All about Lupron – what you don’t know can harm you



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I. Bone Loss From Lupron Is Not Limited To Women

Male Animals: 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 crown-rump, tibia, and femur length and reduced bone mineral density of the humerus and lumbar spine." (16)

[pic]

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

Hyperparathyroidism, 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 GnRH-a[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_____

[pic]

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 (1991-1995 PDR) |DEXA* (1996 PDR)(1) | |DEXA* (Hornstein) |

| |(2) | | |(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, placebo-controlled, 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.720-725.

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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