ECTS symposium 5

Anabolic treatment of osteoporosis

Limitations to anabolic stimulation of bone formation

Roland Baron, Professor, Harvard Medical School, Boston, Massachusetts, USA

T

Baron R. and Kneissel M. Nature Medicine, 2013

Sclerosteosis and Van Buchem: Bone Specific Activation of WNT Signaling

Sclerosteosis and Van Buchem syndrome

• Human genetics:Increased bone density, thick cortices in:

--Sclerosteosis: All null mutations in Sost, the gene that encodes Sclerostin

--Van Buchem: deletion with decreased Sclerostin expression

-- Carriers have high bone mass and no side effects

)

Padhi et al., JBMR 2011

Effects of a Single Dose of Romosozumab on BMD at the Spine and Hip

Sclerostin Antibodies Increase Bone Formation in both Trabecular and Cortical Bone via both Modeling and Remodeling in rats and monkeys

PTH is Anabolic but Bone Resorption Increases

Bone Formation – e.g P1NP

Bone Resorption – e.g CTX

Leder at al., JCEM 2014

Teriparatide OW: Effects on Fracture Risk

Fujita et al., CTI, 2014

Abaloparatide: PTHrP-based Mechanism of Action

Abaloparatide: Lumbar Spine BMD at 48 weeks

Clinical use of anabolic drugsAdolfo Diez-PerezProfessor of Medicine, The Autonomous University of Barcelona, Catalonia

Effect of Teriparatide on New Vertebral FracturesFracture Prevention Trial

RR = relative risk vs. placeboARR = absolute risk reduction

% o

f w

om

en w

ith

>

1 f

ract

ure

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

Clinical Criteria for Treatment Failure(IOF Working Group on TF)

• Two or more incident fragility fractures• One incident fracture AND:

• No change in bone turnover markers OR• No increase in BMD

• No change in bone turnover markers AND no increase in BMD

Diez-Perez A et al. Osteoporos Int 2012;23:2769-74

Is an anabolic superior to an oral AR?Efficacy in Postmenopausal Osteoporosis

Body JJ et al. J Clin Endocrinol Metab 2002; 87: 4528-35

Alendronate Teriparatide (n=73) (n=73)

Total n 10 3women w Fx (13.7%) (4.1%)*

Skeletal siteRadius 3 0Ankle 2 0Ribs 1 2Foot 1 1Other 3 0

* P = 0.042

Bone Mineral Density Non-vertebral Fractures

Is an anabolic superior to an oral AR?

Favors treatment Favors control

1. Murad MH et al. J Clin Endocrinol Metab. 2012;97:1871-80.2. Freemantle N et al. Osteoporos Int 2013; 24: 209-17.

Network meta-analysis of effectiveness1

Mixed treatment analysis2

- Comparative analysis of the pivotal randomized controlled trials

Saleh A et al. HSS J 2012; 8: 103-10Patel V et al. J Musculoskelet Neuronal Interact 2013; 13: 251-4

Two out of 9 incomplete fractures healed with TPTD

baseline one year on TPTD

Atypical fractures

PTH (1-84) and Alendronate Aloneor in Combination

Black DM et al. N Engl J Med 2003;349:1207-15.

Teriparatide + Denosumab

Leder BZ et al. J Clin Endocrinol Metab. 2014 Feb 11: [Epub ahead of print]

While spine and hip BMD continued to increase in the second year in all groups, these year-2 increases did not differ between groups.