The patient is a 48-year-old white woman who is postmenopausal (her last menstrual period was 12 months ago). She is
married and has 2 teenaged children. The patient's history is remarkable for RA, for which she has taken sulfasalazine and
naproxen for the past 4 years. In the past year, the patient has received local glucocorticoid injections on several occasions
with temporary pain relief.
However, the disease has become more active for the past 3 months and the pain is currently unresponsive to NSAIDs. The
patient has just been switched from sulfasalazine to methotrexate. Her current medications include 1 tablet of naproxen 500
mg bid, methotrexate10 mg/week, folic acid 1 mg/day, and a daily multivitamin.
Physical Examination: Height: 5'3" (160 cm) ;Weight: 158 lb (71.8 kg) ;Blood Pressure: 136/82 mm Hg;Cardiac: no extra
sounds, no murmur, apical rate 82 bpm
Chest: clear ;Musculoskeletal: swollen and/or tender joints noted bilaterally at wrists, phalanges (primarily proximal),
hips, and knees. No joint crepitus or instability noted. Total involvement of more than 10 joints. Decreased range of motion
at hands, hips, and knees. Skin: no lesions or rashes Neurologic: no abnormalities noted
Laboratory Results: CBC: Hgb 11.8 g/dL; Hct 35%; WBC 8,600; Platelets 139,000 ;ESR: 60 mm/hr ;RA titer: 1:64 ;CRP (C-reactive
protein) 1.4 mg/dL Electrolytes, BUN and creatinine, and LFTs all WNL ;Urinalysis: negative for blood and protein
Glucocorticoids should be considered for symptom relief in this patient. Methotrexate is a disease-modifying antirheumatic
drug (DMARD) with the potential to delay progression of RA. DMARDs are generally slow acting with a delay of 1 to 6 months
before their full clinical response is appreciated.
Glucocorticoids are indicated for patients with RA to alleviate symptoms and improve level of functioning. Although some
evidence suggests that low-dose glucocorticoid therapy, used in combination with a DMARD, may reduce the rate of progression
in patients with early, active RA, there is no evidence for this benefit in a patient with long-standing RA. Because there
are more than 10 tender and swollen joints in this patient, local glucocorticoid injections are no longer a practical solution.
RA is a chronic progressive autoimmune disorder characterized by symmetric polyarthritis and sometimes complicated by
multisystem involvement. The patient with RA typically experiences periods of remission alternating with periods of reactivation
and disease flares. The treatment plan may have to be revised numerous times during the course of the disease.
Untreated, RA may lead to progressive joint destruction, deformity, disability, and premature death. Patients with active,
polyarticular, rheumatoid factor-positive RA have a very high probability of developing joint damage within 2 years of the
onset of disease; thus, rheumatologists generally recommend early, aggressive, ongoing treatment.
The goals of treatment for a patient with RA are to halt progress of the disease, alleviate pain, maintain functioning,
and maximize quality of life. Because of the complexity of the disease, there are many situations in which it would be helpful
to consult with a rheumatologist.
As the rheumatologist continue to assess the patient's current level of functioning and quality of life, she informs
him that she has moderate-to-severe joint pain, particularly in her hands and knees, 1 to 2 hours of debilitating morning
stiffness, and moderate fatigue, requiring her to take an afternoon nap. She previously worked as a pastry chef, but now is
unable to work or do heavy housework. On good days she is still able to do light housework, cook, and drive.
Because glucocorticoids serve a different purpose in the regimen of a patient with longstanding RA, they cannot be considered
a substitute for determining if the regimen is adequately controlling disease progression. DMARDs may be used in combination
to achieve disease control, although this often, may, increases the toxicity of the regimen (some trials have suggested otherwise).
In a patient with RA, glucocorticoids often offer dramatic, rapid relief of the joint pain associated with disease flares,
particularly while the patient is waiting for a DMARD to halt disease progression. Glucocorticoids are often required to control
disease symptoms when NSAIDs are unable to provide sufficient relief.
Initiate therapy with a low-dose, long-acting oral glucocorticoid and plan to continue for 3-6 months. A long-acting,
low-dose glucocorticoid (less than or equal to 10 mg prednisone daily or equivalent) is highly effective for relieving symptoms
in patients with active RA.
Because the patient has had just changed to a new DMARD (methotrexate), it could take 6 months before control of her
RA is achieved. While it is desirable to minimize use of glucocorticoids as much as possible, it is realistic to assume that
the patient will require 3 to 6 months of therapy prior to tapering.
When needed, low-dose glucocorticoids are recommended for patients with uncomplicated RA, since the development of adverse
events occurs in a dose-dependent fashion. Every effort should be made to limit glucocorticoid therapy as much as possible
in both dose and duration of use. Low-dose oral glucocorticoids may be of particular benefit to patients at times when the
disease is severe enough to affect the patient's function, sleep, or ability to work.
Glucocorticoids are also used for patients with refractory RA in whom trials of NSAIDs and numerous DMARDs have failed.
For patients receiving systemic glucocorticoids who exhibit stable or improving disease, tapering of the dosage and eventual
discontinuation of the medication should be attempted.
Glucocorticoid-dependent RA patients with severe or refractory disease may also be candidates for tumor necrosis factor
(TNF) blocking agents such as etanercept or infliximab, which also may be glucocorticoid-sparing.
The patient should add calcium and vitamin D supplementation to her current daily regimen, in order to reduce the risk
of bone loss during glucocorticoid therapy. The decision to continue naproxen or methotrexate would not be altered by the
initiation of glucocorticoid therapy.
The patient should be informed that one of the potential side effects of glucocorticoid therapy is bone loss and risk
of glucocorticoid-induced osteoporosis (GIO). Bone loss occurs in the majority of glucocorticoid-treated patients. A threshold
dose for glucocorticoid-related bone loss is not certain; however, patients treated with prednisone 7.5 mg/day or higher for
more than 6 months experience significant and rapid bone loss in the spine and hip.
Treatment with calcium and vitamin D supplementation is recommended for all patients at risk of osteoporosis. This patient
should have a total daily calcium intake of 1500 mg/day (from a combination of dietary intake plus supplement ation) and she
should take a daily vitamin D supplement (400 to 800 IU).
A further assessment of the patient's risk for development of GIO should be conducted, and a baseline measurement of
bone mineral density (BMD) should be obtained. It is already known that the patient is having a disease flare; thus, there
is no need to repeat ESR or CRP.
A decision to initiate oral glucocorticoid therapy in a patient with RA should include a global assessment of the patient's
risk factors for osteoporosis. The patient should be informed about potential side effects, the importance of compliance,
and the danger of abrupt cessation of the medication after long-term use. The physician might also suggest that the patient
wear a medical alert bracelet indicating treatment with glucocorticoids, if chronic therapy is anticipated.
The patient's identified risk factors for osteoporosis include white race and postmenopausal status. She should also
be assessed regarding other potential risk factors such as history of hip fracture in a first-degree relative, smoking, and
adult weight under 127 lb.
The patient smokes a pack of cigarettes/day, which is another risk factor for osteoporosis. She does not drink alcohol.
The ACR recommends that a BMD assessment be conducted as a baseline measurement for patients initiating long-term glucocorticoid
treatment (i.e. greater than 6 months of therapy).
According to the American Association of Clinical Endocrinologists (AACE), "postmenopausal women taking more than 7.5
mg of prednisone (or equivalent) for more than 3 weeks should be considered for a preventive strategy with the use of bisphosphonates,"
if their baseline BMD is low. A baseline BMD measurement is therefore indicated when preventive therapy is being considered
in a postmenopausal woman.
The ACR and American College of Radiology suggests that initial BMD evaluation by dual energy x-ray absorptiometry (DXA)
be conducted at a central site, preferably at the lumbar spine or femoral neck.
The patient is sent for a BMD measurement of the lumbar spine by DXA. Her report returns with a T score of 0.50 standard
deviations (SD) below normal (0.50 SD).
According to the World Health Organization (WHO) classification system, a T score value between 0.5 SD and +0.5 SD is
considered normal, and thus the patients BMD is within normal limits. The WHO classifies osteopenia (borderline-low BMD) as
a BMD with a T score that is equal to or more than 1 SD below normal but less than 2.5 SD below normal (between 1.0 SD and
2.5 SD).
Osteoporosis is defined as a BMD with a T score that is equal to or more than 2.5 SD below normal (more than 2.5 SD).
The T score compares the patient's BMD with a young, healthy reference population.
While the patient's BMD is within normal limits at baseline, the initiation of glucocorticoid therapy in any patient
is of great concern, since the most rapid bone loss is known to occur in the first few months of glucocorticoid therapy.
The ACR considers the initiation of glucocorticoid therapy to be a special situation, for which it has specific recommendations:
1) Modify lifestyle risk factors for osteoporosis 2)Smoking cessation or avoiidance. 3)Reduction of alcohol consumption
if excessive. 4)Instruction in weight-bearing exercise. 5)Initiate calcium supplementation 6)Initiate supplementation with
vitamin D (plain or activated form). 7)Prescribe bisophhonate (use with caution in premenopausal women).
A bisphosphonate is indicated to prevent GIO in this patient. The most recent guidelines from the ACR suggest initiating
therapy with a bisphosphonate to prevent bone loss in all postmenopausal women in whom long-term glucocorticoid treatment
at 5 mg/day is being initiated for the first time with an expected duration of more than 3 months.
In addition, a discussion of the pros and cons of initiating estrogen or hormone replacement therapy (ERT or HRT) in
this patient should be undertaken at this time. This discussion should inform the patient that HRT has the potential to prevent
bone loss, however in this case, it could not be considered a substitute for initiating therapy with a bisphosphonate.
A bisphosphonate can be prescribed whether or not the patient receives HRT. Data suggest that HRT is adequate therapy
to prevent bone loss in postmenopausal women receiving chronic, low-to-moderate dose glucocorticoid therapy. Currently, however,
there are no published reports regarding the efficacy of HRT for the prevention of bone loss at the initiation of glucocorticoid
treatment, or the degree of the protective effect of HRT when moderate-to-high doses of glucocorticoids are used for long-term
treatment.
Specifically, the ACR recommends that bisphosphonates should be used in conjunction with calcium and vitamin D supplementation
in the following groups of glucocorticoid-treated patients:
1)Patients in whom glucocorticoid therapy is being initiated for the first time with plans for treatment duration of
more than 3 months. (Cautious use is suggested for premenopausal women.) 2)Patients receiving long-term glucocorticoid therapy,
with documented osteoporosis based on BMD measurements or the presence of an osteoporotic fracture. 3)Patients receiving long-term
glucocorticoid therapy who have had fractures while receiving HRT or in whom HRT has not been well tolerated. 4)Both alendronate
and risedronate are approved by the FDA with the indication of treatment of GIO; furthermore, risedronate has a specific indication
for prevention of GIO.
The ACR currently recommends either alendronate or risedronate for the prevention and treatment of glucocorticoid-induced
bone loss. Specific prescribing recommendations of the ACR are as follows:
1) Glucocorticoid-treated premenopausal women, postmenopausal women receiving HRT, and men should be treated with either
alendronate 5 mg/day or risedronate 5 mg/day. 2)Glucocorticoid-treated postmenopausal women not receiving HRT should be treated
with either alendronate 10 mg/day or risedronate 5 mg/day.
The patient is initiated on a glucocorticoid and a bisphosphonate. Her current medication regimen now includes prednisone
7.5 mg qd, risedronate 5 mg qd, naproxen 500 mg bid, methotrexate 10 mg/week, folic acid 1 mg qd, calcium carbonate 500 mg
bid, vitamin D 400 IU qd, and a daily multivitamin.
The patient's regimen is complicated and she must be informed of the specific concerns associated with each medication.
Toxicities that require monitoring with this regimen include gastrointestinal (GI) bleeding, GIO, hypertension, hyperglycemia,
renal damage, hepatotoxicity, and myelosuppression.
Monitoring for myelosuppression, renal toxicity, and hepatic toxicity during methotrexate therapy will continue as long
as the patient continues this therapy.
Fortunately, there is no significant risk of drug-drug interaction in this regimen.
While it is important to reinforce that the patient must not discontinue any of these medications without informing the
physician, the risks associated with abrupt cessation of glucocorticoid therapy should be stressed. Instructions for the use
of a bisphosphonate should be made explicit as well. In addition, if the patient responds quickly to prednisone, it would
be reasonable to consider discontinuation of naproxen, in order to decrease her risk of GI adverse effects.
How long should the patient be administered bisphosphonate? This will be determined based upon the duration of glucocorticoid
therapy, however the bisphosphonate should not be continued in this patient once glucocorticoid therapy is withdrawn. Treatment
with a bisphosphonate, concomitant with a future required course of glucocorticoids, would be determined by a reevaluation
of the patient's risk of bone loss at that time.
The risk of bone loss is most acute during the first 3 months of an initial course of glucocorticoid therapy. The patient
should not remain on a bisphosphonate once glucocorticoids are discontinued, although risk of GIO should be reevaluated prior
to using glucocorticoids again.
A study in postmenopausal women with RA assessed the relative effects of disease activity, disability, and past and current
use of low-dose glucocorticoids on BMD. The mean BMD was similar in women who had previously used glucocorticoids and those
who had never used them, suggesting that, while low-dose glucocorticoids are associated with bone loss during their use, recovery
following discontinuation may occur.
The patient experiences a remission of RA and is able to taper slowly off of glucocorticoids after 20 weeks of therapy.
After discontinuation of glucocorticoid therapy, the bisphosphonate is also withdrawn.
When should the patient have a repeat evaluation of BMD? The patient would need a repeat BMD measurement prior to the
initiation of another course of glucocorticoids. Because she had a normal BMD at baseline and intervention was initiated to
prevent bone loss during her initial glucocorticoid therapy, there is no need to repeat BMD measurement, unless a decision
regarding the use of Bisphosphonates needs to be made in the future.
If the patient's bone mass has remained stable, a bisphosphonate would not be indicated for further glucocorticoid therapy.
The patient should continue to take calcium and vitamin D supplements indefinitely. Furthermore, a discussion regarding the
risks and benefits of initiating HRT in this postmenopausal woman should also be initiated when her RA disease has been stabilized.
Strategies for the primary prevention of osteoporosis include all of the following, 1)Recommending adequate lifelong
calcium intake across the lifespan. 2)Educating girls and young women about the adverse effects on bone health associated
with excessive dieting and weight loss. 3)Educating adolescents about the adverse effects on bone health associated with smoking.
Children and adolescents generally have sufficient stores of vitamin D from exposure to sunlight and intake of milk that
is fortified with vitamin D.
