U.S. patent application number 09/285566 was filed with the patent office on 2001-11-15 for method for treating osteoporosis in castrated prostatic cancer patients.
Invention is credited to BELL, ROBERT G..
Application Number | 20010041699 09/285566 |
Document ID | / |
Family ID | 23094802 |
Filed Date | 2001-11-15 |
United States Patent
Application |
20010041699 |
Kind Code |
A1 |
BELL, ROBERT G. |
November 15, 2001 |
METHOD FOR TREATING OSTEOPOROSIS IN CASTRATED PROSTATIC CANCER
PATIENTS
Abstract
The present invention provides a method for preventing or
treating osteoporosis in a castrated prostatic cancer patient, by
administering to the patient an amount of from 10 mg to 300 mg
cyproterone acetate per day. The present therapy is compatible with
the patients' anticancer treatment.
Inventors: |
BELL, ROBERT G.; (PALM
HARBOR, FL) |
Correspondence
Address: |
MARK E WADDELL
BRYAN CAVE
245 PARK AVENUE
NEW YORK
NY
101670034
|
Family ID: |
23094802 |
Appl. No.: |
09/285566 |
Filed: |
April 2, 1999 |
Current U.S.
Class: |
514/178 |
Current CPC
Class: |
A61K 31/57 20130101 |
Class at
Publication: |
514/178 |
International
Class: |
A61K 031/57 |
Claims
What is claimed is:
1. A method for preventing or treating osteoporosis in a castrated
prostatic cancer patient, comprising administering to said patient
an amount of from 10 mg to 300 mg cyproterone acetate per day.
2. The method according to claim 1 wherein the administering is
continuous.
3. The method according to claim 1 wherein the administering is
continuous for at least sixty days from the start of administration
and intermittent thereafter.
4. The method according to claim 1 wherein the administering is for
at least about 30 days.
5. The method according to claim 1 wherein the administering is for
at least about 6 months.
6. The method according to claim 5 wherein the administering is for
from about 6 months to about 9 months.
7. The method according to claim 1 wherein the administering is for
at least about 9 months.
8. The method according to claim 1 wherein the administering is for
over 1 year.
9. The method according to claim 1 wherein the administering is for
at least about 2 years.
10. The method according to claim 9 wherein the administering is
for from about 2 to about 3 years.
11. The method according to claim 1 wherein the amount is from 25
mg to 150 mg cyproterone acetate per day.
12. The method according to claim 1 wherein the amount is from 25
mg to 100 mg cyproterone acetate per day.
13. The method according to claim 12 wherein the amount is from 50
mg to 100 mg cyproterone acetate per day.
14. The method according to claim 11 wherein the administering is
for at least about 6 months.
15. The method according to claim 11 wherein the administering is
for greater than one year.
16. The method according to claim 1 wherein the patient is a
chemically castrated prostatic cancer patient.
17. The method according to claim 1 wherein the patient is an
orchiectomized prostatic cancer patient.
18. The method according to claim 1 wherein the administering is
once per day.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a treatment for slowing or
preventing the progression of osteoporosis in surgically or
chemically castrated prostatic cancer patients.
BACKGROUND OF THE INVENTION
[0002] Osteoporosis is generally the occurrence of a reduction in
the quantity of bone, or the atrophy of skeletal tissue. This
disorder is evidenced by a decrease in bone density throughout the
body. Although the mechanism of osteoporosis is not entirely
understood, it is believed that there is an imbalance between bone
production and bone resorption, resulting in net bone resorption or
breakdown. The condition can begin to occur as early as age 30. The
process is typically more rapid in postmenopausal women than in
men. Bone loss in males can be recognized at about 65 years of age.
A significant bone loss is seen in men at about 80 years of age,
and is accompanied by increased hip, spine and wrist fractures.
[0003] Surgical and chemical (e.g., LH-RH agonists) castration are
widely used for the treatment of patients with prostate cancer. A
number of side effects occur as a result of such therapy. Impotence
and the occurrence of hot flashes are among the more distressing
side effects to patients.
[0004] A less noted side effect of surgical or chemical castration
is osteoporosis. It has been reported that orchiectomy for prostate
cancer is often followed by severe osteoporosis (Daniell, H. W., J.
Urol. 157:439-444, 1997). Castration of man and many animal species
retards skeletal growth and development. Orchiectomy in rats can
cause osteoporosis detectable from within two to four months.
(Winks and Felts, Calcif. Tissue Res. 32:77-82 (1980); Verhas et
al., Calcif. Tissue Res. 39:74-77 (1986)).
[0005] Unlike the evident side effects of orchiectomy or LH-RH
agonist treatment, the pronounced onset of osteoporosis can be
insidious since the risk of osteoporetic fracture increases
rapidly. Moreover, these patients are preoccupied with adjusting to
their treatment and addressing basic quality of life issues rather
than taking measures to deter bone loss. Because of pain or their
overall condition, many of these patients are not up to exercising,
for instance.
[0006] It is thought that the sudden reduction in androgen levels
effected by surgical castration or medical castration (e.g., LH-RH
agonist treatment) in these men causes or is an important factor
contributing to the degree of bone loss that can occur. (Daniell,
H. W. J. Urol. 157:439-444, 1997). The correlation between the
reduction in levels of adrenal estrogen in women during the
menopause and the onset of osteoporosis is well known. In both
sexes, the clinical situation can be described as an acquired
gonadal insufficiency. Furthermore, it has been suggested that
androgens increase the synthesis of bone matrix. Studies in animals
have shown that testosterone administration increases the overall
quantity of bone. (Silberberg and Silberberg, 1971; see Finkelstein
et al., Ann. Int. Med. 106:354-361, 1987).
[0007] Estrogen replacement therapy has been the therapy of choice
for osteoporosis in post-menopausal women. For men, estrogens may
be effective to treat osteoporosis, but at the risk of gynecomastia
and increased cardiovascular morbidity.
[0008] U.S. Pat. No. 5,541,172 to Labrie et al. addresses methods
of treatment of diseases responsive to activation of the androgen
receptor. The patent indicates methods for prevention and therapy
of breast and endometical cancer, as well as osteoporosis. An
androgenic steroid is administered such that circulating serum
levels are maintained at low concentrations of between 1.0 and 50.0
nanomoles per liter. This cumulative dose is provided by
administering the steroid within a sustained release formulation to
avoid fluctuating blood levels.
[0009] Also discussed by the Labrie et al. patent are contentions
that some synthetic progestins possess, in addition to their
progesterone-like activity, varying degrees of androgenic activity.
Labrie et al. indicate that progestins frequently have a high
affinity for the androgen receptor at the low plasma concentrations
mentioned. The patent reports on the use of medroxyprogesterone
acetate and megestrol acetate. It also indicates that certain
synthetic progestins or anabolic steroids including, for example,
nor-testosterone, ethisterone and cyproterone acetate, possess
androgenic activity at low concentrations in the in vitro system of
human breast cancer ZR-75-1 cells.
[0010] The Labrie et al. patent advises assessing the specific
interactions of a compound at the indicated concentrations with the
androgen receptors, including estrogen, progesterone and
glucocorticoid-mediated activities. At low concentrations, the
compounds of interest to Labrie et al. do not interact with the
glucocortioid receptor. Thus, masculinizing side effects of
androgens in the treatment of women can be avoided. The patent
further advises evaluating by in vitro assay the effects of a
potential compound on the various receptors indicated in ZR-75-1
human breast cancer cells. The focus of the patent on the treatment
of women who have diseases responsive to activation of the androgen
receptor, particularly estrogen-dependent diseases, is
apparent.
[0011] U.S. Pat. No. 5,567,695 to Labrie is related to the above
discussed Labrie et al. patent and similarly reports a method for
preventing osteoporosis. An androgenic steroid having a Ki of less
than 2.times.10.sup.-8M for the androgen receptor and having a
receptor-mediated inhibitory effect on the growth of human breast
cancer ZR-75-1 cells is used, where the dosage is sufficiently low
to maintain a cumulative androgenic steroid serum concentration
below 50 nanomoles per liter. Similar to the above Labrie et al.
patent, the compounds are indicated to have the special property of
potent androgenic activity at these low blood concentrations, while
exhibiting little glucocorticoid activity, and therefore, they
produce no visible masculinizing effects.
[0012] It has been suggested that progestational agents can
potentiate bone mineralization, although the definitive effect of
progesterone on bone is apparently not known. (Loprinzi, et al., N.
Engl. J. Med. (1994) 331:347-352).
[0013] Cyproterone acetate ("CPA") is disclosed in U.S. Pat. No.
3,234,093, which is incorporated herein by reference. CPA, a
synthetic 21-carbon hydroxyprogesterone derivative, is a steroidal
antiandrogenic agent that inhibits the action of adrenal and
testicular androgens on prostatic cells, resulting in total
androgen blockade. Additionally, due to the antigonadotropic
effects of its progestogenic activity, CPA causes a centrally
mediated reduction in testicular secretion of androgens. The
progestational activity of CPA is considered relatively weak.
(Goldenberg, S. L. et al., Pharmanual 1994, Current Perspectives on
the Expanding Role of Androcur,.RTM.Pharma Libri Publishers Inc.,
at p. 21).
[0014] CPA is approved for use in many countries throughout Europe,
Asia, Australia, South America and Canada. It is used as a
component of oral contraceptives and in the treatment of acne,
seborrhea, hirsutism, precocious puberty, hypersexuality and in the
treatment of prostate cancer. The pharmaceutical preparations
Androcur.RTM., Cyprostat.RTM., Diane.RTM. and Dianette.RTM. are
CPA-based products. Manufacturers of these products include
Schering AG, Berlin, Germany and Berlex, Canada.
[0015] Since 1966, CPA has been used in combination with bilateral
orchiectomy to achieve total androgen blockade in the treatment of
prostate cancer. CPA has also been administered as monotherapy for
prostate cancer. The potent antiandrogenic activity of CPA is
"cancerocidal" to prostate cancer cells. Dosages of 250-300 mg/day
are used to bring about a complete anti-androgenic blockade.
Dosages prescribed are usually 200-300 mg/day, divided into 2-3
doses. After orchiectomy a lower daily dose of 100-200 mg may be
recommended. In a study reported in 1972 by Bracci and DiSilvero
(discussed in Goldenberg, S. L. et al., Pharmanual 1994, Current
Perspectives on the Expanding Role of Androcur,.RTM. Pharma Libri
Publishers Inc., p. 23-24), CPA was administered at 100 mg/day or
more with orchiectomy to patients with various advanced tumors for
more than 2 years. The investigators noted that CPA in combination
with orchiectomy has marked therapeutic effectiveness.
[0016] Side effects most frequently recorded with CPA treatment
relate to the hormonal effects of the drug. These include
impotence, inhibition of spermatogenesis and gynecomastia. These
reactions are usually reversible upon discontinuation of therapy or
reduction in dose. The drug is also associated with rapid falls in
serum testosterone levels, which may also produce such central
nervous system effects as fatigue, weakness, and headache.
[0017] CPA has a low incidence of side effects and its
antigonadotropic and antiandrogenic effects are reversible, which
enables intermittent therapy. Unlike other androgen deprivation
therapies, CPA is rarely associated with hot flashes. Prostate
cancer patients receiving CPA combined with surgical or chemical
castration are less likely to experience hot flashes than those who
do not receive CPA. (Barradell et al., Drugs & Aging (1994)
5/1:59-80.)
[0018] The Androcur.RTM. Monograph, Berlex Inc., Canada (1997),
indicates a general improvement in the subjective assessment of the
quality of life in 70% of 367 evaluable patients participating in
worldwide studies on CPA, based on criteria of general improvement
in quality of life. The criteria listed are weight gain and pain
relief. In a large scale randomized clinical trial on patients who
had previously undergone orchiectomy and who had the mere
occurrence of hot flashes and/or outbreaks of sweat, the number of
patients experiencing hot flashes or outbreaks of sweating
decreased after 6 months of treatment with 150 mg/day CPA (50 mg.
t.i.d.). (Kramer, P., et al., In: Murphy G., et al., 3.sup.rd Int'l
Symposium on Recent Advances in Urological Cancer Diagnosis and
Treatment --Proceedings. Paris, France: SCI: 3-7 (1992)).
[0019] Another beneficial effect seen with CPA treatment has been
the prevention of exacerbated bone pain. Patients with Stage C and
D prostate cancer indicated improvement in bone pain with CPA as
monotherapy. (Barradell et al., Drugs & Aging (1994) 5/1:
59-80). Overall, pain relief has been noted in 50-80% of patients
receiving treatment with ANDROCUR.RTM.. (The Androcur Monograph,
Berlex, Canada (1997)). The effect of CPA on pain generally
paralleled its effect on metastasis. Id. When metastasis remained
improved or stabilized, the analgesic requirement was also reduced.
Id.
[0020] It has also been reported that exacerbated bone pain
associated with the flare reaction at the start of LH-RH agonist
treatment is prevented with CPA administered to prevent acute
flare-up of prostatic disease. The Goldenberg, S. L. et al.,
Pharmanual (cited above), indicates that Claes H., et al., in
Murphy GP (Prostate Cancer, Part A: Research, Endocrine Treatment,
and Histopathology, New York, N.Y.: Alan R. Liss (1987) 229-236),
found that 58.5% of 17 patients who received goserelin alone
experienced a transient increase in bone pain compared with none of
7 patients who received goserelin acetate plus 200 mg/day CPA. For
the short-term prevention of tumor flare, CPA has been administered
with an LH-RH agonist generally at 150 to 300 mg/day dosages. Also
for tumor flare, CPA has been administered at 100 mg/day in
combination with 0.1 mg/day of the estrogen diethylstilbestrol
(DES). (Bruchovsky et al., Cancer 71: 7282-2790 (1993)).
[0021] Dose-related hepatic toxicity in humans has been reported
with the prolonged use of CPA. Toxicological studies have revealed,
however, that administration of CPA to humans does not pose a
serious risk of hepatotoxicity. A retrospective liver toxicity
analysis was performed on 89 patients with advanced prostatic
cancer who underwent orchiectomy and who received continuous
additional antiandrogenic treatment with 50 mg/day CPA. (Hinkel et
al., Eur. Urol. (1996) 30:464-470). CPA was administered to these
patients for a period spanning from 2 to 152 months starting at the
time of diagnosis. Various medications were frequently prescribed
besides CPA treatment. Although a proper control group was lacking,
in no case was CPA discontinued due to its side effects. After
evaluating the patients' liver function, the authors concluded that
CPA is a reliable drug to inhibit androgen synthesis with maximum
efficacy and safety in the treatment of prostate cancer.
[0022] A review on the toxicology of CPA was published by Rabe et
al. (Drug Safety (1996 (Jan.)); 14(1):25-38). In a multi-center
surveillance study of long term CPA use in over 2500 patients, the
treatment group included men and women. The men were treated at
dosages of either more than 200 mg/day or from 100 to 200 mg/day
CPA. No correlation was found between the duration of CPA treatment
and the prevalence of liver enzyme elevations. Not a single case of
hepatocellular carcinoma was observed. The authors concluded that
there were no observations that would indicate an increased risk of
proliferative liver change as a result of CPA treatment.
[0023] The Androcur.RTM. Monograph, Berlex, Canada (1997) reports
on the pharmacokinetics of CPA in humans. It indicates that the
mean plasma concentration of CPA in male subjects following oral
administration of one 50 mg dose is about 700 nmol/L. Continual
dosing of 50 mg per day CPA would be expected to result in a plasma
level of CPA maintained at an estimated concentration from about
500 to about 750 nmol/L, and upon a longer period of continual
dosing, the cumulative plasma level would likely be closer to a
steady state level of about 750 nmol/L or higher. Blood levels of
CPA are known to be generally dose dependent.
[0024] The minimum dosage of CPA for an antigonadotropic effect in
men may not be precisely known. The threshold value for an
antiandrogen effect in men was indicated to be 50 mg according to
U.S. Pat. No. 3,895,110, which issued in 1975. Presumably then, the
threshold value for an anticancerocidal dosage in prostate cancer
patients may also be 50 mg.
[0025] CPA is generally not considered an androgenic compound. In
fact, CPA is therapeutically classified as an anti-androgen
(Androcur Monograph, Berlex, Canada, 1997), and is used clinically
for its potent anti-androgenic activity in the treatment of
prostate patients, as discussed. In a critical review of possible
paradoxical androgenic activity of CPA (El Etreby et al., The
Prostate 11:361-375 (1987)), the authors caution that the
circumstances under which paradoxical androgen-like effects may
develop are of significance. For example, inhibition of complete
involution of the ventral prostate of castrated adult rats by CPA
was shown to be very weak, and these results were not seen with
higher doses of CPA. It was suggested that the effect may not be
related to an asserted androgenicity, but rather, to an inhibitory
effect on prostatic catabolic activities. The authors also explain
that CPA does not meet the classical definition of an androgenic
steroid "because of its inability to restore the normal size and
function of adult prostates even if administered to castrated
animals with involuted prostates at doses high enough and for a
sufficiently long time." (El Etreby et al.) Estrogens have a
testosterone-reducing effect that is based to a large extent on the
increased release of inhibitory factors from the hypothalamus in
addition to a direct effect on the pituitary gland.
[0026] Goldenberg et al. (J. Urol. (1988) 140: 1460-1465) reported
that CPA and low dose DES may be co-administered to achieve a
synergistic androgen withdrawal effect in the treatment of advanced
prostatic carcinoma. CPA administered at 200 mg/day with 0.1 mg
daily DES showed a marked decrease in serum testosterone, with no
change upon decreasing CPA to 100 mg/day in the combination. In a
subsequent report, Goldenberg et al. (Urology 47 (6) (1996)
882-884) indicate that 100 mg CPA and 0.1 mg DES per day result in
a persistent decrease in serum testosterone with a lower incidence
of side effects than the 200 mg/day CPA combination. Bruchovsky et
al. (Cancer 71: 2782-2790 (1993)) report elimination of flare
reaction by pretreatment with CPA and low-dose DES. Patients were
pretreated with 100 mg per day CPA and 0.1 mg/day DES for 4 weeks.
Goserelin acetate was then given and CPA/DES was continued. DES
administration was discontinued at 8 weeks to eliminate associated
minor toxicity.
[0027] Goldenberg et al. (J. Urol. (1988) 140: 1460-1465) indicate
that a weakening of the antigonadotropic effect of CPA, seen after
6 to 9 months, was not observed with the continued
co-administration of DES.
[0028] Chlorotrianisene, an estrogen which was sold in the United
States under the name TACE.RTM., was indicated for the palliative
therapy of advanced prostatic carcinoma and for moderate to severe
vasomotor symptoms associated with the menopause, among other
things. For long-term treatment of progressive prostatic cancer, 12
mg to 25 mg daily was prescribed. (Physicians' Desk Reference, 35th
Edition (1981)).
[0029] It has also been forwarded that estrogens may increase
prostatic cancer growth. In the treatment of prostate cancer, U.S.
Pat. No. 5,610,150 discloses a combination therapy for prostate
cancer treatment that includes an antiandrogen, a sex steroid
biosynthesis inhibitor and an antiestrogen for the prevention of
the biosynthesis of estrogen.
[0030] It has been reported that serum osteocalcin (OC) can be
useful clinically as a marker to monitor patients with bone
metastases. After testing with various anticancer treatment
strategies, low dose CPA included, Tarle, M. (Urol. Res. (1991)
19:39-44) reported that OC concentration can serve as a nonspecific
marker of bone lesions in patients with prostatic carcinoma. As a
bone-derived protein related to mineralization processes during
bone healing, elevated OC can indicate remission in patients with
advanced prostatic cancer.
[0031] There is no suitable treatment for osteoporosis in
surgically or chemically castrated prostatic cancer patients. A
method for treating osteoporosis that is compatible with androgen
ablation therapy of prostate cancer will fulfill an important
medical need.
SUMMARY OF THE INVENTION
[0032] The present invention provides a method for preventing or
treating osteoporosis in a castrated prostatic cancer patient, by
administering to the patient an amount of from 10 mg to 300 mg
cyproterone acetate per day. The present therapy is compatible with
the patients' anticancer treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0033] While androgens are generally favorable for use in the
treatment of osteoporosis, androgens are contraindicated for
prostatic cancer patients. Although reduced in vivo androgens are
strongly correlated with the onset of osteoporosis, it is
recognized that the anti-androgenic steroid cyproterone acetate is
effective to treat osteoporosis in castrated prostatic cancer
patients. Without wishing to be bound by any theory, it is thought
that CPA, due to its progestational nature, has a positive effect
on supporting bone metabolism and bone density in castrated
prostatic cancer patients. Moreover, CPA is compatible with the
patients' anticancer treatment.
[0034] CPA can be administered at a dosage equivalent to from 10 mg
per day of a solid oral dosage form to an effective amount that is
tolerated by a castrated prostatic cancer patient, for prevention
or treatment of osteoporosis. For example, a dosage up to 300 mg
per day solid oral CPA can be used. Preferably, lower amounts of up
to 200 mg CPA per day, more preferably up to 150 mg CPA per day,
are used. Preferably, the minimum dosage is 25 mg per day. Dosage
amounts are preferably selected from, for instance, 25 mg, 50 mg,
100 mg and 150 mg CPA per day in a solid oral dosage form.
[0035] Castrated prostatic cancer patients, in accordance with the
present invention, are those prostate cancer patients who have
undergone surgical castration, e.g., bilateral orchiectomy, or who
have undergone or are undergoing chemical or medical castration,
e.g., by administration of an LH-RH agonist such as Lupron.RTM. or
Zoladex.RTM.. These patients can additionally be undergoing or have
undergone pure antiandrogen treatment such as with flutamide. The
patients can be undergoing other treatments, as long as
administration of CPA therewith is approved by the patients'
physicians or otherwise not contraindicated.
[0036] Generally, the treatment term is for thirty days or longer,
e.g., preferably at least about 180 days. Longer periods are
recommended to continually deter or protect against bone loss. A
period of at least 6 months, e.g., at least 9 months, is desirable.
A preferred length of treatment is from 9 to 12 months. Treatment
can also be for greater than 12 months. Administration can be for
as long as 2 years or more, e.g., from 2 to 3 years, since CPA
administered according to the present invention is well tolerated
long-term. This is important because patients may survive for many
years after their diagnosis.
[0037] The treatment term can be continuous or intermittent,
preferably at the discretion of the physician and/or the patient
under a doctor's supervision. Treatment is preferably continuous,
i.e., CPA is taken every day. Continuous treatment is preferably
for at least thirty days, e.g., about 180 days, more preferably for
at least 6 months.
[0038] For intermittent therapy, after a period of treatment the
patient withdraws from taking the drug for a length of time, and
then resumes taking the drug as desired. As a guideline for
intermittent treatment, the patient can take CPA continuously for
more than 30 days immediately before a period during which no CPA
is taken. The time during which the patient then does not take CPA
generally does not exceed about 30 days. Administration is
preferably continuous for at least sixty days from the start of CPA
treatment and then can be intermittent at some time thereafter.
Typically CPA is given continuously until PSA is at castrate
levels. Withdrawal and intermittent administration, if employed,
are preferably initiated after castrate levels are reached. Optimum
treatment will vary from patient to patient.
[0039] The dosage is generally administered once per day, which is
favorable in terms of patient compliance. Other dosage regimes such
as twice or three times a day administration may be implemented. A
solid oral dosage is preferably formulated as 50 mg CPA. Other
dosage amounts, e.g., a 100 mg or 25 mg oral dose of CPA, may be
formulated. The dosage form is preferably a tablet. Other solid
dosage forms such as capsules are contemplated.
[0040] Alternatively, CPA can be provided in other dosage forms
such as a liquid oral dosage, an indictable depot (solution or
suspension), e.g., in a 100 mg/ml concentration, and an intranasal
or a transdermal delivery system, for example, as a patch. The
amount of CPA provided in each dosage form would provide equivalent
blood levels of CPA as does from 10 mg to 300 mg solid oral dosage
of CPA per day, preferably as does from 25 mg to 150 mg solid oral
dosage form of CPA per day.
[0041] CPA therapy can begin at any time. Preferably, it begins
about the time the cancer treatment begins, i.e., just before, the
same time or shortly after orchiectomy or the start of treatment
with the chemical castration agent. It is advantageous to begin CPA
treatment early to offset loss of bone. Other beneficial effects
may also occur, e.g., an additional anticancerocidal effect,
alleviation of tumor flare and prevention of hot flashes.
[0042] CPA can be used in accordance with the present invention to
treat castrated prostatic cancer patients having any stage of
prostatic cancer to deter or treat osteoporosis.
[0043] It is also recognized that CPA in combination with a low
dose estrogen is useful in treating castrated prostatic cancer
patients for osteoporosis. Moreover, the combination can have a
synergistic effect on the treatment of osteoporosis. The lowest
synergistically effective dosage of estrogen is preferred in order
to minimize undesirable side effects. The estrogen can be
administered every day or on alternate days.
[0044] A preferred estrogen of the combination is DES. Dosages in
accordance with the present invention are from 10 mg to 300 mg CPA,
preferably 25 mg to 150 mg CPA, combined with about 0.01 mg to
about 3 mg DES per day or every other day. Preferred dosages are
from 50 mg CPA to 100 mg CPA per day in combination with 0.01 mg to
0.1 mg DES per day or every other day. The optimum treatment dosage
with minimum undesirable side effects can vary from patient to
patient.
[0045] It is also recognized that CPA can be used in combination
with the estrogen chlorotrianisene to treat castrated prostatic
cancer patients for osteoporosis. Dosages in accordance with the
present combination are from 10 mg to 300 mg CPA, preferably 25 mg
to 150 mg CPA combined with from about 0.1 mg to about 25 mg
chlorotrianisene per day. It is recognized that from 0.1 mg up to
12 mg chlorotrianisene in combination with CPA is effective in the
treatment of osteoporosis. Dosages of 50 mg CPA to 100 mg CPA in
the combination are more preferable. It is recognized that the
combination with chlorotrianisene provides an effective treatment
with low associated toxicity.
[0046] Other estrogens can be used. Naturally derived estrogens
such as the conjugated estrogens in Premarin.RTM. may be
administered. Synthetic conjugated estrogens such as ethinyl
estradiol, quinestranol and mestranol may also be used. Further
examples of estrogens are estradiol, estradiol valerate, piperazine
estrone sulphate, estrone, estriol, estriol succinate and
polyestriol phosphate.
[0047] Treatment duration, dosage forms and other parameters
discussed above for CPA alone are applicable. A combination
formulation of CPA with a low dose estrogen can be administered as
a combined formulation or as two separate dosage units.
[0048] Castrated prostatic cancer patients undergoing treatment
with CPA in accordance with the present invention can begin taking
a low dose estrogen with their CPA therapy at any time. Commencing
combination therapy prior to six months from the start of CPA
administration may be particularly beneficial as it could alleviate
any potential weakening of the antigonadotropic effect of CPA.
[0049] Typical clinical measurements to determine osteoporosis use
specialized x-ray machines that measure a patient's hip or spine.
To assess a patient's bone mineral density, bone density
measurements can be made by absorptiometry (single/dual photon
absorptiometry, single/dual x-ray photon absorptiometry and
dual-energy quantitative computerized tomography). The measurement
preferably can be made at two points of the arm (1/3 and {fraction
(1/10)} of the forearm length from a distal end of the radius).
Studies have shown that measuring heel density can also accurately
predict osteoporosis. A newer device, the Sahara Clinical Bone
Sonometer, uses ultrasound to assess a patients' bones by
measurement of heel density.
[0050] Other markers can be used to assess bone absorption and/or
resorption. (Reginste et al., 1993, Genant et al., 1996). Plasma
and urinary calcium and phosphate levels, plasma alkaline
phosphatase, calcitonin and parathormone concentrations, as well as
urinary hydroxyproline and calcium/creatinine ratios are some of
these markers. Both traditional (urinary calcium/creatinine and
hydroxyproline/creatinin- e) and currently used specific (urinary
pyridinoline/creatinine and deoxypyridinoline/creatinine) markers
of bone resorption can be used. Development of specific and
sensitive assays to measure biochemical markers reflecting the
overall rate of bone formation and bone resorption has markedly
improved the non-invasive assessment of bone turnover in various
metabolic bone diseases, especially osteoporosis. Human osteocalcin
and bone alkaline phosphatase as markers are measured by what may
be the most sensitive means to assess bone formation. Immunoassays
are available to the intact osteocalcin molecule as well as its
major proteolytic fragment, and to bone alkaline phosphatase. For
bone resorption, the total urinary excretion of pyridinoline
crosslinks measured by high pressure liquid chromatography has
shown its superiority over all other markers for the clinical
assessment of osteoporosis. The recent development of immunoassays
recognizing either the free pyridinoline crosslinks or pyridinoline
crosslinked-type I collagen peptides in urine and serum should
allow a broad use of this sensitive resorption marker.
[0051] As the clinician is aware, bone density can vary widely even
among people with healthy bone. In assessing whether any patient
has an increased risk of developing osteoporosis, or has developed
osteoporosis, risk factors such as whether the patient is a smoker
or is small-framed should be considered. The targeted group of
patients, castrated prostatic cancer patients, are considered to
have a high risk of osteoporosis. A determination of bone density
is preferably made prior to the surgical or chemical castration
treatment to obtain an indication of the state of the patients'
bones before this risk factor is introduced, for comparative
purposes.
[0052] From the foregoing description, one skilled in the art can
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications. Preferred embodiments set forth
by way of illustration are not intended as limitations on the
variations possible in practicing the present invention.
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