Editorship Treatment Gaps and Patient New England Journal - - PowerPoint PPT Presentation

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Treatment Gaps and Patient Concerns: Where Do We Go from Here?

Clifford J Rosen MD rosenc@mmc.org MMCRI –Scarborough, Maine

Conflict of Interest Statement

• Editorship

–New England Journal –eLife –UpToDate

Outline

• Brief Overview of Osteoporosis Treatments
• State of Prescribing- 2019
• Treatment Gaps and What to Do About those?
• What do Patients Worry About?
• What can we do?

1-trauma; 2- prediction of subsequent fractures

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We Knew This 25 Years Ago!!! But have we made advances?

1 2 3 4 5 6 Previous Vert Frx No Vert Frx Low BMD Mid BMD High BMD 5.8 3.4 2.3 1.7 1.0 0.2 Risk of New Vertebral Fractures (% / yr)

*Ross 1991 ** Black, JBMR 1999

>2 VFx  10 times risk of future VFx**

BMD: SOF Very Long-Term Prediction (no models): a Single Hip BMD* is Remarkably Predictive for 25 years!

Cumulative incidence (%) Years since baseline

7.6% 14.1% 20.1% 29.6% 5 10 15 20 25 30 35 5 10 15 20 25 Highest Quartile Quartile 2 Lowest BMD Quartile Quartile 3

Black, et al. JBMR 2017; Napoli, ASBMR, 2016

* Age-adjusted

Currently Available Treatments

Estrogen Prevents Fractures: the WHI

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Fracture Risk Reduction with the Bisphosphonates Denosumab Treatment Reduces Vert Fractures

Cummings, NEJM 2009

Effect of Teriparatide on Incidence of Vertebral and Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis

Neer RM, et al. N Engl J Med. 2001;344:1434-41

2 4 6 8 10 12 14 16 18 20

Non-vertebral fractures

Patients (%) with fracture P< 0.01

53%

20 g PTH

2 4 6 8 10 12 14 16 18 20

New vertebral fracture

Patients (%) with fracture

P< 0.01

65%

20 g PTH Placebo Placebo

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Abaloparatide Reduces Fractures vs PTH 1-34 Romozsozumab Reduces Vert Fractures

Romosozumab Reduces Spine but not non-spine Frx

2019 Treatment Summary

• Treat the most affected individuals
• Fracture Prediction is Straightforward-

– Age – Previous Fracture – Low BMD – FRAX

• Anti-Resorptives reduce fractures consistently if there is

adherence to treatment regiments

• Anabolic therapies can also reduce fracture and boost BMD

more than the anti-resorptives

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Meta-Analysis of Osteoporosis Treatments; Endocrine Society Guidelines

Relative Risk and 95% CI Effect of treatment compared to placebo Direct calculation Eastell, et al JCEM March 2019

Algorithm for the Management of Postmenopausal Osteoporosis

Eastell R, Rosen CJ, Black DM, Cheung AM, Murad H, Shoback D. JCEM, 2019; 104(5)

OSTEOPOROSIS TREATMENT: REMARKABLE PROGRESS YET PROFOUND CHALLENGES

“Millions of Americans are missing out on a chance to avoid debilitating fractures from weakened bones, researchers say, because they are terrified of exceedingly rare side effects from drugs that can help them.”

In assessing both existing and potential treatments and optimizing duration, researchers should make use of innovative designs and approaches Future clinical trials should evaluate new agents or multicomponent interventions (e.g., oral care, FLS) that potentially lack the side effects of current anti-resorptive treatments and may have greater efficacy More evidence and research are needed to determine which patients are optimal candidates for drug holidays and sequential therapies, and possible strategies for mitigating serious adverse events associated with long-term bisphosphonate or denosumab use (i.e., AFF and ONJ). More research is needed to prevent and characterize AFF and ONJ as rare serious adverse events are associated with long-term bisphosphonate or denosumab use.

More research on barriers to osteoporotic drug therapy is needed.

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Gaps In Treatment- What Are The Current Issues?

• What to Do After a Drug Holiday is Over?
• How long is long enough in treatment?
• Can we predict serious adverse events ?
• Can anabolic treatments be repeated and if not

what do we do?

• How Do We Monitor Efficacy Most Efficiently

Mind the Gap!!!!

PREVALENCE OF BISPHOSPHONATE USE FROM 1996 TO 2012

PROBABILITY OF OSTEOPOROSIS MEDICATION USE FOLLOWING HIP FRACTURE WITHIN 12 MONTHS AFTER DISCHARGE

Solomon et al. JBMR 29:1929, 2014

CHANGING HIP FRACTURE RATES: A CAUSE FOR CONCERN?

Lewiecki, et al. ASBMR 2016, 1077

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What Are Patient Concerns About Treatment Regimens- Meta-Analysis

• 1-Efficacy
• 2-Cost
• 3-Fear of Fractures !!!!!
• 4-Other Adverse Events

Eastell, 2019

Atypical Femoral Fractures

THE PROBLEM FOR THE FIELD OF OSTEOPOROSIS: AFFs

• Patient/physician attitudes shaped by
• Media attention to AFFs
• Concern that they may be vastly under-

reported

• Osteoporosis is not that serious a problem
• Clear that simply quoting statistics to

patients without carefully listening and addressing their concerns is not going to work

THE CHALLENGE

• Urgent need to demonstrate to patients

that we have heard their concerns and are addressing them in the short-, intermediate- and long-terms

• Key is to diagnose AFFs before they occur

and over the longer term, better identify those patients at increased risk even before starting osteoporosis medications

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What Can We Do?

• Promote the value of DXA to help screen and

treat high risk individuals

• Recognize that a fracture in a postmenopausal

woman is a sentinel event requiring treatment

• Re-educate the public on the value of
• steoporosis medications
• Innovate and encourage newer safer

treatments or better technology to predict adverse events SHORT TERM FOR AFFs Education

• Patient education regarding prodromal

symptoms, e.g., groin and hip pain

• Physician education regarding taking these

symptoms seriously and defining an appropriate, cost-effective evaluation plan to exclude incipient AFF

• Brief, standardized and simple-to administer

questionnaires for common prodromal symptoms of AFF that could be linked to prescription renewals by physicians

SHORT TERM Monitoring

• Agreement from bone density manufacturers

to modify existing DXA scanners to obtain a femur “monitoring scan” that includes the region of the femur where AFFs occur

• Ideally covered by Medicare/insurance – could

be done with or independent of standard BMD testing

• Consider this a part of the cost of therapy, and

not to be confused with BMD monitoring for efficacy – as such, cost of this safety monitoring test should be very low

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INTERMEDIATE TERM Identification of higher risk patients

• Compared femur geometrical data in

56 AFF patients vs 112 controls with traumatic or fragility fractures

Majoub, 2016 JBMR

LONG TERM Pharmacogenomics

• Mutations in geranylgeranyl diphosphate synthase

(GGPS1) identified by whole-exome sequencing in 3 sisters who sustained atypical femoral fractures during treatment with bisphosphonates

• Mutations impaired GGPPS function; GGPPS also

inhibited by bisphosphonates

• Identified other susceptibility variants
• Larger, collaborative pharmacogenomics studies

needed

Roca-Ayats et al. NEJM 376:1794, 2017

Take Home Messages

• Listen to the Patient !!!! What are the concerns?
• Initiate Patient Education in a timely manner

without constraints

• Be up to date on the recent literature to better

inform with shared decision making

• If all else fails, don’t be afraid to call ` a

Consultant!!!!! Another opinion always helps

36

Benefits of Therapy: Fractures prevented in 1,000 osteoporotic women treated for 3 years*

Fractures prevented

Spine 71 Non- vertebral 29 (hip) (11) Spine/non spine 100 Based on results from from large RCTS: FIT, HORIZON, VERT NA, others

* Like women in FIT, HORIZON trials

Black, Rosen. NEJM 1/16

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