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6.

12: Osteoarthritis Priority Medicines for Europe and the World "A Public Health Approach to Innovation"

Background Paper

Osteoarthritis Opportunities to Address Pharmaceutical Gaps

By Saloni anna! Phar"#$# MPH % &ctober '(()

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Table of ontents
Su""ary################################################################################################################################################* +# Introduction########################################################################################################################################) '# Si,e and -ature of $isease Burden####################################################################################################) Incidence and prevalence ###################################################################################################################) .ountry i"pact ##################################################################################################################################/ *# .ontrol Strategy ################################################################################################################################% Prevention###########################################################################################################################################0 able +# herapeutic options in osteoarthritis Error1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found! ! ##############3 -on4phar"acological treat"ent#############################################################################################################3 Phar"acological treat"ent#####################################################################################################################3 Intra4articular treat"ent##########################################################################################################################3 Surgical 3 -on4phar"acological therapy revie5#################################################################################################3 Phar"acological therapy revie5#######################################################################################################+( Affordability! feasibility and sustainability#######################################################################################+) )# Ma6or Proble"s and .hallenges for $isease .ontrol 7Why $oes the $isease Burden Persist89##############################################################################+/ 2isk factors for incidence and progression of osteoarthritis#############################################################+/ rends###############################################################################################################################################+: /# Past;.urrent 2esearch into Phar"aceutical Interventions for &A####################################################+: :# .urrent Phar"aceutical Product <Pipeline= for &A reat"ent########################################################+% %# &pportunities for 2esearch into -e5 Phar"aceutical Intervention##################################################+0 0# >aps Bet5een .urrent 2esearch and Potential 2esearch Issues that .ould Make a $ifference#######+0 3# .onclusion ######################################################################################################################################+3 +(# 2eferences######################################################################################################################################'+

Anne!es

6.12: Osteoarthritis "ummar#


&steoarthritis 7&A9 is the "ost co""on type of arthritis or degenerative 6oint disease# 1 It is a leading cause of chronic disability# he disease "ost co""only affects the "iddle4aged and elderly! although younger people "ay be affected as a result of in6ury or overuse# Age is the strongest predictor of the disease and therefore increasing age and e?tended life e?pectancy 5ill result in a greater occurrence of the disease# Patients affected by this disease suffer fro" pain and loss of function# &A is regarded as a co"ple? disease 5hose cause is not co"pletely understood# @urther"ore! effective bio"arkers! diagnostic aids and i"aging technology are not available to assist in the "anage"ent of &A# here are also several areas 5here infor"ation is still lackingA these include1 epide"iology! pathophysiology! environ"ental risk factors! genetic predisposition and lifestyle factors#2! $ At present! there is no cure for &A# he "anage"ent of &A is broadly divided into non4 phar"acological! phar"acological! and surgical treat"ents# Surgical "anage"ent is generally reserved for failed "edical "anage"ent 5here functional disability affects a patientBs Cuality of life# Phar"acological "anage"ent includes control of pain and i"prove"ent in function and Cuality of life 5hile li"iting drug to?icity# E?perts in this field suggest that appropriate therapy for &A co"bines one or "ore phar"acological agents 5ith e?ercise! 5eight loss and physical therapy 7i#e# non4 phar"acological therapy9# here are a nu"ber of drugs under develop"ent for sy"pto"atic and disease "odification! and several studies are also evaluating alternative therapies# here are several drugs on the "arket 5hose clinical effectiveness and long4ter" safety still need to be deter"ined# his assess"ent is especially i"portant since &A reCuires long4ter" disease "anage"ent and the disease pri"arily affects people over the age of :( 5ho are "ost prone to drug to?icity! and for 5ho" the potential for drug interactions are high# Infor"ation on the i"pact of the disease to society and the cost of disease "anage"ent 7including phar"acological and non4phar"acological treat"ents9 needs to be re4 evaluated# @inally! "ost e?perts e"phasi,e that "ore research efforts need to be directed to5ards ne5 diagnostics! bio"arkers and i"aging technology# his is an essential area of research in &A since it 5ill help to deter"ine 5ho is likely to get &AA severity and progression of diseaseA patient response to drugs! and the develop"ent of disease "odifying drugs that have the potential to halt or reverse the disease#Error1 2eference source not found! Error1 2eference source not found

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6.12: Osteoarthritis 1. %ntroduction


here are "ore than +(( different types of arthritis#Error1 2eference source not found he "ost co""on type of arthritis is osteoarthritis 7&A9 or degenerative 6oint disease# It is a co""on chronic! progressive "usculoskeletal disorder characteri,ed by gradual loss of articular cartilage# he disease "ost co""only affects the "iddle4aged and elderly! although it "ay begin earlier as a result of in6ury or overuse# It is often "ore painful in 5eight bearing 6oints such as the knee! hip! and spine than in the 5rist! elbo5! and shoulder 6oints# All 6oints "ay be "ore affected if they are used e?tensively in 5ork or sports! or if they have been da"aged fro" fractures or other in6uries#Error1 2eference source not found! )

2. "i&e and 'ature of (isease )urden


Musculoskeletal conditions are a "a6or burden on individuals as 5ell as health and social care syste"s! 5ith significant indirect costs# %ncidence and pre*alence Diterature is li"ited on the incidence and prevalence of &A because of the proble"s of defining it and deter"ining its onset# World5ide esti"ates indicate that 3#:E of "en and +0E of 5o"en :( years have sy"pto"atic &A#/ &A is a "a6or cause of i"paired "obility# In +33(! &A 5as esti"ated to be the eighth leading non4fatal burden of disease! accounting for '#0E of total years of living 5ith disability#Error1 2eference source not found &A is the highest4ranking disease a"ong the "usculoskeletal diseases and contributes to appro?i"ately /(E of the disease burden in this disease group 7See Background .hapter /9# &verall disease burden ranking according to this co"piled data sho5s a ranking of +' for co"bined '/ EF countriesA +/th ranked for old EF and 3th rank for the +( EF accession countries# +i,ure 1 )urden of disease of OA b# a,e ,roups and re,ions

Osteoarthritis (DALYs, by age groups & regions, 2002)


7.00%

6.00%

5.00%

% of total

4.00%

3.00%

2.00%

1.00%

0.00% 0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+ Age groups EU25-M EU25-F EU15-M EU15-F EU-10-M EU-10-F W-M W-F

6.12--

6.12: Osteoarthritis
-ote fro" @igure +! the peak in the burden of disease 7$ADGs9 in each of the three regions1 >lobal! EF+/! EF'/! and EF+( are different# In EF +(! the onset of &A is at an earlier age! perhaps resulting in "ore disability! loss of productivity and increased health care costs# Hnee &A is likely to beco"e the fourth "ost i"portant global cause of disability in 5o"en and eighth "ost i"portant in "en#Error1 2eference source not found &A contributes to a higher disease burden in "en belo5 the age of /( and in 5o"en over the age of /(# According to e?pert opinions presented in the EFDA2 co""ittee report! radiographic evidence of knee &A in "en and 5o"en over :/ is found in *(E of patients#Error1 2eference source not found @igure ' sho5s the prevalence of &A of the knee by age group! se? and region#Error1 2eference source not found In general &A is "ore prevalent in Europe and FSA than in other parts of the 5orld#Error1 2eference source not found +i,ure 2. Pre*alence of osteoarthritis.rror: /eference source not found

ountr# impact Aggregate nu"bers on the overall i"pact of &A are not available# herefore! statistical highlights and the i"pact of arthritis fro" individual countries that have reported infor"ation are presented# UKError: Reference source not found In England and Wales bet5een +#* and +#%/ "illion people have sy"pto"atic &A# In '((( "ore than 0(!((( hip or knee replace"ents 5ere perfor"ed at a cost of I)(/ "illion# As a cause of disability 7such as 5alking and cli"bing stairs9 in the elderly &A is second to cardiovascular disease# Altogether +(E to +/E of adults over :( have so"e degree of &A# @our "illion people out of 0' "illion people suffer fro" so"e for" of autoi""une conditions affecting 6oints# Most people participate in a universal "edical health insurance syste"# he key issues in the fight against arthritis include access to "edications! access to speciality care! uncoordinated treat"ent! and di"inished state budgets#

German#:

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6.12: Osteoarthritis
anada.rror: /eference source not found he direct and indirect costs of arthritis in .anada eCuates to appro?i"ately J+0 billion per year# &ver four "illion .anadians out of *+!(+)!((( people have arthritis# .urrently there are appro?i"ately '%( rheu"atologists in .anadaA ho5ever! +/( of the" are close to retire"ent leaving +'( rheu"atologists to care for ) "illion suffering arthritis patients# here are appro?i"ately *%!((( hip and knee replace"ent surgeries every year in .anada# he key issues in the fight against arthritis facing .anada include1 access to "edications! access to rheu"atology care! access to orthopaedic care! funding for research and illness disability# Population of +'% "illion people# +%E of population is over :/ 7this percentage is e?pected to gro5 by '/E in the ne?t three decades9# /E of the population has so"e for" of arthritis# he key issues in the fight against arthritis facing Kapan include access to "edications! access to speciality care# It is esti"ated that over )+ "illion people out of '0/ "illion people in the Fnited States have arthritis# In the Fnited States about : percent of adults over *( have &A of the knee and about * percent have &A of the hip# he occurrence of the &A increases 5ith age! rising '4 to +(4fold in people fro" *( to :/ years of age# An esti"ated /( "illion people 5ill be diagnosed 5ith arthritis by '(+*# he current econo"ic burden of arthritis in its various for"s is appro?i"ately J0'#) billion# $irect costs are J*)#: billion 7hospitals! doctors! transportation! nursing ho"es9 &nly *E of the cost is for drugs# Indirect costs are J)%#0 billion 7pri"arily lost 5ages and lost productivity9# Arthritis is a greater factor in li"iting activity than heart disease! hypertension! blindness! or diabetes# @igure * sho5s the levels of physical activity reported by 5o"en 5ith arthritis in the FS# &nly ')E of people 5ith arthritis report and achieve levels of physical activity that are reco""ended for health# he re"ainder are essentially inactive or insufficiently active#

1apan.rror: /eference source not found

2"34 54 6

6.12-6

6.12: Osteoarthritis
+i,ure $. 7e*els of ph#sical acti*it# reported b# 8omen 8ith arthritis in the 2" +(! Error1 2eference source not
found

$.

ontrol "trate,#

Patients 5ith &A suffer fro" pain and loss of function# &b6ectives of &A "anage"ent are to reduce the level of pain! reduce infla""ation! slo5 cartilage degradation! i"prove function and reduce disability# his section revie5s phar"acological and nonconventional! non4phar"acological &A therapies# (ia,nosis and medical mana,ement Error1 2eference source not found! Error1
2eference source not found! Error1 2eference source not found! Error1 2eference source not found! ++! +'! +* 2eference source not found! Error1

he aetiology of &A is "ultifactorial# )iochemical mar9ers of disease acti*it# are not #et a*ailable for routine clinical care. Plain radiographs are the current "ost co""on 5ay of assessing disease progression! although there are proble"s 5ith standardi,ation of 6oint positioning 5ith respect to the knee# A radiographic grading syste" is used to define! identify and note &A progression# Ho5ever! L4 rays are not readily available in "any parts of the 5orld# he WH& reco""ends a definition of &A based on sy"pto"s and a sy"pto"4based grading syste" 5ould be preferred for disease progression# Ho5ever! there are currently no validated tools in this area# Error1 2eference source not found An assess"ent of effect of a therapy should include a "easure of health status in addition to radiological assess"ents# Persons 5ith &A are a heterogeneous population! ranging 5idely in age! disease i"pair"ent! functional goals! and interests# herefore "anage"ent of the patient 5ith &A should be co"prehensive and individuali,ed! taking into account the anato"ical distribution! the phase and the progression rate of the disease# .o"orbid conditions such as cardiac disease! hypertension! peptic ulcer disease or renal disease "ust be taken into account! as 5ell as the patientBs needs and e?pectations#

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6.12: Osteoarthritis
he "anage"ent plan of &A patients also needs to be regularly revie5ed and ad6usted in light of their response and adherence# his 5ill vary bet5een patients and location# he "anage"ent of &A is broadly divided into non4phar"acological! phar"acological! and surgical treat"ents# Surgical treat"ent is generally reserved for failed "edical "anage"ent 5ith functional disability affecting a patientBs Cuality of life#

Pre*ention Preventing the onset of &A reCuires lifestyle changes#Error1 2eference source not found! +) Primary prevention# hese are "easures to prevent the condition fro" occurring# here are only a fe5 effective pri"ary prevention strategies for arthritis# hese include1 Weight control1 &besity is considered a risk factor for &A# hus! "aintaining or reducing 5eight can lo5er the risk for certain arthritic conditions# &ccupational in6ury prevention1 Avoiding repetitive 6oint use and its in6uries can help prevent arthritis# Sports in6ury prevention1 aking the necessary precautions to prevent in6ury such as 5ar"ing up and using proper eCuip"ent can help reduce 6oint in6uries# Secondary prevention# his involves early diagnosis so that appropriate early intervention can be utili,ed# :o8e*er4 this is difficult in OA since no effecti*e biomar9ers are a*ailable to determine the pro,ression of the disease. @urther"ore! radiographic evidence is often needed to identify and "ark disease progression# Access to health care facilities and availability of L4rays is proble"atic in "any parts of the 5orld#Error1 2eference source not found! +/ Tertiary prevention# his focuses on reducing the conseCuences of a disease# >oals of these prevention strategies are to reduce! delay the onset of co"plications and disability# ertiary prevention strategies for arthritis are ai"ed at reducing pain and disability! and i"proving Cuality of life# he follo5ing enco"pass tertiary prevention strategies1 self4"anage"ent 75eight control! physical activity! education9A ho"e help progra"sA cognitive behavioural interventionsA rehabilitation services and "edical surgical treat"ents#Error1 2eference source not found

6.12-5

6.12: Osteoarthritis
Table 1. Therapeutic options in osteoarthritis .rror: /eference source not found! Error1 2eference source not found! Error1 2eference
source not found! Error1 2eference source not found! 16! 13

'on-pharmacolo,ical treatment Education 7patient and spouse or fa"ily9 Social support Physiotherapy 7physical therapy9 &ccupational therapy Weight loss E?ercise &rthotic devises Daser Pulsed EM@ 7Electro"agnetic field therapy9 Fltrasound ranscutaneous electrical nerve sti"ulation 7 E-S9 Acupuncture -utrients Herbal re"edies Mita"ins;"inerals Pharmacolo,ical treatment Paraceta"ol;Aceta"inophen -SAI$S 7-on4steroidal anti4infla""atory drugs9 Nplus "isoprostol or a proton pu"p inhibitorOP .&L4' inhibitors 7cyclo4o?ygenase4' selective non4steroidal anti4infla""atory drugs9 &pioid analgesics Hor"ones Psychotropic drugs Nco""ent4 can this be elaborated using a couple of e?a"ples8 hese are also not covered in phar"acological treat"ent sections belo5O SGSA$&A 7Sy"pto"atic Slo5 Acting $rugs for &A 7avocado;soybean unsaponifiables 7ASF9! chondroitin! diacerein and glucosa"ine9 opical -SAI$S opical capsaicin %ntra-articular treatment .orticosteroids Hyaluronans idal irrigation "ur,ical Arthroscopy &steo"y FH2 7unico"part"ental knee replace"ent9 H2 7total knee replace"ent9 PMisoprostol and proton pu"p inhibitors are reco""endations by A.2 and are reco""ended in patients 5ho are at increased risk of gastrointestinal adverse effects# 'on-pharmacolo,ical therap# re*ie8 According to various reco""endations! non4phar"acological treat"ent of &A should include education! e?ercise! physical aids 7such as canes! insoles and knee braces9 and 5eight reduction#Error1 2eference source not found! Error1 2eference source not found

6.12-6

6.12: Osteoarthritis
EducationError1 2eference source not found! Error1 2eference source not found A "etaanalysis concluded that patient education in disease "anage"ent! 5eight reduction and e?ercise 5as '(E as effective as -SAI$ therapy in reducing 6oint pain#Error1 2eference source not found here are several studies that de"onstrate the benefits of education in reducing pain! increasing coping skills! and reducing visits to the pri"ary care# Effective educational techniCues include individuali,ed educationA regular telephone calls! group education! patient coping skills! and spouse assisted coping skills#Error1 2eference source not found

E?erciseError1 2eference source not found! Error1 2eference source not found! +0 E?ercise is considered the "ost i"portant intervention in the "anage"ent of &A# E?ercise builds "uscle strength and endurance! i"proves 6oint fle?ibility and "otion# he British Medical Kournal 7BMK9 syste"atic revie5 of rando"i,ed controlled trials 72. s9 on the effect of e?ercise on &A concluded that both e?ercise and physical therapy reduce pain and disability in people 5ith hip and knee &A#

Weight lossError1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found Although 5eight loss is reco""ended! the effect of 5eight loss on &A has only been evaluated in t5o studies# hese studies sho5ed that 5eight loss reduced the risk of developing sy"pto"atic &A in 5o"en! reduced pain and i"proved function# Most authors conclude that 5hile the evidence is poorly docu"ented 5eight loss is a sensible reco""endation in the "anage"ent of &A#

Physical aidsError1 2eference source not found!Error1 2eference source not found here is li"ited data on the effects of physical aids on &A! although! physical aids are considered a sensible approach in the "anage"ent of &A# A BMK .linical revie5 concluded that 2. s in people 5ith knee &A found li"ited evidence that 6oint bracing or taping i"proves Cuality of life and sy"pto"s# he revie5 also found that there 5as insufficient evidence to co"pare the effects of different insoles#

Pharmacolo,ical therap# re*ie8 At present! there is no cure for &A# Phar"acological "anage"ent of &A re"ains control of pain and i"prove"ent in function and Cuality of life 5hile li"iting drug to?icity# E?perts in this field suggest that appropriate therapy for &A co"bines one or "ore phar"acological agents 5ith e?ercise and other bio"echanical techniCues#Error1 2eference source not found A risk4benefit analysis of these "ust be considered 5hen prescribing these drugs since adverse effects are co""on and the long4ter" efficacy of these drugs is variable or yet to be deter"ined#Error1 2eference source not found! Error1 2eference source not
found! +3

Anne? :#+'#+ provides a detailed analysis on the current effectiveness of "edical "anage"ent of &A# Belo5 are the su""ari,ed highlights of the literature findings#

Analgesics4 paraceta"ol;aceta"inophen Error1 2eference source not found ! Error1 2eference source not found! Error1
2eference source not found! '(

Both the A"erican .ollege of 2heu"atology 7A.29 and European Deague Against 2heu"atis" >uidelines 7EFDA29 reco""end paraceta"ol;aceta"inophen as the first list line agent# EFDA2 reco""endations also state that based on it overall cost! efficacy and to?icity profile! it should be the preferred long4ter" oral analgesic# A BMK clinical evidence revie5 found li"ited evidence that si"ple analgesics such as paraceta"ol! reduced pain co"pared 5ith placebo# Ho5ever! a revie5 by EFDA2 reports that paraceta"ol is as effective as -SAI$S in the "anage"ent of &A# @urther"ore! it can be taken safely over the long ter"#

6.12-1;

6.12: Osteoarthritis
A recent study has also raised concern about the safety of aceta"inophen in doses of greater than 'g;day# he study suggests that high dose aceta"inophen "ay results in an increased risk of gastrointestinal to?icity eCuivalent to -SAI$s#Error1 2eference source not found! '+

-on4steroidal anti4infla""atory drugs 7-SAI$s9 Error1 2eference source not found! Error1 2eference source not
found! Error1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found

-SAI$s have both anti4infla""atory and analgesic properties! but there is no evidence that they "odify the course of &A# here is li"ited evidence that these agents vary in efficacy 5ithin this therapeutic drug category# According to syste"atic revie5s conducted by BMK! -SAI$s are "ore effective than placebo in reducing painA ho5ever! their long4ter" efficacy 7past ' years9 has not been studied# Also! syste"atic revie5s of 2. s by BMK! found no good evidence that oral -SAI$S differ fro" paraceta"ol;aceta"inophen in pain relief#Error1 2eference source not found According to the '((* EFDA2 revie5! the e?pert co""ittee states that there is evidence that -SAI$s are "ore efficacious than paraceta"ol for so"e patients# he reco""endations suggest that given the lo54grade infla""atory co"ponent of &A! -SAI$s 5ould be the Qlogical drugs in patients unresponsive to paraceta"olB#Error1 2eference source not found 2isk factors for -SAI$4induced upper gastrointestinal adverse effects include1 patientBs greater than :/ years! conco"itant use of anticoagulants and glucocorticoids and history of peptic ulcer disease or upper gastrointestinal bleed! s"oking and alcohol consu"ption#Error1 2eference source not found! '' - In the FS an esti"ated '(E to *(E of all hospitalisations due to peptic ulcer disease are secondary to -SAI$ use#Error1 2eference source not found - >astroduodenal ulcers occur in +/E to *(E of patients 5ho take -SAI$s#Error1 2eference source not found Another serious co"plication associated 5ith -SAI$S includes renal failure# 2isk factors for renal failure include1 age greater than :/! hypertension! congestive heart failure! conco"itant use of diuretics! conco"itant use of angiotensin4converting en,y"e inhibitors! and e?isting renal failure#Error1 2eference source not found! Error1 2eference source not found A.2 and EFDA2 reco""end that -SAI$s should be considered in patients unresponsive to paraceta"ol! and patients 5ho are at risk of gastrointestinal to?icity should use effective gastroprotective agents or selective .&L4' inhibitors# here is evidence that "isoprostol! proton pu"p inhibitors and H' blockers "ay reduce the gastrointestinal adverse effects induced by -SAI$s# Ho5ever! the cost utility or prophylactic use of these agents is controversial and reCuires phar"aco4eocono"ic analysis#Error1 2eference source not found! Error1 2eference source not found

6.12-11

6.12: Osteoarthritis
.ycloo?ygenase4' 7.&L4'9 Inhibitors Error1 2eference source not found !
2eference source not found!Error1 2eference source not found! Error1 2eference source not found Error1 2eference source not found! Error1

.&L4' inhibitors have been found to be "ore effective than placebo in relieving pain in &A#Error1 2eference source not found! Error1 2eference source not found his class is 6ust as efficacious as -SAI$s for pain relief but 5ith a reduction of up to /(E in perforation! ulcers and bleeding#Error1 2eference source not found here are reports that the cardiovascular and renal adverse effects are co"parable to -SAI$s and the risk factors associated 5ith renal failure are the sa"e as -SAI$s 7listed above9# Error1 2eference source not found .oncern about loss of antiplatelet activity 5ith .&L4' inhibitor group "ay contribute to e?cess cardiovascular co"plication! especially in the elderly 5ho are at a higher risk of cerebral and vascular thro"bosis#Error1 2eference source not found .onco"itant use of lo5 dose aspirin for cardiovascular prophyla?is appears to di"inish .&L4' inhibitor gastroprotective effect# here are no 2. s to co"pare the efficacy of different .&L4' inhibitors#Error1 2eference source not found HaC et al report that the esti"ated cost of s5itching high4risk patients 5ith &A to .&L4' inhibitors 5ould lead to an esti"ated incre"ental cost of I'/ "illion to the -HS#Error1 2eference source not found .&L4' inhibitors are 5idely used in the FS and Europe! and are currently Qblock busterB drugs on the phar"aceutical "arket! ho5ever the "ost cost effective strategy for their use is still unclear#Error1 2eference source not found Both A.2 and EFDA2 state that patients 5ho are at an increased risk of gastrointestinal co"plications! .&L4' inhibitors or -SAI$s plus a gastroprotective agent "ay be used#Error1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found opical agentsError1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found

According to A.2 and EFDA2 guidelines! topical -SAI$s and topical capsaicin have clinical efficacy and are safe# BMK clinical revie5 concludes that topical -SAI$s reduce pain co"pared to placebo! ho5ever li"ited evidence 5as found that capsaicin i"proves pain co"pared to placebo# opical treat"ent is an additional option for patients 5ho have inadeCuate control 5ith oral agents or 5ho reCuire local treat"ent# Ho5ever! further 5ell4conducted trials are needed in this area#
found! Error1 2eference source not found

.orticosteroids;glucocorticoidsError1 2eference source not found! Error1 2eference source not found! Error1 2eference source not Intra4articular! long acting corticosteroids are 5idely used in the "anage"ent of knee &A# he short4ter" therapy is considered to be beneficial in patients 5ho have local infla""ation and s5ollen 6oints# In6ections "ay be used as "onotherapy or in co"bination 5ith syste"ic drugs# here are no 2. s co"paring the effectiveness of co"bination therapy# Most revie5 articles that have evaluated intra4articular corticosteroids studies conclude that there appears to be a short4ter" efficacy lasting '4) 5eeks co"pared to placebo# A syste"atic revie5 and one 2. found li"ited evidence that intra4articular corticosteroids reduced pain for +4) 5eeks# here is evidence that intra4articular in6ections are effective 5ith short4ter" relief# Ho5ever! the evidence for predictors of response re"ains unclear and further studies are needed to deter"ine this# A.2 guidelines reco""end no "ore than *4 ) in6ections per year and should be reserved for disease flares only# Infection into the &A 6oint is considered to be a rare co"plication associated 5ith this intra4 articular corticosteroid therapy# .urrent reco""endations are to use intra4articular steroids 5hen other analgesics and -SAI$s are ineffective or contraindicated#

6.12-12

6.12: Osteoarthritis
Miscosupple"ents4hyaluronic acidError1 2eference source not found! '*! ') he in6ection of viscosupple"ents! 5hich include hyaluronan and hylan >4@ '(! is being used in the treat"ent of knee &A# Hyaluronan is unaltered hyaluronic acid! 5hich is in6ected 5eekly for /45eeks# Hylan >4@ '( is hyaluronic acid but 5ith a higher "olecular 5eight# his preparation is in6ected 5eekly over a three45eek period# Intra4articular viscosupple"ents have fe5 side effects# Most co""on reported adverse effects include1 locali,ed reactions! transient local s5elling! pain and erythe"a# he clinical effectiveness of viscosupple"ents re"ains controversial# here is a very recent "etaanalysis evaluating published or unpublished! English and non4English! single4 or double4 blinded! rando"ised controlled trials co"paring intra4articular hyaluronic acid 5ith intra4articular placebo in6ection for the treat"ent of knee &A#Error1 2eference source not found QIntra4articular hyaluronic acid has a s"all effect 5hen co"pared 5ith an intra4articular placebo# he presence of publication bias suggests even this effect "ay be overesti"ated# .o"pared 5ith lo5er4"olecular4 5eight hyaluronic acid! the highest4"olecular45eight hyaluronic acid "ay be "ore efficacious in treating knee &AB#Error1 2eference source not found he potential of hyaluronic acid preparations to preserve cartilage still re"ains to be deter"ined# A EFDA2 revie5 of '( studies sho5ed that +0;'( trials sho5ed that hyaluronic acid to be "ore effective than placebo in relieving pain# EFDA2 states 5hile there is evidence for its use! its delayed onset! cost and logistical issues can offset its use in &A "anage"ent#Error1 2eference source not found SGA$&A 7Sy"pto"atic Slo5 Acting $rugs for &A 7avocado;soybean unsaponifiables 7ASF9! chondroitin! diacerein and glucosa"ine9 >lucosa"ine! chondroitin sulfate and collagen hydrolysate >lucosa"ine and chondroitin sulfate are regulated as drugs in European countries and as a nutritional supple"ent in the FS# >iven this! in the FS! there are no for"al reCuire"ents for nutritional supple"ents to prove their efficacy and clai"s cannot be "ade for the treat"ent of "edical conditions#'/ .urrent evidence suggests that it is not kno5n 5hether different glucosa"ine! or glucosa"ine chondroitin preparations by different "anufacturers are eCually effective in the therapy of &A# @urther evidence! and 5ell conducted 2. are needed to deter"ine the long4ter" effects and safety of these drugs#Error1 2eference source not found! Error1 2eference source not found! ': Glucosamine# >lucosa"ine! an a"inosaccharide! can be ad"inistered orally! intra"uscularly! or intra4articularly# here are nu"erous glucosa"ine preparations on the "arket# Most studies have evaluated glucosa"ine sulfate# Most of these studies have sho5n a variable response in the relief of pain co"pared to placebo 5ith various dosage for"s# Ho5ever! there is li"ited literature on the adverse effects or long4ter" effects of these drugs# >lucosa"ine also has a slo5er onset of action co"pared to -SAI$s and the phar"acology by 5hich it e?erts pain relief still re"ains unclear#Error1 2eference source not found ! '% A .ochrane revie5 of 2. s evaluating the effectiveness and to?icity of glucosa"ine deter"ined there is evidence that glucosa"ine is effective! but further research is necessary#Error1 2eference source not found @urther research is also needed in the follo5ing areas1 assess"ent of the long4ter" efficacy and safetyA effectiveness! relative purity and content of the different glucosa"ine preparationsA 5ho 5ould "ost benefit fro" glucosa"ine and finally! 5hat are the appropriate doses and routes of ad"inistration to both "a?i"i,e efficacy 5hile li"iting adverse effects#Error1 2eference source not found! Error1 2eference source
not found

Chondroitin sulfate# .hondroitin! derived fro" bovine and calf cartilage has an oral bioavailability of about +(E# .o"pared to -SAI$S! chondroitin has a delayed onset and therapeutic response#Error1 2eference source not found A "etaanalysis of chondroitin sulphate concluded that this product "ay be effective in &A! but further investigation in larger 2. s for longer ti"e periods are needed to prove its effectiveness as a sy"pto" "odifying drug in &A#Error1 2eference source not found! Error1 2eference source not found! '0 Collagen hydrolysate1 .ollagen hydrolysate "ay be beneficial in the treat"ent of &A! since it contains a"ino acids that "ay play a role in the develop"ent of collagen# hey are available! ho5ever! in the for" of food supple"ents and there is very li"ited evidence to clinically de"onstrate their effectiveness#Error1 2eference source not found

6.12-1$

6.12: Osteoarthritis
Diacerein1 2evie5s of 2. S of diacerein! an interleukin4+ inhibitor sho5ed that it 5as effective in reducing pain#'3 here have been fe5 reported adverse effects 5ith this drug# $iacereinBs role in the "anage"ent of &A still needs to be deter"ined# he drug "ay have the potential as an add4 on therapy to -SAI$s or viscosupple"ents#Error1 2eference source not found Avacado/Soybean unsaponifiable residues (ASU ! ASF is a co"pound consisting of avocado oil and soybean# Invitro studies have sho5n that this co"pound has an inhibitory effect on a nu"ber of "olecules that "ay affect &A# here is! ho5ever! very li"ited evidence sho5ing its effectiveness# he co"pound is available and used in @rance# Well4conducted trials are needed to evaluate the potential of this co"pound in the "anage"ent of &A# *(

Mita"insError1 2eference source not found A revie5 of the role of vita"ins in the "anage"ent of &A states that o?idative da"age "ay accelerate &A progression#Error1 2eference source not found Mita"in A! .! and E have antio?idant properties that "ay be beneficial in the "anage"ent of &A# Well4designed 2. are needed to deter"ine the effectiveness! disease4"odifying potential! reco""ended dosage guidelines and adverse effects in &A "anage"ent# Herbals*+! *'! ** Dong D et al! conducted a syste"atic revie5 of herbal "edicines for the treat"ent of osteoarthritis# Studies in the revie5 e?a"ined1 articulin @! capsaicin crea"! devils cla5! eay"ov! gitadyl! phytodolor! reu"ale? and stinging nettle leaf# Pro"ising evidence 5as found for the effective use of so"e herbal preparations in the treat"ent of &A# Also! there is so"e evidence that these preparations "ay reduce the use of -SAI$S# @urther"ore! the revie5ed herbal "edicines appear to be safe#Error1 2eference source not found !
Error1 2eference source not found

he area of herbal "edicines in &A is under4researched and "erits further attention# @uture trials should focus on clinical effectiveness of herbal therapies! outco"e "easures and valid "easures of &A# Studies should also co"pare and assess the i"pact of herbals "edicines on allopathic "edication! specifically -SAI$s#Error1 2eference source not found! Error1 2eference source not found A nu"ber of alternatives e?ist for the treat"ent and prevention of &A# So"e of these include Mita"in E! Boron! Mita"in $! Ascorbic acid! Manganese! S4Adenosyl"ethionine! Avocado;Soybean e?tract and Articulin @# Mery li"ited evidence is presented on the safety and effectiveness of these agents and further 5ell4conducted studies are needed#Error1 2eference source not found

"ur,ical treatment Surgical treat"ent of osteoarthritis is usually considered after failure of nonsurgical therapies# here are four surgical procedures1 osteoto"y! arthroscopy! arthrodesis and arthroplasty# he four procedures have different indications and variable benefits# otal 6oint arthroplasty! the "ost surgically advanced in &A treat"ent! is the "ainstay of surgical treat"ents#Error1 2eference source not found otal 6oint replace"ent is highly successful and by "ost "easures a"ong the "ost effective of all "edical interventions# Pain! and disability of end4stage &A can be eli"inated! restoring patients to near4nor"al function! and this operation is highly cost4effective#Error1 2eference source not found he "ost co""on failures of total 6oint replace"ent surgery include aseptic loosening and osteolysis! 5hich occur as a result of the corrosion bet5een the i"planted "aterial and the cells# Error1 2eference source not found .urrently there are no 2. s! 5hich have co"pared surgery 5ith nonsurgical intervention# Although EFDA2 ackno5ledges the difficulties in study design! the e?pert co""ittee reco""ends that predictors of response! indications for 6oint replace"ent! effect of different surgical techniCues and long4ter" effect of 6oint prosthesis should be e?a"ined# @urther"ore! postoperative care and outco"e assess"ent should also be studied for these procedures#Error1 2eference source not found Affordabilit#4 feasibilit# and sustainabilit# Di"ited literature is available on the affordability! accessibility and cost of currently approved therapies and their i"pact and "anage"ent of &A# @urther studies are reCuired to address this issue#

6.12-1-

6.12: Osteoarthritis
Studies need to asses 7+9 the cost of drug therapy for disease "anage"ent and 7'9 the co"bination of non4phar"acological and phar"acological treat"ent "odalities# he econo"ic i"plications of arthritis include the financial burden of health care costs! and loss of inco"e resulting fro" disability or li"itations on 5ork# Arthritis is ranked second! after heart disease! as a cause of "issed 5ork in the developed 5orld#Error1 2eference source not found Econo"ic indicators for &A are difficult to develop# his is because data can be collected on the "edical resources 75hich is dependent on cultural! econo"ics! and health care provisions9! than on the condition itself# Also! 5hile lost days of 5ork "ay be deter"ined! a large population affected are elderly and not 5orking# he esti"ated health4care cost of &A 5as FS J:') "illion in +33*43)# his is appro?i"ately '+E of the total "usculoskeletal disorders e?penditure#Error1 2eference source not found he total cost! treat"ent! co"plications and the disability that result fro" arthritis is esti"ated at J:/ billion# &f this! the esti"ated "edical costs are J+/ billion annually! 5hich include physician visits and hospitalisations# he re"aining balances are indirect costs resulting fro" 5age losses#Error1 2eference source not found

-. <a=or Problems and hallen,es for (isease ontrol >?h# (oes the (isease )urden Persist@A
he aetiology of &A is "ultifactorial and includes both generali,ed and constitutional factors 7e#g# ageing! se?! obesity! heredity! and reproductive variables9 and local adverse "echanical factors 7e#g# trau"a! occupational and recreational usage9# here are also genetic co"ponents in the prevalence of &A! 5ith heritability esti"ates fro" t5in studies of (#*3 to (#:3! independent of kno5n environ"ental or de"ographic confounders#Error1 2eference source not found ! *) &A is associated 5ith pain and functional disability and as the disease progresses! physical disability arising fro" pain and loss of functional capacity reduces Cuality of life and increases the risk of further "orbidity and "ortality#Error1 2eference source not found /is9 factors for incidence and pro,ression of osteoarthritis Age is the strongest predictor of the develop"ent and progression of &A# able ' sho5s the risk factors for incidence and progression of &A of the knees! hips and hands# Table 2. /is9 +actors for %ncidence and Pro,ression of Osteoarthritis.rror: /eference source not found! Error1 2eference source not found! Error1 2eference source not found! Error1 2eference source not found /is9 factor Age -or"al ageing process causes increases progression '%E of those aged :*4%( had radiographic evidence of knee &A! increasing to ))E in over 0( age group rau"a .ollateral liga"ent! "eniscal tears and 6oint fractures lead to increased risk for &A Men 5ith a history of kno5n in6ury 5ere at /4: fold increased risk of developing &A &ccupation More co""on in those perfor"ing heavy physical 5ork $ockers! "iners and far"ers found to have &A E?ercise High i"pact sports present an increase for &A >ender and Men under the age of /( have a higher prevalence and incidence ethnicity Wo"en over /( have a higher prevalence and incidence 7"enopause "ay be a trigger# Ho5ever there is conflicting evidence if hor"one replace"ent therapy protects against &A9 $ifference is less "arked after the age of 0( >enerally "ore co""on in Europeans than in Asians >enetics here is genetic susceptibility to the disease .hildren of parents 5ith early onset &A are at a higher risk of developing &A the"selves

6.12-10

6.12: Osteoarthritis
/is9 factor &besity Strongest "odifiable risk factor Being over5eight at an average age of *:4*% is a risk factor for developing knee &A hreefold increase risk of progression of &A for people in the lo5er decile of vita"in . and $ blood levels Increasing bone density "ay lead to increased loading through 5eight bearing 6oint cartilage

$iet Bone density

Trends Increasing age and e?tended life e?pectancy 5ill "ost likely result in greater incidence and prevalence of &A# he burden 5ill be greatest in developing countries 5here life e?pectancy is increasing! but access to therapy is not readily available#Error1 2eference source not found ! Error1
2eference source not found

0. PastB urrent /esearch into Pharmaceutical %nter*entions for OA


.urrently all the treat"ent advances in &A offer palliative care and help to reduce the sy"pto"s of pain# Fnfortunately! there have been no ne5 drugs that can prevent! halt or reverse &A progression! although phar"aceutical co"panies are actively pursuing develop"ent of such therapies# Anne? :#+'#+ evaluates therapies currently used or have been indicated in the "anage"ent of &A# he follo5ing section 7and Anne? :#+'#'9 provides infor"ation on the areas of current research# "nhibition of brea#do$n of cartilage by collagenolytic en%ymes or matri& metalloproteinases (''Ps # MMPs! a fa"ily of degradative en,y"es! have been identified as occurring in the develop"ent and nor"al turnover of tissues# hese en,y"es have been sho5n to increase in activity after 6oint in6ury# Specific MMPs have been identified! 5hich are believed to affect the degradative process in &A# MMP4+* has been sho5n to play a central role in cartilage degradation# MMPs present an i"portant target for potential phar"acological develop"ent! since these en,y"es "ay alter disease process# Fnfortunately all the ne5 MMPs tested in hu"ans to date have resulted in to?icity in other organ syste"s! 5hich have prevented their continued develop"ent# A recent study 5ith do?ycycline! a potent MMP! in individuals 5ith &A provides evidence that MMP inhibitions "ay be effective in slo5ing do5n cartilage loss in &A#Error1 2eference source not found! */ Therapy that stimulates repair activity by chondrocytes # he release of MMPs! by chondrocytes appears to be affected by a 5ide range of conditions and processes# @or e?a"ple! increased 5eight and preceding 6oint in6ury can increase the risk of &A# Studies that have atte"pted to "i"ic these effects in vitro! through bio"echanical factors and increased chondrocytes loading has resulted in increased proteoglycan synthesis and an increased release of degradative en,y"e activity# A nu"ber of cytokines and cell4signalling "olecules such as interleukin4+ 7ID4+9 and nitric o?ide 7-&9 have also been sho5n to play an i"portant role in chondrocytes activity# Hence! these "olecules have also beco"e a potential target for phar"acological intervention and studies of such agents are planned or ongoing#Error1 2eference source not found! Error1 2eference source not found! *: (isphosphonates# 2esorptive agents or bisphosphonates 7such as alendronate and clodronate9 "ay provide i"portant benefits in the sy"pto"atic relief of &A# Initial results of the studies have not been "ade available yet# Also! this class of drugs are not clinically approved for &A therapy#Error1 2eference source not found Gro$th factors# >ro5th factors are being evaluated in the "anage"ent of &A and its affect on cartilage#Error1 2eference source not found! Error1 2eference source not found 2efer to Anne? :#+'# for "ore infor"ation# Alternative medicines1 he FS .ongress created he -ational .enter of .o"ple"entary and Alternative Medicine 7-..AM9 given the gro5ing use of alternative "edicines# .urrently -..AM and the -ational Institute of Health 7-IH9 are supporting a large 2. evaluating the effectiveness of glucosa"ine and chondroitin in the treat"ent of &A# .rror: /eference source not found

6.12-16

6.12: Osteoarthritis 6. urrent Pharmaceutical Product Pipeline for OA Treatment

.urrently there are a li"ited nu"ber of phar"aceutical products in the pipeline# Both the European Agency for the Evaluation of Medicinal Products 7EMEA9 and the FS @ood and $rug Ad"inistration 7@$A9 5ere revie5ed to deter"ine this infor"ation# able :#+'#* sho5s the ne5 "edications in develop"ent for &A# Table $. 'e8 medications in de*elopment for osteoarthritis $3
%n*esti,ational dru, name %ndication and description ompan# (e*elopment status

):'%3/ 7.athepsin H inhibitor9

AB 3:*

.P4/))!)*3 MD4*(((

Pennsaid opical Solution

Pralnacasan

&steoarthritis &steoporosis .athepsin H is believed to play a role in degrading bone# *0 .athepsin H inhibitors have the potential to provide a ne5 therapeutic agent for the treat"ent of &A#*3 &steoarthritis 2heu"atoid arthritis AB 3:* is a .&L4' inhibitor like celeco?ib and rofeco?ib already on the "arket# he drug is intended for the sy"pto"atic treat"ent of &A)(# &steoarthritis -o available infor"ation &steoarthritis A ne5 class of anti4infla""atory and analgesic drugs# Also kno5n as .&L;D&L inhibitors# his class are inhibitors of both cycloo?ygenase and leukotrienes and have the potential to reduce gastrointestinal to?icity# )+! )' &steoarthritis 2heu"atoid arthritis Pennsaid is a topical for"ulation of diclofenac! a non4steroidal anti4infla""atory drug 7-SAI$9! 5hich is used for the treat"ent of the sy"pto"s of osteoarthritis# )* &steoarthritis An orally bioavailable inhibitor of interleukin 7ID94 +beta converting en,y"e# his drug has the potential to beco"e a disease4"odifying drug for the treat"ent of &A and infla""atory diseases#))!
)/

>la?oS"ithHline

Phase I

Abbott Daboratories

Phase II

Pfi,er @orest Daboratories

Phase II Phase III

$i"ethaid 2esearch

Application sub"itted to @$A

Aventis Phar"aceuticals

Phase II

Marious .&L4' inhibitors

A nu"ber of co"panies are developing ne5 .&L4 ' inhibitors 5ith the intention of achieving greater responder rates and;or reduction in pain score# $ifferences 5ithin the .&L4' class have not yet been established#

Marious co"panies

6.12-13

6.12: Osteoarthritis 3. Opportunities for /esearch into 'e8 Pharmaceutical %nter*ention


See Anne? :#+' he area of drug develop"ent in &A is of a significant public health conseCuence# .urrent therapies on the "arket only help to i"prove pain and function# here are no drugs that can prevent! reverse or halt the disease# Several Cuestions re"ain unans5ered in the areas of epide"iology! pathophysiology and diagnosis of the disease# hese need to be studied to support the effective develop"ent of novel disease "odifying agents# here are also a large nu"ber of drugs 7including alternative therapies! vita"ins! and nutraceuticals9 5hose clinical effectiveness still needs to be deter"ined through better4 conducted clinical trials# he follo5ing are highlights for opportunities for research in &A as put for5ard by various e?pert "e"bers on A.2 and EFDA2 and authors1 .linical predictors of response to phar"acological and non4phar"acological interventions need to be deter"ined# $eter"ine the long4ter" effects! efficacy and safety of .&L4' inhibitor use# Investigate pooled;co"bination treat"ents! 5hich reflect everyday clinical practice# @urther investigate the difference bet5een efficacy 7trial data9 and clinical effectiveness of "any phar"acological treat"ents using validated and reliable outco"es "easures that reflect disease activity! da"age and Cuality of life# Investigate the efficacy of topical -SAI$S and conduct co"parative trials# $evelop"ent of disease "odifying osteoarthritis drugs! such as local delivery of anti4 infla""atory cytokines# E?plore the effectiveness of alternative therapies in reducing sy"pto"s of &A# Study the gastrointestinal safety of high4dose aceta"inophen# .o"pare the effectiveness bet5een paraceta"ol4aceta"inophen and co?4' inhibitors# .onduct phar"aco4econo"ic studies to deter"ine the cost effectiveness of &A therapy and its long ter" "anage"ent# Evaluate the safety! effectiveness! and long ter" effects of SGA$&A drugs# hese studies bridge the range of research fro" basic science to Phase IM studies#

5. Gaps )et8een urrent /esearch and Potential /esearch %ssues that ould <a9e a (ifference
Most rheu"atologists have suggested that osteoarthritis is often considered a silent disease! because although there is infla""ation in the 6oint it occurs "uch less than in rheu"atoid arthritis# &nly 5hen the patients develop pronounced infla""ations are the sy"pto"s of pain noticeable to the patient# Most e?perts in this field have articulated that this is particularly an area 5here research into ne5 diagnostics! bio"arkers and i"aging technology is going to be i"portant and useful for the "anage"ent of &A# Bio"arkers are an essential area of research in &A and arthritis as a 5hole! since it 5ill help the "edical co""unity to deter"ine1 - Who is likely to get arthritis8 - Severity and progression of disease - 2esponse to drugs and 5hat types of drugs are effective - Populations at risk of developing to?icity .o"ple"entary and alternative "edicines are of great interest to consu"er groups affected 5ith &A#Error1 2eference source not found In the FS! co"ple"entary and alternative "edicines are the "ost rapidly gro5ing area at the -IH 7-ational Institute of Health9# here is substantial research opportunity potential in this area#): While e?citing breakthrough treat"ents continue to beco"e available for rheu"atoid arthritis! highly effective therapies do not e?ist for &A# .urrently! the research to support treat"ents in &A is not as advanced as co"pared to rheu"atoid arthritis# Interestingly! it has been discovered that the cytokines

6.12-15

6.12: Osteoarthritis
that are driving infla""ation and destruction of bone and cartilage in rheu"atoid arthritis "ay also drive the destructive process in &A#Error1 2eference source not found his discovery "ay potentially be helpful since so"e of the kno5ledge about rheu"atoid arthritis "ay be transferred and applied to osteoarthritis# @urther"ore! 5ith better understanding through research of the "olecular process! progress "ay be achieved in the develop"ent of "edications to effectively control the sy"pto"s and disease progression of &A as 5ell#Error1 2eference source not found he follo5ing are areas that need research1Error1 2eference source not found! Error1 2eference source not found Strengthen evidence4based "edicine by closing the gap bet5een "olecular research and clinical disease research for &A# $rug develop"ent in &A has been lacking! because in order to diagnose! "onitor and develop treat"ents for &A! researchers and drug co"panies reCuire effective bioche"ical and i"aging "arkers to assess disease progression# .urrent evaluation "ethods of ?4rays and blood tests are insufficient to deter"ine the progression and outco"e of ne5 treat"ents# As a result! a recent FS4 based public private partnership! called the osteoarthritis Initiative 7&AI9! intends to co"bine resources for the purpose of finding biological "arkers related to the progression of &A# &AI 5ill collect data over the ne?t /4% years on individuals at high risk for the develop"ent of &A# his data 5ill be used for the develop"ent of potential ne5 &A treat"ents# &AI is a co"bined effort in the FS by -IH 7-ational Institute of Health9! >la?oS"ithHline! Merck! -ovartis Phar"aceuticals .orporation and Pfi,er# &AI 5ill provide appro?i"ately 0 "illion dollars annually to si? clinical research centres to establish and "aintain a database of &A! 5hich 5ill include evaluation data! radiological i"ages and a biospeci"en repository# All the data 5ill be available to researchers 5orld5ide#)% A nu"ber of other issues need to be resolved#Error1 2eference source not found "nter country differences1 .ertain drugs are available in parts of Europe! 5hereas others are not available in other countries or the FS# he difference in the availability of drugs "ay result in differences in clinical practice and level of patient e?pectation of &A drugs# Class of compounds1 .ertain co"pounds! such as glucosa"ine and chondroitin sulphate are considered drugs in parts of Europe! ho5ever! in the FS they are considered food supple"ents# hese differences "ay have the follo5ing conseCuences1 '/ 4 $ifferences in Cuality assurance# 4 -o reCuire"ents to deter"ine the efficacy or the safety of food supple"ent products# )evel of evidence of efficacy1 $espite certain drugs being on the "arket for several decades! such as ASF 7Avocado;Soybean unsaponifiable9 residues in @rance! their efficacy 5as not deter"ined until recently# '/ he position of "any recent health authorities has facilitated i"prove"ent in the level of evidence and the observed treat"ent effect of drugs# &n the other hand! there are nu"erous unpublished studies# E"phasis on "ost peer revie5 6ournals is about the statistically significant effect of these treat"ents# To ans8er this and to determine the le*el of efficac#4 trials should compare the obser*ed effect of ne8 treatments to con*entional dru,s such as '"A%(s.

6.

onclusion

he prevalence of &A is increasing and this places a globally "a6or burden on individualsA health syste"s! and social care syste"s# &A! the "ost co""on arthritis condition! is a "a6or cause of i"paired "obility and disability for the ageing populations# While there are several drugs available on the "arket that "itigate pain and i"prove function! there are no drugs that can cure! reverse or halt disease progression# &A is also no5 regarded as a co"ple? disease 5hose etiology is not co"pletely understood# In addition there are also several areas 5here infor"ation is still lackingA these include epide"iology! path physiology! environ"ental risk factors! genetic predisposition and lifestyle# Infor"ation related to these topics "ay assist in the overall "anage"ent and planning of this disabling condition# here are a nu"ber of drugs in the pipeline under develop"ent and several studies also evaluating alternative therapies# here are! ho5ever! several drugs on the "arket 5hose clinical effectiveness and long4ter" safety still need to be deter"ined# his is especially i"portant since &A reCuires long disease "anage"ent and the disease pri"arily affects people over the age of :(! 5ho are "ost prone to drug to?icity# In addition! data is lacking about the therapeutic effectiveness of certain

6.12-16

6.12: Osteoarthritis
drugs 5ithin a class as 5ell as bet5een classes# Infor"ation on the i"pact of the disease to society and both the cost of "edicines and cost of disease "anage"ent 7including phar"acological and non phar"acological treat"ents9 need to be evaluated# @inally! 5hile there is substantial research in this area! "ost e?perts e"phasi,e that research into ne5 diagnostics! bio"arkers and i"aging technology is going to be i"portant and useful for the "anage"ent of &A and the develop"ent of disease "odifying drugs#

6.12-2;

6.12: Osteoarthritis 1;. /eferences

6.12-21

+ '

http1;;555#arthritis#org;conditions# Arthritis @oundation# Accessed @ebruary ++! '(()#

Kordan HM! Arden -H! $oherty M! Bann5arth B! et al# EFDA2 2eco""endations '((*1 An Evidence Based Approach to the Manage"ent of Hnee &steoarthritis1 2eport of a ask @orce of the Standing .o""ittee for International .linical Studies Including herapeutic rials 7ES.ISI 9# Ann 2heu" $is# '((*A :'1++)/4++//#
*

http1;;555#rheu"atology#org;publications;guidelines;oa4"g"t;oa4"g"t#asp8audR"e"# he A"erican .ollege of 2heu"atology 7A.29# Dast accesses @ebruary +0! '(()# Alt"an 2$! Hochberg M.! Mosko5it, 2W! Schnit,er K# 2eco""endations for the "edical "anage"ent of &steoarthritis of the hip and knee# Arthritis and 2heu"atis"# '(((A )*739 +3(/4+3+/#
) /

HaC I! Murphy E! $arce K# &steoarthritis# Postgrad Med K '((*A %31*%%4*0*#

Wolf A$! Pfleger B# Burden of Ma6or Musculoskeletal .onditions# Policy and Practice# Special he"e4Bone and Koint $ecade '(((4'(+(# Bulletin of the World Health &rgani,ation '((*! 0+ 7391 :):4:/:#
: % 0

http1;;555#arthritis#org;ari;state;default#asp# Arthritis and 2heu"atis" International# State of the World# Brandt H$ -on4surgical reat"ent of &steoarthritis1 A Half .entury of <Advances=# Ann# 2heu"# $is '(()A :*1 ++%4+''

http1;;555#arthritis#org;ari;state;default#asp# Arthritis and 2heu"atis" International# Huder A# State of the World# Dast accessed @ebruary +'! '(()#
3

http1;;555#nia"s#nih#gov;ne;oi;oaepipappenSa#ht"# -ational Institute of Health 7-IH9# -ational Institute of Arthritis and Musculoskeletal and Skin $iseases 7-IAMS9# Dast accessed '(()4('4+3
+(

Prevalence and i"pact of arthritis a"ong 5o"enTFnited States +303U+33+# ''*+ 'orb 'ortal *#ly +ep +33/A ))1*'34*)
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