seminar 28-11-2015 prof. p. geusens
TRANSCRIPT
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
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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
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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
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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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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
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8-12-2015
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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