is my treatment working doctor?
TRANSCRIPT
Is my treatment working doctor?
DXA, bone markers, definition of ‘success’
Dr John Lindsay
NOS Meeting
Galgorm Resort & Spa
5th October 2017
Objectives
• To consider utility of current anti-osteoporosis therapies
• Review the use of DXA monitoring during treatment
• Explore role of bone turnover markers, interpretation and recent guidelines
• Consider ‘definition of success’
Osteoporosis Medications
Anti-resorptive
Alter quality
Anabolic
Extra-skeletal
e.g. reduce falls
• Goals of currently available
medications:
• Reduce the risk of fracture
• Improve bone strength
- Increase bone mass
- Possibly improve bone
architecture
Spine
Bone
Tu
rno
ve
r
Bone
Min
era
lD
en
sity
FemurBF
Fra
ctu
reR
ate
PreMP Range
BR
Time
Rapid decrease in bone
resorption (BR), followed by a
decrease in bone formation (BF)
Time
Refill remodeling space +
secondary mineralization Increase in BMD spine >
hip
Reduction in
fracture risk
BisphosphonatesReduce BTMs, Increase BMD and Reduce Fracture Risk
Bisphosphonates Reduce Vertebral Fracture RiskData from pivotal trials
ZOL 5 mg
Risedronate
Alendronate
Ibandronate
Years Years Years Years
0‐1 0‐2 0‐3 0‐1 0‐2 0‐3 0‐1 0‐2 0‐3 0‐1 0‐2 0‐3
Rel
ativ
eR
isk
Red
uct
ion
(%)
71%
0
10
20
30
40
50
60
70
60%
70%65%
55%
41%
62%
48%
58%61%
52%
65%
Teriparatide Increases BMDRCT of 1637 women with postmenopausal osteoporosis
and 1 vertebral fractures treated an average of 18 months with placebo, 20 µg PTH (1-34)
NSNS
P<0.001
P<0.001
0 6 12 2418 30 36
The effect of denosumab on time to first hip fracture through 36 months in the overall FREEDOM population1,2
ARR = absolute risk reduction; RRR = relative risk reduction1. Adapted from Cummings SR, et al. N Engl J Med. 2009;361:756-765..2. Prolia® (denosumab), Summary of Product Characteristics last accessed February 2013
Placebo, n 3,906 3,799 3,672 3,538 3,430 3,311 3,221
Denosumab, n 3,902 3,796 3,676 3,566 3,477 3,397 3,311
Number of patients at risk
Cu
mu
lati
ve In
cid
ence
(%
)
Month
0.0
0.4
0.8
1.2
0.7%
1.2%
Placebo
Denosumab 60 mg Q6M
RRR = 40% ARR = 0.5 %2
p = 0.04
Long-term Denosumab
Bone et al. Lancet Diabetes Endocrinol 2017; 5: 513–23
Monitoring Osteoporosis Therapy
• Goal of treatment = reduce fragility fracture occurrence
• Fragility fracture incidence is low; absence of fracture during therapy
does not necessarily mean treatment is effective
• However, fracture occurrence on therapy does not necessarily indicate
treatment failure
• Surrogates such as BMD and biochemical markers to monitor treatment
can be useful
• Changes in an ideal surrogate marker during therapy should reflect
changes in fracture risk
NNT to prevent a secondary vertebral and non-vertebral fracture
Saito Osteoporos Int 2017.DOI 10.1007/s00198-017-4175-0
Medication Secondary vertebral fracture (ACR = 2.88%)
Secondary non-vertebral fracture (ACR = 8.65%)
NNT (95% CI) NNT (95% CI)
Bisphosphonate 74 (66, 85) 28 (23, 43)
Etidronate 71 (54, 119) Effectiveness not established
Alendronate 77 (64, 96) 24 (18, 53)
Risedronate 89 (85, 92) 21 (16, 55)
Pamidronate 62 (46, 159) Effectiveness not established
SERMs 89 (81, 99) Effectiveness not established
PTH 56 (47, 76) 32 (21, 116)
Calcitonin 152 (87, 3333) N/A
NNT to prevent a secondary vertebral and non-vertebral fractureNNT number needed to treat, ACR assumed control risk, CI confidence interval, SERMs selective estrogen receptor modulators, PTH parathyroid hormone, N/A not available
Long-term Bisphosphonates
Adler et al. JBMR 2016; 31: 16–35
Reasons to Measure Serial BMD
• Untreated patients
◦ Significant loss may be an indication for treatment
and is associated with an increased fracture risk1
• Treated patients
◦ To monitor the response to therapy
- Increase or stable bone density is associated with
fracture risk reduction
- A loss of BMD is cause for concern
• Consider further evaluation (adherence, secondary
causes) for those who are losing BMD2
1Nguyen TV et al JBMR 2005;20(7):1195-12012Lewiecki EM J Clin Densitom. 2003;6(4):307-14
Fracture Risk Doubles with every SD decrease in BMD
0
5
10
15
20
25
30
35
-5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0
Bone Density (T-score)
Relative
Risk for
Fracture
Approach to Monitoring
• Compare “apples withapples”
• Critically assess the DXA images on the two comparison studies
• The region of interest (ROI) must be the same
• The measured area should be comparable
• Compare the BMD, not the T-score
• How much of a difference is real?
• If there is a difference, what does it mean?
• If the ROI appears the same but the area is different, look for improper
positioning, incorrect scan analysis, and/or artifacts (fractures, degenerative
changes,etc.)
L1-L4 BMD 0.896 g/cm2
T-score = -2.4L1-L4 BMD 0.853 g/cm2
T-score = -2.7
Loss = 0.043 g/cm2 (4.8%), exceeds least significantchange
65 year old, initial spine T-score = -2.4, treated with a bisphosphonate for 1 year Repeat DXA reports bone loss
Baseline Follow-up
The Importance of Comparing
“Apples With Apples”
Comparing “Apples With Apples”Importance of Hip Positioning on Femoral Neck BMD
Baseline
1.009 g/cm2
Follow up (initial)
1.017 g/cm2
+0.008 g/cm2
Follow up (repositioned)
0.966 g/cm2
−0.043 g/cm2
Least Significant Change (LSC)
• Precision error at your centre
• Desired confidence level(95%)
• Perform precision study on patients representative of
your typical patientpopulation
◦ This will help prevent over-calling of significant change
LSC = (precision error) × 2.77
to have 95% confidence that the change isreal
Serial BMD
Baseline spine BMD
Repeat spine BMD
Difference
0.866 g/cm2
0.832 g/cm2
0.034 g/cm2
LSC 0.028 g/cm2
Exceeds or Equals LSC Yes
• Change is significant
• Note that % change is:
−(0.034/0.866) × 100 = loss of 4% ± LSC
= 4% ± 2.8%
Selection of Skeletal Site and Region of
Interest for Monitoring Changes
• PA spine preferred
◦ Best precision
◦ Most responsive to therapy
◦ Use L1-L4 value if possible
• If PAspine cannot be used
◦ Total hip preferred (better precision)
◦ Femoral neck (poor precision)
If There Is a Difference in BMD at
Follow-up, What Does it Mean?
• What is a satisfactory response to treatment?
◦ Significant gain in BMD?
◦ Stable BMD?
• What is cause for concern?
◦ Failure to gain?
◦ Significant loss?
Cummings, et al. JAMA 1998:280:2077-2082
Fracture reduction is greater than would be predicted by BMD increase
Monitoring Therapy With BMD
• If there is loss of BMD that exceeds LSC (95%
confidence)
– Check compliance with medication
– Assure proper administration
– Check calcium and vitamin D intake
– Look for underlying disease or condition
• What about bone turnover markers for monitoring response to treatment-is there a role?
Bone Turnover Markers Change Sooner
than BMD but Have More Variability
• Bone Mineral Density:
◦ BMD changes slowly (= static measurementof
skeletal status)
◦ Low within-person variability
◦ Measurement = precise
◦ Small changes in response to antiresorptive therapy
• Markers
◦ Dynamic measure of skeletalstatus
◦ Larger changes in responseto therapy (within
months)
◦ ± great variability
1-2 yrs
D
0
3-6 months
Delmas P. Osteoporos Int 2000;11(Suppl.6):66-76.
D
LSC0
Bone Turnover Markers
Markers of bone resorption
◦ C-telopeptide (CTx)*
◦ N-telopeptide (NTx)
- Degradation products of type 1
collagen
Markers of bone formation
◦ Procollagen type 1 N- terminal
propeptide (P1NP)*
◦ Bone specific alkaline
phosphatase (BSAP)
◦ Osteocalcin
◦ C-terminals propeptide of type 1
procollagen
*recommended by IOF and IFCC
Mellanby Centre, Sheffield, Bone Turnover Markers Course
Early Changes in Bone Turnover Markers are
Associated with Long-term Changes in BMD
RCT, postmenopausal women >65 yrs (n=373) ALN, HRT, ALN+HRT vs. PBO for 3 years
Decrease in NTX at 6 months (%) Decrease in Bone ALP at 6 months (%)
8 8
6 6
4 4
2 2
0 0
<46 46-66 ->66
10 10
12 12
<46 46-66 ->66
Total Hip
PASpine
%change
inB
MD
%change
inB
MD
Adapted from Greenspan et al., J Clin Endocrinol Metab 2005, 90: 2762-2767
Total Hip
PASpine
Greater BSAP Reduction With Alendronate
at 1 Year is Associated with Greater Fracture
Risk Reduction at Years 2.5 - 4.5
Patients
With
Fra
ctu
re(%
)
7.3
1.0
9.8
0.8
8.7
4.3*3.8*
6.8*
0.2*
0
2
4
6
8
10
Spine Hip Non-Spine
Placebo (n=3,066)
Alendronate (<30% reduction BSAP)
Alendronate (> 30% reduction BSAP)
*p < 0.01 vs placebo
Adapted from Bauer DC, et al. J Bone Miner Res. 2004;19:1250-1258.
Bone Turnover Markers and BMD ResponseMedication BTMs Spine Hip
Oestrogen
Bazedoxifene/CEE ()
Alendronate
Risedronate
Ibandronate
Zoledronic acid
Calcitonin ~ ~
Raloxifene ()
Denosumab
Teriparatide
Variation in BTMs
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.
Conditions that affect BTMs
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.
Recent Fracture
Impact of drugs
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.
TRIO Study
Naylor et al. Osteoporosis Int. 2016 Jan;27(1):21-31.
By 12 weeks more than 80% of patients had decreased >LSC for CTX-I (56%) and PINP (38%)
Assessment of concordance
Diez-Perez A. Osteoporosis Int 2017
Alternative approaches
• Decrease BTMs below the mean of healthy pre-menopausal women. Thresholds of:
– 35 μg/L for PINP
– 312 ng/L for serum CTX-I
• Close to the average values obtained in several studies; may vary according to the assay used
Eastell R, Szulc P. Lancet Diabetes Endo 2017
Early Changes in Bone Markers Predict BMD
Response to Parathyroid Hormone Therapy
P1NP
Bauer et al., J Clin Endocrinol Metab 2006, 91: 1370
Options for clinical practice
• Monitoring individual response to treatment
– Further research required
• Absence of a change may indicate
– Poor concordance
– Inappropriate injection of Teriparatide
– Secondary osteoporosis
– Real absence of response to treatment
• ??monitor offset of treatment or negative impact on bone in drug development
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.
Mellanby Centre, Sheffield, Bone Turnover Markers Course
Concordance
Never Sometimes Mostly Always
DXA BMD
Falling >LSC Stable within LSC Rising >LSC
BTMs
No response Resorption/formation response
Fracture
Multiple Single None
Is my treatment plan working doctor?
SUC
CES
S?
Summary & Conclusions
• Explored utility of current anti-osteoporosis therapies
• Reviewed the use of DXA monitoring during treatment
• Explored role of bone turn over markers, interpretation and recent guidelines
• Considered factors around ‘definition of success’