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’