DISCLOSURES SUNDEEP KHOSLA, M.D. NONE 1 7/5/2017 OVERALL - - PDF document

7/5/2017 1

ADDRESSING PATIENT CONCERNS REGARDING COMPLICATIONS OF ANTIRESORPTIVE THERAPY

Sundeep Khosla, M.D. Mayo Clinic, Rochester, MN

DISCLOSURES SUNDEEP KHOSLA, M.D. NONE

7/5/2017 2

OVERALL CONCLUSIONS

• There has been remarkable progress in our understanding of the

pathogenesis of osteoporosis and new drugs available to treat the disease

• However, despite this remarkable progress in drug development, there

are major challenges to implementing appropriate treatment

APPROVED (US FDA) AND PENDING THERAPIES FOR OSTEOPOROSIS

Anti-resorptive

• Estrogen:

Oral, transdermal

• SERM:

Raloxifene

• Calcitonin:

Salmon, human

• Bisphosphonates:

Alendronate, risedronate, ibandronate, zoledronic acid

• RANKL Ab:

Denosumab Anabolic

• PTH:

Teriparatide, Abaloparatide Mixed

• Sclerostin Ab:

Romosozumab

• Cathepsin K inhibitor:

Odanacatib

7/5/2017 3

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.”

US GOOGLE SEARCH ACTIVITY FOR FOSAMAX

Jha et al. JBMR 30:2179, 2015

Lawsuit for ONJ Study on AF link ABC News story on Fosamax and AFF

7/5/2017 4

PREVALENCE OF BISPHOSPHONATE USE FROM 1996 TO 2012

Jha et al. JBMR 30:2179, 2015

THE PROBLEM FOR THE FIELD OF OSTEOPOROSIS

• Increasingly, patients who clearly need osteoporosis therapy are either

not being offered or choosing not to take bisphosphonates (or other

• steoporosis drugs) due to the fear of Atypical Femur Fractures (AFFs)
• Incidence estimates for AFFs with prolonged bisphosphonate use vary

widely (3.2 to 50-100 in 100,000 person-years) (Shane et al. JBMR 29:1, 2014)

• Nonetheless, best estimates are that with bisphosphonate therapy, 80

to 5,000 fragility fractures would be prevented for every AFF possibly induced by treatment (Black and Rosen, NEJM 374:254, 2016)

7/5/2017 5

THE PROBLEM FOR THE FIELD OF OSTEOPOROSIS (Cont’d)

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

7/5/2017 6

SHORT TERM 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

• f this safety monitoring test should be very low

7/5/2017 7

SHORT TERM Monitoring (Cont’d)

• Hologic currently offers this option – now FDA approved –

but only on its new scanner

7/5/2017 8

SHORT TERM Monitoring (Cont’d)

• Needs to be made available as a low cost update to all

existing scanners

• “Monitoring scan” analogous to monitoring LFTs for

patients on a statin, renal function on patients started on ACE inhibitors

SHORT TERM Monitoring (Cont’d)

• GE Lunar now offering a similar option as an update to existing

software

• Just approved by FDA
• Quantify focal thickening
• Visualization
• Single scan
• Can retrospectively analyze patient database

7/5/2017 9

GE LUNAR SOFTWARE FOR AFF DETECTION

McKenna et al. J Clin Densitometry 16:579, 2013

ANY EVIDENCE THAT THIS APPROACH WILL WORK?

7/5/2017 10

McKenna et al. J Clin Densitometry 16:579, 2013

ANY EVIDENCE THAT THIS APPROACH WILL WORK?

McKenna et al. J Clin Densitometry 16:579, 2013

ANY EVIDENCE THAT THIS APPROACH WILL WORK?

• 257 patients > age 50 yr, on bisphosphonate therapy for >

5 yr

• Extended femur scan at the time of routine DXA
• Abnormal DXA images (e.g., “flaring”, “beaking”) suggested

in 19 (7.4%)

• On x-ray, 7 showed no abnormality, 5 showed an unrelated

radiographic abnormality, and 7 (2.7%) showed evidence

• f incomplete AFF – 5 with periosteal flare and 2 with a

visible fracture line (also had thigh pain)

7/5/2017 11

McKenna et al. J Clin Densitometry 16:579, 2013

ANY EVIDENCE THAT THIS APPROACH WILL WORK?

• 257 patients > age 50 yr, on bisphosphonate therapy for >

5 yr

• Extended femur scan at the time of routine DXA
• Abnormal DXA images (e.g., “flaring”, “beaking”) suggested

in 19 (7.4%)

• On x-ray, 7 showed no abnormality, 5 showed an unrelated

radiographic abnormality, and 7 (2.7%) showed evidence

• f incomplete AFF – 5 with periosteal flare and 2 with a

visible fracture line (also had thigh pain)

CAVEATS

• Convenience sample of patients, whereas population data on

clinical AFFs indicate a far lower prevalence, at worst in the range of 0.13% to 0.22% (Park-Wyllie et al. JAMA 305:783, 2011)

• In addition, the majority of patients with radiographic changes

consistent with partial or incomplete AFF may not, in fact, progress to clinical AFFs (Min et al. JCEM 102:545, 2016)

• Nonetheless, monitoring patients for such radiographic changes

would clearly identify a potentially high risk sub-group for more extensive imaging and consideration of drug discontinuation as appropriate

7/5/2017 12

FOLLOW UP STUDY

• May 2013 – Sep 2014: 173 patients on bisphosphonate therapy

for > 5 years

• 0/173 patients had any DXA features of AFF
• Associated with a clear decrease in bisphosphonate

prescriptions in Ireland

McKenna et al. J Endo Soc 1:211, 2017 McKenna et al. J Endo Soc 1:211, 2017

BISPHOSPHONATE USE IN IRELAND

7/5/2017 13

SHORT TERM Monitoring

• Can be instituted fairly rapidly
• Proactive, makes sense clinically, something we can do

today to begin to address patient concerns

• Guard against false reassurance: Does not imply that

patients or physician ignore symptoms, even if they occur soon after a “negative” monitoring scan

Mahjoub et al. JBMR 31:767, 2016

INTERMEDIATE TERM Identification of higher risk patients

• Compared femur

geometrical data in 56 AFF patients vs 112 controls with traumatic

• r fragility fractures

7/5/2017 14

Mahjoub et al. JBMR 31:767, 2016

INTERMEDIATE TERM Identification of higher risk patients (Cont’d)

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

7/5/2017 15

ADDITIONAL LONG TERM APPROACHES

• New drug development
• Better coordination of recommendations and guidelines

regarding screening and treatment of osteoporosis

• Enhanced patient engagement strategies

ONGOING AND PLANNED INITIATIVES

• 2 recent perspectives:
• Khosla & Shane, “A Crisis in the Treatment of Osteoporosis”,

JBMR 31:1485, 2016

• Khosla, Cauley, Compston, Kiel, Rosen, Saag, Shane,

“Addressing the Crisis in the Treatment of Osteoporosis: A Path Forward”, JBMR 32:424, 2017

• Special session at the 2016 ASBMR Meeting
• Individual meetings with Hologic and Lunar regarding availability
• f femur monitoring software

7/5/2017 16

ASBMR Call to Action to Address the Crisis in the Treatment of Osteoporosis

• The 30-year downward trend in hip fractures in the U.S. – a case study for

medical success - has hit a plateau in the last few years.

• Worldwide osteoporosis causes more than 8.9 million fractures/year.
• By 2050, the worldwide incidence of hip fracture is projected to increase by

310% in men and 240% in women compared to rates from 1990.

• Allowing these patients to go untested and untreated frequently leads to

debilitating fractures that cause disability, loss of independence and even death.

• Thirty-seven organizations have come together to sign this call to action

pledging to intensify their current efforts to increase the screening, diagnosis and treatment of high-risk individuals to prevent fractures.

37 Organizations Have Pledged to Increase Efforts for the Call to Action

• American Society for Bone and Mineral Research
• American Academy of Orthopaedic Surgeons
• American Academy of Physician Assistants
• American Association of Clinical Endocrinologists
• American Bone Health
• American College of Rheumatology
• American Medical Society for Sports Medicine
• American Orthopaedic Association
• American Osteopathic Academy of Orthopedics
• American Society for Surgery of the Hand
• Australia New Zealand Bone and Mineral Society
• Bulgarian Society of Osteoporosis and Osteoarthritis
• Czech Society for Metabolic Bone Diseases
• Dutch Society of Cancer and Bone Metabolism
• European Calcified Tissue Society
• European Union Geriatric Medicine Society
• Finnish Osteoporosis Association
• Georgian Association of Skeletal Metabolism Diseases
• Hellenic Osteoporosis Foundation
• International Geriatric Fracture Society, Inc.
• International Osteoporosis Foundation
• International Society for Clinical Densitometry
• Michigan Consortium for Osteoporosis
• National Bone Health Alliance (US)
• National Osteoporosis Foundation (US)
• National Osteoporosis Society (UK)
• Northern California Institute for Bone Health, Inc.
• Orthopaedic Research and Education Foundation
• Orthopedic Research Society
• Orthopedic Trauma Association (US)
• Osteoporosis Australia
• Osteoporosis Canada
• Osteoporosis New Zealand
• Syrian National Osteoporosis Society
• University of Rochester Department of Orthopaedics and

Rehabilitation

• U.S. Bone and Joint Initiative
• 4BoneHealth

7/5/2017 17

MULTI-STAKEHOLDER INITIATIVE BY ASBMR AND CENTER FOR MEDICAL TECHNOLOGY POLICY (CMTP)

• Identify and prioritize key barriers to appropriate rates of
• steoporosis screening, diagnosis, and treatment to prevent

fractures, incorporating the attitudes, values, and preferences

• f key stakeholders
• Collaborate with ASBMR and key stakeholders to develop

strategic options for addressing identified barriers

• Develop a plan for disseminating and implementing the

strategy

NIH OFFICE OF DISEASE PREVENTION (ODP): FRACTURES

• Objective, external review of current state-of-the-science related to fracture

prevention and important gaps in knowledge

• Effort involving multiple NIH Institutes (led by NIAMS and NIA, partnering

with NIDDK, NCATS, NCCIH, NIDCR, Office of Research on Women’s Health)

• ODP will work with AHRQ to solicit proposals from Evidence-Based

Practice Centers to prepare an evidence report addressing the key questions being posed

• Followed in ~2 years from now by a conference

(similar to previous NIH Consensus Conferences)

7/5/2017 18

QUESTIONS/DISCUSSION