5. frank buttgereit. fin40 min rheumatic diseases and osteoporosis

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Medizinische Klinik m.S. Rheumatologie & Klinische ImmunologieUniversittsmedizin Charit Rheumatic diseases and osteoporosisFrank Buttgereit

Secondary osteoporosisGlucocorticoid-induced osteoporosisEmerging drugs for osteoporosis

AGENDA


AGENDA

Secondary osteoporosis: BackgroundPrimary osteoporosis is age related and occurs in post-menopausal women and in men in the absence of an underlying disease. Secondary osteoporosis is defined as low bone mass with microarchitectural alterations in bone leading to fragility fractures in the presence of an underlying disease and/or medication.Mirza & Canalis Eur J Endocrinol May 13, 2015 Glucocorticoid-induced osteoporosis (GIOP)is the most common formof secondary osteoporosis. Table 1Table 2

Secondary osteoporosis: Background

Mirza & Canalis Eur J Endocrinol May 13, 2015

Although endogenous hypercortisolism or Cushings syndrome can be associated with bone loss, most of the patients suffering from GIOP receive glucocorticoids for the treatment of a variety of diseases.

Secondary osteoporosis: What is new?

Autoantibodies to osteoprotegerin are associated withincreased bone resorption in rheumatoid arthritisHauser et al., Ann Rheum Dis, April 2015

Periarticular/systemic bone loss: important complication of RAThe pathogenesis is complex: Local and systemic release of cytokines which promote osteoclastic bone resorptionProduction of RANKL by activated T cellsImmobilityGlucocorticoid useDirect osteoclast activating effects of antibodies directed against citrullinated proteins (ACPA)


Autoantibodies to osteoprotegerin are associated withincreased bone resorption in rheumatoid arthritisHauser et al., Ann Rheum Dis, April 2015

Periarticular/systemic bone loss: important complication of RAThe pathogenesis is complex: Local and systemic release of cytokines which promote osteoclastic bone resorptionProduction of RANKL by activated T cellsImmobilityGlucocorticoid useDirect osteoclast activating effects of antibodies directed against citrullinated proteins (ACPA)

osteo-blasts

osteoclastIL-1&6

osteoclastprecursor cell T cellRANKLantagonist OPG: = soluble receptor

+

+

TNFa

RANKRANK

TNFa, IL1 & IL6 induce bone resorption

direct inductionof osteoclastformationIL-6

OPG


Key messagesA subset of RA patients develops functional antibodies to osteoprotegerin (OPG). The presence of these antibodies is associated with disease activity and increased bone resorption. RANKLosteoclastic bone resorption

++RANKLosteoclastic bone resorptionAntagonistOPG

+--RANKLosteoclastic bone resorption

AntagonistOPG

Antibodiesto OPG++++-Autoantibodies to osteoprotegerin are associated withincreased bone resorption in rheumatoid arthritisHauser et al., Ann Rheum Dis, April 2015

Effect of osteoprotegerin (OPG) antibody positive and negative samples on receptor activator of nuclear factor B (NFB) ligand (RANKL) induced NFB signalling.

Barbara Hauser et al. Ann Rheum Dis doi:10.1136/annrheumdis-2014-2072192015 by BMJ Publishing Group Ltd and European League Against Rheumatism

Anti-OPG +Anti-OPG -

Effect of osteoprotegerin (OPG) antibody positive and negative samples on receptor activator of nuclear factor B (NFB) ligand (RANKL) induced NFB signalling. The vertical axis shows levels of NFB activation in HEK293 cells in response to the effects of RANKL, OPG and purified IgG from patient samples. The cells were stimulated with 50g/mL RANKL and 100g/mL OPG, in the presence or absence of purified IgG from patients with RA that tested positive (samples #1 and #2) or negative for OPG antibodies (samples #3 and #4) as detected by ELISA in this study. The data shown are mean and SEM from three experiments, corrected to vehicle-treated control wells adjusted for cell number. Differences between groups are indicated by ***p=0.001 and +++p=0.004, not significantly (ns) different from RANKL and OPG-treated wells. Patient samples #3 and #4 were not significantly different from RANKL and OPG-treated cells.




Secondary osteoporosis: SLE

Objective: To examine the relationship between bone mass and carotid measurements in SLE and controlsMethods:Cross-sectional study, 111 SLE-patients vs. 111 age- and sex-matched controls; carotid intima media thickness (cIMT; B-mode ultrasound) and (BMD; DXA) were measuredKey results:- see figure

Ajeganova et al., Arthritis Res Ther, 2015

Ajeganova et al., Arthritis Res Ther, 2015

BMD was negatively associated with cIMT (SLE and controls)SLE-patients had a higher burden of carotid atherosclerosis than controls, i.e. higher cIMT at lower BMD

Objective: To examine the relationship between bone mass and carotid measurements in SLE and controlsMethods:Cross-sectional study, 111 SLE-patients vs. 111 age- and sex-matched controls; carotid intima media thickness (cIMT; B-mode ultrasound) and (BMD; DXA) were measuredKey results:- see figure

Ajeganova et al., Arthritis Res Ther, 2015Conclusion:Diagnosis & treatment of bone loss in SLE should include cardiovascular risk assessment. Conversely, detection of atherosclerosis should prompt diagnosing and preventing complications of osteoporosis.

Curr Opinion Rheum (2013)Secondary osteoporosis: AS

Osteoporosis is a common problem for patients with AS. Newer data suggest that the prevalence of osteoporosis is 25% and vertebral fractures is 10% in patients with AS.

Secondary osteoporosis: Imaging in AS

Recommendation No. 10In patients with axial SpA without syndesmophytes in the lumbar spine, osteoporosis should be assessed by hip DXAand AP-spine DXA. In patients with syndesmophytes in the lumbar spine, osteoporosis should be assessed by hip DXA, supplemented by either spine DXA in lateral projection or possibly QCT of the spine.




Secondary osteoporosis: GCA

Objective: Giant cell arteritis: incidence, GC use, and comorbiditiesMethods:Retrospective analysis of UK Clinical Practice Research datalink Key results:4,671 patients with GCA; incidence 1.0 / 10,000 person years33.4% received a cumulative GC dose of 10g;osteoporosis is strongly associated with GCA: RR 2.9 (tables)

Petri et al., Arthritis Care Res, March 2015

Discussion: especially osteoporosis, some infections, cardiovascular conditions, diabetes mellitus, appear to have a high burden specific to the GCA population. GC use likely contributes to this burden, as other investigators have shown for rheumatoid arthritis ; however, given the limitations of the study design, we were unable to ascertain causality.

Petri et al., Arthritis Care Res, March 2015

The magictriangle

The magictriangle

Osteoporosis

Objective: Giant cell arteritis: incidence, GC use, and comorbiditiesMethods:Retrospective analysis of UK Clinical Practice Research datalink Key results:4,671 patients with GCA; incidence 1.0 / 10,000 person years33.4% received a cumulative GC dose of 10g;osteoporosis is strongly associated with GCA: RR 2.9 (tables)

Petri et al., Arthritis Care Res, March 2015Conclusion: Most likely, both the disease itsself and its treatment with GC contribute to the fact that osteoporosis is strongly associated with GCA!


AGENDA

Glucocorticoids (GC) are widely used: about 1.2% of the US population receive GC Phase II IV RA trials investigating biological drugs; concomitant treatment with GC: 39 70% In Sweden, 28,698 out of 58,102 RA patients alive in 2008 received GC treatment = 49% GC exposure Data from National database of the German Collaborative Arthritis Centres:

Overman et al., Arthritis Care Res (2013)Neovius et al. Ann Rheum Dis (2011)(internal report data for 2010)Glucocorticoid-induced osteoporosis:BackgroundButtgereit, Ann Rheum Dis (2011)

immunosuppressioninflammation In RA: radiographicprogression

Benefits Risks

osteoporosis

myopathyoedema lipid metabolismcatabolismglaucomacataractinfections

Glucocorticoid therapy in rheumatology

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Glucocorticoid-induced osteoporosis:What is new?

Key issues addressed: EpidemiologyPathophysiologyWho to treat?With what agent?

Rizzoli & Biver, Nat Rev Rheum, February 2015:Pathophysiology

Glucocorticoid-induced osteoporosis:Bone remodeling

Glucocorticoid-induced osteoporosis:Bone remodeling

Glucocorticoid-induced osteoporosis:GC effects on bone

Glucocorticoid-induced osteoporosis:GC effects on bone

34Rasterelektronenmikroskopisches Bild eines OsteoklastenDie rasterelektronenmikroskopische Darstellung kncherner Strukturen zeigt diese in dreidimensionaler Form, hier einen einzelnen Trabekel, dem in seiner Mitte ein Osteoklast aufsitzt. Vorne rechts erkennbar die Grabspuren anderer Osteoklasten. In diesem Bild kann veranschaulicht werden, dass durch die osteoklastre Resorption nicht nur Knochenmasse abgebaut wird, sondern auch eine Vernderung der Knochenoberflche entsteht eine Vernderung der Oberflchenspannung. Diese Vernderung der Oberflchenspannung ist vergleichbar mit dem Anritzen eines Glases mit dem Glasschneider nach dem Anritzen wird die Festigkeit reduziert. Je mehr derartiger Resorptionslakunen auftreten, um so strker wird die Festigkeit des Knochens beeinflusst.Die Zahl, Gre und Tiefe der Resorptionslakunen beeinflussen die Festigkeit jedes einzelnen Trabekels.Die roten Dreiecke dokumentieren den Angriffspunkt der Bisphosphonate.

Normalspongiosaarchitecture

Osteoporotic vertebrae

Severe osteoporosis

Enteral calcium/phosphate absorption Renal calcium/phosphate excretion

modest PTH transient serumCa2+ GIOP: Other causes

Vitamin D receptor sensitivity Synthesis /secretion of sexual hormones Synthesis of bone growth factors (e.g. BMPs) Collagen synthesis Patschan & Buttgereit Bone 2001Mirza & Canalis Eur J Endocrinol May 13, 2015

Glucocorticoid-induced osteoporosis:What is new?

Key issues addressed: EpidemiologyPathophysiologyWho to treat?With what agent?

Rizzoli & Biver, Nat Rev Rheum, February 2015:Who to treat?

Different interpretations of available data and variation in local health-economic conditions different intervention thresholds! Thresholds often used:For dose: 5 or 7.5 mg prednisone equivalent per dayFor duration: 3-month minimum durationFor T-score: -1.0 or -1.5 FRAX: Indication for intervention is based on absolute fracture risk, e.g.:

FRAX takes into account 2.5 7.5 mg/d (past or present)< 2.5 mg/d: revising risk > 7.5 mg/d: revising risk see e.g. Japanese guidelines

YAM = young adult mean

Rizzoli & Biver, Nat Rev Rheum, February 2015:Who to treat?

Different interpretations of available data and variation in local health-economic conditions different intervention thresholds! Thresholds often used:For dose: 5 or 7.5 mg prednisone equivalent per dayFor duration: 3-month minimum durationFor T-score: -1.0 or -1.5 FRAX: Indication for intervention is based on absolute fracture risk, e.g.:

FRAX takes into account 2.5 7.5 mg/d (past or present)Low-dose (< 2.5 mg/d) GC exposure: revising risk High-dose (>7.5 mg/d) GC exposure: revising risk

2.5 - 7.5 mg prednisone equivalent per day

Rizzoli & Biver, Nat Rev Rheum, February 2015:

4 For prolonged treatment, the GC dosage should be kept to a minimum, and a GC taper should be attempted in case of remission or low disease activity; the reasons to continue GC therapy should be regularly checked.

44


Rizzoli & Biver, Nat Rev Rheum, February 2015:With what agent?

Calcium and Vitamin DProphylactic treatment with Vit D and calcium can be recommended as a minimum preventive strategy for GIOP in patients receiving GC therapy. Strhle et al., Climacteric, April 2015 (Review)Less than 800 mg Ca2+/day: associated with increased loss of BMD in peri-/postmenopausal women and fracture risk 1 1.2 g Ca2+/day: sufficient for general fracture prevention No convincing evidence that calcium supplements increase cardiovascular risk.Long term total calcium intake of 2500 mg/day (from food and supplements) continues to be classified as safe; it should, however, not be exceeded for an extended period of time.


Rizzoli & Biver, Nat Rev Rheum, February 2015:With what agent?

Anti-osteoporotic drugsThe bisphosphonates alendronate, etidronate, rise-dronate, zoledronic acid and the anabolic agent teriparatide are recommended as first-line therapeutic options for GIOP in all guidelines published since 2012. Bisphosphonates remain standard of care.No convincing evidence that GIOP and postmeno-pausal osteoporosis respond differently to anti-osteoporotic treatments.


AGENDA

Treatment of osteoporosis:Background

I. Stop him !

II. Help him !


I. Stop him !

I. Inhibition of bone resorption:Established medications & novel developments

LippunerSwiss Med Wkly. 2012Bisphosphonates are todays mainstay of osteoporosis treatment. Problems: Fracture risk reduction is 50% for spine and hip fractures, but is only 20% for nonvertebral fractures; potential adverse effects. Also SERMs (Raloxifen, Bazedoxifen) reduce bone resorption. BisphosphonatesSERMS


LippunerSwiss Med Wkly. 2012BisphosphonatesSERMS

Denosumab is a monoclonal antibody that inhibits RANKL this prevents its binding to RANK-Receptors of osteoclasts maturation, function and survival of osteoclasts is reduced inhibition of bone resorption.

Odanacatib inhibits cathepsin K, a lysosomal cysteine protease. Cathepsin Kis expressed by osteoclasts during the process of bone resorption, and actsas the major collagenase responsible for the degradation of the organic bone matrix during the bone remodeling process.

LippunerSwiss Med Wkly. 2012


Odanacatib was shown to be orally bio-available, highly selective for and reversibly binding to cathepsin K, andis being evaluated for the treatment of osteoporosis.

Treatment of osteoporosis:What is new?from WikipediaBeing developed by MSD Sharp & Dohme

This paper describes the background, designand participant characteristics for a phase 3registration trial.

Objective: To investigate efficacy and safety of Odanacatib in the treatment of PMO: the phase III Long-Term ODN Fracture Trial (LOFT). Methods:db-RCT; n=16.713; 65 y.; T-score -2.5 or prior vertebral Fx and T-score -1.5; ODN 50 mg vs. PBO 1x/wk (+ Vit D, + Ca2+) Key result: Planned interim analysis: The DMC recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. 8256 participants entered the study extension.

Bone et al., Osteop Int, March 2015

http://www.mercknewsroom.com

Objective: To investigate efficacy and safety of Odanacatib in the treatment of PMO: the phase III Long-Term ODN Fracture Trial (LOFT). Methods:db-RCT; w 65 years, n=16.713; T-score -2.5 or prior vertebral Fx + T-score -1.5; ODN 50 mg vs. PBO 1x/Wo (+ Vit D, + Ca2+) Key result: Planned interim analysis: The DMC recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. 8256 participants entered the study extension

Bone et al., Osteop Int, March 2015Conclusion: Most likely, LOFT will demonstrate ODN to effectively reduce fracture risk in PMO. Full publication will describe benefit/risk profile in detail.


II. Help him !

II. Stimulation of bone formation: Established medications & novel developments

The intermittent use of recombinant human N-terminal 1-34 PTH (teriparatide) (and full length 1-84 PTH) activates osteoblasts more than osteoclasts. Effects are mediated via binding to G-protein-dependent, PTH receptor-1 inthe cell membrane overall increase in bone (anabolic effects)



PTH related protein (PTHrp), a protein with homology to PTH at the N-terminus, binds to the same receptor. Abaloparatide is a synthetic peptide analog of PTHrp which showed a marked bone anabolic activity in animal studies dose-finding study in postmenopausal women with osteoporosis. II. Stimulation of bone formation: Established medications & novel developments


Activation of the canonical Wnt/-catenin signaling machinery in osteoblasts leads to increased bone mass and strength. Sclerostin and dickkopf-1 are endogenous inhibitors decreased bone mass and strength. Monoclonal antibodies directed against sclerostin or dkk1 bone anabolic properties. II. Stimulation of bone formation: Established medications & novel developments

McClung MR et al. N Engl J Med (2014)Romosozumab (Celltech/UCB; Amgen): A mAB directed against sclerostin

Romosozumab, a humanized monoclonal antibody against sclerostin.Phase 2, a randomized, placebo-controlled trial.

McClung MR et al. N Engl J Med (2014)

Dr. McClung: Additional studies are underway to evaluate the effectiveness of romosozumab to reduce fracture risk in women with postmenopausal osteoporosis. If successful, romosozumab may be an important treatment option for patients with severe osteoporosis who are in need of skeletal restoration. http://www.4bonehealth.orgRomosozumab (Celltech/UCB; Amgen): A mAB directed against sclerostin

Figure 2 Percentage Change from Baseline in Bone Mineral Density. Data are least-squares means, and I bars indicate 95% confidence intervals. The asterisk indicates P

5. frank buttgereit. fin40 min rheumatic diseases and osteoporosis

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