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I. Bone Loss From Lupron Is
Not Limited To Women
According to Dr. Mann and
colleagues, when male monkeys were
given a GnRHa for the first four
months of postnatal life, "Growth of
the skeleton was diminished as
evidenced by shorter adult crownrump, tibia, and femur length and
reduced bone mineral density of the
humerus and lumbar spine." (16)
Male Animals:
Dr. Townsend stated that "Dr.
Goldray et al. demonstrated a
reduction in individual vertebral
bone mineral density in 10 of 17
men [59%] during their first year
of treatment" with a GnRH-a for
benign prostatic hypertrophy.
(18)
Dr. Townsend stated that
"Knowing the incidence of
osteoporosis and bone
fractures among men receiving
LHRH-a for the treatment of
prostate carcinoma is important
in the evaluation of bone pain
and bone fractures because it
can help physicians avoid making
incorrect diagnosis of metastasis
to bone." (18)
CHILDREN
Dr. Antoniazzi and colleagues
tested only girls with central
precocious puberty. (19) They
found that there was a
"reduction of trabecular bone
mass, which appears to be the
primary consequence of
GnRHa therapy." (19)
Dr. Saggese and colleagues
stated that "GnRH-a treatment is
also associated with bone loss in
girls with central precocious
puberty." (20) "During GnRH-a
treatment, patient BMD [bone
mineral density] decreased
significantly (6 months: 6.0%; 12 months: -8.0%). (20)
"GnRH-a treatment caused a
significant decrease in BMD
[bone mineral density]." (20)
WOMEN
Dr. Dawood stated "That there is
significant loss in trabecular
bone
mass as early as 3 months after
beginning GnRH agonist therapy
in patients with endometriosis,
uterine leiomyomas and
mastalgia, is now well supported
by abundant data from both
double-blind and open-label
randomized studies." (8)
Dr. Dawood also stated that "We
have observed that ALL patients
with endometriosis who
participated in our studies with
buserelin and depot leuprolide
acetate had bone loss at the end
of treatment with the GnRH
agonists." (10)
II. How Dangerous Is Bone
Loss?
According to the National
Osteoporosis Foundation:
1. As many as 20% of
those who suffer
osteoporosis
related hip
fractures die
within 6 months.
(3)
2. Complications of
osteoporosis are the 12th
leading cause of death in
America. (3)
3. A woman's risk of
developing a hip
fracture is equal
to her combined
risk
of
developing
breast, uterine
and
ovarian
cancer. (3)
The above information was NOT
derived from Lupron exposed
individuals.
(3)
III. Types of Osteoporosis (7)
There are many types (causes) of
osteoporosis:
A. HEMATOLOGICAL
OSTEOPOROSIS
Myeloma, Lymphoma,
Leukemia, Mast Cell
Disease, Thalassemia
B. ENDOCRINE
OSTEOPOROSIS
Hyperparathyroidis
m, Cushing's
Syndrome,
Hyperthyroidism,
Hypogonadism,
Diabetes Mellitus
C. NUTRITIONAL
OSTEOPOROSIS
Scurvey, Malnutrition,
Calcium Deficiency,
Malabsorption
D. CONGENITAL
OSTEOPOROSIS
Osteogenesis Imperfecta,
Homocystinuria
E. PRIMARY
OSTEOPOROSIS
Postmenopausal
Osteoporosis (type I), Senile
Osteoporosis (type II)
Idiopathic Osteoporosis,
Juvenile Osteoporosis
F. SECONDARY
OSTEOPOROSIS
Alcoholism, Liver Disease,
Renal Disease
IV. An Effect On
Bone Marrow
1. CANCER
According to the Physicians Desk
Reference, another GnRH
analogue showed "an increased
incidence of histiocytic
sarcomas [cancer] of the bone
marrow in vertebral column
and femur" in mice. (4)
2. According to PDA documents, "In
the various toxicology studies [in
animals], ... potentially the most
serious effect of Leuprolide, in
my view, is its effect on spinal
[vertebral] column bone
marrow." (6)
3. Dr. Dawood stated that "at the
end of 6 months of treatment of
endometriosis with GnRHa[nalogues], many studies and
reviews now have established
clearly that there is significant,
albeit variable, bone loss of the
vertebrae and/or femoral
neck" in women. (5)
V. Bone Studies
Used To Assess The
Effect Of GnRH
Analogues
1. HISTOMORPHOMETRY vs.
DENSIOMETRY
a. Histomorphometry =
Biopsy and microscopic
analysis used to
evaluate bone
microstructure.
b. Densiometry = Bone
scan (QCT,
DPA/DEXA*) used to
measure bone
mass/density.
2. HISTOMORPHOMETRY:
No information is available
on histomorphology in
humans exposed to GnRH-a
prior to Dr. Compston's
article in 1995. Information
regarding histomorphometric
analysis of bone structure
(bone biopsy) after exposure
of humans to Lupron is NOT
available in the FDA reports,
the package insert, the PDR
or any other published
literature before 1995 (10
years after the drug was
approved for advanced
prostate cancer).
The Figure below illustrates
the structural changes
occurring in bone (illiac
crest) on a microscopic level
after taking a GnRH
analogue..
BEFORE - Normal
AFTER 6 months of treatment
with GnRH
analog_____
Figure 2. Iliac crest cancellous bone before (A) and after (B) 6 months of treatment with GnRH analogs in a 28 year old woman,
showing severe disruption of the cancellous microstrudure in the posttreatment biopsy
Reprinted by permission of the publisher from “The Effects of Gonadotropin-Releasing
Hormone Agonists on Iliac Crest Cancellous Bone Structure in Women With Endometriosis” by Compstone, MD.
Bone, Vol. 16 No 2, pp261-267; Copyright 1995 Elsevier Science Inc.
Please note that in picture (A) the bone structure (dark area) is interwoven
and there are connections up and down and from side to side. In picture (B)
the bone structure (dark areas) only go up and down and are NOT connected.
Dr. Compston stated that "Disruption of cancellous [trabecular]
microstructure in the spine is likely to be more severe than that
demonstrated in the iliac crest." (9)
Dr. Compston stated that "In this study we have performed a detailed
histomorphometric analysis of bone structure and remodeling
in women before and after 6 months of treatment with GnRH
analogues."
Dr. Compston stated that "Our results suggest that bone loss induced
by GnRH analogs may be associated with adverse effects on
cancellous [trabecular] microstructure which are unlikely to be
reversed following cessation of therapy." (9)
Dr. Compston stated that "To date [1995], studies of the skeletal
effects of GnRH analogs have been limited to measurement of
bone mass by densitometric techniques [QCT, DPA/DEXA*] and
assessment of biochemical indices of bone turnover, [blood and urine
tests] approaches which do not enable analysis of the changes in
cancellous [trabecular] microstructure associated with bone
loss." (9)
3. B0NE DENSITOMETRY - Bone Scans (QCT, DPA/DEXA*)
(Used to evaluate bone mass/density)
a. TRABECULAR VERTEBRAL BONE LOSS OF THE SPINE USING
QCT (Quantitative Computed Tomography) WITH LUPRON:
1. Investigator Dr. Wheeler: -15.1% bone loss; 3.75 mg/6 months, 8
patients; for indication of endometriosis (Lupron Endometriosis Study
Group) (14).
2. Investigator Dr. Dawood: -14.0% bone loss; 3.75 mg/6 months, 6
patients; for indication of endometriosis (5).
3. Investigator Dr. Dawood: -13.8% bone loss; 3.75 mg/6 months, 6
patients; for indication of endometriosis (10).
4. Investigator Dr. Friedman: -13.5% bone loss; 3.75 mg/6 months, 7
patients; for indication of fibroids (The Leuprolide Study Group) (15).
5. Investigator Dr. Dlugi: -11.8% bone loss; 3.75 mg/6 months, 8 patients;
for indication of endeomtriosis (The Lupron Study Group)(13).
b. PACKAGE INSERT / PHYSICIANS DESK REFERENCE:
ENDOMETRIOSIS:
According to the 1991, 1992, 1993, 1994, and 1995 package insert/PDR,
"after 6 months of LUPRON DEPOT (leuprolide acetate for depot
suspension) treatment, vertebral trabecular bone density measured by
quantitative computed tomography (QCT) decreased by an average
of 13.5% compared to pretreatment levels." (2)
In 1996, the package insert/PDR for Lupron was changed. Instead of
reporting vertebral trabecular bone density with QCT, the
manufacturer reported vertebral [trabecular is omitted] bone density
with DEXA*. The package insert/PDR states that "A controlled study in
endometriosis patients showed that vertebral bone density as measured by
DEXA* [NOT QCT] decreased by an average of 3.9% at 6 months compared
with the pretreatment value." (1)
*DEXA is "essentially another form of DPA with no radionuclide
source." (5)
*DEXA "is essentially DPA using the Hologic QDR-1000
densitometer." (8)
FIBROIDS;
According to the 1996 package insert/PDR, "use of LUPRON DEPOT
3.75 mg for uterine leiomyomata [fibroids] for longer than 3 months
or in the presence of other known risk factors for decreased bone
mineral content may cause additional bone loss and is not
recommended (1)
C. TRABECULAR BONE vs. CORTICAL BONE and QCT vs DEXA*/DPA
c.
1 . TRABECULAR BONE vs. CORTICAL BONE:
a. Dr. Dawood stated that "GnRH agonists [Lupron] can have a
significant negative impact on trabecular bone mass." (8)
b. Dr. Dawood stated "That there is significant loss in trabecular
bone mass as early as 3 months after beginning GnRH agonist
therapy in patients with endometriosis, uterine leiomyomas and
mastalgia, is now well supported by abundant data from both
double-blind and open-label randomized studies." (8)
2.
QCT (19911995 PDR)
(2)
DEXA*
(1996
PDR)(1)
DEXA*
(Hornstein)
(11)
6 months of
Lupron
13 . 5%
3 . 9%
3 . 2%
12 months of
Lupron
Not Available
Not
Available
6 . 3% (nearly
double the loss
seen at 6 months see above)
?
?
a. Dr. Dawood stated that "Because QCT of the spine measures
only the trabecular bone and DPA measures both trabecular and
cortical bone, any significant change affecting mainly the
trabecular bone is more readily detected earlier by the QCT."
(12)
b. Dr. Dawood stated that "Because DPA measures both trabecular and cortical bone,
a significant reduction in true trabecular bone mass actually may be diluted by the
total bone mass, thus giving a lack of significant change." (5)
c. Dr. Dawood stated that "DPA may not detect significant early changes and an
apparent lack of change may be observed." (8)
d. Dr. Dawood stated that "Using QCT bone loss was obvious and significant by 3 months
after initiating GnRH agonist." (8)
e. Dr. Dawood stated that "QCT always shows significant trabecular
bone loss of the vertebrae and hip with GnRH agonists." (8)
*DEXA is "essentially another form of DPA with no radionuclide source."
(5)
*DEXA "is essentially DPA using the Hologic QDR-1000
densitometer." (8)
VI. DOSE (7)
Dr. Dawood stated that "Bone loss occurred with ALL the GnRH agonists tested
irrespective of the route of administration and the relative potencies of the
preparations, but the amount of bone loss appears to be related to the dose of
GnRH agonist used." (8) No formal dosing studies were done prior to the approval
of Lupron for endometriosis, fibroids, or precocious puberty.
VII. Comparing The Bone Loss With Lupron
To Bone Loss in Menopause
The amount of bone loss seen with Lupron is far greater than the bone loss seen in
menopause.
Dr. Fogelman stated that "Normal women in early postmenopausal years may be
losing spinal bone loss at a rate of 4 to 5% [per year] when measured by QCT."
(17) According to the 1991-1995 PDR for Lupron, "vertebral trabecular bone
density measured by QCT decreased by an average of 13.5% [in 6 months and
not a year] compared to pretreatment levels. (2)
Dr. Hornstein showed that bone loss doubled when Lupron exposure was doubled
(12 months instead of 6 months). (11)
Does this mean that it is possible that the 13.5% vertebral trabecular bone
loss measured by QCT after 6 months (1991-1995 PDR) will double to 27.0% if
Lupron is given for a full year?
More To Come
REFERENCES
1. Physicians Desk Reference. Lupron. 1996; p. 2559.
2. Physicians Desk Reference. Lupron. 1991, 1992, 1993, 1994, 1995.
3. The National Osteoporosis Foundation. "Stand UP To Osteoporosis." 1995.
4. Physician's Desk Reference. Zoladex. 1996; p. 2859.
5. Dawood MY, Ramos J, Khan-Dawood FS. Depot leuprolide acetate versus danazol for
treatment of pelvic endometriosis: changes in vertebral bone mass and serum estradiol
and calcitonin. Fertility and Sterility. 63: 6: 1995; p. 1177-1183.
6. US Food And Drug Administration. NDA # 19-010; Review and Evaluation
of Pharmacology and Toxicology Data. 1984.
7. Stein JH. Internal Medicine. Third Edition. Little, Brown and Company. 1990; p. 2349.
8. Dawood MY. Hormonal therapies for endometriosis: implications for bone metabolism.
Acta Obstetricia et Gynecologica Scaninavica. 73: 159: 1994; p. 22-34.
9. Compston JE, Yamaguchi K, Croucher PI, Garrahan NJ, Lindsay PC, Shaw RW. The
Effects of Gonadotropin-Releasing Hormone Agonists on Iliac Crest Cancellous Bone
Structure in Women With Endometriosis. Bone. 16: 2: 1995; p. 261-267.
10. Dawood MY, Impact of medical treatment of endometriosis on bone mass. Am J Obstet
Gynecol. 168: 2; February 1993; p. 674-684.
11. Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and
Hormonal Add-Back in Endometriosis: A 12-Month Study. Obstetrics & Gynecology.
1998; 91: 1: p. 16-24.
12. Dawood MY, Lewis V, Ramos J. Cortical and trabecular bone mineral content in women
with endometriosis: effect of gonadotropin-releasing hormone agonist and danazol.
Fertility & Sterility. 52: 1: 1989; p. 21-26.
13. Dlugi AM, Miller JD, Knittle J, Lupron Study Group. Lupron depot (leuprolide acetate
for depot suspension) in the treatment of endometriosis: a randomized, placebocontrolled, double-blind study. Fertility & Sterility. 54: 3: 1990; p. 419-427.
14. Wheeler JM, Knittle JD, Miller JD, for the Lupron Endometriosis Study Group.
Depot leuprolide acetate versus danazol in the treatment of women with
symptomatic endometriosis: A multicenter, double-blind randomized clinical trial.
Am J Obstet Gynecol. 169: 1: 1993; p. 26-33.
15. Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD, for The Leuprolide Study
Group. Treatment of Leiomyomata Uteri With Leuprolide Acetate Depot: A Double-Blind,
Placebo-Controlled, Multicenter Study. Obstetrics & Gynecology. 77: 5: 1991; p.720725.
16. Mann DR, Akinbami MA, Gould KG, Tanner JM, Wallen K. Neonatal Treatment of Male
Monkeys with a Gonadotropin-Releasing Hormone Agonist Alters Differentiation of
Central Nervous System Centers that Regulate Sexual and Skeletal Development.
Journal of Clinical Endocrinology and Metabolism. 1993; 76: 5: p. 1319-1324.
17. Fogelman I. Gonadotropin-releasing hormone agonists and the skeleton. Fertility
and Sterility. 57: 4: 1992; p.715-723.
18. Townsend MF, Sanders WH, Northway RO, Graham SD. Bone Fractures Associated with
Luteinizing Hormone-Releasing Hormone Agonists Used in the Treatment of Prostate
Carcinoma. Cancer. 1997; 79: 3: p. 545-550.
19. Antoniazzi F, Bertoldo F, Zamboni G, Valenti R, Sirpresi S, Cavallo L, Adami S, Tato L.
Bone mineral metabolism in girls with precocious puberty during gonadotropin-releasing
hormone agonist treatment. European Journal of Endocrinology. 133: 1995; p. 412-7.
20. Saggese G, Bertelloni S, Bertelloni GI, Battini R, Franchi G. Reduction of bone
density: an effect of gonadotropin releasing hormone analogue treatment in central
precocious puberty. European Journal of Pediatrics. 152: 1993; p. 717-720.
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