Original Paper RESEARCH Accepted: July 11, 2006 Published online: August 31, 2006 Psychosocial Functioning, Self-Perception and Body Image and Their Auxologic Correlates in Growth Hormone and Oestrogen-Treated Young Adult Women with Turner Syndrome Katrien Lagrou a Christelle Froidecoeur a Francisca Verlinde a Margaretha Craen b Jean De Schepper c Inge François d Guy Massa a
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5fels_cp.inddT h e n e w e n g l a n d j o u r n a l o f m e d i c i n e This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. A 66-year-old woman who is overweight reports bilateral knee pain of gradual onset
during the past several months that increasingly has limited her activities. Last week,
when walking down the stairs, she nearly fell when her knee gave way. She does not
recall having injured her knee, and she has no morning stiffness and no pain in other
joints. She has tried taking up to eight extra-strength (500 mg each) acetaminophen
tablets daily without success and has never had ulcers or stomach bleeding. How
should the patient be evaluated and treated?
Approximately 25 percent of persons 55 years of age or older have had knee pain on From the Boston University School of Med- icine, Boston. Address reprint requests to most days in a month in the past year,1 and about half of them have radiographic Dr. Felson at A203, 80 E. Concord St., Bos- osteoarthritis in the knee, a group considered to have symptomatic osteoarthritis. ton University School of Medicine, Boston, Many without radiographic osteoarthritis of the knee probably have osteoarthritis MA 02118, or at [email protected]
that is not yet visible on radiography, an imaging procedure insensitive to early N Engl J Med 2006;354:841-8.
Copyright 2006 Massachusetts Medical Society. Osteoarthritis of the knee increases in prevalence with age and is more common in women than in men. Risk factors include obesity, knee injury, previous knee sur-gery, and occupational bending and lifting.2 Osteoarthritis of the knee can be part of a generalized diathesis, including osteoarthritis of the hand, which may be inherited. The natural history of osteoarthritis of the knee is highly variable, with the disease improving in some patients, remaining stable in others, and gradually worsening in others. Osteoarthritis is a leading cause of impaired mobility in the elderly.3 Many persons with knee pain have limitations in function that prevent them from engaging in their usual activities.
Osteoarthritis affects all structures within a joint. Not only is hyaline articular cartilage lost, but bony remodeling occurs, with capsular stretching and weakness of periarticular muscles. In some patients, synovitis is present, laxity of the liga-ments occurs, and lesions in the bone marrow develop that may represent trauma to bone.4 Osteoarthritis involves the joint in a nonuniform and focal manner. Localized areas of loss of cartilage can increase focal stress across the joint, leading to further cartilage loss. With a large enough area of cartilage loss or with bony remodeling, the joint becomes tilted, and malalignment develops. Malalignment is the most potent risk factor for structural deterioration of the joint,5 since it in-creases further the degree of focal loading, creating a vicious cycle of joint damage that ultimately can lead to joint failure. Local inflammation in the synovium and the cartilage may contribute to pain and joint damage.6 The following three joint compartments combine to form the knee: the lateral tibiofemoral compartment, the medial tibiofemoral compartment, and the patello-femoral compartment. Although any of these three compartments may be a source n engl j med 354;8 www.nejm.org february Downloaded from www.nejm.org at LANDES on March 2, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e of the pain associated with osteoarthritis, pain Since the knee does not bend much during emanates most often from the patellofemoral walking on level ground, the patella does not joint.7 Bone,8 synovial inf lammation, and a articulate with the underlying femur, and pain stretched joint capsule filled with f luid9 are during this activity is not likely to originate in likely to be sources of pain; bursitis can also the patellofemoral joint. With more knee bend-cause symptoms.10 Hyaline articular cartilage is ing, such as that which occurs during sitting, un likely to be a source of pain, since it contains stair climbing, or jumping, the patella articulates no nociceptive fibers.
with the femoral trochlea, and pain during these activities is typical of that originating in the S t r a t e g i e s a n d E v i d e n c e patellofemoral joint. A history of the knee giving way may indicate the presence of an internal de- Diagnosis
rangement such as a meniscal tear or a tear of The pain of osteoarthritis is usually related to the anterior cruciate ligament. However, it may activity. For osteoarthritis of the knee (Fig. 1), also reflect weakness of the muscles that support activities such as climbing stairs, getting out of a the joint. Pain in the knee at night reflects either chair, and walking long distances bring on pain. severe symptomatic disease or pain from causes Morning stiffness usually lasts less than 30 min- other than osteoarthritis, such as inflammatory utes.11 Patients often note that their knees “give arthritis, tumors, infection, or crystal disease way,” a so-called instability symptom.
Examination of the patient should include test- ing for various possible causes of knee pain (Ta-ble 1). Since arthritis of the hip can cause referred pain to the knee, range of motion of the hip should be assessed to see whether movement at the hip joint induces knee pain or whether there is groin tenderness. Bursitis (either anserine or trochanteric) should also be ruled out. Trochan-teric bursitis is part of a syndrome of lateral hip and thigh pain that can extend distally to the tensor fascia lata and even to the iliotibial band, causing lateral knee pain that occurs especially with bending of the knee. Examination of the iliotibial band and more proximal structures in the lateral thigh can identify the source of pain (Table 1). Both anserine and trochanteric bursitis can be treated effectively with a local injection of a corticosteroid.
Tenderness at the junction of the femur and tibia (the joint line) should be evaluated, as should the presence of an effusion. Examination of the patient should include an evaluation of whether the legs are varus (bowlegged) or valgus (knock- kneed), a physical finding that usually signifies marked malalignment. The knees are farther apart than the feet in the frontal plane when a person with varus malalignment is standing, and the knees are closer together than the feet in a person with valgus malalignment. Varus and val-gus malalignment are strong risk factors for wors-ening radiographic disease4,5 and are probably Figure 1. Osteoarthritis of the Medial Side of the Knee.
associated with functional limitations.5 In addi-tion, gait should be observed to determine wheth- n engl j med 354;8 www.nejm.org february Downloaded from www.nejm.org at LANDES on March 2, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. Table 1. Features That Distinguish Various Causes of Chronic Knee Pain from Osteoarthritis.*
Features According to History
Features of Physical Examination
Bloody synovial fluidPossibility of an abnormal radiograph Prominent mechanical symptoms Tenderness over the joint line * Knee pain is defined as chronic if it is present for at least six weeks. MRI denotes magnetic resonance imaging.
† Tenderness of the iliotibial band is usually lateral to the knee over the insertion site of the iliotibial band in the fibular head or superior to that, where it courses over the lateral femoral condyle.
‡ No physical examination maneuver for meniscal tears has both high sensitivity and specificity.12 Tenderness at the joint line has a sensitivity of 79 percent and a specificity of 15 percent, whereas a McMurray test has a sensitivity of 53 percent and a specificity of 59 percent. A McMurray test is positive if a click is palpable over the medial or lateral tibiofemoral joint line during flexion and extension of the knee during varus (medial tear) or valgus (lateral tear) stress. These data are derived from studies of acute tears,12 and diagnostic data are not available for chronic tears.
§ A Lachman test is positive if there is excessive anterior translation of the tibia at 30 degress of knee flexion.
er there is antalgia (a limp secondary to pain) ligament tears are common15; diagnosing them is and whether gait has slowed because of knee not likely to change treatment. Repairing menis-pain. If the patient uses a cane, appropriate use cal tears in patients with osteoarthritis is unlikely of the cane should be assessed during gait.
to improve the disease course or ameliorate pain; The location of tenderness in the knee is some- meniscal tears are not associated with pain in times helpful in diagnosis, although its reproduc- osteoarthritis.14,16
ibility is limited.13 Tenderness over the medial or
lateral joint lines often signals disease there but Laboratory Tests
is also common with meniscal tears.12 Patello- No blood tests are routinely indicated in the work-
femoral tenderness provides evidence of involve- up of a patient with chronic knee pain unless
ment of the patellofemoral compartment with symptoms and signs suggest rheumatoid arthri-
either osteoarthritis, inflammatory arthritis, or tis or other forms of inflammatory arthritis (Ta-
other conditions (Table 1). Tears of the anterior ble 1). Examination of synovial fluid is indicated
cruciate ligament, if acute, may cause pain. The if inflammatory arthritis or gout or pseudogout
anterior cruciate ligament prevents translation is suspected or if joint infection is a concern; a
of the tibia anteriorly during flexion of the knee, white-cell count below 1000 per cubic millimeter
and when there is anterior cruciate ligament in- in the synovial fluid is consistent with osteoar-
sufficiency, a Lachman test is more often posi- thritis, whereas higher white-cell counts suggest
tive than is an anterior drawer test (Table 1).12 In inflammatory arthritis. The presence of crystals
patients with advanced osteoarthritis, meniscal is diagnostic of either gout or pseudogout.
tears are nearly universal14 and anterior cruciate
Radiography is indicated in the workup of a n engl j med 354;8 www.nejm.org february Downloaded from www.nejm.org at LANDES on March 2, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e patient if knee pain is nocturnal or is not activ-ity-related. If knee pain persists after effective therapy for osteoarthritis, a radiograph may reveal clues to a missed diagnosis. In patients with osteoarthritis, the radiographic findings corre-late poorly with the severity of pain (Fig. 2), and radiographs may be normal in persons with dis-ease.17 Although chondrocalcinosis may be seen on the radiograph, it is an age-related finding that is inconsistently associated with knee pain.18 Avascular necrosis can be diagnosed with radiog-raphy, although if it is seen, it is often too late Figure 2. Radiograph Showing Osteoarthritis of the
to treat it. Magnetic resonance imaging (MRI) is Medial Side of the Knee.
likely to reveal changes that indicate the presence Narrowing of the medial joint space (arrow) and osteo- of osteoarthritis, but it is not suggested in the workup of older persons with chronic knee pain. MRI findings of osteoarthritis, including menis- ity of conventional NSAIDs has been the use of cal tears, are common in middle-aged and older COX-2 inhibitors,23 although the results of recent adults14 with and without knee pain.
trials showing increased cardiovascular risk with these agents has limited their use.24 Alternatively, Treatment
the combination of NSAIDs and misoprostol or Treatment of osteoarthritis involves alleviating proton-pump inhibitors has been shown in ran-pain, attempting to rectify mechanical malalign- domized trials to reduce the number of endoscop-ment, and identifying and addressing manifesta- ically confirmed ulcers associated with NSAIDs tions of joint instability.
Nonsteroidal Antiinflammatory Drugs, Cyclooxygenase-2 Inhibitors, and Acetaminophen Injections of hyaluronic acid into the knee joint For treating the pain of osteoarthritis of the knee, have been approved by the Food and Drug Ad-head-to-head randomized trials showed that non- ministration for the treatment of osteoarthritis. steroidal antiinflammatory drugs (NSAIDs) and However, data on efficacy are inconsistent. Two cyclooxygenase-2 (COX-2) inhibitors are more ef- recent meta-analyses27,28 reported statistically sig-ficacious than acetaminophen.19,20 However, the nificant but limited efficacy. In one meta-analy-superiority of NSAIDs over acetaminophen (at sis, publication bias (preferential publication of doses of 4 g per day) is modest.20 In one large positive studies) was seen, which can inflate meta-crossover trial,19 the average reduction in pain analysis estimates from published studies. The during the first treatment period, on a scale of identification of two large, unpublished trials 0 to 100, was 21 in patients treated with NSAIDs whose data showed no efficacy,28 and the obser-and 13 in those given acetaminophen (P<0.001). vation that injections of hyaluronic acid appeared Because of the greater toxicity of NSAIDs, acet- to be less effective in large than in small trials, aminophen should be the first line of therapy. suggest that even limited efficacy may be an over-Acetaminophen appears less effective, however, estimate.
among patients who have already received treat-ment with NSAIDs; in the crossover trial there Glucosamine and Chondroitin Sulfatewas no improvement overall with acetaminophen Glucosamine and chondroitin sulfate are widely in patients treated after a six-week course of used for the treatment of osteoarthritis, although NSAIDs.19 Low doses of antiinflammatory medi- their mechanisms of action are unclear. Most ran-cations (e.g., 1200 mg of ibuprofen per day)21 are domized controlled trials have reported greater less efficacious but better tolerated than high pain relief with treatment with either compound doses (e.g., 2400 mg of ibuprofen per day).22 One than with placebo28 and have found little toxicity, strategy to decrease the potential gastric toxic- usually no more than that associated with place- n engl j med 354;8 www.nejm.org february Downloaded from www.nejm.org at LANDES on March 2, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. Table 2. Pharmacologic Treatment for Osteoarthritis of the Knee.
Patients with liver disease or alcoholism should avoid. Take with food. High rates of gastrointestinal side effects, in- cluding ulcers and bleeding, occur. Patients at high risk for gastrointestinal side effects should also take either a proton-pump inhibitor or misoprostol.† There is an increased con- cern about side effects (gastrointestinal or bleeding) when taken with acetylsalicylic acid. Can also cause edema and renal insufficiency.
High doses are associated with an increased risk of myocardi- al infarction and stroke. Can cause edema and renal insuf-ficiency.
Side effects are similar to those with placebo.
Side effects are similar to those with placebo.
Common side effects include dizziness, sedation, nausea or vomiting, dry mouth, constipation, urinary retention, and pruritus. Respiratory and central nervous system depression can occur.
Varies from 3 to 5 weekly Mild to moderate pain at injection site.
* NSAIDs denotes nonsteroidal antiinflammatory drugs.
† Patients at high risk include those with previous gastrointestinal events, persons 60 years of age or older, and persons taking corticosteroids.25 Trials have shown the efficacy of proton-pump inhibitors and misoprostol in the prevention of ulcers and bleeding.26 Misoprostol is associated with a high rate of diarrhea and cramping; therefore, proton-pump in-hibitors are more widely used to reduce NSAID-related gastrointestinal symptoms.
bo. Publication bias was found as part of a meta- are lacking about the optimal number or frequen-analysis of published trials evaluating these treat- cy of corticosteroid injections. Opiate analgesic ments, and this suggests that efficacy results from agents are more efficacious than placebo in con-only published reports may be inflated.28,29 Four trolling pain, but side effects and dependence are trials published since this meta-analysis, includ- concerns. Topical compounds such as capsaicin ing two that were large enough to detect modest have been modestly better than placebo in reducing treatment effects, have shown no efficacy of glu cos- the pain of osteoarthritis of the knee (Table 2).34amine.30,31 Results of a recently completed multi-center trial of glucosamine and chondroitin, Nonpharmacologic Treatmentwhich was funded by the National Institutes of Too little attention is paid to nonpharmacologic Health, appear in this issue of the Journal.32 treatments (Table 3). In patients with osteoar-thritis of the knee, weakness of the quadriceps muscles is caused by disuse and by inhibition of In randomized trials, intraarticular corticosteroid muscle contraction in the presence of adjacent injections have relieved pain more effectively than capsular swelling (so-called arthrogenous muscle placebo for one to three weeks on average, after inhibition).35 The severity of pain is directly cor-which their comparative efficacy wanes.33 Data related with the degree of muscle weakness.36 n engl j med 354;8 www.nejm.org february Downloaded from www.nejm.org at LANDES on March 2, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e Table 3. Nonpharmacologic Treatment for Osteoarthritis of the Knee.
Malalignment is induced over a long period by Treatment
anatomic alterations of the joint and bone, and correcting it is challenging. Evidence from ran-domized trials is sparse regarding the efficacy of Avoid if joint pain worsens. Progressive training is most effective. Exercises in a pool or partial- therapies to correct malalignment across the knee weight-bearing exercises are often tolerated bet- joint. In one trial of patients with osteoarthritis ter than equivalent full-weight-bearing exercises.
of the medial side of the knee and varus malalign- ment, wearing a neoprene sleeve over the knee A cane should be held contralateral to the affected decreased knee pain moderately and significant- knee with the hand at the level of the greater tro- ly as compared with no treatment42; the use of a chanter of the hip. The cane and the affected leg should contact the ground at the same time.
valgus brace (which also can lessen varus malalign-ment)41 decreased pain significantly more than Indicated when malalignment is noted on examina- tion and pain is unresponsive to other medical Other ways of correcting malalignment across treatments. Braces or taping can cause skin irri- the knee include the use of wedged insoles or tation and can impede the return of blood flow orthotics in footwear. In patients with osteoar- thritis and varus malalignment of the knees, a Reduces pain on average only moderately after sev- shoe wedge (thicker laterally) moves the center of loading laterally during walking, a change that extends from foot to knee, lessening medial load Although strong muscles may promote structural across the knee. Although such modifications to deterioration in malaligned knees,37 strengthen- footwear decrease varus malalignment,43 one ing the muscles is still important because stronger randomized trial44 showed no reduction in pain muscles improve the stability of the joints and as compared with a neutral insert.
lessen pain. Patellofemoral pain may be caused by tilting Exercises are likely to be most effective if they or malalignment of the patella. Patellar realign- train muscles for the activities a person performs ment with the use of braces or tape to pull the daily. Range-of-motion exercises, which do not patella back into the trochlear sulcus of the femur strengthen muscles, and isometric exercises, or reduce its tilt may lessen pain. In clinical trials which strengthen muscles, but not through a in which tape was used to reposition the patella range of motion, are unlikely to be effective. To into the sulcus without tilt, knee pain was re-reduce pain and improve function, randomized duced as compared with placebo.45,46 However, trials have demonstrated the efficacy of isokinet- patients may find it difficult to apply tape, and ic or isotonic strengthening (i.e., strengthening skin irritation is common. Commercial patellar that occurs when a person flexes or extends the braces are also available, but their efficacy has knee against resistance).38,39 Low-impact aerobic not been studied formally.
exercise is also effective38 in lessening pain. Exer-cise regimens may differ for persons with patel- lofemoral symptoms. If the knee hurts during an exercise, then that exercise should be avoided. Guidelines are available for the treatment of knee The involvement of a physical therapist is often osteoarthritis47-49 but predate the publication of warranted.
many of the trials of interventions discussed in In a recent randomized trial, the combination this review.
of exercise and modest weight loss (mean, 4.6 kg) — but not weight loss alone — reduced pain and Sum m a r y a nd R e c om menda t ionsimproved physical function in patients with os-teoarthritis of the knee as compared with educa- Knee pain related to activity, such as in the woman tion about nutrition, exercise, and arthritis.40 In in the vignette, is characteristic of osteoarthritis. a large controlled trial, acupuncture was shown Physical examination should be performed to rule to reduce pain in patients with osteoarthritis of out findings suggestive of other causes of knee the knee,41 as compared with no acupuncture and pain and to assess for abnormalities associated sham acupuncture, but the effect was small.
with osteoarthritis, such as varus or valgus de- n engl j med 354;8 www.nejm.org february Downloaded from www.nejm.org at LANDES on March 2, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. formity. Radiographs of the knee are not indi- inforce the importance of exercise by asking the cated routinely, although I would order these in patient to demonstrate her exercises and report the case described in the vignette, given the lack how often she does them. Weight loss should be of response to acetaminophen. If there is an effu- recommended along with exercise. sion, arthrocentesis should be considered. Although data are limited to support the use On the basis of data from randomized trials of a neoprene sleeve, I would recommend that and the lack of efficacy of acetaminophen, I would the patient use one when she walks, even in the treat the patient with an NSAID as needed (with absence of varus deformity, because of her symp-food), and given her age, I would add a proton- toms of pain and because her knee gives way. pump inhibitor. Topical capsaicin has been shown Should the sleeve be ineffective, I would fit her to be of moderate benefit in reducing pain and for a valgus knee brace if she would be willing could also be considered. An intraarticular corti- to wear one and if she has a varus deformity.
costeroid injection could alleviate pain for the Supported by a grant (AR47785) from the National Institutes I would refer the patient to physical therapy No potential conflict of interest relevant to this article was for exercises to strengthen the quadriceps and I am indebted to Douglas Gross for helpful suggestions about for an evaluation of function, and I would re- exercise, and to Jennifer Mendez for technical assistance.
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