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Benjamin Z Leder, Joy N Tsai, Alexander V Uihlein, Paul M Wallace, Hang Lee, Robert M Neer, Sherri-Ann M Burnett-Bowie F M Strippoli Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial Lancet July 3, 2015

http://dx.doi.org/10.1016/ S0140-6736(15)61120-5

2015年8月27日 8:30-8:55 ８階 医局 埼玉医科大学 総合医療センター 内分泌・糖尿病内科

Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University Sellami Mnif Houda

Denosumab Teriparatide Teriparatide

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Lancet 2013; 382: 50 –56 12 months study J Clin Endocrinol Metab, May 2014, 99(5):1694 –1700 24 months study

Introduction

No approved therapy is able to restore skeletal integrity in most osteoporotic patients Long-term use of osteoporosis drugs is controversial two or more therapies Combined teriparatide and denosumab. Continuously increased bone mineral density more than either drug alone Discontinuously treatment results in rapidly declining bone mineral density

OBJECTIVE:

To assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments.

METHOD:

Randomised controlled trial (DATA-Switch) : preplanned extension of the denosumab and teriparatide administration study (DATA) 94 postmenopausal osteoporotic women randomly assigned to receive

24 months of teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs

. DATA-Switch: Switch Teriparatide group Denosumab group Denosumab group Teriparatide Group receiving both received an additional 24 months of Denosumab alone (combination to denosumab group). •Bone mineral density (spine, hip, and wrist ) and biochemical markers of bone turnover : measured at 6 , 12 ,18 and 24 months after the drug • transitions

Primary endpoint

: the percent change in posterior-anterior spine bone mineral density over 4 years.

• Secondary endpoints: the percent change in total hip, femoral neck, and radius shaft bone mineral density and the percent change in serum osteocalcin and C-telopeptide concentrations.

RESULTS:

In women switching from teriparatide to denosumab, mean (SD) lumbar spine bone mineral density continued to increase resulting in 48 month increases of 18·3% In women switching from combination therapy to denosumab, the net 48-month increase in bone mineral density was 16·0%

No significant differences between the groups increase p=0·0005 p=0·0203)

Bone mineral density increased more after the treatment transition in the teriparatide to denosumab group (24-48 Months) net 0 –48-month decrease of –1·8% The 0 –48 month bone mineral density increases in the combination to denosumab G

were signifi cantly larger than

those either in the teriparatide to denosumab group (p=0·0075 ) or the denosumab to teriparatide group ( p=0·0099).

9·1% 8·3%

-(0-48 Months) Increased more in the comb to denosumab group than in either the

8·6%

teriparatide /denosumab G

(

p=0·0446) or the denosumab to teriparatide G ( p<0·0001 ) -Increase in Teri/Deno Deno/Teri (p=0·0002) was better than

6·6% 4·9% decreased ( 24 -36 months before) then increase ( 36- 42 months)

Increases by 275%

159% Increases by 183% Bone formation (Osteocal) was not suppressed until 12 –24 months of denosumab treatment both markers were maximally suppressed at all post-switch timepoints Bone resorption (C-telopeptide) was maximally suppressed after 1 month of denosumab Teri G has significantly higher level p <0.0001, and p<0.0023 (Moths 25-30) 40 pc above baseline

Significant hypercalcaemia (blood calcium >10·8 mg/dL confi rmed on repeat testing) : identified in one patient during months 24 –48 (

denosumab to teriparatide group

). Serious adverse events reported in six participants in the

teriparatide to denosumab

group (ductal carcinoma in situ of the breast, syncope, chronic obstructive pulmonary disease exacerbation, elective cervical laminectomy, fundoplication procedure, and non-ST elevation myocardial infarction 4 participants in the

denosumab to teriparatide

group (appendicitis, laryngitis or pharyngitis,

nephrolithiasis

without hypercalcaemia, and anaemia due to a gastric ulcer), and three participants in the

combination to denosumab group

(breast cancer, atrial fi brillation, and atrial fi brillation with stroke)

Possibly related to TTT (teriparatide

In postmenopausal osteoporosis, switching therapy from teriparatide to denosumab further increases bone mineral density at all measured sites, whereas switching therapy from denosumab to teriparatide results in transient bone loss at the hip and spine and progressive bone loss at the radius shaft. Additionally, we have shown that 24 months of combined therapy followed by 24 months of denosumab alone is associated with largest cumulative bone mineral density increases at the hip and radius, increases that are greater than have been reported with any currently available therapy taken for a similar duration. the importance of the order of anabolic versus antiresorptive therapy with denosumab. The bone loss that occurs in patients switching from denosumab to teriparatide was an unexpected finding

IN CONCLUSION

In postmenopausal osteoporosis, the order in which denosumab and teriparatide are used has a significant effect on overall treatment effectiveness. Specifically, teriparatide does not adequately prevent bone loss after denosumab, whereas denosumab stabilises and further increases bone mineral density when used after teriparatide or combination therapy. The largest increases in bone mineral density at the hip and wrist, and the largest bone mineral density increases possible in any clinical context, are achieved in women treated with 24 months of combined teriparatide plus denosumab followed by 24 months of denosumab monotherapy. These should the approach to the initial and sequential treatment of osteoporotic women, particularly those with established disease who are at an acutely high risk of fragility fracture

Three important points can be derived from the DATA-Switch study: first, when embarking on sequential monotherapy, a course of teriparatide followed by denosumab translates into a sustained increase of BMD; second, combination therapy with teriparatide and denosumab leads to the greatest BMD gain compared with individual therapy when followed by denosumab; and third,

denosumab followed by teriparatide monotherapy should be avoided

as it results in a transient loss of BMD at the spine and the hip and progressive loss of BMD at the distal radius (see figure 3 in Leder and colleagues’ paper).

*Lorenz C Hofbauer, Tilman D Rachner Division of Endocrinology, Diabetes, and Bone Diseases, Technische Universität Dresden Medical Center, 01307 Dresden, Germany (LCH, TDR); and Center for Regenerative Therapies Dresden, Germany (LCH)

www.thelancet.com Published online July 3, 2015 http://dx.doi.org/10.1016/S0140-6736(15)61175-8

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した

閉経後骨粗鬆症患者

77

人

を

対象

に、

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の

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り

替

えに

伴

う

骨密度

の

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を

無作為化比較試験

で

検証

（DATA-Switch

試験

）。 48カ

月時

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の

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