potentially conflicting entities

• Employed by New Mexico Clinical Research & Osteoporosis Center, which has received the following in the past one year:– Research grant support from Amgen, Radius, Mereo– Consulting and scientific advisory board fees from Amgen, Radius, Alexion,

Sandoz– Honoraria for service with speakers’ bureaus of Alexion, Radius– Support for project development with University of New Mexico

• Board positions with the ISCD, NOF, OFNM

• Guideline committees with ISCD, NOF, AACE

Objectives• Define indications for pharmacologic treatment of

osteoporosis• Describe mechanism of action for different drug classes

for treating osteoporosis• Determine strategies for selecting initial therapeutic

agents and changing therapy• Apply methods for understanding and explaining to

patients the balance of benefits and risks with treatment

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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 (e.g., architecture, turnover, damage accumulation, mineralization)

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, PhD.

DXA Measures Bone Density

DXA = Dual-energy X-ray Absorptiometry

WHO Classification of BMDT-score

Normal -1.0 or higherOsteopenia Between -1.0 and -2.5

Osteoporosis -2.5 or lowerSevere Osteoporosis -2.5 or lower + fragility fracture

WHO Study Group 1994. ISCD Official Positions. 2015.

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.

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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, AIs, ADT, etc.

• Correlation between T-score and fracture risk is a gradient, not a threshold

DXA Measures Bone Quality (TBS)

TBS = Trabecular Bone Score

Bone Density Bone Quality

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Osteoporosis: Good News• Improving awareness• Excellent diagnostic tools• Fracture risk assessment algorithms• Effective and safe treatments• Inexpensive generic drugs• Better understanding of pathogenesis• Federal initiatives to improve care

Osteoporosis: Bad News• Underdiagnosis and undertreatment• Poor adherence to therapy• Poor understanding of risk/benefit ratio• Restrictions on coverage of BMD testing, drugs, vitamin

D testing, bone turnover markers • Severely diminished drug pipeline • DXA quality concerns• Medicare cuts in DXA reimbursement

Treatment Gap Getting Worse

Solomon DH et al. J Bone Miner Res. 2014;29:1929–1937.

Review of US insurance claims data (commercial + Medicare) in 96,887 patients hospitalized with hip fracture, 2002-2011

40%

21%

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Reduced Bisphosphonate Prescription Rates Starting in 2008

Jha S et al. J Bone Miner Res. 2015;30:2179-2187.

17.9%

14.8%

13.2%

11.3%

693

884

738

500

550

600

650

700

750

800

850

900

10%

12%

14%

16%

18%

20%

22%

24%

26%

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Fractures per 100,000 Wom

enAge 65+

Age-adjusted to the 2014 Age Distribution

Perc

ent o

f Wom

enAg

e 65

+

Lewiecki EM et al. Osteoporos Int. 2018;29:717-722.

11,464 additional hip fractures$459 million additional expenses2,293 additional deaths

DXA Medicare Payments

DXA Testing

$82

Osteoporosis Diagnosis

$139

Hip Fracture Rates

$42

US Hip Fracture Trends 2002-2015

Who should be treated, how should they be treated,and how can we do it better?

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Fracture Risk Assessment

Intervention Thresholds

Treatment

Follow-up

Will I end up like my mother?

Evaluation / Discussion

Ann is a 55 year-old woman who feels well. She has had no known fracture. She smokes ½ pack per day and has a mother with hip fracture at age 78. She asks you if she should have a bone density test.

Your answer is …A. YesB. NoC. MaybeD. You need more information

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%

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You order a DXA for Ann. The report states:Lumbar spine T-score = -2.8, osteoporosis, fracture risk is highFemoral neck T-score = -2.1, osteopenia, fracture risk is

moderate33% radius T-score = - 0.9, normal, fracture risk is low

The correct diagnosis is …A. OsteoporosisB. OsteopeniaC. NormalD. All of the above

Fracture risk is …A. HighB. ModerateC. LowD. All of the above

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.NBHA Report. Siris ES et al. Osteoporos Int. 2014;25:1439-1443.

In the OfficeFocused history• Prior fractures• Family history of fractures• Childhood development• Falls• Medications, supplements• Osteoporosis treatments• Historical max. height• Lifestyle• Surgery• Diet• Review of systems• More

Physical exam• Height (stadiometer)• Falls risk assessment• Gait• Sclerae• Kyphosis• Rib-pelvis space• Skeletal deformity• Rash• Tremor• Hepatomegaly• Flexibilty• More

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Measure Height with Wall-mounted Stadiometer

Spine imaging if historical height loss > 1.5 inches

Laboratory EvaluationAlmost 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• sIFE, 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.

54%46%

243 women with hip fractures in Study of Osteoporotic Fractures

T-scoregreaterthan-2.5

T-score-2.5orless

Wainwright SA et al. J Clin Endocrinol Metab. 2005;90:2787-2793.

Most Women with Hip Fracture have T-score > -2.5

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NOF Treatment Guidelines

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%

For postmenopausal women and men age 50 and older, after appropriate evaluation for secondary causes

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2014.

Universal Recommendations• Regular weight-bearing and muscle-strengthening

physical activity• Falls prevention• Avoid tobacco use and excess alcohol• Identification and treatment of risk factors for fracture• Calcium 1000-1200 mg/day, ideally from diet• Vitamin D 800-1000 IU/day, target ≥ 30 ng/mL

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2014.

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Pharmacological TherapyInhibit 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)

All of these can increase BMD, improve bone strength, and reduce fracture risk.Only anabolic agents can build new bone and restore degraded bone structure.Anabolic agents are superior to antiresorptives for high risk patients.

Bone Remodeling

http://www.endotext.org/parathyroid/parathyroid1/parathyroid1.html

Zaidi and Chambers, 1987

Osteoclast

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Normal Bad Very Bad

Courtesy Dr. A. Boyde

Progression of Osteoporosis

Anabolic vs. Antiresorptive Therapy

Treatment Sequence Matters• Anabolic therapy superior to antiresorptive for fracture risk reduction in high

risk patients

– GIO, TPT vs. ALN. Saag KG et al. N Engl J Med. 2007;357:2028-2039.

– Severe PMO, TPT vs. ALN. Hadji P et al. Osteoporos Int. 2012;23:2141-2150.

– Severe PMO, TPT vs. RIS. Kendler DL et al. Lancet. 2017;S0140-6736(17)32137-2.

– Severe PMO, Romo vs. ALN. Saag KG et al. N Engl J Med. 2017;377:1417-1427.

• Potent antiresorptive therapy before anabolic may attenuate or delay onset of effect (hip BMD decrease with teriparatide after denosumab)

• Antiresorptive therapy after anabolic is essential to consolidate or enhance therapeutic effect

Cosman F et al. J Bone Miner Res. 2017;32:198-202.

Sequence of Osteoporosis TherapyAntiresorptive Anabolic

Anabolic Antiresorptive

Anabolic Anabolic

Antiresorptive Antiresorptive

Delay or attenuation of anabolic effect;decreased BMD with TPT after Dmab

Antiresorptive is essential after anabolic; initial therapy with anabolic is best choice for high risk patients

Probably neutral

Greater BMD effect with more robust antiresorptive, especially Dmab after BP

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Individualizing Initial TreatmentAgent Comments

Oral bisphosphonates Pro: inexpensive, work well in many patientsCon: GI distress, avoid with low GFR, bad rep in lay press

Zoledronic acid Pro: very long dosing interval, post-hip fracture data Con: acute phase reaction, avoid with low GFR, IV

Denosumab Pro: long dosing interval, greatest BMD increase, SCCon: FDA list of “side effects” (back pain, high cholesterol, etc.)

Raloxifene Pro: not a BP, decreases breast cancer riskCon: VTE, hot flashes, no proven hip fracture decrease

Teriparatide Pro: anabolic [SEQUENCE MATTERS]Con: high cost, daily injection, refrigeration, rat osteosarcoma

Abaloratide Pro: anabolic [SEQUENCE MATTERS]Con: high cost, daily injection, rat osteosarcoma

Personal opinion.

• Initiate therapy with medication that has high likelihood of achieving an acceptable level of fracture risk

• Response to therapy is essential but not necessarily sufficient

• Patient may respond well but remain at high risk of fracture• For patient started on treatment because of T-score ≤ -2.5,

consider target > 2.0• Greater increase in BMD are associated with greater

reduction in fracture risk

ASBMR-NOF Working Group. Cummings SR et al. J Bone Miner Res. 2017;32:3-10.

Treat-to-Target

Jaw Rot

Brittle Bones

Femur Snaps

HeartburnBloodClots

Fatal Stroke

Back Pain

Muscles Ache

Joint Pain

Atrial Fib

Osteoporosis Wheel of Fear

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10-Year Probabilities25%

12.5%

0.01% 0.11% 0.06%0%

5%

10%

15%

20%

25%

30%

FxRiskUntreated

FxRiskTreated

ONJTreated FatalMVA Murder

Untreated fracture risk estimate calculated by FRAX. ONJ estimate is ~1/100,000 patient-treatment-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;364:1728-1737. Risk estimates assume long-term bisphosphonate therapy resulting in 50% reduction in fracture risk. MVA and murder data from the CDC at http://www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_10.pdf. Image copyright © 2011 Lewiecki EM.

72 year-old woman with FN T-score = -3.0

Includes 0.5% Atypical Femur Fracture Risk

Includes 0.01% Atypical Femur Fracture Risk

“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.

ASBMR Task Force. Adler RA et al. J Bone Miner Res. 2016;31:16–35.

Consider “Drug Holiday” for 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

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No Holiday with Other Osteoporosis Medications

Stopping non-bisphosphonate (estrogen, raloxifene, denosumab, teriparatide, abaloparatide) is followed by rapid loss of effect.

Fracture Liaison Service (FLS)

• Secondary fracture prevention by systematic identification and management

of fracture patients

• Objectives

– Assess risk of future fractures

– Evaluate for factors contributing to skeletal fragility

– Educate about skeletal health

– Assure that treatment to reduce fracture risk is started, if needed

– Monitor to see that objectives are achieved

• Key person: FLS coordinator - CNP or discharge planner

• Technology: patient registry, task tracker, quality measures, etc.

Capture the Fracture. International Osteoporosis Foundation. Osteoporos Int. 2013;24:2135-2152.Fracture Prevention Central. National Bone Health Alliance. Curr Osteopooos Rep. 2013;11:348-353.Own the Bone. American Orthopedic Association. J Bone Joint Surg Am. 2008;90:163-173.

Gerald Champion Regional Medical CenterChristus St. Vincent Regional Medical CenterUNMHIn development: Presbyterian

When to Refer to an Osteoporosis Specialist

• Low trauma fracture with normal BMD• Recurrent fractures or continuing bone loss despite

treatment• Unexpectedly severe osteoporosis (e.g., very low BMD in

young patient)• Uncommon features (e.g., low alk phos, low P) • Uncommon secondary causes (e.g., bariatric surgery, celiac

disease)• Complicating conditions (e.g., CKD, hyperpara)

Adapted from AACE Guidelines. Endocr Pract. 2016;22 (Suppl 4).

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Bone HealthRegister at www.ofnm.org

Average Number of Participants Per Bone Health TeleECHO Session

13

19

32

42

051015202530354045

2015 2016 2017 2018

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UNM Bone Health TeleECHO

36 month data.

Participants in:CanadaMexicoChileBrazilTrinidad and TobagoIrelandEnglandDenmarkRussiaUkraineArmeniaUnited Arab Emirates

Other bone ECHO hubs:MichiganWashington, DCIrelandMoscowMore to come

Self-Efficacy Outcomes Measures

Before ECHO

After ECHO*

Bone Health ECHO learners with direct patient care responsibilities who attended more than 10 clinics (n=10)

Lewiecki EM et al. J Endocr Soc. 2017;1(12):1428-1434.

Expert

Very competent

Competent

Average

Slight skills

Vague skills

No skills

N/A

*P = 0.005 (very large effect size; Cohen and Sawilowsky)

Register at www.ofnm.org

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Summary• Osteoporosis is a common disease with serious

consequences due to fractures

• Effective and safe medications to reduce fracture risk are available

• Osteoporosis is a lifelong disease that deserves lifelong attention

Contact me for more information: mlewiecki@gmail.com