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Osteoporosis II

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Inflammation in RA is a very complex process. We believe it starts when one  of the class of cells that guards the body against foreign invaders ( in ordinary inflammation these are usually bacteria or viruses) comes into contact with something that triggers the alarm. One form the alarm takes is a whole battery of chemical messengers,called cytokines,that are released into the joint.
 These recruit other cells,the white blood cells that attack and kills other cells and vacteria. One form this killing takes is the release into the immediate area of very "corrosive"" chemicals. Joint tissue,an innocent bystander,is damaged.
 Furthermore,cytokines stimulate the lining of the joint (synovial lining ) to grow and produce other chemicals that break down cartilage. Cytokines are released into the blood stream,and cause fever and fatigue. The body is so finely balanced,there are also cytokines released that tend to damp down the inflammation.
Unfortunately,in the RA joint these "good" cytokines tend to become overwhelmed by the "bad" or pro-inflammatory cytokines. One of the key cytokines that promote inflammation is TNF-alpha. IL-1  alpha is another-there are many members of the
Glucocorticoid use is the most common form of drug-related osteoporosis,and its long term administeration for disorders such as RA.Osteoporosis is defined as a skeletal disorder charachterized by comprimisal bone strength predisposing  to an increased risk of fracture. Bone strength reflects the integration of two more of the criterias.
Bone density is expressed as grams per area or volume in any given individual is determined by peak bone mass and amount of bone loss.Bone quality refers to architecture,turnover,damage accumulation (e.g., microfractures) and minerilization.
It is important to acknowledge a common misperception is that osteoporosis is always the result of bone loss. Bone loss commonly as one ages,but an individual who does not reach optimal (i.e. peak) bone mass during childhood, and adolescense may develop osteoporosis  without the occurrance of accellerated bone loss.
Hence sub optimal bone growth in childhood and adolescence is an important as bone loss to the development of osteoporosis.

Osteoporosis is a condition that features loss of the normal density of bone and fragile bone.

Osteoporosis leads to literally abnormally porous bone that is more compressible like a sponge, than dense like a brick. This disorder of the skeleton weakens the bone leading to an increase in the risk of breaking bones (bone fracture).

Normal bone is composed of protein, collagen, and calcium. Bones that are affected by osteoporosis can fracture with only a minor fall or injury that normally would not cause a bone fracture.

The fracture can be either in the form of collapsing (as in a compression fracture of the vertebrae of the spine) or cracking (as in a fracture of the hip.

The spine, hips, and wrists are common areas of osteoporosis-related bone fractures, although osteoporosis-related fractures can also occur in almost any skeletal bone area.

What are the symptoms of osteoporosis?

The osteoporosis condition can operate silently for decades, because osteoporosis doesn't cause symptoms unless bone fractures.

Some osteoporosis fractures may escape detection until years later. Therefore, patients may not be aware of their osteoporosis until they suffer a painful fracture. Then the symptoms are related to the location of the fractures.

Fractures of the (vertebre) spine can cause severe "band-like" pain that radiates around from the back to the side of the body. Over the years, repeated spine fractures can cause loss of height or curvature of the spine or chronic lower back pain.chronic , which gives the individual a hunched-back appearance often called a "dowager hump."

A fracture that occurs during the course of normal activity is called a minimal trauma fracture. For example, some patients with osteoporosis develop stress fractures of the feet while walking or stepping off a curb.

Hip fractures typically occur as a result of a fall. With osteoporosis, hip fractures can occur as a result of trivial accidents. Hip fractures may also be difficult to heal after surgical repair because of poor bone quality.

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.