REVIEW ARTICLE

Corticosteroid injection into the osteoarthritic knee: drug

selection, dose, and injection frequency
R. J. Douglas

Sport Doctor, Sportsmed SA,

SUMMARY
Review criteria and message for the 32 Payneham Road, Stepney,
Objective: Although some disagreement exists amongst practitioners as to the SA, Australia
clinic
efficacy of corticosteroid injection into the osteoarthritic knee, this procedure • The paper determines that intra-articular injection
Correspondence to:
remains the most common reason to perform knee joint injection. There is of corticosteroid into the osteoarthritic knee is a Robert J. Douglas, Sport
disagreement too over the most efficacious corticosteroid for the procedure; the safe and routine medical procedure; Doctor, Sportsmed SA, 32
• The corticosteroid agent with greatest efficacy is Payneham Road, Stepney, SA,
dose required at injection; the frequency, and total quantity of corticosteroid that
uncertain and is unlikely to be clinically Australia
can be injected into the knee. This paper examines the controversies surrounding Tel.: +61 (8) 83628111
significant. Drug selection appears to be dictated
the efficacy of corticosteroid injection into the osteoarthritic knee, and attempts to by training tradition, and individual practitioner Fax: +61 (8) 83626635
provide guidance as to appropriate corticosteroid selection, dose, and treatment preference; Email: rabs01@hotmail.com
interval. Method: Searches were made of electronic databases, and appropriate • There is little agreement between practitioners on
Disclosure
papers were identified and hand-searched. Results and Conclusion: Although the optimal dose and dosage of each
The Author states that he has
numerous investigations have been conducted in an attempt to identify the optimal corticosteroid agent, and there is no evidence to no financial or other conflicting
corticosteroid agent, and its optimal dosing regimen for the intra-articular support the use of corticosteroid doses beyond interest that may impact upon
those recommended by Manufacturers; the writing and ⁄ or presentation
treatment of osteoarthritis, a consensus has not been established. The current
• The traditional teaching that frequent injection of of this paper.
recommendations for dosing interval appear to have arisen as a consequence of a
corticosteroid into the osteoarthritic knee causes a
misinterpretation of previously published works. This paper recommends that destructive arthropathy is incorrect, and arises from
practitioners refine and individually tailor their selection of agent and dosing a misinterpretation of the original research articles.
regimen to patient needs and clinical response.

There are two ways to inject (or aspirate) the knee
– my way and the wrong way.
(Traditional)
Introduction
The knee is the largest synovial joint in the body (1).
It is subject to a wide variety of insults which may
necessitate aspiration and ⁄ or injection of the joint.
Aspiration of the knee joint may be performed for
the diagnosis of an unexplained effusion, or the evac-
uation of a painful one (2). Injection of the knee can
be undertaken for radiological investigation of the
knee (3), for the injection of corticosteroid into a
joint suffering from a non-infectious inflammatory
process (4), or for the injection of viscosupplementa-
tion (5). Of these indications for aspiration or injec-
tion of the knee joint, the most common is the
injection of corticosteroid in cases of osteoarthritis
(OA) of the knee.
In Australia, musculoskeletal (MSK) conditions
(which includes the various arthritides) are the third
leading reason (equal to that for ‘cardiovascular
problems’) for a visit to a General Practitioner (GP)
(17%), following ‘respiratory problems’ (22%), and
‘unspecified general problems’ (19%) (6). Interest-
ingly, the proportion of MSK presentations that are
due to OA is unknown. Similarly, there is no data
available regarding the breakdown of clinical presen-
tations to Sport Doctors or Sport Physicians.
Osteoarthritis is the most common musculoskele-
tal (MSK) condition affecting Australians, with a
reported prevalence of 15% of the population, or just
under 3 million people (in 2000) (7). Peat et al. (8).
reported that 10% of patients aged 55 or more in
the UK and Netherlands experience painful, disabling
OA of the knee, and a quarter are severely disabled.
A recent American report (9) found that symptom-
atic knee OA occurs in 10% of men and 13% of
women aged 60 years or older. It has been estimated
that the incidence, or number of new cases ⁄ year in
Australia, is some 27,000 new cases of radiological
OA for women, and approximately 15,500 new cases
for men (10). Guillemin et al. (11). determined that
knee OA prevalence in French men and women ran-
ged from 2.1%–10.1% and 1.6%–14.9% respectively,

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Int J Clin Pract, July 2012, 66, 7, 699–704. doi: 10.1111/j.1742-1241.2012.02963.x 699
700 Corticosteroid injection into the osteoarthritic knee
and varied by geographical region. In a Chinese
cohort, Hunter et al. (12). reported the prevalence of
radiographic tibiofemoral OA to be 21.9% in men
and 41.8% in women, and the prevalence of radio-
graphic patellofemoral OA to be 25.9% in men and
35.7% in women. Symptomatic knee OA was deter-
mined to be present in 9.7% of men and 20.3% of
women. Tveit et al. (13). reported that knee OA is
more commonly found in male former elite athletes,
and that knee OA is associated with a previous knee
injury in former impact athletes, but not in non-
impact athletes.
The initial recommended treatments for OA are
the various non-pharmacological modalities (patient
education, various self-management programmes,
diet, and other therapies) and pharmacological thera-
pies (involving non-opiate oral analgesics as well as
the application of topical agents). The use of intra-
articular (IA) corticosteroid can be considered in
patients that are unresponsive to these treatments,
and is recommended when signs of local inflamma-
tion with joint effusion are present (14). The first
reported use of IA corticosteroid in knee OA was by
Hollander (4) in 1953, and the first clinical trial of
IA steroid use for knee OA was reported by Miller,
White and Norton (15) in 1958.
A major Cochrane review by Bellamy et al. (16).
evaluated the efficacy and safety of IA corticosteroids
in the treatment of knee OA. The review determined
that there was evidence of benefit for both pain and
patient global assessment at one week post-injection,
and that there was no evidence for effect on function
(but data for this measure was sparse). There was evi-
dence at 2–3 weeks post-injection that corticosteroid
was more effective than placebo in the reduction of
pain. From 4 to 24 weeks post-injection, there was no
compelling evidence of benefit, although some mid-
and late-stage benefit in favour of corticosteroid was
noted. The authors concluded that it appears that the
beneficial effects of IA corticosteroid are rapid in
onset, but may be relatively short-lived (1–3 weeks).
There was no evidence of long-term efficacy. It is
unknown why there is inter-patient variability in
response to the various IA corticosteroids available.
Despite there being numerous publications con-
cerning the use of IA corticosteroids in the treatment
of the symptoms of knee OA, there is little agree-
ment as to the most efficacious agent, nor is there
agreement on the dose and dosing regimen of these
agents.
This paper aims to examine the selection of
corticosteroid agent, the dosing regimen, and fre-
quency of injection of corticosteroid agent into the
osteoarthritic knee, and makes recommendations as
to the safe and optimal usage of these medications.
Method
A search of the literature was conducted via the
Cochrane database, PubMed, and Google. Papers rel-
evant to the intra-articular injection of corticosteroid
were identified and hand-searched. Pharmacology
textbooks were searched for corticosteroid physico-
chemical data. Information from all sources was uti-
lised to tabulate relevant pharmacodynamic
parameters for representative corticosteroids.
Discussion
Which corticosteroid to inject? what dose?
As discussed by Bellamy et al. (16). there are very
few direct comparison randomised controlled trials
comparing efficacy of the different IA corticosteroids.
Of the few studies undertaken, only Valtonen (17)
detected a statistically significant difference in the
improvement of joint pain and in the range of joint
movement, following the use of 20 mg triamcinolone
hexacetonide versus 6 mg betamethasone. There were
no statistically significant differences in other out-
come measures. A systematic review by Hepper et al.
(18). found a trend for triamcinolone to be more
effective in pain reduction when compared to other
corticosteroid agents. Miller, White and Norton (15)
found that there was no relationship between IA cor-
ticosteroid effect and the volume of fluid preparation
injected into the knee joint. Studies comparing the
efficacy of IA corticosteroid with other IA pharma-
ceutical agents, or techniques (19,20) have utilised
triamcinolone hexacetonide 20 mg as comparator
product.
Centeno and Moore (21) in a mail survey of
members of the American College of Rheumatolo-
gists found that the corticosteroid most favoured by
respondents was methylprednisolone, and was the
preferred IA corticosteroid for those trained in the
Eastern United States (US); those trained in the
Midwest and Southwest US preferred triamcinolone
hexacetonide; and those trained in the Western US
preferred triamcinolone acetonide. Only triamcino-
lone hexacetonide was chosen primarily because of
efficacy. Regardless of drug concentration, all respon-
dents used a dose of one ampoule of 1 ml of cortico-
steroid preparation. There are no other equivalent
studies.
From the known pharmacodynamic and pharma-
cokinetic parameters of the most commonly utilised
IA corticosteroids it is possible to directly compare
the parameters for each drug, and to theoretically
determine an IA dosing regimen for each. Table 1
outlines some important parameters for the most
commonly utilised IA corticosteroids.
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Int J Clin Pract, July 2012, 66, 7, 699–704

Table 1 Comparative pharmacokinetic parameters for the major injectable corticosteroid drugs
Potency Duration of
Drug (22) action (Hrs) (23)
Hydrocortisone 1 8–12
Methylprednisolone 5 12–36
Triamcinolone 5 18–36
Betamethasone* 25 36–54
*Proprietary preparations of injectable betamethasone contain a mixture of betamethasone sodium phosphate and betamethasone acetate.
As can be seen from Table 1, there is a direct
inverse relationship between the potency of each cor-
ticosteroid, and both its duration of action and its
solubility in water at 25 C. The usual (standard)
dose of each corticosteroid does not follow a strict
inverse relationship between corticosteroid potency
and injected dose, as solubility also determines the
diffusion rate of the drug from the injection site.
Thus, a (relatively) more insoluble corticosteroid
should remain at the site of injection for longer, pos-
sibly increasing the length of beneficial effect.
In conclusion, it would appear that the ‘perfect’
corticosteroid for IA injection would have high
potency, and both a long duration of action and a
low solubility, allowing the corticosteroid to remain
for longer at the injection site, with a resultant
expected increase in efficacy. These parameters also
allow for the lowest possible dose of the medication
to be injected. Both betamethasone and triamcino-
lone closely fit these criteria, and appear to be the
injectable corticosteroids of choice, at standard rec-
ommended doses. In Australia, standard proprietary
preparations of betamethasone are presented as 1 ml
ampoules, with each 1 ml containing 5.7 mg beta-
methsone, as betamethasone sodium phosphate
3.9 mg (in solution) and betamethasone acetate
3 mg (in suspension) in an aqueous vehicle. There-
fore, the standard dose of the corticosteroid is one
ampoule. Triamcinolone is available as either a
10 mg in 1 ml, or 40 mg in 1 ml ampoule. The rec-
ommended IA dose of triamcinolone is 20–40 mg.
This discrepancy (and thus a potential cost differ-
ence) in the commercial presentation of the two cor-
ticosteroids may influence their selection in the IA
injection of the inflamed joint.
In a recent article, Sher (28) advocated the utilisa-
tion of two ampoules (12 mg) betamethasone (but
only one ampoule (6 mg) if the patient was suffering
from Diabetes Mellitus). From the limited informa-
tion available from published studies (17,19,20) there
would appear to be no added benefit from the IA
injection of two ampoules of betamethasone
(11.4 mg), nor is there an apparent benefit from
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Int J Clin Pract, July 2012, 66, 7, 699–704
Corticosteroid injection into the osteoarthritic knee 701
Solubilitymg ⁄ Recommended
l @ 25 C dose(23,27)
285 (24) 50 mg
120 (25) 40 mg
80 (26) 20–40 mg
58(phosphate) 30(acetate) (24) 5.7 mg
increasing the injected dose of triamcinolone to
beyond 40 mg - there appears to be no additional ben-
efit from increasing the injected corticosteroid dose
beyond that recommended by the manufacturers.
What limits the IA corticosteroid dosing
regimen?
Despite there being several studies of experimentally-
induced OA that have demonstrated the beneficial
effect of IA corticosteroid upon the size, severity and
progression of both articular cartilage lesions and
osteophyte formation (29–32), there is ongoing con-
cern regarding the possible adverse effects of repeated
IA corticosteroid injection upon the OA-affected
joint. Chandler and Wright (33) were the first
Authors to report radiological deterioration of the
knee joint and the articular cartilage, sometimes con-
siderable, after prolonged administration of IA
hydrocortisone in the absence of infection. In 1959
Chandler et al. (34). described a patient with OA of
the hip joint who developed a relatively painless
destruction of the hip joint after monthly injections
of 50 mg hydrocortisone for 18 months. They coined
the term ‘Charcot arthropathy’, since the affected
joint resembled a Charcot joint radiologically and
histologically. An overlooked part of their analysis
was that they considered the deterioration to be a
manifestation of an ‘overuse’ injury due to:
‘‘…undue weight-bearing and mobility…’’
following the relief of pain due to corticosteroid
interference with the normal protective processes of
the joint, and not a steroid effect per se. Bentley and
Goodfellow (35) noted similar severe destructive
changes in the knees of a 73-year-old woman with
OA who received 600 mg IA hydrocortisone over a
period of 12 weeks, and a total of 1600 mg over
14 months into the (L) knee. She also received a
total hydrocortisone dose of 1000 mg into the (R)
knee. Macroscopic and microscopic appearances of
the joints were reported to be quite different from
those usually seen in advanced OA.
There are other studies of the knee joints of patients
who had received multiple IA corticosteroid injections
702 Corticosteroid injection into the osteoarthritic knee
that failed to show significant evidence of destruction
or accelerated deterioration (36,37). Saxne, Heinegard
and Wollheim (38) observed a decrease in the proteo-
glycan content of synovial fluid of patients undergoing
IA corticosteroid therapy. They reported that their
findings strongly suggest that IA corticosteroid injec-
tion reduces the production of IL-1, TNF-a and prote-
ases that may degrade articular cartilage. However,
this study used a heterogeneous group of patients suf-
fering from a range of articular arthritides, and their
findings may not translate to the use of IA corticoste-
roid in cases of isolated OA. In the only reported study
in a primate model (39) no appreciable joint damage
was found – there was only minimal, reversible change
of the joint surface.
Studies of IA corticosteroid use in other animal
models (mice, rats and rabbits) have suggested that
multiple IA injections of corticosteroid may alter car-
tilage protein synthesis and consequently damage the
articular cartilage. Mankin and Conger (40) reported
the deleterious effects of IA injections of hydrocorti-
sone acetate on the articular cartilage in rabbits.
They found that the injection of corticosteroid tem-
porarily reduced the synthesis of the articular carti-
lage matrix. Silberberg, Silberberg and Hasler (41)
reported articular cartilage damage in mice. Salter,
Gross and Hall (42) demonstrated a loss of the nor-
mal lustre of the articular surface, thinning of the
cartilage and damage of the articular cartilage within
the middle zone of the cartilage matrix after the
administration of hydrocortisone tertiary-butyl ace-
tate into the knees of rabbits. They determined that
the degree of destructive change in the articular car-
tilage was directly proportional to the number of IA
corticosteroid injections administered. Moskowitz
et al. (43). also observed these lesions and deter-
mined that the number of cysts was proportional to
the number of IA corticosteroid injections. Two
papers co-Authored by Kunin and Meyer (44,45)
reported alterations in the intermediary metabolism
and glycolytic activity in rat epiphyseal cartilage.
Behrens, Shepard and Mitchell (46) described a pro-
gressive loss of the endoplasmic reticulum, mito-
chondria and Golgi apparatus in chondrocytes from
the knees of rabbits treated with IA hydrocortisone
acetate. Papachristou, Anagnostou and Katsorhis
(47) reported changes in the histological appearance
of rabbit articular cartilage after injection with vary-
ing IA doses of hydrocortisone, and determined that
the magnitude of histological change was propor-
tional to the amount of hydrocortisone injected.
They concluded that IA corticosteroid injection alters
the cartilage chondrocytes, producing abnormal
changes in the cytoplasm and nucleus of these cells,
resulting in cell degradation.
Although there is a large body of evidence from
animal studies demonstrating a direct toxic effect of
corticosteroid upon intra-articular structures, studies
in man are inconclusive. Although some published
reports suggest that the clinical and radiological dete-
rioration found in human joints after IA injection of
corticosteroid may be due to the specific deleterious
effects of corticosteroids on the metabolism of artic-
ular cartilage cells, there is evidence that the genera-
tion of the ‘Charcot joint’ secondary to IA
corticosteroid may be due to an overuse of the trea-
ted joint rather than a direct effect of corticosteroid
upon the joint structures.
It would appear that current limitations to the
injection of IA corticosteroid is founded upon wide-
spread concern for the possibility of direct toxic
effect of corticosteroid upon IA structures and that
this is due to a misunderstanding of the conclusions
of the paper by Chandler et al. (34) It appears that it
is not currently possible to determine what limits to
place upon IA corticosteroid use, beyond those of
practitioner ‘common sense.’
How often can you inject corticosteroid into
the knee?
Although several reports (33–35) have demonstrated
serious adverse effects after sustained, regular injec-
tion of IA corticosteroid, and McGarry et al. (48).
warned of the potential dangers of IA injection in
the obese, other investigators have demonstrated few
adverse effects (36,49).
All published information concerning the frequency
of IA corticosteroid injection appears to be based
upon professional opinion - a search of the published
medical literature failed to identify a study that had
investigated how often IA corticosteroid can be
injected into an osteoarthritic joint. Sher (28) stated
that if a first injection of IA corticosteroid fails to
demonstrate any effect, then there is little point in a
repeat injection. Zuber (50) has suggested that
injection can be repeated after six weeks, but no more
frequently than every 6–8 weeks. Neustadt (51)
suggested that there be 8–12 weeks between injections,
while Lane and Thompson (52) suggested that injec-
tions be administered no more than 3 monthly. Both
Zuber (50) and Neustadt (51) cautioned that there be
no more than 2 or 3 IA injections of corticoste-
roid ⁄ weight-bearing joint ⁄ year. Sher (28), Lane and
Thompson (52) and Genovese (53) have suggested
that the limit should be three or four injections of
corticosteroid ⁄ weight-bearing joint ⁄ year. Balch et al.
(37). has recommended ‘judicious’ use of IA cortico-
steroid as published studies did not support the
contention that repeated IA injection of corticosteroid
will inevitably lead to joint destruction. Friedman and
ª 2012 Blackwell Publishing Ltd
Int J Clin Pract, July 2012, 66, 7, 699–704
 Corticosteroid injection into the osteoarthritic knee 703

Moore (54) and Walker-Bone et al. (55). have also
advised on the ‘judicious’ use of IA corticosteroid in
OA. Unfortunately, no author to this time has pro-
vided a definition of ‘judicious use.’
In 1967, Salter, Gross and Hall (42) concluded
that:
‘‘While it is unlikely that a single intra-articular
injection of hydrocortisone is harmful, multiple
intra-articular injections of hydrocortisone in a given
joint are probably deleterious to the articular
cartilage and should be avoided in order to prevent
the iatrogenic complication of hydrocortisone
arthropathy.’’
This advice is certainly still relevant for the current
use of IA injection of corticosteroid. My personal
approach is to use IA corticosteroid injection in
those for whom it is not possible to arrange timely
prosthetic knee insertion; in those for whom delaying
the insertion of a prosthesis is desirable (generally
the young); in patients that have contra-indications
to prosthesis surgery; and in patients anticipating a
short-term heavy use of a sore osteoarthritic joint.
Finally, IA corticosteroid injection should be per-
formed under sterile (‘no touch’) conditions to mini-
mise the risk of IA infection.
Summary
OA is a common problem in many communities and
is a commonly seen presentation in both General
and Sport Medicine Practice.
Although there are several corticosteroid com-
pounds available for use in the IA injection of the
knee joint, there is scant comparative data for the
compounds, although there appears to be a tendency
for trimacinolone to be the most efficacious
compound. Available research on corticosteroid use
by Practitioners demonstrates the great influence of
training tradition upon corticosteroid selection.
Disagreement exists amongst Medical Practitioners
as to the optimal dose of each corticosteroid for
injection into the knee joint. There is no evidence to
suggest that doses other than those recommended by
the manufacturers for each compound should be
administered. Presentation of the commercially avail-
able preparations of the different corticosteroid com-
pounds may influence their usage patterns.
There is disagreement too on dosing frequency.
Although there is a large body of evidence from ani-
mal studies demonstrating a direct toxic effect of
corticosteroid upon intra-articular structures, studies
in humans are inconclusive. There is evidence that
the generation of the ‘Charcot joint’ secondary to
large doses of corticosteroid may be due to an over-
use of the treated joint rather than a direct effect of
corticosteroid upon the joint structures.
There is too little experimental or observational data
to draw any conclusions as to an optimal frequency of
IA corticosteroid injection, and current usage patterns
are determined by practitioner opinion.
Finally, IA injection of corticosteroid is a treat-
ment adjunct and should not be used as monothera-
py for patients with chronic, stable OA (49).
This paper highlights the need for practitioners to
refine, and individually tailor, their selection of corti-
costeroid and dosing regimen in the treatment of
OA of the knee and other joints.
Acknowledgements
The Author wishes to thank Dr. Tonia Mezzini of
Clinic 275, Royal Adelaide hospital, Adelaide, South
Australia, for her assistance with the preparation of
the manuscript.

www.aihw.gov.au/publication-detail/?id=6442472433 phase population-based survey. Osteoarthritis

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Paper received February 2012, accepted April 2012
ª 2012 Blackwell Publishing Ltd
Int J Clin Pract, July 2012, 66, 7, 699–704