4. Secondary osteoporosis: Background
Primary 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 form
of secondary osteoporosis.”
Table 1
Table 2
5. Secondary osteoporosis: Background
Mirza & Canalis Eur J Endocrinol May 13, 2015
“Although endogenous hypercortisolism or Cushing’s
syndrome can be associated with bone loss, most of the
patients suffering from GIOP receive glucocorticoids for
the treatment of a variety of diseases.”
6. Secondary osteoporosis: What is new?
Autoantibodies to osteoprotegerin are associated with
increased bone resorption in rheumatoid arthritis
Hauser et al., Ann Rheum Dis, April 2015
Periarticular/systemic bone loss: important complication of RA
The pathogenesis is complex:
Local and systemic release of cytokines which promote
osteoclastic bone resorption
Production of RANKL by activated T cells
Immobility
Glucocorticoid use
Direct osteoclast activating effects of antibodies directed
against citrullinated proteins (ACPA)
7. Secondary osteoporosis: What is new?
Autoantibodies to osteoprotegerin are associated with
increased bone resorption in rheumatoid arthritis
Hauser et al., Ann Rheum Dis, April 2015
Periarticular/systemic bone loss: important complication of RA
The pathogenesis is complex:
Local and systemic release of cytokines which promote
osteoclastic bone resorption
Production of RANKL by activated T cells
Immobility
Glucocorticoid use
Direct osteoclast activating effects of antibodies directed
against citrullinated proteins (ACPA)
9. Secondary osteoporosis: What is new?
Key messages
A subset of RA patients develops functional antibodies to
osteoprotegerin (OPG). The presence of these antibodies is
associated with disease activity and increased bone resorption.
RANKL
osteoclastic
bone resorption
++
RANKL
osteoclastic
bone resorption
Antagonist
OPG
+--
RANKL
osteoclastic
bone resorption
Antagonist
OPG
Antibodies
to OPG
++++ -
Autoantibodies to osteoprotegerin are associated with
increased bone resorption in rheumatoid arthritis
Hauser et al., Ann Rheum Dis, April 2015
11. Secondary osteoporosis: Background
Mirza & Canalis Eur J Endocrinol May 13, 2015
“Although endogenous hypercortisolism or Cushing’s
syndrome can be associated with bone loss, most of the
patients suffering from GIOP receive glucocorticoids for
the treatment of a variety of diseases.”
13. Objective:
To examine the relationship between bone mass and carotid
measurements in SLE and controls
Methods:
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 measured
Key results:
- see figure
Ajeganova et al., Arthritis Res Ther, 2015
14. 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
15. Objective:
To examine the relationship between bone mass and carotid
measurements in SLE and controls
Methods:
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 measured
Key results:
- see figure
Ajeganova et al., Arthritis Res Ther, 2015
Conclusion:
Diagnosis & treatment of bone loss in SLE should
include cardiovascular risk assessment.
Conversely, detection of atherosclerosis should
prompt diagnosing and preventing complications of
osteoporosis.
16. 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.
17. Secondary osteoporosis: Imaging in AS
Recommendation No. 10
In patients with axial SpA without syndesmophytes in the lumbar
spine, osteoporosis should be assessed by hip DXA
and 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.
18. Secondary osteoporosis: Background
Mirza & Canalis Eur J Endocrinol May 13, 2015
“Although endogenous hypercortisolism or Cushing’s
syndrome can be associated with bone loss, most of the
patients suffering from GIOP receive glucocorticoids for
the treatment of a variety of diseases.”
20. Objective:
Giant cell arteritis: incidence, GC use, and comorbidities
Methods:
Retrospective analysis of UK Clinical Practice Research datalink
Key results:
4,671 patients with GCA; incidence 1.0 / 10,000 person years
33.4% 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
21.
22. 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
CARDIOVASCULAR
RISK
INFLAMMATION GLUCOCORTICOIDS
++
-
The
magic
triangle
24. Objective:
Giant cell arteritis: incidence, GC use, and comorbidities
Methods:
Retrospective analysis of UK Clinical Practice Research datalink
Key results:
4,671 patients with GCA; incidence 1.0 / 10,000 person years
33.4% 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
Conclusion:
Most likely, both the disease itsself and its
treatment with GC contribute to the fact that
osteoporosis is strongly associated with GCA!
26. 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:
Background
Buttgereit, Ann Rheum Dis (2011)
39. 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 day
For duration: 3-month minimum duration
For 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
41. 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 day
For duration: 3-month minimum duration
For 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
44. 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.
46. Rizzoli & Biver, Nat Rev Rheum, February 2015:
With what agent?
Calcium and Vitamin D
“Prophylactic treatment with Vit D and calcium can be
recommended as a minimum preventive strategy for
GIOP in patients receiving GC therapy.”
Ströhle 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.
48. Rizzoli & Biver, Nat Rev Rheum, February 2015:
With what agent?
Anti-osteoporotic drugs
“The 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.
53. I. Inhibition of bone resorption:
Established medications & novel developments
Lippuner
Swiss Med Wkly. 2012
Bisphosphonates are today´s 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.
Bisphosphonates
SERMS
54. I. Inhibition of bone resorption:
Established medications & novel developments
Lippuner
Swiss Med Wkly. 2012
Bisphosphonates
SERMS
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.
55. Odanacatib inhibits cathepsin K, a lysosomal cysteine protease. Cathepsin K
is expressed by osteoclasts during the process of bone resorption, and acts
as the major collagenase responsible for the degradation of the organic bone
matrix during the bone remodeling process.
Lippuner
Swiss Med Wkly. 2012
I. Inhibition of bone resorption:
Established medications & novel developments
56. Odanacatib was shown to be orally bio-available, highly
selective for and reversibly binding to cathepsin K, and
is being evaluated for the treatment of osteoporosis.
Treatment of osteoporosis:
What is new?
from Wikipedia Being developed by MSD Sharp & Dohme
This paper describes the background, design
and participant characteristics for a phase 3
registration trial.
57. 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
59. 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 2015
Conclusion:
Most likely, LOFT will demonstrate ODN to
effectively reduce fracture risk in PMO. Full
publication will describe benefit/risk profile in detail.
62. 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 in
the cell membrane overall increase in bone (“anabolic” effects)
Lippuner
Swiss Med Wkly. 2012
63. Lippuner
Swiss Med Wkly. 2012
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
64.
65. Lippuner
Swiss Med Wkly. 2012
Activation of the canonical Wnt/ß-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
66. McClung MR et al. N Engl J Med (2014)
Romosozumab (Celltech/UCB; Amgen):
A mAB directed against sclerostin
67. 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.org
Romosozumab (Celltech/UCB; Amgen):
A mAB directed against sclerostin
68. Objective:
Effects of romosozumab (Ro) followed by denosumab (De)
Methods:
419 postmenopausal women (55-85 y.) with T-Scores ≤ -2 and ≥
-3.5) received Ro (5 regimens) or PBO for 2 years; thereafter
either De or PBO for a 1-year extension.
Key results:
Ro (especially 210 mg QM) rapid & marked in BMD.
Women transitioned to De continued to accrue BMD at a similar
rate. Transition PBO: BMD returned towards pretreatment levels.
EULAR 2015; OP0251 McClung et al., USA
69. 15.7%
6.0%
Adverse events were belanced between PBO, Ro and De, with the exception
of injection site reactions in the Ro group, most reported as mild.
EULAR 2015; OP0251 McClung et al., USA
70.
Conclusion:
Ro led to rapid and marked in lumbar spine and
total hip BMD over 2 years. This continued with De,
but resolved after transition to PBO.
Objective:
Effects of romosozumab (Ro) followed by denosumab (De)
Methods:
419 postmenopausal women (55-85 y.) with T-Scores ≤ -2 and ≥
-3.5) received Ro (5 regimens) or PBO for 2 years; thereafter
either De or PBO for a 1-year extension.
Key results:
Ro (especially 210 mg QM) rapid & marked in BMD.
Women transitioned to De continued to accrue BMD at a similar
rate. Transition PBO: BMD returned towards pretreatment levels.
EULAR 2015; OP0251 McClung et al., USA
71. Take home messages
Secondary osteoporosis has a high burden to
patients with inflammatory rheumatic diseases.
Both the disease itsself and its treatment contribute
to pathogenesis.
GIOP is the most common form.
Algorithms exist for effective diagnosis, prevention
and treatment.
There are both effective treatments available and
promising drugs in the pipeline.
