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diminish with shorter glycosaminoglycan side chains resulting in decreases of net

aggregate proteins. Type I collagen within the extracellular matrix increases, and

keratin sulfate concentrations decrease. Some of the biochemical changes are

reflective of those produced in culture by immature tissue. The deposition of calcium

crystals represents a curious finding. It is unknown whether calcium deposition has a

direct involvement or is reflective of increased chondrocyte activity. Eventually, the

initial water swelling of the cartilage is replaced by cartilage with reduced

propensity to allow bone to distribute the force and slide on bone.

5 Distinct

alterations in cartilage matrix metabolism favor catabolism. Chondrocytes are unable

to maintain production of essential macromolecules necessary for healthy cartilage.

However, the syntheses of those enzymes that break down the matrix are increased by

the same chondrocytes. The enzymes that degrade proteoglycans and collagen are

called aggrecanases and collagenases, respectively. The control of these enzymes is

complicated by enzymatic activation of latent proteins and inactivation by proteinase

inhibitors. In OA, the expression and production of proteinases is increased.

Collagen is typically cleaved by matrix metalloproteinases (MMPs), MMP-1, MMP8, and MMP-13. Most recently, the role of inflammation and inflammatory mediators

produced by cartilage is being more closely investigated. Upregulated by IL-1 and

TNF, MMPs cleave collagen and break down other important elements of the

extracellular matrix. Ultimately, the imbalance between cartilage maintenance and

degradation leads to erosion and eventual cartilage destruction.

5

OVERVIEW OF DRUG THERAPY

The current treatment of OA is to provide analgesia allowing performance of

activities of daily living (ADLs), facilitate participation in physical or occupational

therapies, and recommend appropriate self-managed exercise programs. There are no

disease-mitigating strategies that have demonstrated acceptable safety and efficacy in

the treatment of OA. The initial treatment for OA pain and stiffness is acetaminophen

given on a routine basis for a 2- to 3-week trial in doses typically less than 4 g/day

or less than 3 g/day in patients older than 65 years, unless clinically contraindicated.

Acetaminophen offers a considerable degree of safety over nonsteroidal antiinflammatory drugs (NSAIDs) for mild-to-moderate OA disease. However, many

clinical trials have demonstrated significantly better efficacy of NSAIDs as

compared with acetaminophen in selected patients, such as those who present with

both pain and inflammation, because acetaminophen lacks significant antiinflammatory effects.

6–8 These patients are more likely to exhibit more moderate-tosevere disease.

5,9,10 Unintentional liver injury may result from overuse of

acetaminophen above recommended doses, in combination with over-the-counter

acetaminophen containing products, or the opioid–acetaminophen products available

by prescription. A trial of a selective or nonselective NSAID would be a reasonable

consideration in patients with inadequate response to acetaminophen or presenting

with pain and inflammation. A careful risk and benefit analysis must be

individualized for each patient starting an NSAID. Adverse events of GI bleeding,

diminishing renal function, liver toxicity, and cardiovascular risk of the specific

medication considered need to be carefully assessed and a plan for therapeutic

monitoring implemented. Additionally, consideration of drug–drug interactions or

drug–disease interactions is also warranted. Topical therapies may be therapeutic for

selected patients unable to tolerate oral NSAIDs and are becoming more widely

recommended by professional practice guidelines.

11,12 Topical therapies include

capsaicin creams, capsaicin gels, capsaicin liquids, capsaicin lotions, capsaicin

topical patches, lidocaine topical patch, lidocaine topical creams, ointments, and

gels, diclofenac topical gel, diclofenac topical patch, and diclofenac topical solution.

In patients presenting with effusions of the knee, aspiration of the affected joint and

intra-articular injections of corticosteroids may be therapeutic once infectious

etiologies have been ruled out. In patients with inadequate relief in symptoms and

worsening functions, there are few alternatives outside of surgical interventions.

Intra-articular injections of hyaluronic acid derivatives are the last of the

conservative strategies before surgical interventions are considered. Tramadol may

represent a useful option for many patients unless precluded due to seizures or

misuse history or drug–drug interaction potential. There are currently no

recommendations for the use of oral glucocorticoids in the treatment of OA. A trial of

6 months of glucosamine and chondroitin can be discussed with those patients

interested in pursuing this type of therapy. The use of oral or transdermal opioids or

opioid/acetaminophen combinations for pain management should be discouraged

because of the limited evidence demonstrating benefit and the high potential for

adverse drug reactions.

CLINICAL MANIFESTATIONS

Clinical Presentation of Osteoarthritis

CASE 43-1

QUESTION 1: R.T., a 64-year-old nonsmoking woman, presents to her primary-care physician reporting pain

and stiffness in her right knee. The pain is usually worse in the morning and lasts for about 15 to 20 minutes and

then subsides throughout the day. She reports some increased difficulty taking care of her grandchildren while

her daughter is working. Her medical history is significant for hypothyroidism, hypertension, and hyperlipidemia.

Social history is negative for tobacco and alcohol use. R.T. currently takes amlodipine 5 mg daily, levothyroxine

88 mcg daily, and simvastatin 40 mg daily. On physical examination, there is a varus misalignment of the knees.

The right knee has no swelling or synovial effusions, and crepitus is noted on examination of passive motion. A

radiograph shows right knee joint space narrowing with osteophyte formation at the joint margins.

Laboratory values and vitalsigns obtained at this visit include the following:

Blood pressure (BP), 135/78 mm Hg

Heart rate (HR), 80 beats/minute

Height, 64 inches

Weight, 205 pounds

BMI, 35.2 kg/m

2

Sodium, 140 mEq/L

Potassium, 4.5 mEq/L

Blood urea nitrogen (BUN), 10 mg/dL

Creatinine, 0.9 mg/dL

Estimated glomerular filtration rate (eGFR), 63 mL/minute

Thyrotropin (TSH), 3.08 mIU/mL

White blood cells (WBC), 5 × 10

3

/μL

Red blood cells (RBC), 4.7 × 10

6

/μL

Hemoglobin, 12.7 g/dL

Hematocrit, 38.2%

Uric acid, 5 mg/dL

C-reactive protein (CRP), 0.9 mg/dL

Erythrocyte sedimentation rate (ESR), 18 mm/hour

Anti-CCP antibodies, negative

Total cholesterol, 160 mg/dL

High-density lipoprotein (HDL), 45 mg/dL

What signs and symptoms suggestive of OA are present in R.T.?

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CASE 43-1, QUESTION 2: How do the subjective and objective findings of OA correlate with disease

pathogenesis in R.T.?

R.T. presents with unilateral right knee pain that is worse in the morning and

subsides throughout the day. The OA diagnosis can be made by a good history and

physical examination. Laboratory studies are not needed to confirm the diagnosis of

OA, but a normal ESR rules out inflammatory conditions such as gout or septic

arthritis. Radiographs demonstrate joint space narrowing that is consistent with OA.

However, radiographs do not reliably assess disease severity.

The characteristic joint space narrowing as seen on radiograph without joint

destruction is characteristic for OA. Osteophyte formation and bone rubbing against

bone are most likely responsible for the pain, stiffness, and crepitus demonstrated on

physical examination. Crepitus is an audible “crackling” sound that can be heard with

passive or active movement of the joint. Instead of the opposing joint surfaces gliding

past each other, the movement of the joint now creates the characteristic crunching or

crackling sounds. Additionally, the varus misalignment contributes to the stress on the

knee joint and some of the functional impairments R.T. reported to her primary-care

physician. A varus misalignment is described as the patient in a standing position

with his/her knees appearing further apart (bow-legged), and valgus is when the

knees are closer together. Both of these deformities can affect a patient’s function and

quality of life.

The clinical presentation of OA is usually unilateral pain and stiffness of the knee,

hip, or cervical or lumbar spine; the distal interphalangeal joints generally are not

painful. More often than not, OA tends to affect more than one joint. There are some

distribution associations described between knee and hand OA and knee and hip OA.

Elbows, wrists, and shoulders tend not to be affected by OA. Diagnostic criteria

from the American College of Rheumatology (ACR) hip criteria have a sensitivity

and a specificity of 91% and 89%, respectively, and a sensitivity of 91% and

specificity of 86% for knee OA.

3 These criteria usually are not used in clinical

practice outside of research studies. Clinical trials typically provide outcome data

based on assessment tools such as the Western Ontario and McMaster Universities

(WOMAC), predominantly used for knee OA. A WOMAC functional subscale exists

to assess for functional disability.

13 Patients usually present to their primary-care

provider with complaints of increased pain or stiffness lasting less than 30 minutes,

usually in the morning or after periods of prolonged immobility. They usually will

report decreases in their ADL, functional status, and overall health-related quality of

life. Typically, household activities such as kneeling, stair climbing, and walking

tend to be limited. The associated decrease in activities, range of motion, and overall

physical activity contribute to muscle weakness and unsteadiness.

Problems with sleep and depression can occur, compromising attempts to lose

weight, increase activity, and participate in physical or occupational therapy or in

Tai Chi. Joint involvement can be characterized with swelling, easily recognized in

the fingers and knees. Joints usually are tender when examined during active motion

or application of pressure. Bursitis, tendonitis, muscle spasms, and torn meniscus can

cause limitations in range of motion and need to be ruled out. Synovial effusions can

be chronic but can also present during times of disease exacerbations. The patellar

tap test or the wave test can elucidate joint effusions. Patients with advanced disease

may present with the expected loss of cartilage, but also deformities in surrounding

bone and soft tissue affecting the ligaments. Joint misalignment is common and

contributes to joint unsteadiness. Fingers of patients with the characteristic Bouchard

and Heberden nodes are misaligned. Muscle atrophy is demonstrated by simply

measuring the circumference of the quadriceps muscles. The use of radiographs is

usually not necessary for the diagnosis of OA, but rather is used to rule out conditions

such as avascular necrosis, Paget disease of the bone, rheumatoid arthritis, or gouty

arthropathies. However, radiographs can be useful to establish disease severity or

monitor for disease progression. The clinical features described on radiographs that

are characteristic of OA are joint space narrowing, osteophytes at the joint margins,

and sclerosis of subchondral bone. As demonstrated in the above case study, R.T.’s

knee radiograph revealed joint space narrowing with osteophyte formation.

An ultrasound can be useful for detecting or confirming joint effusion, popliteal

cysts, or other erosive inflammatory conditions. Laboratory assessments are usually

unnecessary, because the ESR and CRP are typically within reference ranges. Serum

uric acid can help differentiate between similar inflammatory presentations. Synovial

fluid aspiration is appropriate if septic or inflammatory arthritis is suspected. In the

patient with OA, the WBC count is less than 2,000 μL, synovial fluid is clear, and

crystals are absent. There are no relevant biomarkers of bone or cartilage remodeling

that are used in the routine care of patients with OA. Magnetic resonance imaging

(MRI) scans represent an exciting area of research for assessing cartilage, synovium,

and bone, but are not routinely used in the diagnosis of OA.

CASE 43-1, QUESTION 3: Cytokines are involved in the pathophysiology of OA. Is it possible to modulate

these cytokines and thereby slow or delay the disease process to benefit R.T. before her condition worsens?

The role of IL-1 and TNF in rheumatoid arthritis pathogenesis represented exciting

discoveries that have led to highly effective disease remissions. However, in OA, the

role of these cytokines in upregulating MMP and the exact mechanism that they play

in the disease process have not been clearly elucidated and have not resulted in any

disease-mitigating therapies.

TREATMENT OF OSTEOARTHRITIS

CASE 43-1, QUESTION 4: What nonpharmacologic therapies should be recommended in R.T.?

Nonpharmacologic Management of OA

Nonpharmacologic modalities are a primary strategy for OA treatment. As previously

discussed, there are no interventions that effectively attenuate the disease process.

Pharmacologic strategies have significant untoward effects and modest efficacy in the

management of OA pain and disability. Patients typically have difficulty adhering to

self-management, aerobic, or strength-training programs. Many times,

nonpharmacologic strategies are not even attempted until pharmacologic

interventions have failed or side effects necessitate discontinuation of the offending

agent.

The ACR outlines a variety of patient education, self-management, weight loss,

aerobic, and physical and occupational therapies.

14 A study in middle-aged patients

with knee OA has demonstrated equivocal efficacy in comparing self-management

with strength training and the combination of both programs. Outcomes assessed

were pain, disability, and physical conditioning during the 2 years of the trial.

13 One

clinical trial examined the comparison of NSAID therapy with quadriceps home

exercise. Quality-of-life surveys and pain scores were not different between the

groups reviewed in this small trial.

15

In older patients, Tai Chi has established

efficacy through randomized controlled trials in the treatment of knee OA. Wang et

al.

16 demonstrated the beneficial effects of Tai Chi not only in improving physical

function and lessening

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pain in patients with OA, but also in having a positive effect on their mental health

and overall quality of life. Trial limitations included a small sample size (40

patients) and 3-month study duration. It is unknown whether those demonstrated

benefits were sustained. Patients can be referred to the Arthritis Foundation website

(http://www.arthritis.org) for further information on various programs or activities

in their areas. The Osteoarthritis Research Society International (OARSI) reiterates

the effectiveness of nonpharmacologic interventions of self-management, weight loss,

exercise, referral to physical therapy, and effective use of bracing for varus or valgus

misalignments.

11,12 Nonpharmacologic interventions remain the most effective, yet

underutilized, interventions for the treatment of OA.

11,17

R.T. should be encouraged to lose weight and participate in either selfmanagement or a structured exercise program that includes aerobic and strengthtraining exercises. Additionally, R.T. should be encouraged to participate in local

Tai Chi classes. Weight loss should be the primary goal in obese patients with OA of

the knee. Exercise improves muscle strength and helps prevent falls. The use of knee

bracing may offer some degree of support in patients with misalignments of the knee

joints.

CASE 43-1, QUESTION 5: What is the initial pharmacologic treatment recommendation for R.T.?

Pharmacologic Management of Osteoarthritis

A trial of acetaminophen 1,000 mg PO 3 to 4 times a day should be attempted for 2 to

3 weeks. More aggressive medications are usually reserved for those patients who

have failed acetaminophen. Medications such as NSAIDs can increase blood

pressure, cause GI ulceration, inhibit renal prostaglandins that are vasodilatory and,

therefore, diminish renal function, and potentially increase cardiovascular risks.

Given R.T.’s past medical history of peptic ulcer disease and lack of knee

inflammation on physical examination, the initial trial of acetaminophen is warranted.

ACETAMINOPHEN

Acetaminophen remains the first choice for the treatment of mild-to-moderate OA of

the hands and knees. Clinical practice guidelines from the American College of

Rheumatology (ACR), the American Academy of Orthopedic Surgery (AAOS), the

European League Against Rheumatism (EULAR), and the Osteoarthritis Research

Society International (OARSI) differ in their strength of recommendation, dosing, and

length of therapy for acetaminophen.

11,14,18,19

Chronic acetaminophen use in patients who consume more than three alcoholic

drinks per day can increase risk of GI bleeding and elevations of liver enzymes.

20 A

12-week randomized, controlled trial reported in 2007 that extended-release

acetaminophen 3,900 mg/day was safe, well tolerated, and more effective than 1,950

mg/day in patients with hip and knee OA.

21 More recently, it has been suggested that

select patients presenting with both pain and inflammation without contraindications

begin an initial trial with an NSAID instead of acetaminophen.

12

CASE 43-1, QUESTION 6: What is the role of topical agents in the treatment plan for R.T.?

TOPICAL THERAPY

There are numerous prescription and nonprescription topical analgesics available,

containing capsaicin, diclofenac, lidocaine, or methyl salicylate. Both the ACR and

OARSI practice guidelines conditionally recommend topical NSAID therapy as a

potential first-line therapy for joint-specific OA.

11,14 Topical capsaicin cream is

applied to the hands or knees 3 to 4 times daily. If used, R.T. should be counseled

regarding proper application, initial burning and sensitivity reactions, and

expectations of benefits that may take up to a few weeks. There are no systemic

effects or drug interactions with topical capsaicin cream.

11

Currently, three topical diclofenac products are commercially available in the

United States, including a 1% gel, a 1.5% solution, and a 1.3% patch. Topical

diclofenac 1% gel, alone or in combination with oral acetaminophen, represents

another therapeutic option. Topical diclofenac 1% gel is indicated in the treatment of

OA of the upper extremities such as the hands, elbows, and wrists, and the lower

extremities such as ankles, feet, and knees. The gel is applied according to “dosing

cards” in either 2-g or 4-g measurements. The dose for the upper extremities is 2 g 4

times a day and 4 g 4 times daily to the lower extremities.

22

Diclofenac topical solution 1.5% w/w in dimethyl sulfoxide, USP (DMSO) 45.5%

w/w represent another treatment option for the signs and symptoms of OA of the

knee. In two, 12-week, randomized, placebo-controlled trials, oral and topical

diclofenac solution was equivocal for the outcome measures of pain and physical

function.

23,24 Patients receiving the topical solution reported minor skin irritation, but

fewer GI symptoms and abnormal liver function tests than those patients receiving

oral diclofenac.

The diclofenac 1.3% patch, although available, is indicated only for the treatment

of acute pain due to musculoskeletal sprains and strains.

CASE 43-1, QUESTION 7: What monitoring parameters would be appropriate for R.T.?

Although improved tolerability and decreased toxicity profiles appear promising

for topical NSAIDs, the warnings about typical NSAID-related adverse effects are

similar for oral and topical agents.

25 Data are lacking for true upper gastrointestinal

bleed or cardiovascular event risk with topical versus oral administration. Outside of

short-term efficacy trials, the risk for systemic complications with chronic therapy

has not been investigated. Additionally, limited comparative efficacy data exist

comparing topical diclofenac with other oral NSAIDs or topical capsaicin. Oral and

topical NSAIDs should not be used concomitantly unless potential benefit greatly

outweighs the risk due to reports of increased incidence of rectal bleeding and

abnormal laboratory findings when used together.

26 The combination of

acetaminophen and topical diclofenac may be therapeutic for some patients while

avoiding other combinations with a higher degree of untoward effects. This

combination, however, has yet to be evaluated in the rigor of randomized trials. The

risk of significant GI bleeding would be theoretically less with topical preparations

as a result of less systemic absorption.

12,23,24,27

In a 2010 systematic review, oral and

topical NSAIDs were noted to have similar rates for discontinuation because of a

high incidence of topical reactions with the latter.

28

It is unclear whether these skin

reactions are caused by the type of formulation, vehicle, or other ingredients in the

preparation.

R.T. does not have a history of liver disease or hepatitis C, so a short trial of

acetaminophen does not require any monitoring for medication safety. However, it

would be important to ask her to keep a daily pain log and complete a comfort

assessment on her next visit. These tools are freely available online from multiple

sources. This will engage the patient in her own care as well as provide the clinician

with information regarding baseline data, medication efficacy, and the impact of

medication on functional impairment. Additionally, limitations or improvements in

ADLs and instrumental activities of daily living (IADLs) can provide useful

information in helping the clinician determine whether any changes in the plan of care

need to occur.

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