8-12-2015

1

HOT LectureHow tO Treat osteoporosis?

EULAR, Rome, 2015

Piet Geusens, MD, PhDProfessor of Rheumatology

Maastricht UMC, Netherlands& UHasselt, Belgium

How to identify 50+ women and menat high risk for fractures,

And how to reduce their fracture risk?

Maastricht UMC & UHasselt

Maastricht UMC & UHasselt

Bone quality ↓

Estrogen/

androgen

deficiency

Calcium

homeostasisAgeOxidative

stress

Diseases,

medications

Fracture

Falls ↑

Immune

system

Multifactorial etiologyand multifacetted results of fractures

Nutrition

Muscle

force

Frailty

Morbidity Mortality

Re-fracture

Fracture prevention in women and men older than 50 years : A 5-step decision plan

MUMC&UHasselt Netherlands Guidelines “Osteoporosis and Fracture Prevention”, 2011

van den Bergh, Nature Rev Rheum, 2012, 568

1

Case finding

2

Risk evaluation

3

Differential

diagnosis

4

Therapy

5

Follow

up

1/ After recent fracture

2/ Diseases/medications

3/ Other clinical risk factors

Clinical risk factors

DXA

Imaging of the spine

Medical history

Clinical examination

Laboratory examination

Communication

Life style

Calcium and vitamin D

Medication (PO, IV, SC)

Fall prevention

Compliance

Tolerance

Efficiency

Duration of therapy

2/ Diseases/medications

3/ Other risk factors

1

Case finding

2

Risk evaluation

1/ Recent fracture

Vertebral

NHNV

Hip

Tools:BMDImaging of the spineClinical risk factors

Aims:Diagnosis

osteoporosispresence of subclinical vertebral fracture

Fracture risk calculationBMDpresence of vertebral fractureclinical risk factors

Therapeutic decisions at start and during follow upvertebral or hip fractureosteoporosisosteopenia

+ vertebral fracture+ clinical risk factors

MUMC&UHasselt

Fracture Rates, Population BMD Distribution and Number of Fractures in NORA

Siris, E. S., et al. Arch Intern Med 2004 164:1108-12,MaastrichtUMC & UHasselt

Osteopenia Osteoporosis

Osteopenia

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P. Geusens

8-12-2015

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The relationship between femoral neck T-score and the 23-month total fracture risk

MUMC&UHasselt Siris, OI, 2007, 761

The relationship between femoral neck T-score and the 23-month total fracture risk

MUMC&UHasselt Siris, OI, 2007, 761

The fracture cascadein 834 consecutive fracture patients in the Fracture

Liaison Service (Maastricht University)

Risk factors Only Bone Bone + Fall RFs Only Fall No RFsRFs RFs

Number 183 334 170 147% 22% 40% 20% 18%

Huntjens, BMC Musculoskelet Disord. 2013 MUMC&UHasselt

RF: risk factor

MUMC&UHasseltLeslie, OI, 2014

Clinical risk factors to calculate fracture risk

Fracture risk calculators(externally validated and accessible via web)

AUCs for fracture risk prediction

• FRAX, +/- BMD 0.64-0.89

+ SECOB

• Garvan, +/- BMD 0.67-0.80

+ fall risk

• Qfracture, no BMD 0.67-0.89

+ SECOB + fall risk

www.shef.ac.uk/FRAXwww.garvan.org.auhttp://www.qfracture.orgMUMC&UHasselt

Marques, ARD, 2015Rubin, JBMR, 2013SECOB: secondary osteoporosis and other metabolic bone diseases

AUC: area under the curve

DXA+VFA+Fall risk

T -2.5

T 1.0 and>-2.5

T >-1.0

Vertebralfracture

Otherrisk factors

2/ Diseases/medications

3/ Other risk factors

High fall risk

1

Case finding

2

Risk evaluation

1/ Recent fracture

Vertebral

NHNV

Hip

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P. Geusens

8-12-2015

3

Prevalence of known and new SECOBs in 50+ patienyts with a recent fracture at the FLSaccording to sex, age, fracture location and BMD

0

10

20

30

40

50

60

Known SECOB New SECOB Any SECOB

SECOB: secondary oseoporosis and other metabolic bone diseasesFLS: Fracture Liaison Servoce Bours, JCEM, 2011

Bours, Curr Opin Rheum, 2014MUMC&UHasselt

Calcium supplements

Normal physiologic need:calcium 1000-1200 mg/d

Controversy about CV risk of calcium supplements(some signals, not confirmed in other studies)

Bolland, BMJ, 2011Reid, J Cell Biochem, 2015 Paik, OI, 2014Weaver, Curr Osteoporosis Rep, 2014Adebamowo Am J Clin Nutr 2015MUMC&UHasselt

Medical treatment: calcium and vitamin D

– Optimalisation of calcium intake: • Total intake: 1000-1200 mg calcium/day

– e.g.: no milk products* + 4 milk products or 1000 mg calcium supplement

– e.g.: 2 milk products/day + 2 milk products/day or +500 mg calcium supplement

– e.g.: 4 milk products/day no adaptation necessary

– Vitamin D: 800 IU/day• With anti-osteoporosis medication

• In subjects in rest homes

MUMC&UHasselt

*milk product:

- 1 cup of milk

- or yaghourt

- or 1 slice of cheese Maastricht UMC & UHasselt

Bone remodeling during life

AC

TIV

AT

IO

N FR

EQ

UEN

CY

(#

/yr)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Pre-

meno

1 yr

post-

meno

13 yr

post-

meno

Osteo-

porosis

Recker et al, JBMR 2004; 10 : 1628-1633

MUMC & UHasselt

Postmenopausal bone remodeling:

increased bone remodeling with bone loss

http://courses.washington.edu/bonephys/Anderson, Am J Pathol, 2009, 239Baron, Nature Med, 2013, 179

ANTI-RESORPTIVE TREATMENT

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P. Geusens

8-12-2015

4

Osteoclastpre-osteoclast

• Estrogens: decrease fracture risk, side effects

(CV and breast cancer)

• Calcitonin: limited fracture prevention data, risk of cancer?

• Selective estrogen receptor modulators (SERMs):

Raloxifene, Bazedoxifene, Lasofoxifene

Decrease risk of vertebral fractures (and non-

vertebral fractures with lasofoxifene)

Decrease of risk of breast cancer (raloxifene)

CV side effectsRoth, Ann Intern Med. 2014;160:594

Overman, Ann Pharmacother, 2013, 1675

Martinkovitch, Clin Intervent aging, 2014, 1437MUMC&UHasselt

Effect of Denosumab and Bisphosphonates on Osteoclasts

RANKL = RANK ligand; OPG = osteoprotegerin

RANKL

RANK

OPG

Denosumab

Denosumab, a soluble inhibitor, blocks RANKL

Denosumab inhibits osteoclast formation, function, and survival

XBone

Precursor osteoclast

BPs bind to bone mineral at sites of bone resorption

BP are engulfed (endocytosed) by osteoclasts during the process of bone resorption

BP BPBPBP

BP

BPBP BP

BP

Bone

BPs cause loss of resorptive function (via inhibition of FPPS and prenylation of GTP-ases), but ‘disabled’ osteoclasts may persist

BP

BPBP BP

BP

BPBP

BPBP

BoneBP BP

BPBP

BP = bisphosphonate; FPPS = farnesyl pyrophosphate synthase; GTP = guanosine-5'-triphosphateBaron et al., Bone 2011; 48(4):677-692.Russell RG, et al. Osteoporos Int. 2008;19:733-759.

MUMC & UHasselt

Anti-resorptives

- suppress the birth of new remodeling units- newly deposited bone partly maintains bone structure- more complete secondary mineralization of new and old bone- slow increase in BMD- remodeling continues, but fewer and more shallow resorption cavities remove less bone

Seeman, NEJM

Long‐term effects of osteoporosistreatments on total hip BMD

4 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrendo

on which to base the management of these drug holidays

is available. Sometimes, levels of bone turnover markers

are monitored, with levels of PINP (a serum marker of

amino-terminal propeptide of type I collagen) >35 μg/l

providing evidence of offset of the drug effect, and repeat-

ing BMD measurements at ~2 years is common practice.

However, neither measurements have been shown to

predict fractures.37

Safety

Oral bisphosphonates are associated with adverse effects

on the upper gastrointestinal tract in ~20% of patients,38

and intravenous aminobisphosphonates produce an

acute-phase response in about one-third of patients.39

Adequate renal function (that is, glomerular filtration

rate >35 ml/min/1.73 m2) is a prerequisite for the use of

intravenous bisphosphonates. The long-term safety

of these drugs has been reviewed elsewhere.15

Two conditions remain a concern for bisphosphonate

use: osteonecrosis of the jaw (ONJ) and atypical sub-

trochanteric femoral fractures (AFFs). ONJ is clearly

an issue for patients with disseminated cancer who are

treated with monthly infusions of intravenous bisphos-

phonates (or denosumab), and occurs in ~5% of these

patients.40 Similar nonhealing oral lesions have been

described in patients with osteoporosis, irrespective of

whether or not they are treated with bisphosphonates.41–43

Postmarketing reports have suggested that the incidence

of ONJ in patients with osteoporosis who are treated with

bisphosphonates is ~2:100,000 patient-years.40 These

individuals seem to present with less advanced ONJ,44

and a high percentage of their lesions heal.45 Given

that ONJ is a rare event and the causal role of bisphos-

phonates is unclear, ONJ is not a major consideration in

the management of osteoporosis.

By contrast, the occurrence of stress fractures in the

lateral cortex of the femoral shaft (referred to as AFFs) is

a growing concern. These fractures can progress to trans-

verse fractures, which occur after minimal trauma.46 The

incidence of femoral stress fractures seems to increase

sharply with bisphosphonate use: one study suggests that

femoral stress fractures are threefold more frequent with

alendronate use than with risedronate use, and that they

are rare with zoledronate use.47,48 A study conducted in

the USA showed that Asian patients are more susceptible

to femoral stress fractures than patients of other ethnic

groups.49 The incidence of femoral stress fractures seems

to drop dramatically 1–2 years after discontinuation of the

drug.50 Case series, which have reported both proximal

femoral fractures and AFFs, have always shown the latter

to be a small minority (for example, 59 AFFs in a total of

12,777 femoral fractures in Swedish women in 2008).50

A 2014 Swedish study reported the risk of AFF after

4 years of bisphosphonate treatment to be 11 fractures

per 10,000 person-years,47 which suggests that the rate of

AFFs is approaching that of hip fractures in some popula-

tions of elderly individuals and that long-term bisphos-

phonate use might cause as many major fractures as it

prevents. This suggestion is inconsistent with clinical trial

data. The FLEX study,51 for example, showed that between

year 5 and year 10 of alendronate use, the rate of total sub-

trochanteric fractures was 6 fractures per 10,000 patient-

years, whereas the proximal femoral fracture rate was

10-fold higher at 63 fractures per 10,000 patient-years.

Whether any of the subtro chanteric fractures reported in

the FLEX study were atypical is unknown, as radiographs

were not available; however, the atypical proportion of

subtrochanteric fractures is usually <10%.50,52

Prospectively collected trial data in patients with a

clearly documented bisphosphonate dosing history do

not suggest that the incidence of AFFs is approaching

that of conventional femoral fractures.51 However, the

need for continued bisphosphonate therapy should be

periodically reviewed and drug holidays provided for

patients who are no longer defined as osteoporotic by

BMD measurements. These actions will ensure that effec-

tive interventions continue to be provided to patients with

osteoporosis at high risk of fractures.

Estrogen and SERMsGiven that the decline in ovarian estrogen production is

the critical change that results in postmenopausal bone

loss, provision of estrogen from the start of menopause

maintains BMD and reduces fracture risk.53 However, as

estrogen receptors are widely distributed in the body, the

administration of estrogen can affect many tissues and

outcomes. This caveat was made clear in the Women’s

Health Initiative, in which beneficial effects on fractures

and colon cancer incidence were counterbalanced by

changes in cardiovascular, cerebrovascular and venous

thromboembolic events.54,55 This balance seems to be

different for estrogen alone in comparison with estrogen

plus progestins, and is likely to vary further according

to the specific estrogen and progestin used. Complexity

in this area has caused many patients and physicians to

lose enthusiasm for estrogen as a bone-protective therapy,

even though its efficacy is beyond question. A reappraisal

0 1 2 3

Time (year)

Tota

l hip

BM

D c

hange (

%)

4 5 9

0

8

4

2

Nature Reviews | Endocrinology

6 7 8 10

10

6

Denosumab

Zoledronate

Alendronate

Figure 3 | Long-term effects of osteoporosis treatments on total hip BMD. Data derived

from long-term follow-up studies of the FLEX trial28 (alendronate, 5–10 mg per day), the

HORIZON trial30 (zoledronate, 5 mg per year) and the FREEDOM trial69 (denosumab,

60 mg subcutaneous injection every 6 months). As data are derived from separate

studies, formal comparisons between changes in BMD have not been made.

REVIEWS

© 2015 Macmillan Publishers Limited. All rights reserved

Reid, Nat Rev Endo, onlineMUMC&UHasselt

Raloxifene

Patterns of Fluorochrome Labeling in the Proximal Femur in adult monkeys on high dose of denosumab

Representative epifluorescent images of proximal femurs from the A) Sham and B) DMAb 25 mg/kg groups. Fields within B were magnified to show C) trabecular bone (yellow), D) inferior periosteum, and E) superior endocortex. F) A polarized light photomicrograph illustrates the collagen orientation in C, with the smooth underlying cement lines highlighted in red.

Ominsky, JBMR, 2015, online

OSTEO-ANABOLIC TREATMENT

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P. Geusens

8-12-2015

5

Maastricht UMC & UHasselt

Bone remodeling during lifeA

CT

IV

AT

IO

N FR

EQ

UEN

CY

(#

/yr)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Pre-

meno

1 yr

post-

meno

13 yr

post-

meno

Osteo-

porosis

Recker et al, JBMR 2004; 10 : 1628-1633 MUMC & UHasselt

Teriparatide injections act as anabolics:remove old bone and deposit new bone

Cathepsin K

Osteoclast

Collagen degradation

RANK

Osteoblast

Wnt signaling

LRP Frizzeld

Wnt

DKK

Osteocyte

RANKL

Denosumab

rhPTH (1-34) (Teriparatide)

Sclerostin

pre-osteoclast

pre-osteoblast

RANKL Sclerostin

BP

BP

Bisphosphonates

BP

MUMC&UHasseltLems, Geusens, Curr Opin Rheumatol, 2014, 245

Efficacy of treatments for the prevention of non-vertebral and hip fractures

Murad, JCEM, 2012, 1871

Russell, Curr Opin Pharmacother, 2015, 115

Incidence of fragility fracture at 36 monthsin the FREEDOM study

21

Figure legends

Figure 1 Incidence of fragility fracture at 36 months in the FREEDOM

study. Values above the bars are risk reduction (95% confidence interval).

ARR, absolute risk reduction; n, number of subjects with a new fragility

fracture; N, number of subjects randomized; RRR, relative risk reduction

Cli

mact

eric

Do

wn

load

ed f

rom

in

form

ahea

lth

car

e.co

m b

y U

niv

ersi

ty o

f M

aast

rich

t o

n 0

6/0

9/1

5F

or

per

son

al u

se o

nly

.

Palacios, Climacteric, 2015

New vertebral or low-trauma nonvertebral fractures

MUMC&UHasselt

Teriparatide Reduces Risk of New Vertebral Fractures

Fracture Prevention Trial

RR = relative risk vs. placebo

ARR = absolute risk reduction

Multiple New Fractures

% o

f w

om

en

with

>1

ve

rte

bra

l fr

actu

re

0

1

2

3

4

5

Placebo(22 / 448)

TPTD20(5 / 444)

% o

f w

om

en

wit

h

>1

fractu

re

Placebo

(22 / 448)

TPTD20

(5 / 444)

ARR = 3.78%

RR 77%*

Multiple

Neer, et al.N Engl J Med 2001; 344:1434-1441

*P<0.001 vs. placebo

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P. Geusens

8-12-2015

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Teriparatide Reduces Risk of Nonvertebral Fractures

Fracture Prevention Trial

% o

f w

om

en

wit

h

>1

fractu

re

Nonvertebral Fragility Fractures

% o

f w

om

en

wh

o h

ad

> 1

fra

gili

ty fra

ctu

re

0

1

2

3

4

5

6

Placebo(30 / 544)

TPTD20(14 / 541)

*P=0.02 vs. placebo

ARR = 2.92%

RR 53%*

Nonvertebral fragility

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

Anti-resorptive drugsSide effects

• Osteonecrosis of the jaw (ONJ, BONJ, BRONJ)

– Rare during osteoporosis treatment, risk range between 1 in 1000 and 1 in 263,000 patient-years, with minimal evidence for an association of risk with duration of therapy

– Frequent in cancer patients on zoledronate or denosumab

– Frequent questions in daily practice from patients, dentists, maxillo-facial surgeons

• Prevention: elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene

• Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy

• Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful

• Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use.

Kahn, JBMR, 2015, 3McClung, Am J Med, 2013

Atypical Femur Fractures

There was no significant increase in risk associated with bisphosphonate use, but

the study was underpowered for definitive conclusions

Black, NEJM, 2010, 1761McClung, Am J Med, 2013 Shane, JBMR, 2014ESCEO, OI, 2014

Incidence: 1.8/10,000 patients/year for up to 2 years of treatment and 8.4/10,000 patients/year with use of more than 2 years

Incidence much lower than hip fracture reduction

Prodromes of thigh or groin in >50% of cases

Imaging: RX, bone scintigraphy, MRI

Anti-resorptive drugsSide effects

• Atrial fibrillation– Only in zoledronate HORIZON trial

– Conflicting results in meta-analysis and cohort studies

• Flu-like symptoms

– Zoledronate, mainly after first infusion

• Hypocalcemia

– Measure calcium before BPs and denosumab

– Examples of high risk:

• Renal insufficiency CKD stage 4-5

• Vitamin D definciency

• Hypoparathyroidism

• Decreased calcium absorption, e.g. gastric bypass

• Fracture healing

– No negative effetcs of anti-resorptive treatmentBlack, NEJM, 2007Dave, Am J Nephrol, 2015Kreutl, Swiss Med Weekly, 2014Abrahamson, J Int Med, 2009Ng, ANZ Surg, 2014MUMC&UHasselt

Oral Bisphosphonate Prescriptions, Intertrochanteric Hip Fractures and AFF 1996-

2012 US

This article is protected by copyright. All rights reserved 21

Figure 3

This article is protected by copyright. All rights reserved 23

Figure 5

Intertrochanteric fractures AFF

This article is protected by copyright. All rights reserved 20

Figure 2

Bisphosphonate use

Jha, JBMR, 2015, online

This article is protected by copyright. All rights reserved 19

Figure 1

US Google search activity for the term “Fosamax”®

ONJ

AtrFibr

AFF

“may represent better targeting of bisphosphonate therapy”

Cumulative incidence of hospitalized infectioncomparing denosumab vs. zoledronate

Curtis, A&R, 2015, onlineMedicare in 2006-2012

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P. Geusens

8-12-2015

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Bisphosphonates and mortalityand quality of life

• Mortality

– Compared to placebo: reduced mortality afterrecent hip fracture with zoledronate and in meta-analysis of BPs

– DUBBO study in women (Australia)

– Compared to normal population: decrease in women >60 yrs, not in men (Denmark)

• Quality of life

– Alendronate, zoledronate Black, NEJM, 2007Center, JCEM, 2011Abramson, JBMR, 2015, onlineCauley, JBMR, 2011MUMC&UHasselt

Death hazard as a function of sex and age at beginning treatment

Abrahamsen, JBMR, 2015

Residual life expectancy after beginning osteoporosis

treatment:

real world experience

50-year-old women: 26 years man: 18 years

75-year-old women: 14 years man: 8 years

MUMC&UHasseltAbrahamsen, JBMR, 2015

MUMC&UHasseltFreemantle, Osteoporos Int. 2012, 317

Time to treatment non-adherence

Denosumab vs. alendronate

Persistence with and adherence todenosumab at 12months

Hadji, OI, 2015, onlineMUMC&UHasselt

Non-vertebralfracture after 1 yr

therapy

Doubt, questions

Intolerance

Teriparatide in severe osteoporosis

Strongly recommended

Can be useful

Clinical suspicion of new vertebral fracture

DXA after 2-3 yrs

NonCompliance

Consult

Bone markers

Other medication or IV, SC

RX

Structured clinical monitoring (min. after 3 months, then yearly)Start

therapy

Follow up

MUMC&UHasselt

Copyright

P. Geusens

8-12-2015

8

Long-term studies with alendronate andzoledronate

Reid, Nat Rev Endo, 2015

Alendronate 5 + 5 yearsClinical vertebral fractures were reduced by ~50%In those with femoral neck T-scores <–2.5, continuation of alendronate reducednonvertebral fractures by 50%

Zoledronate 3 + 3 yearsPartial loss of vertebral fracture efficacy associatedwith drug discontinuation, particularly in womenwhose femoral neck T-score remained <–2.5

MUMC&UHasselt

Yearly Incidence of New Vertebral Fractures Through 8 Years

The Pivotal Phase 3 Study – Extension

n = number of subjects

with ≥ 1 fracture.

N = number of

randomized subjects who

remained on study at the

beginning of each period.

*Annualized incidence:

(2-year incidence) / 2.

Lateral radiographs

(lumbar and thoracic)

were not obtained at years

4 and 7 (years 1 and 4 of

the extension).

Placebo Long-term Denosumab Cross-over Denosumab

1/2* 4/5*30.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Yea

rly In

cide

nce

of

New

Ver

tebr

al F

ract

ures

(%

)

Years of Denosumab Treatment

198034

151425

149650

Nn

369182

318698

3702 324735

345324

340032 107

2.2

3.1 3.1

0.90.7

1.10.9

1.7 1.7

FREEDOM EXTENSION

210158

161418

156738

4/5* 7/8*6

Nn

369182

318698

3702 324735

345324

340032 107

2.2

3.1 3.1

0.90.7

1.1

1.4

1.1 1.2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Yea

rly In

cide

nce

of

New

Ver

tebr

al F

ract

ures

(%

)

Years of Denosumab Treatment

FREEDOM EXTENSION

1 2 3

Adapted from Papapoulos S, et al. Presented at: American Society of Bone and Mineral Research Annual Meeting; October 4-7, 2013; Baltimore, Maryland.

After 3-5 yr therapyRe-evaluation,

including clinicalrisks and DXA (and VFA or Xray when

suspicion of vertebral fracture)

High risk:- T <-2.5 in femoral neck- New fracture- Severe secondary osteoporosis-Glucocorticoids 7.5 mg/d

Low risk:- No new clinical risk factors- T >-2.5 in femoral neck

Continue bisphosphonates or other medication or

SC, IVTeriparatide if new

fracture

- Life style- Calcium + vit.D- Stop medication

Follow up after 2-3 yrs or if new fractures

and including clinical risksand DXA (and VFA or Xray

when suspicion of vertebralfracture)

Structured clinicalfollow up

After 1.5-2 yr therapy with teriparatide/PTH

(1-84):Re-evaluation, including

clinical risks and DXA (and VFA or Xray whensuspicion of vertebral

fracture)

Anti-resorptivedrugs

Recommended

Strongly recommended

Can be useful

Duration of therapy

Guideline Netherlands, 2011McClung, Am J Medicine, 2013MUMC&UHasselt

Denosumab Re-treatment and Changes in Lumbar Spine and Total Hip BMD

Phase 2: Postmenopausal Women With Low BMD

Adapted from Miller PD, et al. Bone. 2008;43:222-229.

Lumbar Spine Total Hip

Pe

rce

nt

Ch

an

ge

(LS

Me

an

±S

E)

Months

-6

-4

-2

0

2

4

6

8

Months

0 6 12 18 24 36 48-4

-2

0

2

4

6

8

10

12

14

0 6 12 18 24 36 48

Re-treatment

60 mg Q6M

Discontinued

Treatment

Re-treatment

60 mg Q6M

Discontinued

Treatment

Placebo

30 mg Q3M

Pe

rce

nt

Ch

an

ge

(LS

Me

an

±S

E)

Treatment failure

• Lack of definition (Diez-Perez, OI, 2014)

– “Effective”: • No new vertebral fracture (imaging!)

• No new other fracture

– “Ineffective”:• New fracture after 1 year adequate anti-resorptive treatment

• Bone loss in spite of adequate anti-resorptive treatment

• Teriparatide in case of new fracture during adequate treatment with anti-resorptives > 1 year

MUMC&UHasselt

DXA+VFA+Fall risk

T -2.5

T 1.0 and>-2.5

T >-1.0

Vertebralfracture

Low risk:- Life style- No medication

Medicaltherapy

Follow Up

High risk:- Therapy or follow up- Life style

Otherrisk factors

2/ Diseases/medications

3/ Other risk factors

High fall risk

Investigation&

correction of new

secondaryosteoporosis

1

Case finding

2

Risk evaluation

3

Differential

diagnosis

4

Therapy

5

Follow

up

1/ Recent fracture

Vertebral

NHNV

Fall prevention strategies

Investigation&

correction

Hip

Copyright

P. Geusens

8-12-2015

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Components of bone and muscle and resistanceto fracture

Torres, Curr Rheumatol Rep, 2013

Bone remodeling and modeling

Neuromuscularperformance

Muscle- Mass- Power- Strength- Remodeling- Damage

Balance

Cathepsin K

Osteoclast

Collagen degradation

RANK

Osteoblast

Wnt signaling

LRP Frizzeld

Wnt

DKK

Osteocyte

RANKL

Denosumab Anti-sclerostin

rhPTH (1-34) en (1-84)

Sclerostin

pre-osteoclast

pre-osteoblast

RANKL Sclerostin

BP

BP

Bisphosphonates

BP

Odanacatib

Lems & Geusens, Curr Opin Rheumatol. 2014, 245

Questions for the (next) future

• Can we ameliorate case finding?

– FLS and alternatives EULAR/EFORT

• Role of new measurement techniques of bone quality in daily practice

• Can we further reduce the risk of NVNH fractures?

• Direct comparisons between drugs on fracture prevention

• Can we decrease post-fracture morbidity?

• Can we treat to target, and what is the definition of target?

• Role of future therapies:

– Odanacatib, a specific cathepsin-K inhibitor

– New osteo-anabolics: anti-sclerostin antibodies

• Effect of combination and sequential therapies on fracture risk

• How to improve adherence?

• Cost-effectiveness of case finding and therapy?

• What is real-life evidence?

• Can we improve fracture healing?

• Sarcopenia: definition, treatment?

• Fracture prevention in <50 years old?MUMC&UHasselt

Fracture prevention in women and men older than 50 years : A 5-step decision plan

MUMC&UHasselt Netherlands Guidelines “Osteoporosis and Fracture Prevention”, 2011

1

Case finding

2

Risk evaluation

3

Differential

diagnosis

4

Therapy

5

Follow

up

1/ After recent fracture

2/ Diseases/medications

3/ Other clinical risk factors

Clinical risk factors

DXA

Imaging of the spine

Medical history

Clinical examination

Laboratory examination

Communication

Life style

Calcium and vitamin D

Medication (PO, IV, SC)

Fall prevention

Compliance

Tolerance

Efficiency

Duration of therapy

Copyright

P. Geusens

8-12-2015

10

Capucijnen Crypte Capuchin Churchof the Immaculate Conception(1645), Via Veneto, Rome

How tO Treat osteoporosis?a HOT Lecture, … a HOT Topic,

… in a HOT city

KörperweltenProfessor anatomie Günther von Hagens

Copyright

P. Geusens