OsteoporosisWhich Drug, When to Start,

How Long to Treat

Family Medicine Refresher Course

April 2, 2019

Janet A. Schlechte, M.D.

Janet A. Schlechte, M.D.

has no relationships with any proprietary entity producing

health care goods or services consumed by or

used on patients.

Disclosure of Financial Relationships

•Pathogenesis of post menopausal bone loss has been elucidated

•BMD can be measured reproducibly by DXA and diagnostic criteria are established

•Tools for estimating individual fracture risk are available

•Fracture protection occurs rapidly

THE GOOD NEWS

• Number of patients treated for osteoporosis has declined by 40% since 2008

• Patients often stop medication because of safety concerns

• Most drugs are anti-remodeling agents• Physicians are uncertain about when

to treat and for how long

THE BAD NEWS

• Which drug is best?

• How long to treat?

• Concerns about AFF and ONJ

• Drug holiday

Issues

JCEM 2012;97:311

Remodeling and Modeling of Bone

Bisphosphonates RANKLAlendronate DenosumabRisedronateIbandronateZoledronic Acid

PTH PTHrPTeriparatide Abaloparatide

Treatment of Osteoporosis

NEJM 2007;356:1809

Effect of Bisphosphonate on Hip Fractures

Antifracture Efficacy of Bisphosphonates

Vertebral Hip Nonvertebral

Alendronate + + +

Risedronate + + +

Ibandronate + – –

Zoledronic Acid + + +

Year

BM

D C

han

ge

Fro

m B

asel

ine,

Mea

n, %

0

FIT

1 2 3 4 0 1 2 3 4 5

16

14

12

10

8

6

4

2

0

-2

FLEX

Begin Flex

BisphosphonatesHow long to treat?

Placebo

Alendronate

JAMA 296:2927, 2006

Bisphosphonates Time to First Fracture

JAMA 296:2927, 2006

Time to First Fracture, mo

0 12 24 36 48 60 720

5

10

15

20

Time to First Fracture, mo

0 12 24 36 48 60 720

5

10

15

20

Placebo

AlendronateAlendronate

Placebo

Cu

mu

lati

ve In

cid

ence

(%

)

Cu

mu

lati

ve In

cid

ence

(%

)

Nonvertebral Clinical Vertebral

RR, 1.00 (95% CI, 0.76-1.32) RR, 0.45 (95% CI, 0.24-0.86)

Consider a drug holiday when

• T score >-2.5

• No fractures

• No new risk factors

• Patient agrees to close follow-up and repeat DXA

There are no guidelines for when to withdraw a bisphosphonate

Bisphosphonate Drug Holiday

• Consider in low risk patients after 5 years of treatment with alendronate or risedronate and after 3 years of therapy with zoledronic acid

• FDA has not identified subgroups of patients who will benefit from therapy with bisphosphonates for >3-5 years

• Usefulness of bone markers and DXA surveillance not established

NEJM 2009;361:756

Should I Start with Denosumab Instead?

Freedom Trial

• 3 year RCT of Denosumab• 7800 postmenopausal women 60-90• T score -2.5, some had vertebral

fractures• 68% reduction in new vertebral

fractures• 20% reduction in non vertebral

fractures• 40% reduction in hip fracture

NEJM 36:958, 2009

Osteo Intl 2017;28:1723

Effect of Stopping Denosumab

• 52 patients treated for 8 years had decrease of ~6.7% in hip and spine BMD during 1 year of observation

• 10% experienced fractures

• Case reports 5 patients treated for 2-3 years, 8% fractured

Effect of Stopping Denosumab

Curr Osteo Report 2015 Osteo Intl 28:1723, 2017

Drug Holiday for Denosumab?

• 50 women treated with Deno or PTH or both then switched at 2 years

• After 4 years women counseled to reinstitute their previous therapy

• 28 returned for follow-up

• With no follow-up therapy BMD ↓ by 4.2% in hip and 10% in spine

• In those who received follow-up treatment BMD was maintained

Bone 2017

A 70 y.o. female has a T score of -2.9 in her femoral neck. She has taken a bisphosphate for 2 years and announces today that she has stopped the drug.

“My osteoporosis drug is too risky.”

Atypical Femoral Fracture

T score BMD (gm/cm2)

2010 -1.6 0.656

2005 -1.4 0.660

2003 -1.5 0.659

2000 -1.4 0.664

Hip Fracture Sites

BMR 25:2267, 2010

• OR 2.7 (1.2-6.0) 716 cases vs 3580 controls

• 9723 fractures vs 48564 in controls

• Treating 1000 women for 5 years would

- Prevent 30-50 nonvertebral fx

- Prevent 50-115 vertebral fx

- Cause 5 atypical fx

JAMA 305:783, 2011

Atypical Fractures and Bisphosphonates

JBMR 2012;27:2544

Atypical Femoral Fractures and Duration of Bisphosphonate Exposure

• Defects in cholesterol synthetic pathway

• Vitamin D deficiency• Glucocorticoids• PPI?• Normal or low BMD• Comorbid illness• Combination of antiresorptive agents

Causes of Atypical Fractures

• If a patient taking a bisphosphonate develops thigh or groin pain

• X-ray both femurs

• If radiographs normal consider bone scan or MRI to look for stress reaction

Bone and Mineral Research 25:2267, 2010

After Atypical Femur Fractures

• When/if to restart therapy is individual decision based on risk factors

• Do yearly clinical assessment

• ? bone markers

• Monitor BMD

Bisphosphonates and Osteonecrosis

Osteonecrosis of the Jaw

• 1 in 10,000 to 1 in 60,000 patient years compared to 1-10/100 patients with cancer

• Usually associated with high dose therapy with pamidronate and zoledronic acid

• Bone markers do not identify at-risk patients

• Stopping drug pre-procedure not likely helpful

Reassure Your Patients

• Typical intertrochanteric fractures more common than subtrochanteric fractures

• Extended therapy with antiresorptive agents can be associated with ↑ risk of subtrochanteric fracture but overall risk is low

• Concern about subtrochanteric fracture should not deter providers from using bisphosphonate therapy in appropriate patients

Resting

Activation

OsteoclastRecruitment

Resorption

Reversal

OsteoblastRecruitment

Repair

Resting

Osteoid

Bone

Denuded Bone SurfaceOC

MP

POBMC

New Osteoid

OC

OB

PM PO

24

20

-4

16

12

8

0 6 12 18

4

0

24 30

Alendronate

Combination therapy

Parathyroid hormone

Time (months)

Per

cent

cha

nge

Effect of PTH and Alendronate on Spinal BMD

NEJM 349:1216, 2003

Parathyroid Hormone Therapy

• Not first line therapy• Severe osteoporosis or failure of

other therapy• Don’t use if patient has secondary

hyperparathyroidism, hypercalcemia, evidence of skeletal malignancy

• PTH decreases vertebral fracturesbut fracture reduction is slow to develop (9 months)

• Need an anabolic agent with more rapid onset of action

• Analog of PTHrP recently approved

Abaloparatide

• Synthetic analog of PTHrP

• Binds more selectively than PTH to the PTH-1 receptor which stimulates anabolic activity with modest stimulation of resorption

• Transient binding favors bone formation and minimizes bone resorption, also less calcium mobilization

Sclerostin and Osteoblast Proliferation

• Monoclonal antibody against sclerostin

• Multicenter, randomized, placebo controlled

• 419 postmenopausal women

• Romosozumab, teriparatide, alendronate or placebo

• Primary endpoint - percent change in spine BMD at 1 year

Romosozumab

• A 70 y.o. who is taking calcium and vitamin D calls to discuss the safety of calcium therapy.

• She takes 2500 mg of calcium carbonate and 1000 IU of vitamin D daily.

• She is worried about an increase in CV disease due to calcium.

Effect of Calcium/Vitamin D on CVDThe Women’s Health Initiative

Hsia et al. Circulation 2007; 115:846-854

MI + Coronary Death Stroke

What to do

• Link between calcium supplementation and CV events inconclusive

• Promote dietary calcium

• Don’t stop calcium supplement

• Reserve supplements for those unable or unwilling to achieve adequate dietary intake

Take Home Points

• Therapy for osteoporosis is effective and can be targeted to affect bone formation and bone resorption

• Need tools for assessing bone quality and additional anabolic agents

• Use drug holiday in patients taking a biphosphonate

• Reassure patients about safety of available drugs

KEEPCALM

AND

TRUST YOURENDOCRINOLOGIST