[PPT] - Where Are We At With Osteoporosis 2018? WWHF June 2018 Neil PowerPoint Presentation

SLIDE 1

Where Are We At With Osteoporosis 2018?

WWHF June 2018

Neil Binkley, M.D.

University of Wisconsin School of Medicine and Public Health

SLIDE 2

Why Do We Treat “Osteoporosis?” Fracture is What’s Important

SLIDE 3

Less than 1/10 patients with hip fracture being treated

Kim, et. al., J Bone Min Res, 2016 DOI: 10.1002/jbmr.2832

United HealthCare data;

Proportion of patients in each quarter (2004-2013) who received a BP or other

steoporosis med after hip fx
n = 22,000+
Average age 72
68% female

SLIDE 4

Khosla and Shane, J Bone Min Res, 2016 DOI: 10.1002/jbmr.2888

“To draw an analogy from another field, in 2016 it is virtually inconceivable that a patient discharged from the hospital following a myocardial infarction would not be prescribed a full armamentarium of drugs for secondary cardiovascular prevention (eg, a statin, antihypertensive, and others). Yet what is inconceivable for a patient following a myocardial infarction is the norm in the vast majority of patients discharged from hospital after a hip fracture.”

SLIDE 5

Failure Personified

67 year old female; seen by FLS December 2016

COPD with intermittent prednisone bursts Dietary calcium low at ~300 mg/day Received ALN for a few months 2013 History of falls which resulted in:

– Left distal tibial fracture age 63 – Left hip fracture at age 64 – Left distal radius fracture age 65 – Humerus and patella fracture age 67

Most recent DXA April 2014 LS -2.4, FN -2.2 Seen by FLS after humerus/patellar Fx Work up including DXA was initiated

DXA Obtained Fell THE NEXT DAY Right hip fracture Discharged to NH at age 67!

SLIDE 6

“Insanity: doing the same thing over and

ver again and

expecting different results.”

Albert Einstein

A Different Approach to “Osteoporosis” is Needed

SLIDE 7

A Potential Approach to Improve the Osteoporosis Care Crisis

Change the focus from osteoporosis to fracture

l Include ALL fractures in older adults l Acknowledge that fractures affect QOL and

independence

Consider osteoporosis as just one part of a syndrome leading to fracture

l Need to address all components of the syndrome, not

just the bones

Binkley, et. al., J Bone Miner Res, 2017 32:1391-1394

SLIDE 8

“…..we have demonstrated that there appeared to be nothing “fragile” about a fragility fracture based

n patients’ communication of their fracture.”

“…. in other words, the term fragility or low trauma,....does not resonate with patients.”

Sale, et. al., Osteoporosis Int 2012, 23:2829-2834

The “Fragility Fracture” Concept Does Not Make Sense to Patients

Fragility Fracture, Osteoporosis-related Fracture, Low- trauma Fracture, etc May Be Part of the Problem

SLIDE 9

Considering ALL fractures over age 50 as requiring evaluation avoids the argument that there’s nothing wrong with me: “Anyone would have fractured if they fell like I did!” “You may well be right; but let’s find out.”

SLIDE 10

Fractures = Need for Evaluation

(Bone Attacks = Disease, Just Like Heart Attacks = Disease) “I had a heart attack climbing

stairs. I have high cholesterol

and blockages in the arteries to my heart.” “I broke my _____ falling down the stairs. It was an accident; anyone would have fractured if they fell like I did.”

SLIDE 11

www.share.iofbonehealth.org/WOD/2012

We Need to Directly State: Fractures Reduce Quality

f Life and Talk about Loss of Independence

SLIDE 12

www.acc.co.nz

SLIDE 13

Think About Muscle Function

Impaired Physical Performance Increases Hip Fracture Risk

Adapted from Cawthon, et. al., J Bone Miner Res, 2008, 23:1037- 1044

Evaluated the association of physical performance and hip fracture risk in MrOS; 5995 men age 65+

“Poor physical function is independently associated with an increased risk of hip fracture in older men.”

SLIDE 14

Sarcopenia: the Age-related Gradual Loss

f Muscle mass, Strength and Function

Sarc for flesh (muscle), penia for deficiency

Fielding, et. al, J Am Med Dir Assoc 2011; 12: 249-256

Term coined in 1989; more recently defined as: “The age- associated loss of skeletal muscle mass and function…. a complex syndrome associated with muscle mass loss alone or in conjunction with increased fat mass.”

SLIDE 15

How many times have you fallen in the past year?

l Did any of these falls cause injury?

Would you please stand up for me?

If history of falls, particularly injurious falls and/or cannot arise without use of arms: Likely has sarcopenia/dysmobility and is at increased risk for falls and fracture

We Do Not Require a Consensus Definition of Sarcopenia: We Can Ask our Patients

SLIDE 16

Consider the Heart Attack Analogy

Treatment is Directed at Various Conditions to Reduce Risk For a Potentially Catastrophic Outcome

Hyperlipidemia Hypertension

Toxins, e.g., tobacco

Diabetes

Family History

Obesity

Heart Attack

Reduced QOL Healthcare Cost Death

Metabolic Syndrome Advancing age

SLIDE 17

The Same Approach Makes Sense for Musculoskeletal Health, i.e., “Bone Attack”

Treatment Should be Directed at Various Conditions to Reduce Risk For a Potentially Catastrophic Outcome

Osteoporosis Sarcopenia

Toxins, e.g., tobacco

Diabetes

Family History

Obesity

Falls, Fractures and Disability

Reduced QOL Healthcare Cost Death

Dysmobility Syndrome Advancing age

Treating Osteoporosis Without Considering Other Parts of the Syndrome Causing Fractures is Comparable to Treating Hyperlipidemia and Ignoring Hypertension and Diabetes in Patients With Metabolic Syndrome

SLIDE 18

With This Approach, Bone Drugs Become Only Part of the Solution

SLIDE 19

Existing and Future Fracture (Dysmobility) Syndrome Treatments Look Like What We are Currently Calling “Osteoporosis” Treatment

Nutrition

l Under-nutrition is common

– ~40% of hip fracture patients have energy/protein malnutrition

l Inadequate protein intake reduces muscle synthesis

– ~40% of older adults not meeting current RDA of 0.8 g/kg daily

– Protein intake of 1.2-1.5 g/kg daily is likely optimal

l Calcium and Vitamin D

Exercise/physical therapy/falls risk reduction Medications

Hanger, et. al. N Z Med J. 1999 26;112:88-90 Morley, J Nutr, Health, Aging, 12;452-456, 2008 Mithal, et. al., Ost Int, 2013; doi 10.1007/s00198-012-2236y

SLIDE 20

Calcium and Vitamin D Nutrition is in Chaos Anyone That Tells You They Know the Right Answer is Kidding Themselves and You

SLIDE 21

Calcium Required for Bone Vitamin D Required for Bone & Muscle How Much is Needed?

Meta-analyses will not resolve this issue (currently) Virtually all RCTs are flawed Don’t expect ongoing large RCTs to resolve this issue

Personal opinion

SLIDE 22

The “Bone” Field Largely Has, and Continues, to Ignore Heaney’s Guidance

Robert Heaney, MD 1927-2016

Heaney RP, Nutr Reviews 2013, 72:48-54

SLIDE 23

Virtually All Studies Fail to Recognize that Nutrients are Not the Same as Drugs

Meta-analyses of flawed studies yield flawed conclusions

SLIDE 24

Most Studies Fail to Recognize That We Are Not All The Same

Binkley, et. al., currently unpublished

Meta-analyses of flawed studies yield flawed conclusions

SLIDE 25

SLIDE 26

Paleolithic Calcium Intake = ~1,000 mg/day

The IOM recommends 1,000 mg of calcium daily age 19-50, 1200 mg for Age 51+

http://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium- and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf Eaton S, Osteoporos Int, 17(suppl 2): S2-3, 2006 Frassetto, et. al., Eur J Clin Nutr 2009: 63; 947-955

SLIDE 27

The NOF and ASPC expert panel says NO

Kopecky, et. al., Ann Int Med 2016:165:867-868

“The NOF and ASPC adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) with the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this

time. …calcium intake from food and supplements that does not

exceed the tolerable upper level of intake (2000 to 2500 mg/d) should be considered safe from a cardiovascular standpoint.”

Do Calcium Supplements Cause Vascular Disease?

SLIDE 28

Calcium Summary: June 2018

Aim for 1,000-1,200 mg/day

Ideally through diet (+ supplements if needed) Close to the “Paleo” diet One “serving” is ~250 mg It is possible to get too much of anything; the jury is still out regarding vascular events

There is no “best” calcium supplement

Don’t spend $$$$ If supplements are needed they should be taken with a meal

Personal opinion

SLIDE 29

Vitamin D Likely Important for Bone & Muscle

Common sense; target the level of highly sun exposed people

Luxwolda, et. al., B J Nutr, V 108 / Issue 09 / November 2012, pp 1557-1561

Mean 25(OH)D 46 ng/mL

SLIDE 30

30 30

36 36.0 .0 35 35.4 .4 34 34.8 .8 34 34.2 .2 33 33.6 .6 33 33.0 .0 32 32.4 .4 31 31.8 .8 31 31.2 .2 30 30.6 .6

+2SD +2SD

2SD

2SD CV CV

10% 10% 9% 9% 7% 7% 6% 6% 5% 5% 4% 4% 3% 3% 2% 2% 1% 1% 8% 8% 29 29.4 .4 28 28.8 .8 27 27.6 .6 28 28.2 .2 27 27.0 .0 26 26.4 .4 25 25.8 .8 25 25.2 .2 24 24.6 .6 24 24.0 .0

Be Aware That “30 ng/mL” is NOT 30 ng/mL

Acc Acceptable le

If your lab is meeting this target, an individual patient 25(OH)D result of 30 ng/mL is actually 24-36 ng/mL VDSP recommends that 25(OH)D assays perform with a CV <10%

Lappe & Binkley, J Clin Densitom, 2015 epub; doi: 10.1016/j.jocd.2015.04.015

SLIDE 31

What to Do? Aim a Little High

Measured “True” Value Maintain Maximum 25(OH)D 20 ng/mL ~15 to ~ 25 ng/mL ~30 ng/mL 40 ng/mL 25(OH)D 30 ng/mL ~24 to ~36 ng/mL 40 ng/mL 50 ng/mL

To Maintain Serum 25(OH)D of ≥20 ng/mL or ≥30 ng/mL

Recognize that the reported value may be low: with this approach, the maximum is likely to be ~40 to ~50 ng/mL, below that attainable by UV exposure

Personal opinion

SLIDE 32

Vitamin D Summary: June 2018

The field remains chaotic (and passionate)….
Vitamin D inadequacy (however defined) is common
Vitamin D is cheap and virtually side effect free
Can’t pick a single dose to assure whatever you believe

to be vitamin D adequacy

Daily dosing makes physiologic sense
Ancestral human 25(OH)D mean is ~ 40 ng/mL
Our current “25(OH)D” measurements are imperfect
Assay improvements are needed; progress being made
RCTs with better study designs need to be conducted;
This is not happening yet; expect chaos to continue

SLIDE 33

Older Adults Need More Protein

Deutz,et. al., Clin Nutr, 33, 929-936, 2014

A protein intake of 1.0-1.2 g/kg of body weight per day is probably optimal for older adults

Mithal,et. al., Osteoporos Int, 24, 1555-1566, 2013

SLIDE 34

Other Nutrients Possibly Important in Bone/Muscle Health (nobody knows…)

Magnesium: maybe but no guidance Strontium: heavier than calcium; deposits in bone thus increasing BMD. Toxicity? (avoid) Vitamin K: doesn’t help Acid diets: controversial Caffeine/soft drinks: replace milk Phytoestrogens: ~20; likely natural SERMS, differential effects and unknown dose

SLIDE 35

When Are “Bone Drugs” Indicated?

NOF

T-score ≤ -2.5 Prior spine or hip fracture Osteopenia with 10 year fracture risk > 20%

FDA-approved medications

Bisphosphonates Denosumab Calcitonin Raloxifene Teriparatide Abaloparatide

SLIDE 36

Many Experts are Not Treating Treat T-score Osteoporosis and Treating Based on Fracture Risk

(Osteoporosis Canada approach)

http://www.osteoporosis.ca/health-care-professionals/guidelines/

> 20% risk; Rx < 10% risk; Don’t’ Rx 10-20%; obtain T/L radiographs or VFA and think about treating

UW now reporting FRAX for all with T-score ≤ -1.1

SLIDE 37

2016 Updated AACE Treatment Guidelines

Camacho, et. al., Endocr Pract. 2016;22(Suppl 4)

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SLIDE 38

We Need to Balance Long-Term Benefits vs. Long Term Risks

Risks GI Acute phase reaction ONJ Atypical femur fractures Nephrotoxicity Eye problems Musculoskeletal pain

Esophageal cancer? Atrial fib?

Benefits Decreased fractures Decreased mortality Maintained Independence & QOL

 Healthcare costs

“I find myself more in fear of the side effects of the recommended medications than I do of my cancer--silly perhaps but nonetheless an issue for me. I don't want my cancer to recur but also don't want my spine to collapse.”

SLIDE 39

Calculators Help Put Actual Numbers to Fracture Risk (Consider using Garvan; esp if falls/fractures)

67 yo female; multiple falls, multiple fractures & a T-score of -2.5

http://www.garvan.org.au

SLIDE 40

Short-term Bone Drug Rx Cuts Fracture Risk ~ in Half There is Virtually No Doubt that This Benefit Outweighs Risks for the First 3- 5 Years of Treatment After Fracture or at High Risk Treat for 3-5 years Should We Be Treating Longer?

SLIDE 41

The Pathophysiology of ONJ and AFF Remain Debated and are Certainly Multifactorial But the Risk Increases With Duration of Therapy

As AFF and ONJ occur with two classes of anti-resorbers (bisphosphonates and denosumab) it seems to me that “oversuppression” of bone remodeling is involved

SLIDE 42

The Oral Surgeons State that Medication Related Osteonecrosis of the Jaw (MRONJ) Increases A LOT After 4 Years of Rx

Name change due to cases with denosumab and antiangiogenic Rx

Ruggiero SL, et. al., J Oral Maxillofac Surg. 2014; 72: 1938-1956

“For patients receiving oral BP therapy to manage osteoporosis, the prevalence of ONJ increases

ver time, from nearly 0% at

baseline to 0.21% after at least 4 years of BP exposure.”

– “Median duration of BP exposure for

patients with ONJ and ONJ-like features was 4.4 years.”

SLIDE 43

Adapted from Dell RM, J Bone Miner Res, 2012;27:2544-50 BP exposure (years) AFF Incidence Rate Age-adjusted per 100,000/year)

1.8 million Kaiser Permanente

enrollees ≥ 45 years of age

Potential AFF identified by ICD-9

diagnosis and CPT procedure codes

– All radiographs reviewed

142 femur fractures met ASBMR

criteria for AFF

– 128 (90%) had previous BP exposure – 14 (10%) no prior BP exposure – Age adjusted incidence rose with increasing duration of BP exposure

~ 1.1 per 1000 pt-yrs after 10 years

AFF Incidence Increases With Duration of Bisphosphonate Exposure (US Data)

SLIDE 44

ASBMR TF Suggested Approach to Management

I’m not treating ANYONE that does not meet

ne of these

three criteria Thus, this is a de facto 10-year Rx recommendation

Adler, et. al., J Bone Miner Res, 2016; 31:16-35

“For treatment up to 10 years with oral bisphosphonates and 6 years with intravenous bisphosphonates, estimates of benefits and risks are based on much weaker data.”

SLIDE 45

“The risk of atypical femoral fracture, but not ostenecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high- risk patients.”

Adler, et. al., J Bone Miner Res, 2016; 31:16-35

Is This Really True?

SLIDE 46

Numbers for Risk of Fracture vs. Risk of AFF/ONJ with Long-term Rx from ASBMR Task Force

NO data that hip or wrist

fractures are prevented

1470 vert fx prevented
113 AFF caused

➢

(assuming; incorrectly) that ALL AFF are caused by BP

26 cases of ONJ caused
1470/139 = 10.6 spine

fractures prevented per AFF/ONJ case caused

Per 100,000 patients Rx; Yr 9-10

Adapted from Adler, et. al., J Bone Miner Res, 2016; 31:16-35

SLIDE 47

My Take on Long-term Treatment

The data for both benefit and risk are very weak
i.e., “evidence based” is not based on evidence
Not at all clear that long-term turnover suppression and BMD

stability/increases are good (and might be bad)

Long-term Rx likely prevents some vertebral fractures
No evidence that we are preventing hip or non-vertebral

fractures with bisphosphonates (sample sizes likely too small)

We are causing some AFF
We are causing some ONJ
How much ONJ and AFF is unclear, BUT an ~10 vertebral

fractures prevented to one substantial adverse event caused does not sound favorable to me

Personal opinion

SLIDE 48

If “doing well,” stable or increasing BMD and no fractures; BP holiday after 3-5 years (almost always)

What to do with denosumab is unclear

If “treatment failure;” teriparatide or abaloparatide Monitor holiday with turnover markers and BMD every other year (no data)

BMD decline or turnover marker increase, the holiday is over

I Recommend BP Holidays All the Time

Personal opinion

NOTE: This is a conservative approach not shared by all in the field

SLIDE 49

Do Not Take Holidays with Denosumab

Discontinuation leads to rapid bone loss

McClung M, Osteoporos Int (2017) 28:1723–1732

One year observational follow up

after up to 8 years of dmab in phase 2 study

8 of 82 (9.8%) experienced at

least 1 fracture

4 had multiple vertebral fractures

“…if denosumab treatment is discontinued for any reason, it seems very prudent that therapy with another anti-remodeling agent, such as a long-acting BP, be continued...”

SLIDE 50

A Multiple Vertebral Fracture Syndrome Has Been Reported Following DMAb Discontinuation

Lamy et. al, J Clin Endocrinol Metab 2017 102:354-358

9 women with 50 rebound-

associated vertebral fractures after dmab discontinuation

All VF were spontaneous; mean # 5.5
VFs occurred rapidly after last dmab

injection (9-16 months)

The fracture risk was low for most of

these women

Studies needed to define Rx

regimens after dmab discontinuation

SLIDE 51

When individuals on antiresorptives are switched to teriparatide, hip BMD declines for at least 12 mo

More pronounced with dmab

“The common practice of switching to teriparatide only after patients have an inadequate response to ARs (fracture or inadequate BMD effect) is not the optimal utilization of anabolic treatment.” “When possible, we suggest anabolic therapy first, followed by potent antiresorptive therapy.”

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

SLIDE 52

Recognize fracture as the problem:

May be fatal Threatens INDEPENDENCE Can be prevented (or at least have the risk for another fracture reduced) Reflects a syndrome, not just “osteoporosis” ALL fractures after age 50 require consideration of evaluation

– It’s not just “I fell”

Summary: Fracture Syndrome (“Osteoporosis”)

What To Do Today?

Personal opinion

SLIDE 53

Reduce falls

– Ask “How many times have you fallen in the past year?” – Observe gait, ask to stand up without use of arms – “The usual” falls risk reduction strategies including a PT consult – Recognize that obesity may increase risk

Optimize calories, calcium, vitamin D and protein status

– 2,000 IU daily is a reasonable place to start – Measure 25(OH)D in those with falls/fractures

Use existing “osteoporosis” medications to treat the bones starting with anabolic agents in those at high risk

– Use antiresorbers for 3-5 years

Personal opinion

Fracture Syndrome (“Osteoporosis”)

What To Do Today?

SLIDE 54

Summary: An Approach to Reduce Fracture Risk

Recognize fracture as the problem

Affects QOL and INDEPENDENCE

All fractures after age 50 need evaluation including basic laboratory & BMD measurement

Calcium, creatinine, alk phos, 25(OH)D, CBC Need to personally review the DXA scan image

Think about falls

Home safety, vision, if weakness or balance issues PT eval

Calcium intake of 1000-1200 mg daily, vitamin D of at least 1,000 IU; consider protein in older adults Treat with bone meds for 3-5 years if fracture risk high

Recent fracture, falls, FRAX MOF ≥ 20%

Personal opinion

SLIDE 55

“The good physician treats the disease; the great physician treats the patient who has the disease.”

Sir William Osler

Treat the Person, Not Just Their Bones

SLIDE 56