Controversies in the Diagnosis and Treatment of Osteoporosis

Kenneth G. Saag, MD, MSc

Jane Knight Lowe Professor

Vice Chair, Department of Medicine

Division of Clinical Immunology and Rheumatology

Director, Center for Outcomes, Effectiveness Research, and Education (COERE)

THE UNIVERSITY OF

ALABAMA AT BIRMINGHAM

Disclosures

• Sources of Research Funding:

• NIAMS, AHRQ, NCATs, NCMRR

• Industry: Amgen, Mereo, Radius

• Immediate Past President, Board of Trustee, National Osteoporosis Foundation

• Secretary, American College of Rheumatology

• Consultant: Abbvie, Amgen, Radius, Roche

Osteoporosis 2019Challenges, Controversies, Possibilities…

• Are calcium and vitamin D effective and safe?

• What are current controversies around testing for osteoporosis?

• What’s new with…

• Bisphosphonates?

• Denosumab?

• Anabolics?

• Kyphoplasty/vertebroplasty?

• What’s on the horizon with romosozumab?

CalciumControversies

• How much is needed?

• Does it cause heart disease?

• Does it reduce fractures?

• From diet vs. supplements?

• If supplements, what types?

Calcium and Vitamin D Recommended Daily Allowances

US Institute of Medicine (IOM) Report November, 2010

Age Range (yrs)

Calcium

(mg/day)

Vitamin D

(IU/day)

9-18 1300 600

19-50

51-70 (men)

1000 600

51-70 (women) 1200 600

> 70 1200 800

“The committee emphasizes that, with a few exceptions, all North Americans are receiving enough calcium and vitamin D.

Higher levels have not been shown to confer greater benefits, and in fact, they

have been linked to other health problems, challenging the concept that

‘more is better’”

IOM, 2010

Bolland MJ. BMJ 2010; 341: c3691

Calcium Meta-analysis

ᵡ

Calcium Meta-analysisLimitations

• No trial had primary cardiovascular outcome

• Endpoint adjudication - only 2 trials by blinded investigators

• Renal function not known

• Calcium may be safer when given with magnesium salts and/or vitamin D

• Need sensitivity analysis with different study selection criteria

Calcium Treatment Compared to Placebo Did NOT

Increase Atherosclerotic Vascular Disease,

Hospitalizations, or Death Outcomes

Analyses used groups with named baseline risk factor.

Adjusted for age, calcium intake, compliance, cardiovascular disease, eGFR, diabetes,

previous/current smoking, & baseline cardiovascular medications unless covariate subject of analysis.

eGFR = estimated glomerular function rate; ASVD = atherosclerotic vascular diseaseLewis JR. JBMR 2011; 26:35

“Calcium with or without vitamin D intake from food or

supplements that does not exceed the tolerable upper level of

intake (defined by the National Academy of Medicine as 2000

to 2500 mg/d) 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. Ann Intern Med. 2016;165:867

Harvey NC. J Bone Miner Res. 2018; 33: 803

Chen F. Ann Intern Med 2019;Epub.

• NIH funded study of NHANES data in 30,899 adults

• “Excess intake of calcium was associated with increased risk for

cancer death”

• “The association seemed related to calcium intake from supplements

(≥ 1000 mg/d vs. no use)” – 1.5 extra deaths per 1000 patient-

treatment-years

0 1 2 3 4 5 6

Swedish Mammography

Cohort (woman)

Adju

ste

d h

azard

ratio o

f death

4

3

2

1

0

Glasses of milk a day

Adju

ste

d h

azard

ratio o

f hip

fra

ctu

re

Adju

ste

d h

azard

ratio o

f any

fra

ctu

re

Cohort of Swedish Men

0 1 2 3 4 5 6

Glasses of milk a day

4

3

2

1

04

3

2

1

0

Milk and Mortality

Michaellsson K

BMJ 2014;

349:g6015

“Milk & Mortality/ Encounters with Vampires”

Calcium Supplements and Fractures

Bolland M. BMJ 2015;351:h4580

Study Calcium Control

Low risk of bias

Grant 2005 364/2617 400/2675

Jackson 2006 2102/18,176 2158/18,106

Prince 2006 110/730 126/730

Reid 2006 134/732 147/739

Total (95% CI) 2710/22,255 2831/22,250

Test for heterogeneity: P=0.77, I2=0%

Moderate risk of bias

Reid 1993 6/68 10/67

Chapuy 1994 240/1537 290/1539

Chevalley 1994 2/62 2/31

Riggs 1998 11/119 12/117

Baron1999 4/464 14/466

Porthouse 2005 58/1321 91/1993

Reid 2008 9/216 8/107

Salovaara 2010 78/1718 94/1714

Total (95% CI) 408/5505 521/6034

Test for heterogeneity: P=0.56, I2=0%

High risk of bias

Dawson-Hughes 1997 11/187 26/202

Peacock 2000 11/126 10/135

Chapuy 2002 69/389 34/194

Avenell 2004 9/64 8/70

Harwood 2004 6/75 5/75

Bolton-Smith 2007 2/62 2/61

Bonnick 2007 9/282 28/281

Sambrook 2012 11/170 14/156

Total (95% CI) 128/1355 127/1174

Test for heterogeneity: P=0.08, I2=44%

Test for heterogeneity between subgroups: p=0.05

All studies 3246/29,115 3479/29,458

Overall: P=0.004

Test for heterogeneity: P=0.17. I2=27%

Weigh

(%)

14

76

4

5

100

2

61

0

2

1

14

2

17

100

15

12

24

11

8

3

12

13

100

Relative risk

(95% CI)

0.93 (0.82 to 1.06)

0.97 (0.92 to 1.03)

0.87 (0.69 to 1.10)

0.92 (0.75 to 1.14)

0.96 (0.91 to 1.01)

0.59 (0.23 to 1.54)

0.83 (0.71 to 0.97)

0.50 (0.72 to 3.38)

0.90 (0.41 to 1.96)

0.29 (0.10 to 0.87)

0.96 (0.70 to 1.33)

0.56 (0.22 to 1.40)

0.83 (0.62 to 1.11)

0.83 (0.73 to 0.93)

0.46 (0.23 to 0.90)

1.18 (0.52 to 2.68)

1.01 (0.70 to 1.47)

1.23 (0.51 to 3.00)

1.20 (0.38 to 3.76)

0.98 (0.14 to 6.76)

0.32 (0.34 to 1.54)

0.77 (0.53 to 1.11)

0.89 (0.81 to 0.96)

No. of events/Total

0 6 12 18 24 30 mo

Placebo

Lum

bar

spin

e (

L2-L

4)

BM

D

Perc

ent

change f

rom

baselin

e

3

2

1

0

-1

1

0

-1

-2

-3

0.45

0.00

0.520.25

-0.23

0.23

-0.35

-1.55-1.90

1.63

0.00

0.520.23

0.870.37

1.711.85

2.76

*

**

*

Fem

ora

l neck B

MD

Perc

ent

change f

rom

baselin

e

Calcium

Placebo

Calcium

Rajatanavin R. Osteoporos Int 2013;24:2871

Calcium Monotherapy on Bone Mineral Density

Vitamin D Controversies • If supplements, How much? Vitamin D2

vs. D3?

• When should we measure it, is it accurate?

• What is optimal target level?

• Does Vitamin D reduce fractures? Increase fx rate? Other Health Benefits?

• Are kidney stones a worry?Armas. JCEM, 2004;89:5387-91

Jackson R.D. NEJM, 2006;254:669

Hanson K. JBMR, 2008;23:1052

Holick, M. JCEM, 2008;93:677-81

Ensrud K. JCEM, 2009;94:2773

Rosen CJ. NEJM, 2011;364:248

Vitamin D Controversies • If supplements, How much? Vitamin D2

vs. D3?

• When should we measure it, is it accurate?

• What is optimal target level?

• Does Vitamin D reduce fractures? Increase fx rate? Other Health Benefits?

• Are kidney stones a worry?Armas. JCEM, 2004;89:5387-91

Jackson R.D. NEJM, 2006;254:669

Hanson K. JBMR, 2008;23:1052

Holick, M. JCEM, 2008;93:677-81

Ensrud K. JCEM, 2009;94:2773

Rosen CJ. NEJM, 2011;364:248

Calcium and Vitamin D Recommended Daily Allowances

US Institute of Medicine (IOM) Report November, 2010

Age Range (yrs)

Calcium

(mg/day)

Vitamin D

(IU/day)

9-18 1300 600

19-50

51-70 (men)

1000 600

51-70 (women) 1200 600

> 70 1200 800

• “In this perspective, we have deliberately avoided a mind-numbing laundry list of the vast number of factual inaccuracies and misinterpretations in this report.”

• “Our recommendation to the public is that the IOM report should be taken with a grain of salt (another nutrient the IOM finds risky)”

Calcium and Vitamin D May Not Protect Against Fractures

• Calcium, Vitamin D, and Calcium + Vitamin D NOT associated with lower incidence of hip, nonvertebral, or total fractures

• Differences form past Meta-analyses and Limitations:

• WHI data updated; exclude patients on HRT

• Few trials included pts with established osteoporosis

• Some trials did not test baseline vitamin D

• Some trials of poor quality with unclear allocation concealment

Zhao J-G JAMA 2017;318:2466

Updated US Preventive Services Task Force Recommendations

on Calcium and Vitamin D• Evidence insufficient to assess balance of

benefits and harms of calcium and vitamin D supplements to prevent fractures for primary prevention in community dwelling

• Premenopausal women and men (any dose)

• Postmenopausal women (at sl higher dose)

• No benefit of lower doses of calcium and vitamin D in postmenopausal women

• Vitamin D USEFUL to prevent falls in older adults at fall risk

• Recommendations Do NOT apply to women at high risk for fractures, osteoporosis or known to be vitamin D deficient

USPSTF, JAMA, online 2018

Calgary Vitamin D Study

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

3 years Change in BMD

400 IU/day 4,000 IU/day 10,000 IU/day

RADIUS TIBIA

Boyd SK, ASBMR 2018, Presentation 1062

%

VITAL StudyDesign

• 25,871 patients - follow-up 6 years

Main Results

• Baseline 25(OH)D - 31 ng/ml

• No differences in invasive cancer or CV events

• No differences based on baseline 25(OH)D (threshold 20 ng/ml)

Limitations

• Effect of very low 25(OH)D not investigated

• Allowed out-of-trial supplementations

Manson J. N Eng J Med 2019;380:33

Calcium and Vitamin D ControversiesSummary Points

• Adequate calcium & vitamin D essential for bone health, vitamin D may have other health benefits

Calcium and Vitamin D ControversiesSummary Points

• Adequate calcium & vitamin D essential for bone health, vitamin D may (or may not?) have other health benefits

• Supplements won’t help If your not deficient or dose inadequate

• Overzealous use of calcium and vitamin D supplements may be deleterious

• Calcium:• Best sourced from diet, citrate for older adults

• 1200 mg/d is adequate for most adults

• Vitamin D:• Avoid dose that will not be adequate or is too high

• 800 IU/D reasonable supplement for those at risk for fractures

• 25 OH Vitamin D level:

• Maintained at ~20 ng/ml

• Target 30 to 50 ng/ml for those at high fracture risk

What’s New/Controversial with Testing?

What Ways Can We Diagnose Osteoporosis?

• T‐score ≤‐2.5 at spine, total hip or femoral neck

• FRAX scores (in those with osteopenia) that meet the NOF treatment intervention threshold: 10 year risk for hip fracture ≥ 3%, or for major osteoporotic fracture ≥ 20%

The diagnosis of osteoporosis should be made in postmenopausal women and in men over 50 who have one ofthe following:

Siris ES1, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ, Harris ST, Jan de Beur SM, Khosla S, Lane NE, Lindsay R, Nana AD, Orwoll ES, Saag K, Silverman S, Watts NB

What Ways Can We Diagnose Osteoporosis?

• T‐score ≤‐2.5 at spine, total hip or femoral neck

• FRAX scores (in those with osteopenia) that meet the NOF treatment intervention threshold: 10 year risk for hip fracture ≥ 3%, or for major osteoporotic fracture ≥ 20%

• Hip fracture, with or without BMD testing

• Low trauma vertebral, proximal humerus or pelvis fracture in the presence of osteopenia

• Some distal radius fractures in presence of osteopenia

The diagnosis of osteoporosis should be made in postmenopausal women and in men over 50 who have one ofthe following:

Siris ES1, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ, Harris ST, Jan de Beur SM, Khosla S, Lane NE, Lindsay R, Nana AD, Orwoll ES, Saag K, Silverman S, Watts NB

What are FRAX Caveats?

• Treatment naïve patients only

• May lead to under-estimate of fx risk (does not account for multiple fxs, steroid dose, etc.)

• May lead to over-estimate of fracture risk (“garbage in, garbage out”)

• Limited data on treating those with high absolute risk but reasonable BMD

Alonso-Coello P. BMJ 2008;336:126

If BMD is normal? Could a patient still have

osteoporosis?

• Only 1/3 of vertebral fractures come to clinical attention

• Among those who have T-score > -2.5, 26% had vertebral fractures †

• Lateral Vertebral Assessment (LVA) may increase the sensitivity of DXA to diagnose osteoporosis

†Greenspan S. JCD 2001; 4:373

Assessing Risk and Diagnosing Osteoporosis What are Indications for Vertebral Imaging?

Criterion Women Men

T-score <-1.5 at spine, total hip

or femoral neck

65-69 years 70-79 years

T-score <-1.0 at spine, total hip

or femoral neck

70 years and older 80 and older

•Low trauma fracture (age >50)

•Historical height loss of 1 1/2

inches or more

•Prospective height loss of 0.8

inches or more

•Recent or ongoing long-term

glucocorticoid treatment

Postmenopausal women and men age 50

and older

NOF. Clinician’s Guide to Prevention and Treatment of Osteoporosis.

Cosman F. Osteoporosis International. 2014;25:2359.

If bone density testing is not available, vertebral imaging may be considered based on age alone.

Which Fractures are Most Strongly Associated

with Osteoporosis*?

Warriner A, J Clin Epi, 2010;64:46.

Red= Strongly associated Yellow= Modestly associated Green = unlikely to be associated

*In the absence of major trauma or known malignancy

Who To Test? What Tests to Do For Osteoporosis Diagnosis?

• All Women > 65 with DXA (B)

• Women < 65 with increased risk (B)*

• With risk factor tool first

• FRAX

• Other tools such as SCORE, OST

• If at increased risk based on a screening tool DXA

Curry S. (USPSTF) JAMA. 2018;319:2521

Gourlay M. JAMA Int Med, online first, 2018*USPSTF primary care population

What is the Optimal Interval between DXAs?Baseline Testing and Development of

Osteoporosis According to Baseline DXA

Gourlay ML. N Engl J Med 2012;366:225.

Result of Baseline

Test

Interval between Baseline Testing and

Development of Osteoporosis

Unadjusted Adjusted

No. of years (95% CI)

Normal BMD 17.4 (11.5 – 26.3) 16.8 (11.5 – 24.6)

Mild osteopenia 16.5 (13.6 – 20.2) 17.3 (13.9 – 21.5)

Moderate osteopenia 4.6 (4.1 – 5.1) 4.7 (4.2 – 5.2)

Advanced osteopenia 1.0 (0.8 – 1.1) 1.1 (1.0 – 1.3)

Critique of DXA Interval Study

• Results are for older white women

• Younger women have greater rates of loss

• Morphometric vertebral fractures not an endpoint

• Lumbar spine BMD not measured

• Second DXA may be more influential in treatment status

If a patient is started on osteoporosis treatment because of T-score ≤ -2.5 and the

next DXA shows T-score > -2.5, does the patient still have osteoporosis?

Yes!

Lewiecki EM. J Bone Miner Res. 2019;34:605

Rationale

• Retaining diagnosis consistent with other chronic diseases

• Adverse consequences of changing diagnosis to osteopenia include . . . – False sense of security

– Stopping medication that is still needed

– Change in allowable frequency of BMD testing

– Loss of insurance coverage for medication

What’s New/Controversial with Bisphosphonates?

Bisphosphonates Drug Holidays

(Covered by Dr. McClung)

Does Zoledronic Acid Work in Osteopenia?

Reid I. N Engl J Med 2018; 379:2407

What’s New/Controversial with Denosumab?

FREEDOM Extension

-2

0

2

4

6

8

10

12

14

16

18

20

22

24

b

21.7%c

b

b

a

a

a

a

b

b

b

16.5%c

Lumbar Spine

Pe

rce

nta

ge

Ch

an

ge

Fro

m B

ase

lin

e

b

b

Bone HG. Lancet Diab Endo 2017;5:513

aa

Effects of Denosumab Treatment on Lumbar Spine BMD and New Vertebral Fractures Through 10 Years

b

b

FREEDOM Extension

2.2

3.1 3.1

0.90.7

1.1

1.51.2

1.4 1.3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Years of Denosumab Treatment

1/2d 4/5d3

1 2 3 4/5d 7/8d6 9/10d

6/7d

Years of Denosumab Treatment

Ye

arl

y In

cid

en

ce

of

Ne

w V

ert

eb

ral F

rac

ture

s (

%)

Study Year

1 2 3 4 50 6 7 8 9 10

Placebo Cross-over DenosumabLong-term Denosumab

a

FREEDOM Extension

-2

0

2

4

6

8

10

12

14

16

18

20

22

24

b

21.7%c

b

b

a

a

a

a

b

b

b

16.5%c

Lumbar Spine

Pe

rce

nta

ge

Ch

an

ge

Fro

m B

ase

lin

e

b

b

Bone HG. Lancet Diab Endo 2017;5:513

aa

Effects of Denosumab Treatment on Lumbar Spine BMD and New Vertebral Fractures Through 10 Years

b

b

FREEDOM Extension

FREEDOM Extension

2.2

3.1 3.1

0.9

1.5

1.91.6

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

2.2

3.1 3.1

0.90.7

1.1

1.51.2

1.4 1.3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Years of Denosumab Treatment

1/2d 4/5d3

1 2 3 4/5d 7/8d6 9/10d

6/7d

Years of Denosumab Treatment

Ye

arl

y In

cid

en

ce

of

Ne

w V

ert

eb

ral F

rac

ture

s (

%)

Ye

arl

y In

cid

en

ce

of

Ne

w V

ert

eb

ral F

rac

ture

s (

%)

Study Year

1 2 3 4 50 6 7 8 9 10

Placebo Cross-over DenosumabLong-term Denosumab

a

Bone Loss after Denosumab Stop

-8.1

-6

-8.4-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Zanchetta MB. Osteoporos Int 2018;29:41

% decline

in BMD

Lumbar Spine Femoral Neck Total Hip

Fractures After Stopping Denosumab(DMAb)

Cummings S. JBMR 2018;33:190

Single Fractures Multiple Fractures

Fractures After Stopping Denosumab(DMAb)

Cummings S. JBMR 2018;33:190

Single Fractures Multiple Fractures

Reid I. Calcif Tissue Int, online first

Immediate Zoledronic Acid May not Attenuate BMD Loss with Denosumab

Horne A. Calcif Tissue Int, online first

Delayed Zoledronic AcidAttenuates Bone Loss After Dmab

More Than Risedronate

(Median 65 days after trial)

If you Stop Denosumab When Should you Start a Bisphosphonate?

Chapurlat R. Joint Bone Spine 2018;85:515

BMD Drops When Switching DMAb to TPTD

Leder B. Lancet 2015;386:1147

What’s New/Controversial with Anabolic Approaches?

Teriparatide vs. RisedronateVERtebral Fracture Comparisons in severe Osteoporosis (VERO) Trial

Kendler DM. Lancet 2018;391:230

Teriparatide vs. RisedronateVERtebral Fracture comparisons in severe

Osteoporosis (VERO) Trial

Kendler DM. Lancet 2018;391:230

VERO Study Conclusions

• Teriparatide significantly more efficacious than an oral bisphosphonate at preventing Vertebral fxs and clinical fxs, but not non-vertebral fractures in patients at high risk for fracture

• Results contradict new American College of Physician (ACP) Osteoporosis Guidelines that do not include anabolics

• Abaloparatide - novel synthetic 34-amino acid peptide created to produce anabolic effect with less stimulation of bone resorption than other PTHR agonists

Abaloparatide Background

• Preclinical models and Phase 2 study findings suggested that abaloparatide

• Produced rapid BMD increases at both vertebral and nonvertebral sites

• Produced less calcium mobilization than PTH

Hattersley G. Endocrinology. 2016;157:141

Abaloparatide Compared to Teriparatide and PBOACTIVE Trial Non-vertebral Fractures

Placebo

Abaloparatide-SC

Teriparatide

Log-rank p-value (Abaloparatide-SC vs. Placebo): 0.0489

Log-rank p-value (Teriparatide vs. Placebo): 0.2157

Log-rank p-value (Abaloparatide-SC vs. Teriparatide): 0.4383

0 100 200 300 400 500 600 700 800

Time to Event (days)

Pe

rce

nta

ge

of

Pa

tie

nts

with

NV

F

5

4

3

2

1

0

Kaplan Meier Curve of Time to First Incident Non-vertebral Fractures (NVF)by Treatment Group (ITT Population)

Miller P. JAMA 2016;316:722

Teriparatide and AbaloparatideAdverse Effects Summary

• Osteosarcomas increased in rats but, so far, not in humans

• Contraindications: XRT, open epiphyses, Paget’s

• Symptomatically generally well tolerated with vasodilation greater with abaloparatide and calcium rise greater with teriparatide

• Limited treatment duration due to safety concerns and short anabolic window

Sclerostin and Anti-Sclerostin

• Produced by osteocytes1

• Inhibits the anabolic Wnt signaling pathway2

• Deficiency results in a sclerosing bone disease (sclerosteosis)3

1. Van Bezooijen R. JBMR. 2005;20:S92. Warmington K. JBMR. 2005;20:S223. Gardner JC. J Clin Endocrinol Metab. 2005;90:6392

Li J. J Bone Mner Res. 2009;24.578

Sclerostin Inhibits Wnt Signaling Pathway

FrizzledLRP

DshAxinAPC

GSK3βΒ-cateninCKIα

TCF

Β-catenin

Β-catenin

Wnt

Β-catenin

target genes activated

MesenchymalStem Cell (MSC)

OsteoprogenitorCell

Pre-Osteoblast

Sclerostin

P P P P

CBPGroucho

target genes repressed

Osteocyte

Antibody To Sclerostin Releases The Wnt Signaling Pathway

FrizzledLRP

Dsh

AxinAPC

GSK3βΒ-catenin

CKIα

TCF

Β-catenin

Β-catenin

Wnt

Β-catenin

target genes activated

Mesenchymal Stem Cell (MSC)

OsteoprogenitorCell

Pre-Osteoblast

Sclerostin

Stimulation of formation

Anti-Sclerostin AntibodyRomosozumab Phase 2, Bone Turnover Markers

McClung M. N Engl J Med 2014;370:412

Anti-Sclerostin AntibodyRomosozumab Phase 2, Bone Turnover Markers

McClung M. N Engl J Med 2014;370:412

Anti-Sclerostin Antibody Fracture Data

FRActure study in postmenopausal woMenwith ostEoporosis (FRAME)

• Reduced new vertebral fracture through months 12 (RRR 73) and 24 (RRR 75)

• Reduced clinical fractures (composite of vertebral and non-vertebral fractures) at 12 months (RRR 36)

• Did not meet secondary endpoint of reducing non-vertebral fractures at 24 months

• 5% injection site reactions, 2 ONJs and 1 AFF

Cosman F. NEJM 2016; 375:1532

Romosozumab ARCH Study Design

12 240Month 186 36

Double-Blind Open-Label

Enrolled(1:1)

N = 4093

Romosozumaba

210 mg SC QMN = 2046

Alendronate 70 mg PO QW

Daily calcium (500-1000 mg) and vitamin D (600-800 IU)

Alendronate 70 mg PO QW

N = 2047Alendronate 70 mg PO QW

Primary Analysis

– Clinical fractures confirmed

for ≥330 patients

– All patients completed

the month 24 visit

– Median (IQR) time on

study at primary analysis

was 33 (27, 40) months

Thoracic and lumbar spine x-rays

Dual-energy x-ray absorptiometryb

Serum for bone turnover markers

aLoading dose of 50,000‒60,000 IU vitamin D ; bBMD assessed at months 6 and 18 in a subset of patients in substudy; n=167. Yellow ovals indicate timepoints for substudy.

Saag K. NEJM 2017; 377:1417

n/N1 = Number of subjects with fractures/Number of subjects in the primary analysis set for vertebral fractures. Missing fracture status was imputed by multiple imputation for

patients without observed fracture at an earlier timepoint. n and % are based on the average across 5 imputed datasets. RRR = relative risk reduction.

RRR = 48%p < 0.001

Su

bje

cts

(%

)

127/2046 243/2047

24 Months

RRR = 37%

p = 0.003

Su

bje

cts

(%

)

n/N1 = 82/2046 128/2047

12 Months

Alendronate-to-AlendronateRomosozumab-to-AlendronateAlendronateRomosozumab

Romosozumab ARCH StudyPrimary Endpoint: New Vertebral Fracture Through 24 mos

Saag K. NEJM 2017; 377:1417

Romosozumab ARCH Study Primary Endpoint: Clinical Fractures at Primary Analysis

Romosozumab Romosozumab-to-Alendronate Alendronate Alendronate-to-Alendronate

12 Months

RRR = 28%

p = 0.027

n = number of subjects at risk for event at time point of interest.

2047 1868 1743

2046 1865 1770

1645 1564 1066 680 325 108

1683 1615 1103 705 347 109

Alendronate to Alendronate (n=)

Romosozumab to Alendronate (n=)

Romosozumab

vs alendronate

Open-label

alendronate

0 6 12 18 24 30 36 42 48

0

5

10

15

20

Month

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Primary Analysis

RRR = 27%

p < 0.001

Median (IQR) time on study at

primary analysis was 33 (27, 40)

months

Saag K. NEJM 2017; 377:1417

Romosozumab ARCH Study Secondary Endpoints:

Nonvertebral Fracture and Hip Fracture

n = number of subjects at risk for event at time point of interest. n = number of subjects at risk for event at time point of interest. Aln = alendronate; Romo = romosozumab.

Nonvertebral Fractures

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Romosozumab Romosozumab-to-Alendronate Alendronate Alendronate-to-Alendronate

0 6 12 18 24 30 36 42 48

Month

0

5

10

15

20

Aln to Aln (n=)

Romo to Aln (n=)

2047 1873 1755

2046 1867 1776

1661 1590 1097 697 330 110

1693 1627 1114 714 350 109

Primary Analysis

RRR = 19%

p = 0.040

Hip Fractures

Cu

mu

lati

ve

In

cid

en

ce

(%

)

2047 1914 1821

2046 1900 1829

1750 1690 1182 755 364 124

1766 1715 1195 772 379 125

0 6 12 18 24 30 36 42 48

0

1

2

3

4

5

6Primary Analysis

RRR = 38%

nominal p = 0.015

Month

Saag K. NEJM 2017; 377:1417

Serious Adverse Events in ARCH

Data are n (%). N = number of subjects who received ≥ 1 dose of investigational product. aAdverse events adjudicated positive by an independent adjudication committee. Cardiovascular deaths includes fatal events adjudicated as cardiovascular-related or undetermined (presumed cardiac-related).

Month 12Double-Blind Period

RomosozumabN = 2040

AlendronateN = 2014

All adverse events 1544 (75.7) 1584 (78.6)

Serious adverse events 262 (12.8) 278 (13.8)

Adjudicated serious cardiovascular eventa 50 (2.5) 38 (1.9)

Cardiac ischemic event 16 (0.8) 6 (0.3)

Cerebrovascular event 16 (0.8) 7 (0.3)

Heart failure 4 (0.2) 8 (0.4)

Cardiovascular death 17 (0.8) 12 (0.6)

Non-coronary revascularization 3 (0.1) 5 (0.2)

Peripheral vascular ischemic event not requiring revascularization

0 (0.0) 2 (< 0.1)

Death 30 (1.5) 21 (1.0)

bIncidence rates through primary analysis were cumulative and included all events in the double-blind and open-label period in subjects who received ≥ 1 dose of investigational product.

Saag K. NEJM 2017; 377:1417

FDA Meeting on Romosozumab

Jan 16, 2019

• FDA Advisory Committee- Recommended approval of Romosozumab (19 yes vs 1 no)

• The cardiovascular signal in trials 20110142 and 20110174 cannot be ignored → Boxed Warning as well as Warning and Precaution for cardiovascular risk

New ASBMR Task Force Report On Vertebral Augmention

• Percutaneous vertebroplasty → no clinically significant benefit over placebo or sham procedure (High to Moderate QoE)

• Balloon kyphoplasty → small clinical benefit over nonsurgical management, percutaneous vertebroplasty, vertebral body stenting, or KIVA. (Low QoE)

• Uncertain whether percutaneous vertebroplasty increases risk of incident or radiographic vertebral fractures (Moderate QoE)

Ebeling PR. J Bone Miner Res 2019;34:3-21

CATEGORY RESORPTION FORMATION

Anti-remodeling agents

- bisphosphonates, RANKL inhibitor

Anti-resorptive agent - cathepsin K inhibitors

Osteoanabolics- PTH and analogues

Osteoanabolic agent - sclerostin inhibitors

Osteoporosis Current and Possible Future Treatment Options

Conclusions• Calcium and vitamin D are necessary for bone

health but too much may not be optimal

• DXA, FRAX and skeletal imaging remain the mainstays of testing in clinical practice–more testing is likely needed over less

• Alternative therapies such as anabolics and shorter lasting anti-resorptives may be useful for patients at high risk, especially during a bisphosphonate break

• Plan an “exit” strategy before stopping denosumab

• Newer approaches focus on potent stimulation of bone formation; safety questions for Romo

Agents Under Development

Acknowledgements

• Giovanni Adami, MD

• Stephanie Biggers, RN

• Jeffrey Curtis, MD, MPH, MS

• Gary Cutter, PhD

• Maria Danila, MD, MSPH

• Jeffrey Foster, MPH

• Meredith Kilgore, PhD

• Peng Li, PhD

• Josh Melnick, MPH

• Sarah Morgan RD, MD

• Amy Mudano, MPH

• Elizabeth Rahn PhD

• David Redden, PhD

• Giovana Rosas, MD

• Amy Warriner, MD

• Nicole Wright, PhD

• Huifeng Yun, BS

R01AR060240 U18HS10389 5UL1 RR025777