2020 OA Vision: Emerging Therapeutics on the OA landscapeOARSI
Philip Conaghan MBBS PhD FRACP FRCP
Director, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds
Deputy Director, NIHR Leeds Biomedical Research Centre
2020 OA Vision: Emerging Therapeutics on the OA landscapeOARSI
Philip Conaghan MBBS PhD FRACP FRCP
Director, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds
Deputy Director, NIHR Leeds Biomedical Research Centre
Prof. Richard Keen's presentation from Osteoporosis 2016: Teaching old dogs new tricks? Combination therapy in osteoporosis.
Find out more at: https://nos.org.uk/conference
Prof. Jon Tobias's presentation from Osteoporosis 2016: What are the properties of the perfect therapy?
Find out more at: https://nos.org.uk/conference
Prof. Richard Eastell's presentation from Osteoporosis 2016: Patients receiving bisphosphonates should take holidays from treatment. The case for holidays.
Find out more at: https://nos.org.uk/conference
A great deal is happening in lupus-related research. This presentation will update participants on recent research developments and their impact on those affected by lupus. Dr. Petri will provide an overview of current lupus research and the prospects for the future of lupus treatments. Learn how to better manage your lupus and make knowledgeable decisions regarding your treatment plan.
Reestenosis, Síndrome coronario agudo. Rol actual de los nuevos antiplaquetarios en el síndrome coronario agudo. Congreso SOLACI Chile 2011.Dr. Ramón Corbalán. Encuentre más presentaciones en la página www.solaci.org/
Treatment of Osteoporosis beyond Bisphosphonates therapy (2).pptxmehmoodriaz9
will gain valuable insights into emerging therapies, innovative strategies, and alternative approaches that hold promise in improving bone health and reducing fracture risk. The presentation will cover recent research findings, clinical trials, and real-world evidence, providing a comprehensive overview of the evolving
Prof. Richard Keen's presentation from Osteoporosis 2016: Teaching old dogs new tricks? Combination therapy in osteoporosis.
Find out more at: https://nos.org.uk/conference
Prof. Jon Tobias's presentation from Osteoporosis 2016: What are the properties of the perfect therapy?
Find out more at: https://nos.org.uk/conference
Prof. Richard Eastell's presentation from Osteoporosis 2016: Patients receiving bisphosphonates should take holidays from treatment. The case for holidays.
Find out more at: https://nos.org.uk/conference
A great deal is happening in lupus-related research. This presentation will update participants on recent research developments and their impact on those affected by lupus. Dr. Petri will provide an overview of current lupus research and the prospects for the future of lupus treatments. Learn how to better manage your lupus and make knowledgeable decisions regarding your treatment plan.
Reestenosis, Síndrome coronario agudo. Rol actual de los nuevos antiplaquetarios en el síndrome coronario agudo. Congreso SOLACI Chile 2011.Dr. Ramón Corbalán. Encuentre más presentaciones en la página www.solaci.org/
Treatment of Osteoporosis beyond Bisphosphonates therapy (2).pptxmehmoodriaz9
will gain valuable insights into emerging therapies, innovative strategies, and alternative approaches that hold promise in improving bone health and reducing fracture risk. The presentation will cover recent research findings, clinical trials, and real-world evidence, providing a comprehensive overview of the evolving
Primary Prevention of Cardiovascular Disease: The Role of Aspirin and StatinsCTSI at UCSF
Presented by Michael Pignone, MD, MPH, at UCSF's symposium "The Role of Risk Stratification and Biomarkers in Prevention of Cardiovascular Disease" in Jan 2012.
IWO Meeting 1 November 2023 - Stopping with Denosumab and Romosozumab, basic mechanisms and clinical aspects door Prof. dr. S. Ferrari, Geneva, Switzerland. (Engelstalige lezing)
IWO Meeting 16 November 2022 - ASBMR young talent: Silvia Storoni (Amsterdam): Prevalence and Hospital Admissions in Patients With Osteogenesis Imperfecta in The Netherlands: A Nationwide Registry Study
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Seminar 08-12-2007 - bisphosphonate mechanism of action
1. Werkingsmechanismen vanWerkingsmechanismen van
bestaande anti-osteoporosebestaande anti-osteoporose
medicatiesmedicaties
Zijn ze van belang in de keuze voor
de individuele patiënt?
Wat kunnen we in de nabije
toekomst verwachten?
azMaastricht
UHasselt
3. Mechanisms of action of drugs to prevent
fractures
Markers of
Bone
resorption
Bone
formation
Architecture Mineralization
Antiresorptives c
Strontium ranelate * * * c
Teriparatide, Preotact
*demonstrated in animal studies
c: unchanged
azMaastricht
UHasselt
4. Routes and frequency of drug
administration and duration of studies
Drug Route Regimen Duration of studies
(years)
Alendronate po d,w 4.2/10
Risedronate po d,w 5/7
Ibandronate po m 3
IV shot 3m
Zoledronate IV 15’ y 3
Calcitonin nasal d 3
Strontium ranelate po d 5
Teriparatide SC d 1.5
Preotact SC d 1.5
Po: oral intake; IV: intravenous administration; SC:
subcutaneous administration; nasal: nasal spray; D:
daily ; W: weekly; Y: yearlyazMaastricht
UHasselt
5. Anti-Fracture Effects of Drugs
in primary analysis of RCT’s
Fractures prevented:
Spine Non-spine Hip
Alendronate x x x
Risedronate x x x
Ibandronate x
Zoledronate x x x
Raloxifene x
Calcitonin x
Strontium ranelate x x
rhPTH 1-34 x x
1-84 x
azMaastricht
UHasselt
6. Anti-Fracture Effects of Drugs
in primary analysis of RCT’s and post-hoc analyses (*)
Fractures prevented:
Spine Non-spine Hip
Alendronate x x x
Risedronate x x x
Ibandronate x x*
Zoledronate x x x
Raloxifene x x*
Calcitonin x
Strontium ranelate x x x*
rhPTH 1-34 x x
1-84 x
azMaastricht
UHasselt
7. Reduction of non-vertebral fractures in analyses atReduction of non-vertebral fractures in analyses at
the end of main anti-fracture studiesthe end of main anti-fracture studies
azMaastricht
UHasselt
8. Risico voor nieuwe fractuur
binnen het jaar na een wervelfractuur
0
5
10
15
20
25
30
Percent(%)ofPatients
25% nieuwe fractuur:
Niet-wervel: 5%
Wervel:
20%
Lindsay R, Geusens P et al, JAMA, 2001, 320azMaastricht
UHasselt
9. 0,0 4,0 8,0 12,0 16,0 20,0 24,0
maanden
0,00
0,03
0,06
0,09
0,12
0,15
%
> 80
50-59
60-69
70-79
n= 537
n= 554
n= 475
n= 591
Refracture incidence in 50+ women and men
(all causes, all locations)
Van Helden, Osteoporosis Int, 2006, 348
Van Geel, BMC Medicine, 2007
Center, JAMA, 2007
azMaastricht
UHasselt
YEARS OF FOLLOW-UP
302520151050
FRACTURE-FREEPROBABILITY
1,0
0,8
0,6
0,4
0,2
0,0
10% subsequent fracture 50% of subsequent fracture
within 2 years within 5 years after initial fracture
10. Anti-Fracture Effects of Drugs
Published data on speed of action (in months)
Fractures prevented:
Spine
Alendronate 12
Risedronate 6
Ibandronate 12
Zoledronate 12
Raloxifene 12
Calcitonin 36
Strontium ranelate 12
rhPTH 1-34 18
1-84 18
azMaastricht
UHasselt
11. Anti-Fracture Effects of DrugsAnti-Fracture Effects of Drugs
Published data on speed of effect (in months)Published data on speed of effect (in months)
Fractures prevented: references
Spine Non-spine
Alendronate 12 12 Pols, Ost Int, 1999, 461
Risedronate 6 6 Roux, CMROpin, 2004, 433
Ibandronate 12 36*
Zoledronate 12 36
Raloxifene 12
Calcitonin 36
Strontium ranelate 12 12 if >80 yrs Seeman, JBMR, 2006, 1113
rhPTH 1-34 18 18
1-84 18
* Cranney, Adachi, EULAR, 2007, Abstract
azMaastricht
UHasselt
12. Comparisons between
anti-osteoporosis drugs
Anti-fracture studies differed in
patient selection and characteristics
fracture endpoints [clinical, vertebral (clinical, morphometric),
non-vertebral (various definitions) or hip)
doses of drugs
statistical approaches (intention-to-treat or per-protocol)
concomitant use of calcium and vitamin D
trial duration
proportion of patients lost to follow-up
azMaastricht
UHasselt
13. Comparisons between
anti-osteoporosis drugs
Head-to-head RCTs with anti-fracture effects as primary endpoint
unlikely to become available
need enormous numbers of patients
would prove extremely costly to conduct
No head-to-head RCTs with fracture prevention as primary
endpoint
Thus, rates of fracture reduction and speed of onset of anti-
fracture effect compared to placebo should not be compared
directly and no inferences should be made regarding superiority of
one efficacious treatment over another
azMaastricht
UHasselt
17. Gastro-intestinal side effectsGastro-intestinal side effects
No significant differences between treatment groups
Number (%) of patients
Alendronate
70 mg OW
(n=515)
Risedronate
35 mg OW
(n=527)
≥1 upper-GI adverse
experience 116 (22.5) 106 (20.1)
Discontinued due to upper-GI
adverse experience 13 (2.5) 16 (3.0)
Discontinued due to serious
upper-GI adverse experience 0 (0.0) 1 (0.2)
azMaastricht
UHasselt
18. Cumulative Hip Fracture Incidence
↓43% *
at Month 12
*Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63%
Baseline Month 6 Month 12
%ofcohortwithahipfracture
0.00
0.10
0.20
0.30
0.40
0.50
0.58
alendronate
risedronate
Silverman et al. Osteoporos Int. January 2007
azMaastricht
UHasselt
19. Extra-skeletal benefits
Raloxifene
reduced the risk of invasive breast cancer in the CORE study by 66%
over 8 years
recently been approved by the FDA for the prevention of ER positive
breast cancer in women at high risk
Estrogens
attenuate severe climacteric symptoms
No first-line treatment of osteoporosis alone, because of side effects
(breast cancer, thromboembolisms, cardiovascular thrombotic events)
Zoledronate, given yearly within 90 days of a hip fracture
all-cause mortality -28% over 3 years when
reason for the reduced mortality in this study is not clear
azMaastricht
UHasselt Geusens et al. Nature Osteoporosis Clin Pract, 2008, in press
20. Safety issues
BP
GI: adequate intake
Osteonecrosis of the jaw: <1/10 000 to 100 000 in osteoporosis
Atrial fibrillation: zoledronate in 1 of 3 studies, not with alendronare and
risedronate
Flu-like symptoms at start (+/- 30% with zoledronate)
Raloxifen
Venous thrombosis
Strontium ranelate
Diarrhea; venous thrombosis; DRESS (<1/10 000)
Teriparatide
Cramps, dizziness
azMaastricht
UHasselt
21. Oplosbaarheid van alendronaat enOplosbaarheid van alendronaat en
generiekengenerieken
Epstein, J Appl Res, 2005, 1
azMaastricht
UHasselt
22. Therapietrouw
Bisfosfonaten, na 1 jaar therapie:
40% met dagelijkse inname
50% met wekelijkse inname
60% met maandelijkse inname
70% met wekelijkse dosis in
fractuurpoli met osteoporose
verpleegkundige
Barrières bij artsen en patiënten
azMaastricht
UHasselt
23. Fundamental Components ofFundamental Components of
N-Bisphosphonate Anti-resorptive ActivityN-Bisphosphonate Anti-resorptive Activity
Availability, Distribution,Availability, Distribution,
Offset of ActionOffset of Action
Bone Mineral
Affinity
Bone Uptake and Release
PotencyPotency
FPPS Enzyme
Inhibition
Osteoclast Function
Ebetino FH, et al. J Bone Miner Res 2005;20(Suppl 1):S259
Kavanagh KL, et al. http://www.rcsb.org/pdb/explore.do?structureId=1YV5; Accessed 5-Dec-06
azMaastricht
UHasselt
24. Differential Binding toDifferential Binding to
Bone MineralBone Mineral
HAP Adsorption Affinity Constants at pH 7.4
0
1
2
3
4
KL/106
Lmol-1
ZOLALNIBNRIS
Adapted from Nancollas GH, et al. Bone 2006;38:617–627
azMaastricht
UHasselt
25. FPPS Enzyme Inhibition Potency (ICFPPS Enzyme Inhibition Potency (IC5050))
Amount of N-BP needed to inhibit 50% of max. enzyme activityAmount of N-BP needed to inhibit 50% of max. enzyme activity
1
Kavanagh KL, et al. PNAS 2006;103:7829-7834. 2
Dunford JE, et al. Unpublished data (2006)
FPP-S
FPP-S
IC50Final (nM)
0 5 10 15 20 25 30 100 200 300 400
ALN
IBN
RIS
ZOL
ALN
RIS
azMaastricht
UHasselt
27. QCT 12-Month Percent Changes from BLQCT 12-Month Percent Changes from BL
Completer Population: Spine BMDCompleter Population: Spine BMD
r=0.3133 r=0.46703
(Average of L1 and L2 for entire vertebra
excluding transverse process, g/cm3
)
(Average of L1 and L2 for
vertebral trabecular BMD, g/cm3
)
P=0.0131
P=0.0194
0
5
10
15
20
25
30
I nt egral Spine Trabecular Spine
PercentChangefromBL
Prior RI S (n= 112) Prior ALN (n= 119)
azMaastricht
UHasselt
28. PercentchangeinBMD
No OP drug use (n=144)
(+6 months) (+18 months) (+30 months)
Antiresorptive starting before 6 months and
continued for at least 24 months (n = 65)
Antiresorptive starting after 6 months and
continued for at least 18 months (n = 34)
Endpoint Visit 1 Visit 2 Visit 3
Lindsay et al. Program & Abstracts, Endocrine Society 84th Ann Mtg June 19-22, 2002; #OR35-6
Lumbar Spine BMD
TPTD20 Followed with Antiresorptive Treatment
Fracture Prevention Trial Baseline through Follow-up Study
azMaastricht
UHasselt
29. Strategie na 5 jaar behandeling metStrategie na 5 jaar behandeling met
bisfosfonatenbisfosfonaten
Start Fractuur T-score AR* Strategie
tijdens 5 jr F.U. na 5 jr
Geen fractuur
T<-2.5 neen T<-2.5 hoog continuren
neen T>-2.0 laag stop + opvolging
Fractuur
Wervel neen any hoog continueren
ja any hoog switch naar PTH
Niet-wervel neen T<-2.5 hoog continueren
T>-2.0 intermediair stop /continueren?
ja any hoog switch naar PTH
AR*: absoluut risico voor fracturenazMaastricht
UHasselt
30. Botombouw na de menopauze
www.courses.washington.edu/ bonephys/opalgo.gif
azMaastricht
UHasselt
32. OB
RANKL OPG
Osteocyt
Resorption Formation Secondary
20 days 100 days mineralisation
OC
Proteases
IGF-1,2
IGF-BPs
Activation
PTH, PTHrP,1.25(OH)2D3
calcium deficiency
Inhibition
Oestrogens
RANK
Mechanic stimuli
TGFB
Bone turnoverBone turnover
LC
PG, NO
Sclerostin
DKK
OC = osteoclast
OB = osteoblast
LC = lining cell
Wnt
azMaastricht
UHasselt
33. Replication
Pre-OB Pre-OC
Bone formation
Osteoblasts
Apoptosis
Bone resorption
Osteoclasts
Activity
Bone Matrix
Synthesis
OPG
RANK RANKL
Dual Effects of Strontium RanelateDual Effects of Strontium Ranelate
Differentiation
CaSR
CaSR
+ Other?
Brennan, CTI, 2006 (ECTS 2006)
34. Anti-RANKL: Effect op merker van botresorptie (CTX-I) met SC injectie om de 6
maanden
Phase 2: Postmenopausal Women with Low BMD
McClung MR, et al. N Engl J Med. 2006;354:821-831
12
NS vs placebo
P < 0.001 vs alendronate
P < 0.001 vs placebo
-100
-80
-60
-40
-20
0
20
0 2 4 6 8 10
Time (Months)
MeanPercentChange
fromBaseline
Placebo, N = 46
Denosumab 14 mg, N = 53
Denosumab 60 mg, N = 47
Denosumab 100 mg, N = 41
Denosumab 210 mg, N = 46
Alendronate 70 mg/wk, N = 46
azMaastricht
UHasselt
35. Wnt signalling and osteoblasts
Baron, Endocrinology, 2007
azMaastricht
UHasselt
36. Disease and Therapy Mediated by theDisease and Therapy Mediated by the
Calcium-Sensing ReceptorCalcium-Sensing Receptor
azMaastricht
UHasselt
37. ConclusionsConclusions
Anti-osteoporosis agents differ in size and speed of anti-fracture effects between
agents, but these differences should be interpreted with caution in the absence of
head-to-head RCTs
Anti-osteoporosis agents differ in:
mechanisms of action between classes
pharmacokinetics within classes
extra-skeletal benefits
side effects
these differences can be helpful when deciding about treatment
Future:
Prevention of developing high risk
Sequential treatment with anabolics followed by preservation with anti-resorptives
azMaastricht
UHasselt
38. Contributors to secondary osteoporosis inContributors to secondary osteoporosis in
patients with osteoporosispatients with osteoporosis
Postmenopausal women, sent to an osteoporosis clinic, with T-score <-2.5, n=664
33% had known contributors to secondary osteoporosis
33% of the other presumably healthy women
had newly diagnosed contributors
Tannenbuam, JCEM, 2002, 4431
39. FRACTURE-FREE PROBABILITY OF WOMEN WITH ONEFRACTURE-FREE PROBABILITY OF WOMEN WITH ONE
FRACTURE (N = 681)FRACTURE (N = 681)
AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)
YEARS OF FOLLOW-UP
302520151050
FRACTURE-FREEPROBABILITY
1,0
0,8
0,6
0,4
0,2
0,0
Years of follow up
1 fracture2nd fracture
16%
54%
azMaastricht
UHasselt
40. Overall Initial and Subsequent Fracture RiskOverall Initial and Subsequent Fracture Risk
by Gender (Dubbo study, mean follow up 15-by Gender (Dubbo study, mean follow up 15-
16 yrs)16 yrs)
Center, JAMA, 2007, 387Center, JAMA, 2007, 387
% of refractures
within 5 years 41% 52%
azMaastricht
UHasselt
Alendronate significantly decreased both NTx (1 month) and PINP (3 months). The suppression of bone turnover with alendronate was maintained through month 12. Conversely, teriparatide significantly increased both markers of bone remodeling. The increases of the bone formation marker, PINP, were vigorous and rapid (113% above baseline at 1 month), peaking at 6 months of treatment (251% increase above baseline. The increases in the bone resorption marker, NTx, were of far smaller magnitude (58% at peak), reached significance only after 3 months of treatment, and lagged behind those of PINP. Thus, the different effects of the two drugs on bone remodeling were evident after 1 month of treatment, and there were significant differences (P<0.001) between the treatment groups in each marker at each time point (months 1,3,6,12). ___________________ McClung, et al. Differential effects of teriparatide and alendronate on markers of bone remodeling and areal and volumetric bone density in women with osteoporosis. J Bone Miner Res 2003:18(Suppl 2):S40.
Key points: After 12 months, the risedronate cohort had a 43% lower incidence of hip fracture than the alendronate cohort. This reduction is based upon an adjusted relative rate reduction. Adjustments were made based on baseline: Hip Age Estrogen use Number of medications History of hospitalizations The percent of cohort with fracture is very similar during the first 3 month (no separation) There is separation of the Kaplan-Meier curves from 3-12 months Background: The time to event plot is crude (unadjusted) fracture incidence, the 43% reduction is adjusted. Patients at risk at each time point (fracture events) BL 3 month 6 month 9 month 12 month Alendronate 21615 (0) 21590 (25) 12993 (54) 8677 (69) 5582 (80) Risedronate 12215 (0) 12202 (13) 6847 (19) 4319 (27) 2584 (29)
Key spoken message: “ There are 2 fundamental components of how nitrogen containing bisphosphonates work and exhibit their anti-resorptive effects. These are how they bind to the bone and how they affect the enzyme which is essential for osteoclast activity” I’m going to start talking on the first one – Bone Mineral Affinity Background Terms “potency” and “affinity”: Potency: The amount of drug needed to produce an effect Affinity: A chemical property (ie, force) that causes the drug to associate with a receptor, protein binding pocket, or other surface. Risedronate image used with permission of F.H. Ebetino, P&G Pharmaceuticals FPPS image: Kavanagh, K.L., Guo, K., Oppermann, U. Human farnesyl diphosphate synthase complexed with the clinical inhibitor risedronate To be Published (http://dx.doi.org/10.2210/pdb1yv5/pdb)
Key spoken message: “ When comparing the mineral binding, we see differences between the bisphosphonates. However, the correlation between bone mineral binding and the clinical efficacy is not fully clear yet’
Key spoken message: “ This shows the amount of bisphosphonate needed to inhibit the enzyme by 50%. We see here heterocyclic bisphosphonates (ie zoledronate and risedronate) have a higher potency for enzyme inhibition than the alkly bisphosphonates (eg alendronate and ibandronate)”
2ef2143t; 13, 15
Protocol 054 - PBO patients Left: PBO patient with BV/TV of 22% - plates with holes Right - PBO patient with BV/TV of 8% - mostly rods Resolution 20 m- surface rendered images