Microsoft word - glucocorticoid effect on bone and glucose levels _und res j human sci vol 1_.doc
Running head: GLUCOCORTICOID EFFECT ON BONE
Glucocorticoid Effect on Bone and Glucose Levels in
Glucocorticoids are among the most potent and widely used immunosuppressant drugs available
but have many detrimental side effects; however, only limited data are available on intervention
studies to prevent these life-long side effects from occurring. The purpose of this study was to
test an experimental rat model mimicking the bone loss and hyperglycemia associated with
glucocorticoid administration. A five-week treatment was compared to a control group. The bone
loss in the glucocorticoid-treated rats was found to be significant in only a brief treatment; the
serum parameters may reflect that the gradual onset of diabetes was beginning. This study has
provided a model of bone loss associated with the glucocorticoid (prednisolone) administered
that can be used to test interventions to inhibit the adverse effects of glucocorticoids.
Dating, Assertiveness, and Misconceptions of Assertion
On September 21, 1948, compound E (cortisone) became the first glucocorticoid to be
administered to a patient with rheumatoid arthritis. Since that time the anti-inflammatory and
immunosuppressive actions of glucocorticoids have benefited patients suffering from lupus and
chronic asthma, along with organ transplant recipients (Avioli, 1984; Frauman, 1996).
Unfortunately, glucocorticoid therapy does have several undesirable side effects. These may
include central obesity, hypertension, impaired wound healing, increased infection rates, and
impaired growth in children (Frauman, 1996).
However, of particular interest and concern are the detrimental effects of glucocorticoids
on bone and on glucose levels. Research has indicated that the use of glucocorticoids results in
osteopenia (bone loss) and hyperglycemia, which can eventually lead to osteoporosis and
diabetes mellitus (Naghavi & Mesgarzadeh, 1975; Ravina, Slezak, Mirsky, Bryden, & Anderson,
1999; Wimalawansa, Chapa, Yallampalli, Zhang, & Simmons, 1997).
Current osteoporosis trends indicate that 10 million individuals in the United States
already have osteoporosis, and more than 18 million are at risk for developing osteoporosis
(National Osteoporosis Foundation 2001). In addition, recent reports from the American
Diabetes Association state that approximately 15.7 million people or 5.9% of the United States
population currently suffer from diabetes mellitus (American Diabetes Association, 2001).
Glucocorticoids have been shown to accelerate bone loss, leading to osteopenia and osteoporosis
and also to impair glucose tolerance, leading to or worsening diabetes mellitus (Wimalawansa et
al., 1997; Ravina et al., 1999). Glucocorticoids are among the most potent and widely used
immunosuppressant drugs available (Frauman, 1996) and due to the side effects, are considered
an enormous problem in clinical practice today (Wimalawansa et al., 1997). However, only
limited data are available on intervention studies to prevent these life-long side effects from
occurring. The purpose of this study was to test an experimental rat model mimicking the bone
loss and hyperglycemia associated with glucocorticoid (prednisolone) administration. This
model will be utilized in testing interventions to ameliorate the adverse side effects of
Twenty, six-month old, female Sprague-Dawley (Harlan-Teklad, Indianapolis) rats were
randomly assigned to groups of ten fed either 100 mg prednisolone/kg diet or control diet with
no added prednisolone. Prednisolone and dosages were chosen based on Lingren’s and
colleagues’ model that concluded prednisolone- induced osteopenia occurs in rats in doses of
100, 50, or 20 mg per kg of diet. To ensure prednisolone-induced osteopenia 100mg per kg diet
The rats were individually housed in an environmentally controlled laboratory at the
institution’s Rat Lab. Rats were maintained on 12:12 light/dark cycles and allowed free access
to distilled water throughout the duration of the study. Guidelines for the ethical care and
treatment of animals established by the Animal Care and Use Committee at the institution were
Rats consumed their assigned diet for five weeks and had free access to deionized water.
During this time, rats were weighed once a week. Throughout the duration of the study, one rat
from the prednisolone group, and one rat from the control group died before completing the
After five weeks, the rats were placed in metabolic cages twelve hours before necropsy
where urine was collected. At the time of necropsy, fasting blood glucose concentrations were
measured using a Bayer Dex Glucometer Diabetes Care System (Albertson's Pharmacy) on a
drop of blood from the tip of the tail. the animals then received an oral glucose load (1g/kg body
weight) and after two hours, their glucose level was again measured. animals were then
anesthetized intraperitoneally with ketamine (100 mg/kg body weight) and sylazine (5 mg/kg
body weight) and whole body scans were performed by Dual Energy X-ray absorptiometry
(DEXA) (Hologic QDR 4500 A, Waltham, MA). The animals were then exsanguinated from the
abdominal aorta. Blood was allowed to clot, centrifuged, serum aliquots frozen at -20ºC until
analysis. Liver, spleen, and kidneys were removed and weighed. Femur, tibia, third, fourth, and
fifth lumbar vertebra were collected from the animals, cleaned of adhering tissues, and frozen at
Bone mineral area and bone mineral content were performed by Dual Energy X-ray
Absorptiometry (DEXA) and analyzed with the small animal software provided by the
Insulin values were assayed with a rat insulin RIA Kit (Linco Cat. # RI-13K, St. Charles,
Mo.) and 125Iodine was measured on a gamma counter. Glucose and fructosamine were analyzed
using a commercially available kit from Roche Diagnostics (Sommerville, NJ). These tests were
performed using the Cobas-Fara II Clinical Analyzer (Roche Diagnostics, Sommerville, NJ).
Data analysis of means and standard errors of the mean were calculated using SAS
(version 8.0, SAS Institute, Cary, NC). The generalized linear model procedure was used for
analysis of variance. The significance level was set at p < 0.05.
During the five-week treatment, the glucocorticoid group had a significant loss in body
weight compared to the control group. The bone mineral area (Figure 1) and bone mineral
content (Figure 2) of the glucocorticoid group were significantly lower in comparison to their
basefline values. This was not observed in the control group. Apparently, the bones of animals in
the glucocorticoid-treated group decreased in size as well as in total mineral content.
There were no significant differences found between the two groups for the blood
parameters measured. The blood glucose concentrations did not indicate that diabetes mellitus
had been induced in the rats. However, even during this relatively short experiment, the
glucocorticoid treated group tended to have increase in their insulin (Figure 3). Elevated insulin
occurs prior to the onset of overt Type II diabetes in humans. Fructosamine had increased by
eight percent, which was not significant (Figure 4). Fructosamine is a measure of glucose
control over the previous two to three weeks and higher fructosamine values reflect a history of
higher circulating glucose. Because fructosamine changes gradually a longer study might be
required to detect glucose changes that could be very important over a lifetime.
To summarize, glucocorticoids are among the most potent and widely used
immunosuppressant drugs available but have many detrimental side effects. However, only
limited data are available on intervention studies to prevent these life-long side effects from
occurring. Therefore, an effective rat model would aid in the effort to reduce negative treatment
effects in humans associated with glucocorticoid treatment.
The bone loss in the glucocorticoid-treated rats was found to be significant in only a brief
five-week period. In addition, the serum parameters may reflect that the gradual onset of
diabetes was beginning. This study has provided a model of bone loss associated with the
glucocorticoid (prednisolone) administered that can be used to test interventions to inhibit the
American Diabetes Association. Retrieved May 1, 2001, from
Avioli, L. V. (1984). Effects of chronic corticosteroid therapy on mineral metabolism and
Advances in Experimental Medicine and Biology, 171, 81-89.
Frauman, A. G. (1996). An overview of the adverse reactions to adrenal corticosteroids.
Adverse Drug Reactions Toxicology Review, 15(4), 203-206.
Mahan, K. L., & Escott-Stump, S. (1996). Food, Nutrition, and Diet Therapy, 9th Ed.
Naghavi, M., & Mesgarzadeh, A. (1975). On attempt to establish a model on steroid-induced
osteoporosis in bones of rats. Acta Medica Iranic, 18, 175-193.
National Osteoporosis Foundation. Retrieved May 1, 2001, from http://www.nof.org.
Ravina, A., Slezak, L., Mirsky, N., Bryden, N. A., & Anderson, R. A. (1999). Reversal of
corticosteroid-induced diabetes mellitis with supplemental chromium. Diabetic Medicine,
Wimalawansa S. J., Chapa M. T., Yallampalli, C.; Zhang, R., & Simmons, D. J. (1997).
Prevention of corticosteroid-induced bone loss with nitric oxide donor nitroglycerin in
male rats. Bone,21, 275-280.
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