The major reason that predisone is tapered.rather then simply discontinued,is predisone when taken for a extended period,of time, can suppress the ability of the adrenal glands to produce natural cortisone. This is because the adrenal glands can shrink (atrophy} when chronically exposed to predisone.

 

When our bodies can't make natural cortisone,it can lead to low blood pressure, nausea, vomiting,dizziness,and abdominal pain. This is called adrenal insufficiency.

 

Slow tapering of predisone minimize the risk of adrenal insufficiency. Some patients also develop muscle and/or joint aching (called steriod withdrawal symptoms) when predisone is tapered too rapidly or abruptly discontinued.

 

When corticosteriods are used in doses of more than the equivalent of  7.5 milligrams of predisone a day,the adrenal gland does not make corisol. This is not a problem if drugs such as predisone are used for short periods only.

 

But when such doses are used continuously for prolonged periods ( three months is considered the cut off  ),cortisol production will be completely suppressed. The patient is now dependent on a source outside the body for corticosteriod.

 

The only safe way to reduce,stop,corticosteriods is slowly,over a period of weeks to months. But even if the patient has managed to achhieve this,the body may not completely recover its ability to produce large amounts of cortisol in circumstances of stress until a year goes by.

 

Because of this,patients who are on ( or have been on ) corticosteriods must be given extra corticosteriod if they are exposed to severe physical stress. Such events as an serious accident or major surgery call for immediate corticosteriod treatment,usually by needle,into a vien.

 

Regrettably,the most effective way to avoid the side effects is not to take them,but this is not always possible. Next best way is to minimize the damage by attempting to keep the dose as low as possible most of the time and keep high-dose treatment short.

 

If at all possible,the daily dose should be taken as a single morning dose,since normal cortisol production is much less likely be suppressed at this time. Corticosteriods should never be stopped suddenly if they have been taken continuously for more then a week or two.

 

Since corticosteriods are essential for life,and are particularily important in helping the body deal with major physical stress,their sudden absence,if for any reasons the patient stops taking daily predisone,can have serious consequences.

 

Toronto,ON and Laval,QC--11/16/01--Actonel (TM),(risedronate) has been approved by Health Canada for the treatment and prevention of glucocorticoid induced osteoposis (GIO) in men and women.

 

Acetonel was originally approved for treatment and prevention of post menopausal osteoporosis (PMO) in the summer of 2000. Only Acetonel has demonstrated a one-year vertebral fracture benefit in both PMO and GIO patients. Additionally,Acetanel has recently been shown to prevent clinical vertebral fractures in PMO patients in as soon as six months.ACR: Acetonel (Risedronate) Once-a-week proves equally effective as acetonel daily in postmenopausal osteoporosis.Acetonel therapy is appropriate for those patients receiving at least 7.5 mg/day of predisone or its oral equivalent for chronic diseases.

 

The New ACR guidlines for patients beginning therapy with glucocorticoids (equivalent to 7.5 mg/day of predisone) for treatment expecting to last 3 months:

 

*Modify lifestyle risk factor for osteoporosis--Smoking cessation or avoidance.  -- Reduction of alcohol consumption if excissive.

*Instruct in weight-bearing physical exercise.

*Initiate calcium supplementation.

*Initiate supplementation with Vitamin D (plain or activated form).

*Prescribe bisphosphonate (premenopausal women should use with caution).

 

In addition to above,for patients receiving long-term glucocorticoid therapy the ACR recommends:

 

*Prescribe treatment to replace genadal sex hormones if deficient.

*Measure bone mineral density (BMD) at lumbar spine and/or hip.

*If BMD is not normal (i.e., T score below -1),then prescribe bisphosphonate (use with caution in women).

*Consider calcitonin as second-line drug if patient can not tolerate bisphosphonate therapy.

*If BMD is normal,follow up and repeat BMD measurement either annually or biannually.

 

According to the National Osteoporosis Foundation (NOF), a diet that is rich in calcium and vitamin D and a lifestyle that includes weight-bearing exercises are the best ways to prevent weakened bones in later life. Getting enough calcium all through one's life help to build and keep bones strong. In 1992 the National Academy of Science (NAS) suggested that people from age 31 to 50 get 100 mg of calcium each day. The NOF recommends people over 50 should get 1200 mg daily.

 

Our bodies use Vitamin D to absorb calcium. The NAS recommends people age 51 to 70 need  400 IU (international unit) each day and those over 70 should reach 600 IU. Be careful,more than 2000 IU of Vitamin D each day, may cause harm to the liver and even lower bone mass.

 

Exercise makes bone and muscles stronger and helps bone loss. It also helps one stay active and mobile. Weight-bearing exercises,done three to four times a week,are best for preventing osteoporosis. Walking,jogging,playing tennis, and dancing are all good weight-bearing exercises. Strengthening and balance exercises can help prevent falls and lessen the chance of breaking a bone. According to the NAS,there is no such thing as being "too old" or "too frail" to do some sort of exercise or movement.

 

The recommendations from the ACR to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids,but more needs to be done. Lenore Buckley,M.D., of Virgina Institue says,further studies of combination therapy are needed to provide new options for the prevention of this serious complication of glucocorticoid use.

 

 

 

Rheumatoid arthritis is a good example of such a condition. Problems with corticosteriods are of two types-those arising from using doses higher than the amount the body normally makes each day ( about 7.5 mg ),and those arising from the sudden withdrawal of the medication. The likelihood,and severity,of both are directly related to the size of the daily dose and the length of time it is given.

 

When the dose of predisone ( or another similar synthetic corticosteriod ) exceeds 7.5 milligrams a day for more the a few weeks or months,signs of hypercortisonism begin to develop. Cushing's syndrome,a disease state where the adrenal glands produce cortisol in excess and develops hypercortisonism is identical.

 

Fully developed,hypercortisonism may include any or all of the following features : Increased appetite and weight gain,especially on the trunk and face. A chubby face is typical of someone on high-dose,long-term predisone. Easy brusing and skin fragility of the arms and legs,especially in older people. Cataract development. Mood changes. Mild euphoria is common,but depression may occur. Insomnia is frequent. High blood pressure. Extra insulin required by diabetics because of higher blood sugars,and pre-diabetics becoming overtly diabetic. Stomach ulcers,if the patient is taking NSAIDs at the same time. Stunting of growth in children.

 

Osteonecrosis is is a specific type of dead bone,the kind that results when an area of bone loses its blood supply. If this happens near a joint-and the hip is a favorite target-the area of dead bone may collapse-ending up in surgery and a total hip replacement. Cortisone-like drugs have been seen for a long time responsible for osteonecrosis,although this is hard to prove. Fortunately, osteonecrosis from predisone is very rare. Crohn's disease and Lupus patients use corticosteriod more,and it may be responsible. for osteonecrosis. in patient's who develop it. There is no question that the long term use of predisone in SLE increases the risk of hardening of the arteries and,in particular,coronary artery disease. These condition increase the risk of stroke and heart attack,substantially there is some debate as to whether or not predisone has the same effect in RA

 

Osteoprorosis; Bone is a living tissue. Old bone is continually being broken down,in patches. This process is followed almost immediately by the laying down of new bone by bone-forming cells. The new processes of breakdown and repair exceeds repair,bone mass (solidity ) is reduced. Thuis is called osteoporosis.

 

Between 10 and 20 % of all patients with RA,who are on long-term corticosteriods,will experience crush fractures of one or more vertebrae in the backbone. The risk of hip fracture in these patients is 50 %.

 

This risk of fracture can be estimated in any patient,on corticosteriods or not,by measuring bone mineral density (DEXA-dual energy X-ray absorptiometry ). Ordinary x-ray won't do-up to half of bone bass must be lost before they will detect the loss.

 

Bone breakdown continues at a constant rate throughout life. The rate of bone repair,slows down in older people. It also slows in those who are physically inactive,in postmenopausal women with the drop in estrogen production,and in those who get inadequate supplies of calcium and vitamin D. Often,many of these factors are combined.

 

Corticosteriods magnify problems in bone repair. They can cause osteoporosis in anyone,young or old,but the effect is obvious in post-menopausal women (who already exhibit many of the osteoporosis risk factors ). They do this quite quickly,particularily within the first 6 to 12 months of treatment. Corticosteriods affects several elements in bone repair. The amount of calcium available for new bone formation is reduced. They both slow dietary calcium absorption in the intestine and speed its removal from blood by the kidney. They stimulate the bone cells that promote bone breakdown and inhibit the bone cells that promote bone growth.

 

What this means is that every patient who is started on predisone for anything,but a very short period should also be atarted on an anti-osteoporosis program.

 

If the patient is a post-menopausal woman,replacement estrogen should be seriously considered. Raloxifene is an alternative to estrogen,although it doesn't help menopausal symptoms like hot-flashes It does resemble estrogen in its beneficial effects on bone,yet if there is a fear of uterus or breast cancer,it does not affect the lining of the uterus or breast tissue,

 

A regular program of aerobic physical activity should be designed with the assistance of a physiotherapist,keeping the problems imposed by arthritis in mind.

 

A daily intake of at least 1,000 milligrams should be achieved. One cup of milk will provide 300 milligrams,a cup of yogurt about 400 milligrams. Calcium-containing antacid tablets are another inexpensive souce.

 

Aow dose (800 or 900 units ) of vitamin D daily is desirable. Vitamin D is essential to normal bone development. People who are elderly or housebound are very often vitamin D deficient,and have a increased risk of fracture.

 

If it is likely that prednisone will be needed for more than a few weeks,a bisphosphonate can be used to slow bone breakdown. Etidronate,alendronate and pamidronate are bisphosphonates. They have been proved effective in both the prevention and the treatment of osteoporosis. Your physician will decide what is best for you.

 

Problems from the sudden withdrawal of corticosteriods is documented elsewhere on the site.

 

Regrettably,it is not always possible to avoid corticosteriods. Your doctor will use the lowest dose necessary to maintain efficacy with the shortest possible period in mind.

One of the major determinants of skeletal weakness is bone loss that occurs after menopause. The bone loss is a consequence of an increased osteoclastic resorption that is only partially compensated by a moderate rise in the rate of bone formation by osteoblasts.

 

Estrogens calcitonin,and early-generation bisphosphonates were considered effective and well-tolerated agents for maintaining bone mineral density (BMD) of trabecular and cortical bone at premenopausal levels by counteracting the exacerbated activity of osteoclasts induced by the sharp postmenopausal decrease in circulating endogenous estrogens.

 

However, primary prevention of osteoporosis initiated in the immediate postmenopause is not yet considered a public health priority by many, including specialists dealing with bone metabolic disorders, primary care physicians, and the general population. Subsequently, caregivers often face complicated situations with women seeking treatment for the first time at later stages of the disease, namely, after the diagnosis of osteoporosis has already been made on the basis of random radiographs, densitometry, measurements, or, even worse, a clinical fracture.

 

None of the available medications has unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once the disease is established. Furthermore, some of these agents are jeopardized by either potential severe toxicity or prohibitive cost, discouraging their widespread or prolonged use. Therefore, new medications are developed with the goal of meeting a better risk-to-benefit (efficacy vs tolerance) ratio in comparison with available medications.

 

The MORE trial was a randomized, placebo-controlled study of raloxifene 60 or 120 mg/day vs placebo (all women received calcium 500 mg and vitamin D 400 IU/day) involving 7705 women who were at least 2 years postmenopause. This study was conducted at multiple centers throughout 25 countries. The primary end point of MORE was the determination of the percentage of women taking raloxifene who had at least 1 new vertebral fracture, as compared with the control group. Secondary end points were the relative risk (RR) of nonvertebral fractures, breast cancer, and cardiovascular events.

 

All women enrolled met the World Health Organization (WHO) criteria for osteoporosis (T-score < -2.5). Approximately one third had prevalent vertebral fractures. The average age was 65 years in patients without prevalent fractures and 69 years in those with prevalent fractures, with body mass indices of 25 and 26, respectively.

 

Evaluable radiographs were available for 6828 women. A central laboratory assessed vertebral fractures in the spinal radiographs. This procedure was carried out by radiologists blinded to treatment group assignment but not to the temporal sequence of the radiograph. Women were grouped according to the presence or absence of an adjudicated vertebral fracture at baseline. An adjudicated fracture was confirmed by at least 2 of 3 determinations, consisting of 2 independent semiquantitative (SQ) assessments and 1 quantitative morphometric (QM) measurement.

 

Normal vertebrae (grade 0) had minimal deformity, with < 20% reduction in the anterior, middle, and posterior vertebral height. Mild vertebral deformities (grade 1) corresponded to a 20% to 25% reduction in vertebral height. Moderate (grade 2) and severe (grade 3) vertebral fractures had decreases in vertebral height of 25% to 40% and > 40%, respectively. Vertebral fractures were also identified using QM criteria, consisting of a decrease in anterior, middle, and posterior vertebral height of > 20% and >4 mm.

 

In clinical trials of osteoporosis therapies, the standard method used to define incident vertebral fractures from radiographs consists of a combination of SQ and QM assessment criteria. Incident vertebral fractures were described as new fractures in vertebrae that were not fractured at baseline.

 

At 36 months, of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/day of raloxifene, and 5.4% of those receiving 120 mg/day of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60 mg/day group: RR = 0.7; 95% confidence interval [CI] = 0.5-0.8; for 120 mg/day group: RR = 0.5; 95% CI = 0.4-0.7).

 

Frequency of vertebral fracture was reduced in women who did not have prevalent fracture. In women with prevalent vertebral fractures who received 60 mg/day of raloxifene, the relative risk of new vertebral fracture was 0.7 (95% CI = 0.6-0.9); it was 0.5 (95% CI = 0.4-0.8) in those with low BMD but no prevalent vertebral fractures at inclusion. Compared with placebo, the 60-mg/day and 120-mg/day dosages of raloxifene increased BMD in the femoral neck by 2.1% and 2.4%, respectively, and in the spine by 2.6% and 2.7%, respectively (P < .001 for all comparisons).

 

At 1 year, raloxifene 60 mg/day decreased the risk for new clinical vertebral fractures by 68% (95% CI = 20% to 87%) compared with placebo in the overall study population and by 66% (95% CI = 23% to 89%) in women with prevalent vertebral fractures, who are at greater risk for subsequent fracture. The risk for clinical vertebral fractures in the raloxifene 60-mg/day group was decreased by 46% (95% CI = 14% to 66%) at 2 years and by 41% (95% CI = 17% to 59%) at 3 years. The cumulative incidence of new clinical vertebral fractures was lower in the group receiving raloxifene 60 mg/day compared with placebo (P < .001).

 

In the overall cohort, the risk of nonvertebral fractures for raloxifene (60 mg/day and 120 mg/day) vs placebo did not differ significantly (RR = 0.9, 95% CI = 0.8-1.1). However, when assessing separately women whose fracture severity grades, at baseline, corresponded to an estimated decrease in vertebral height of > 40% (grade 3), raloxifene 60 mg/day significantly decreased the risk of new vertebral fracture (RR = 0.73, 95% CI = 0.54-0.99) and nonvertebral fracture (RR = 0.53, 95% CI = 0.29-0.99) at 3 years.

 

Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (RR = 0.24, 95% CI = 0.13-0.44; P < .001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR = 0.10, 95% CI = 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR = 0.88, 95% CI = 0.26-3.0).

 

An additional annual mammogram, at 4 years, reflected 3004 additional patient-years of follow-up. At this follow-up, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (RR = 0.28, 95% CI = 0.17-0.46).

These data indicate that 93 osteoporotic older postmenopausal women would need to be treated with raloxifene for 4 years to prevent 1 case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR = 0.16, 95% CI = 0.09-0.30).

 

Raloxifene also significantly reduced the risk of cardiovascular events in a subset of women with increased cardiovascular risk (determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure).

 

In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/day of raloxifene, and 94 (3.7%) with 120 mg/day of raloxifene. RRs were 0.86 (95% CI = 0.64-1.15) and 0.98 (95% CI = 0.74-1.30) for 60 mg/day and 120 mg/day of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately.

 

Among the subset of 1035 women with increased cardiovascular risk at baseline, however, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR = 0.60, 95% CI = 0.38-0.95).  The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P = .94) or among women at increased cardiovascular risk (P = .86) or with evidence of established coronary heart disease (P = .60). Hot flashes were the most common nonserious adverse event, prompting withdrawal in 0.1%, 0.7%, and 0.5% of the women in the placebo, raloxifene 60 mg, and raloxifene 120 mg groups, respectively.

 

Leg cramps were also reported more frequently in the women given raloxifene (7.0% in the 60 mg and 6.9% in the 120 mg groups) than in the placebo group (3.7%). After 3 years, raloxifene increased the risk of venous thromboembolic disease (RR = 3.1, 95% CI = 1.5-6.2) but did not increase the risk of endometrial cancer (RR = 0.8, 95% CI = 0.2-2.7).

 

From a cost-utility analysis of a Swedish database, it appears that raloxifene can be targeted cost-effectively to postmenopausal women with osteopenia with a risk for hip fracture (relative risk 2.6) and to women aged 65 or older or at high risk (relative risk 3.0) for hip fracture.

Alendronate: Dose-dependent effects of alendronate in reducing bone turnover and increasing spinal bone mass were reported in postmenopausal women with low BMD. In this population, the 10-mg/day dose, suggested to correspond to the best risk/benefit ratio for treatment of osteoporosis, induced significant increases in BMD after 2 years and 3 years.

 

 In the 2-year study, mean increases in BMD with alendronate 10 mg/day were 7.21% at the spine, 5.27% for total hip, and 2.53% for total body, whereas biochemical markers of bone remodeling declined by about 50% after 3 months for bone resorption markers and by 6 months for bone formation markers.

 

The 3-year study showed similar results, with increases of 7.2%, 5.5%, and 2.4% for lumbar spine, femoral neck, and trochanter BMD, respectively. The results obtained from 2 studies, in which 3 doses of alendronate were given for 3 years (5 mg/day, 10 mg/day, and 20 mg/day for 2 years, followed by 5 mg/day for 1 year) to women with low BMD (including a 20% subset with prevalent fractures), were pooled.

 

 Compared with the placebo group, a significant reduction in the proportion of female patients with new vertebral fractures (3.2% vs 6.2%; P = .03) and a decrease in progression of vertebral deformities (33% vs 41%; P = .028) were observed.

 

However, the cornerstone of the development of alendronate for osteoporosis was the Fracture Intervention Trial (FIT), a 3-year randomized, controlled trial investigating the effects of alendronate on the risk of fractures in 2027 women with prevalent vertebral fractures and in 4432 women with low femoral BMD but no prevalent fractures.

 

 The dose of alendronate (initially 5 mg daily) was increased to 10 mg daily at 24 months. In the fracture arm of the study, 8% of women in the alendronate group had 1 or more new morphometric vertebral fractures compared with 15% in the placebo group (RR = 0.53, 95% CI = 0.41-0.68).

 

For clinically apparent vertebral fractures, the relative hazard was 0.45 (95% CI = 0.27-0.72). In this arm of the study, a significant reduction in the risk of any clinical fracture (RR = 0.72, 95% CI = 0.58-0.90), hip fracture (RR = 0.49, 95% CI = 0.23-0.99), and wrist fracture (RR 0.49, 95% CI 0.23-0.99) was also reported for alendronate users.

 

In the patients without prevalent spinal fractures, who were treated for a mean duration of 4.2 years, alendronate increased BMD at all sites but did not reduce significantly the incidence of clinical fractures (RR = 0.86, 95% CI = 0.73-1.01) in the whole population. However, alendronate significantly decreased the risk of radiographic vertebral fractures by 44% overall (RR = 0.56, 95% CI = 0.39-0.80) and the risk of clinical fractures by 36% (RR = 0.64, 95% CI = 0.50-0.82) in women with baseline osteoporosis at the femoral neck.

 

When analyzing the results of the FIT study of alendronate administration for 3-4 years in 3658 women with osteoporosis (with existing vertebral fractures or BMD in the osteoporotic range), the estimate of the effect of alendronate on RR of fracture was 0.47 (95% CI = 0.26-0.79) for the hip, 0.52 (95% CI = 0.42-0.66) for radiographic vertebral, 0.55 (95% CI = 0.36-0.82) for clinical vertebral, and 0.70 (95% CI = 0.59-0.82) for all clinical fractures.

 

Increases in spinal BMD with alendronate continued for up to 7 years (0.8% per year after the initial 18 months with the 10-mg/day dose), whereas other skeletal benefits (ie, increases in BMD at other skeletal sites and decreases in biochemical markers) remained stable during the same period.

 

Reduction of fracture risk with alendronate was also shown to be consistent within fracture risk categories, with more fractures being prevented by treating women at highest risk due to advanced age or severe osteoporosis. Interestingly, individual response to alendronate can be monitored through BMD measurements.

 

Women from the FIT study with increases of more than 3% in total hip BMD during the first year of treatment had the lowest incidence of new vertebral fractures after 3 years of treatment (odds ratio [OR] = 0.45, 95% CI = 0.27-0.72).

 

Esophageal erosion and ulcerative esophagitis were reported in association with the use of oral alendronate. However, particular recommendations for alendronate intake (swallowing alendronate with 180-240 mL water on arising in the morning, and remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested) reduce the risk of esophagitis.

 

Dose-ranging studies suggest that the potential for esophageal irritation, observed with daily oral bisphosphonates, may also be substantially reduced with less frequent dosing. Furthermore, less frequent dosing with any medication may enhance compliance, thereby maximizing the effectiveness of therapy. Therefore, a once-weekly (70-mg) formulation of alendronate was developed, which fully satisfied equivalence criteria (lumbar spine, hip or total body BMD, and rate of bone turnover assessed by biochemical markers) relative to daily therapy.

 

Risedronate is a pyridinyl bisphosphonate with high antiosteoclastic potency because of a nitrogen atom in its cyclic structure. In women with a mean lumbar spine T-score of < -2, risedronate (5 mg/day) has been shown to increase BMD after 24 months, by 4% at the lumbar spine, 1.3% at the femoral neck, and 2.7% at the femoral trochanter.

 

 All these changes were significantly different from the evolution observed in the placebo group. The evidence for an antifracture efficacy of risedronate came from 3 randomized controlled clinical trials. In 2458 postmenopausal women who had at least 1 prevalent vertebral fracture, treatment with 5 mg/day of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41% (RR = 0.59, 95% CI = 0.43-0.82) over 3 years.

 

In another study, 1226 postmenopausal women with 2 or more prevalent vertebral fractures were also exposed to the same protocol (risedronate 5 mg/day vs placebo) for 3 years. In this cohort, risedronate reduced the risk of new vertebral fractures by 49% (RR = 0.51, 95% CI = 0.36-0.73) after 3 years.

 

In both studies, a reduction in the incidence of new vertebral fractures was seen after the first year of treatment, but further administration of risedronate during the second and third years did not provide significant additional benefit in terms of fracture reduction. The effects of risedronate on the risk of new nonvertebral fractures were significant, after 3 years, in the less severe osteoporotic population (RR = 0.6, 95% CI = 0.39-0.94) but not in the most severely affected women (RR = 0.67, 95% CI = 0.44-1.04).

 

 Oral ibandronate was compared with placebo in 2946 women who had BMD T-score < -2.0 in at least 1 lumbar vertebra and 1 to 4 prevalent vertebral fractures. Two dosage regimens of ibandronate, either given daily (2.5 mg) or on alternate days for 12 doses every 3 months (20 mg), for 3 years, were investigated. Daily and intermittent oral ibandronate significantly reduced the risk of radiologically confirmed vertebral fractures by 62% and 50%, respectively, compared with placebo and showed a sustained effect over the trial period.

 

This study demonstrates for the first time significant fracture efficacy for intermittent bisphosphonate treatment with a dose-free interval of more than 2 months. Significant reductions in clinical vertebral fractures were also shown in the 2 treatment groups. In a subgroup of women from this trial whose BMD T-score of the femoral neck was < 3 standard deviations at baseline, daily and intermittent oral ibandronate administration reduced the incidence of clinical fracture by 66% and 50%, respectively, and nonvertebral fractures by 69% and 37%, respectively.

 

 These results confirm previous preclinical findings indicating that the efficacy of ibandronate is a function of the relationship between loaded dose and the dosing frequency.This obviously supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance.

Oral once-weekly ibandronate (20 mg) and daily administration of ibandronate (2.5 mg) induced almost identical increases in lumbar spine BMD after 48 weeks, and the once-weekly regimen was proven to be statisticially noninferior to daily administered oral ibandronate. Three-monthly (2 mg) intravenous ibandronate bolus injections were related to even larger increases of lumbar spine BMD after 1 year (5%). Significant benefits were also reported at the femoral neck or at the trochanter.

 

Zoledronate. In a similar prospective study assessing the effects of the dose and dosing interval on changes in therapeutic effects of bisphosphonates, zoledronate was evaluated in a 1-year randomized controlled trial of 351 postmenopausal women with low BMD. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at 3-month intervals. In addition, 1 group received a total annual dose of 4 mg as a single dose, and another received 2 doses of 2 mg each, 6 months apart.

 

Similar increases in BMD were recorded in all the zoledronic acid groups to values for the spine that were 4.3% to 5.1% higher than those in the placebo group and values for the femoral neck that were 3.1% to 3.5% higher than those in the placebo group, suggesting that an annual infusion of zoledronate might be an effective treatment for postmenopausal osteoporosis.

 

New therapeutic approaches have emerged during the past 5 years that significantly improve the daily management of osteoporosis. Alendronate has unequivocally shown its ability to reduce fractures of the axial appendicular skeleton. Its new weekly formulation reduces the discomfort generated by the requirements for its oral ingestion without compromising the activity of the drug, hence improving the potential for patient compliance.

 

 Risedronate is effective but is of marginal interest as a new agent, compared with previous bisphosphonates. On the basis of the preliminary results shared in scientific meetings, however, intermittent regimens with the new agents ibandronate and zoledronate may substantially modify the perspective of bisphosphonate treatments by offering efficient, more user-friendly, and safer therapeutic regimens.

 

 Raloxifene has a rapid and sustained antifracture efficacy both in women with prevalent vertebral fractures and those with low BMD. Although its effect on spinal fractures was undisputed, the recent demonstration of a reduced risk of nonvertebral fractures in the population of women who are actually at high risk to experience such events confirms its position as a first-line approach to osteoporosis management.

 

In the choice between bisphosphonates and raloxifene, the collateral benefits reported with the SERM, ie, the significant reduction in estrogen receptor-positive breast cancer incidence in older osteoporotic women and the decrease in the rate of cardiovascular events, in a high-risk population, may be important considerations.

 

 A potent anabolic action on bone is mediated by the parathyroid hormone fragment PTH(1-34), and Sr ranelate induces an uncoupling between an decreased bone resorption and an increased bone formation. Both compounds have demonstrated ability to reduce the risk of vertebral and nonvertebral fractures, and they undoubtedly correspond to a new paradigm in the treatment of osteoporosis.

 

 Combination use or sequential administration of some of these drugs will, most likely, constitute the next challenge to provide our patients with the most effective and safest therapeutic option in the management of osteoporosis.

 

 Medical report of a woman who was switched from SSZ to MTX and a detailed-treatment and why-regimen: The patient is a middle-aged woman. She has been takeing sulfasalazine and naproxen for the past 4 years. For the last year, the patient has received local gluco -corticoid 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. She is a postmenopausal,white woman.

 

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

 

The rheumatologist decided that 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.

 

 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 increases the toxicity of the regimen.

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.

 

This 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 supplementation) 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. This is often not done in practise.

 

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 patient's 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. Although this patient currently has a normal BMD measurement, initiating glucocorticoid therapy will place her at risk of GIO.

 

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.

 

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.

 

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:

    * Glucocorticoid-treated premenopausal women, postmenopausal women receiving HRT, and men should be treated with either alendronate 5 mg/day or risedronate 5 mg/day.
* Glucocorticoid-treated postmenopausal women not receiving HRT should be treated with either alendronate 10 mg/day or risedronate 5 mg/day.

 

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.

 

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.

 

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.

 

Prescribing routine vitamin D supplementation in children and adolescents;Children and adolescents generally have sufficient stores of vitamin D from exposure to sunlight and intake of milk that is fortified with vitamin D.