Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
I. ".~n~~~. ~..I~nl~..lla:~ L.
CA 02159355 2004-11-30
1
I METHOD AND COMPOSITION FOR
TREATMENT OF OSTEOPOROSIS
FIELD OF TH
This invention concerns novel methods for treating
osteoporosis in humans and, more particularly, involves~a
method and composition for treating osteoporosis with a
combination of an alkalinizing potassium salt and a thiazide
diuretic which is effective in such treatment, which drug
combination reduces the health risks or side effects
associated with thiazide treatment.
$BACKGROUND OF THE INVENTION
Osteoporosis is a metabolic bone disease
characterized pathologically by an absolute decrease in the
amount of bone, and clinically.by increased susceptibility to
fractures. Riggs et al., N. Enal. J. Med. ,(1986), 314:1676;
Rusbach et al., in: Textbook of Endocr'n~ olog3r, Ed(s) Williams,
(1981), p. 922; Riggs, in: Cecil ~gxtbook of Medicine, Ed(sj
Wyngaarden et al., (1985), p. 1456; Riggs et al., Am. J. Mad.,
(1983), 75:899.
There are several biochemical markers which taken
together, can be used to either diagnose a patient as
osteoporotic, or to study the efficacy of treatments'for
osteoporosis. For example, urinary hydroxyproline excretion
rate is widely used as a marker for bone resorption. Rlein et
al., Metabolism 2, Vol. 13, No. 3, March 1964, 272-285;
Charles et al., J. Clin. Invest., Vol. 76, December 1985 2254-
2258; and Deacon et al., Shin. Chim. Acta., 1987, 297-306.
WO 94/22312 PCT/US94/03403 -
2159~~5
2
Pyridinoline and deoxy-pyridinoline, two types of collagen
crosslinks present in bone, which can be detected in urine,
are also markers for bone resorption. Robins, et al.,
European Journal of C1 nir.ai investigation (1991), 21:310-315.
Serum concentrations of osteocalcin serve as a
biochemical marker of the rate of bone fonaation. Osteocalcin
is an integral protein of the organic matrix of bone
synthesized by bone-forming cells (osteoblasts) during the
process of bone formation. A small fraction of the newly
synthesized osteocalcin escapes into the circulatory system,
thus providing a blood marker of the rate of bone formation.
The osteocalcin concentration increases when the bone
formation rate increases, and decreases when the bone
formation rate decreases. Brown, et al., The hancet, May 19,
1984, p. 1091, "Serum Bone GLA-Protein: A Specific Marker For
Bone Formation in Postmenopausal Osteoporosis". Another
reflection of bone resorption/bone formation are changes in
calcium and phosphorus balances (positive or negative) which
are determined by measuring the difference between the total
excretion (feces and urine) and the dietary intake of calcium
or phosphorus ion. (These balances are positive when the
total excretion is less than the dietary intake.)
Thiazide diuretics are widely used for the treatment
of hypertension. In recent years a number of studies have
suggested that they may also have a potential role in the
prevention of bone loss and osteoporotic,fracture, leading to
several recent proposals for randomized, controlled clinical
trials thereof (Lacroix, Comprehensive Thera_pv (1991), 17(8):
30-39; Editorial, "Thiazide Diuretics and Osteoporosis", BJCP,
Autumn 1991, 45(3); Ray, W.A., Editorial, "Thiazide Diuretics
and Osteoporosis: Time for a Clinical Trial?", 1 July 1991,
Annals of Internal Medicine 115(1): 64-65).
The proposals that the thiazide diuretics may be
effective in the treatment of osteoporosis are based on the
recognition that they reduce urinary calcium excretion
(Adland-Davenport et al., Am. J. Obstet. G~necol., (July 15,
1985), 152(6) Part 1: 630-634: Wasnich et al., Obstetrics and
Gynecology, (April 1986), 67(4): 457-462; Ray et al., The
CA 02159355 2004-11-30
3
lancet, (April 1, 1989): 687-690: Steiniche et al., BPMIS,
(1989), 97:302-308; and Lacroix et al., New Eng~. J. Med.,
(Feb. 1, 1990): 286-290), improve calcium balance (Wasnich et
al., gew Ena. J. Med., (Aug. 11, 1983): 344-347; Hunt et al.,
Am. J~ Clin. Nutr., (1989), 50: 517-523= Steiniche et al.,
1989; and La Croix et al., 1990) and decrease bone loss
(Wasnich et al., gr. Med. J., (1990), 301: 1303-1305), coupled
with the recent reported studies associating thiazide use with
a decreased risk of hip fracture (Ray et al., 1989: LaCroix et
al., 1990; and Felson et al., ~, (1991), 265: 370-373).
The thiazide diuretics have, however, been
associated with a recognized set of side effects, particularly
when administered at higher doses. Administration o! the
thiazides commonly causes hypokale~eia (Bloomfield et al.,
1986, J. Clin. Hvnertens, 4:331-3381 Solomon et al.,
Cardiovasc. Pharmacol. (1991) 17:854-859). They cause
postural hypotension,.resulting in increased frequency o!
fainting, dfzziness and loss of consciousness in women (La
Croix, 1991: Hale et al., J. Am. Geriatric Soc. (1984) 32:5-
10). In men, impotence commonly occurs (Papadopoulos, Arch.
Intern. Med., Vol. 140, p. 1341 (1980); and Report of Medical
Research Council Working Party on Mild to Moderate
Hypertension, a Lancet, Sept. 12, 1981, pp. 539-543). In
addition, they may adversely affect electrolytes, carbohydrate
metabolism, lipids and kidney function (Fried et al., in
Diuretics Physiolow Pharmaco~ and Clin,~.cal Use, 1986,
Chapter 4, pp. 66-82).
It is therefore desirable to take advantage of the
hypocalciuric properties of the thiazide diuretics in the
treatment of osteoporotic disease, while avoiding the multiple
side effects thereof.
U.S. Patent No. 5,171,583, granted on December 15,
1992,
discloses a method for ameliorating or preventing
osteoporosis in humans afflicted with or predisposed to
osteoporosis, comprising administering a composition _
containing a therapeutically or prophylactically-effective
amount of a composition of a pharmaceutically-acceptable
WO 94/22312 PCT/US94/03403~
215~~~5
4
alkalinizing potassium salt. An effective dose of the
alkalinizing potassium salt of 40-400 mmoles/70kg patient
weight/day and preferably 40-250 mmoles/70kg/day is disclosed
therein.
In accordance with the present invention, when the
thiazide diuretics are used in combination with the foregoing
alkalinizing potassium salts, a method and composition for
treating osteoporosis is provided which reduces if not
eliminates hypokalemia and the risks and side effects
associated with the use of the thiazides.
BUr~iARY OF THE INVENTION
The present invention thus involves a novel method
for ameliorating or preventing osteoporosis in humans
afflicted with or predisposed to osteoporosis, which comprises
administering to a patient an effective dosage of a
combination drug comprising the following active ingredients:
(a) a pharmacologically-acceptable alkalinizing
potassium salt which produces hydroxyl ions and is thereby
capable of reducing the acidity (by increasing the alkalinity)
of tissue fluids or urine and which is selected from the group
10 consisting of potassium bicarbonate and potassium salts of
carboxylic acids which are transformed (combusted) to
bicarbonate and thus alkalinize ,~ vivo: and
(b) a thiazide diuretic.
Preferably, the alkalinizing potassium salt is
administered in an amount of about 60 to 180
milliequivalents/70 kg patient weight/day, and the thiazide
diuretic is administered in amounts ranging from about 10% to
about 90% of the minimum usual daily oral diuretic dose in
humans.
By combining the pharmacologically-acceptable
alkalinizing potassium salt and the thiazide diuretic,
unexpectedly superior results are obtained in the treatment of
osteoporosis as compared with the results obtained by
treatment with either such active ingredient alone. Otherwise
stated, it is possible in some instances to decrease the
amount of the thiazide diuretic ingredient by as much as 90%
.. ~n fc
94/22312 ' ~ F~' ~x .~
PCT/US94/03403
without materially diminishing the hypocalciuric effect
obtained by it when administered as the sole active
ingredient. The combination drug of the present invention
thus provides the significant benefit of reducing, if not
eliminating, the health risks and side effects which may be
associated with administration of the thiazide diuretic.
DETAILED DESCRIPTION OF THE INVENTION
The two active ingredients of the combination drug
invention, i.e., (a) the pharmacologically acceptable
alkalinizing potassium salt and (b) the thiazide diuretic, may
be administered as separate dosage forms in conjunction with
one another. Alternatively, and preferably, as described more
fully below, the alkalinizing potassium salt may be combined
with the thiazide in a unitary dosage form which can 'be
administered to subjects without the need for independent
administration of these active ingredients.
As used herein, the terms "treatment" or "treating"
cover any treatment of osteoporotic disease, and include:
(1) preventing osteoporosis from occurring in a subject who
does not have osteoporosis or who has not yet been diagnosed
as having it; (2) inhibiting or arresting the development of
the disease; or (3) regressing or reversing the osteoporotic
state.
As further used herein, the combination drug of the
invention is utilized in an "effective dosage" when it causes
the following effects in the patient:
(a) it reduces the urinary hydroxyproline excretion
rate;
(b) it reduces the urinary collagen crosslink
excretion rate; and
(c) it increases calcium and phosphorus balances,
i.e., makes them less negative or more positive.
As also used herein, the term "col.lagen crosslinks"
means pyridinoline and deoxy-pyridinoline crosslinks.
Finally, as used herein the tenri "calcium balance°'
means the difference between the total excretion (feces and
urine) of calcium and the dietary intake of calcium ion.
~ n . ~i~ ~ . ~i ~~ i~. a i ~~~
CA 02159355 2004-11-30
6
Similarly, the term "phosphorus balance" means the difference
between the total excretion (feces and urine) of phosphorus
and the dietary intake of phosphorus ion.
The alkalinizing potassium salts which may be
employed in the process of the present invention are those
which, when present in the body fluids, produce hydroxyl ions
and are thereby capable of reducing the acidity (increasing
the alkalinity) of tissue fluids or urine. A number of
pharmaceutically-acceptable alkalinizing potassium salts are
known, several of which are set forth in Berg et al., ~,,,
Pharmaceut. 8ci. (1977.) 66:1,
Given the disclosure herein, it will be well
within the ability of one skilled in the art to select and
screen pharmaceutically-acceptable alkalinizing salts for the
ability to treat dsteoporosis using well known methods and
techniques. Desirably, a salt will be selected which is
therapeutically effective in amounts readily achievable in
humans while being relatively well tolerated. Different salts
may be chosen depending on~particular routes of administration
and preferred modes o! fos~nulation.
Tha alkalinizing potassium salts which may be thus
administered are preferably selected from the group consisting
of potassium bicarbonate (I0iC03) and pharmacologically
acceptable, non-toxic potassium salts of carboxylic acids such
as potassium gluconate (C6H11K0~) and potassium citrate
(C6HgK30~). The use of potassium bicarbonate is particularly
preferred. The preparation, isolation and purification of
these salts are well known to those skilled in the art, as
they are commonly employed in a therapeutic setting for a
variety of uses other than described herein. Specific
procedures for the preparation of such salts are described in
general terms fn Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pennsylvania, 16th Ed., 1982,
The thiazide diuretics useful in the method and
composition of the present invention comprise any of those
conventionally utilized in the treatment of hypertension.
Such agents are identified in Goodman and Gilman, The
i I. i Yr. i ~ir. i . r1 ~ii I,~dl m~ i 1r.
CA 02159355 2004-11-30
7
Pharmacological Basis of Therapeutics, Eighth Edition, 1990,
pp. 718-721 and 785-788: and in Drug Evaluations Subscription,
AlrlA Div. of Drugs and Toxicology, 1992, Vol. II - Renal-
Urologic Drugs, in Table 5.
As used
herein, the "thfazfde diuretics" include the sulfonaaide
diuretics, e.g., chlorthalidone, whose pharmacological action
is indistinguishable from that of the thiazides (See Goodman
and Gilman, sigpra, at page 718). Preferred thiazide diuretics
useful herein include chlorothiazide, hydrochlorothiazide, and
chlorthalidone.
The thiazide diuretics are believed to be especially
effective in the treatment of osteoporotic disease, in
combination with the alkalinizing potassium salts, since they
are weak carbonic anhydrase inhibitors which impair hydrogen
ion secretion and thus decrease osteoclast resorption of bone.
Although carbonic anhydrase inhibitors also produce acidosis,
it is believed that the alkalinizing potassiua salt prevents
acidotic conditions and thus acts synergistically with the
preferred thiazide diuretics, minimizing tha amount of the
latter required to produce a hypocalciuric effect. It should,
however, be understood that the present invention is not
limited by the foregoing hypothesized mechanism of co-action
between the active ingredients of the preferred composition.
Administration of the pharmacologically acceptable
.alkalinizing potassium salt or the thiazide diuretic
ingredients of the combination drug of the present invention
may be in pharmaceutical compositions described hereinafter
and can be via any of the accepted modes of administration for
agents which are known to be useful in the treatment of
osteoporosis. Each such ingredient may be administered
orally, parenterally, or otherwise. Different active
alkalinizing potassium salts or thiazide diuretics may be
admixed and simultaneously administered, or benefit may be
gained in some instances by their separate, sequential
administration.
Depending on the intended mode, the alkalinizing
potassium salt ingredient may be in the form of solid, semi-
WO 94/22312 ~ 1 ~ 9 3 ~ ~ PCT/US94/0340~
8
solid or liquid dosage forms, such as, for example, tablets,
capsules, pills, powders, granules, crystals, liquids,
suspensions, or the like, preferably in unit-dosage forms
suitable for administration of relatively precise dosages.
Similarly, the thiazide diuretic ingredient may be in the form
of a solid tablet, capsule or pill, preferably in unit-dosage
forms suitable for administration of relatively precise
dosages.
Preferably, the alkalinizing salt and the thiazide
active ingredients are combined in a solid unitary dosage form
in a tablet, capsule or pill, thus obviating the need for
separate administration of these ingredients. The solid
combined dosage form may include conventional pharmaceutical
carriers or excipients, and, in addition, may include other
pharmaceutical agents. Thus, the unit dosage form may be
compounded with conventional nontoxic solid carriers such as,
for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, talcum, cellulose, glucose,
sucrose, magnesium carbonate, and the like. Such compositions
may contain about 50-90% of the active ingredients of the
present invention, preferably about 70-90%.
Alternatively, the alkalinizing potassium salt
ingredient may be administered as a separate dosage form, in
conjunction with the administration of the thiazide diuretic.
The two drugs may thus be administered on the same schedule or
on different schedules in accordance with the normal modes of
administration thereof. When the alkalinizing potassium salt
ingredient is administered as a separate dosage form, it may
be in the form of tablets, pills, capsules, powders, granules,
crystals, sustained-release formulations, and the like, with
any of the previously listed excipients, or may be
administered in a liquid pharmaceutically-administrable
composition. Such liquid compositions can be prepared, for
example, by dissolving the salt, such as potassium
bicarbonate, and optional pharmaceutical adjuvants in a
carrier, such as, for example, water, aqueous dextrose,
glycerol, and the like, to thereby form a solution or
suspension. If desired, the separate alkalinizing salt dosage
94/22312 ~~,~ PCT/US94/03403
F s ;r~ ~ ~~
9
form may also contain minor amounts of nontoxic auxiliary
substances such as pH buffering agents and the like, for
example, sorbitan monolaurate, triethanolamine, sodium
acetate, triethanolamine oleate, etc. Actual methods of
preparing such dosage forms are known, or will be apparent, to
those skilled in this art: see, for example, the aforesaid
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pennsylvania, 16th Ed., 1982. An active potassium
salt ingredient of the combination drug, such as potassium
bicarbonate, for example, may be provided as a dietary
supplement supplied as pills, as granules or powder applied
directly to foodstuffs, or dissolved in drinking water, as
convenient means of administration.
Preferably, the thiazide ingredient of the
combination drug is administered in a daily dosage equivalent
to about 3 to 20 mg of hydrochlorothiazide and the
alkalinizing potassium salt is administered in a daily dosage
of about 60-180, preferably 60 to 120 milliequivalents. At
these levels, the following relative effects are observable in
comparison to the effects when the same amount of the thiazide
diuretic is separately administered:
(a) a reduction in the urinary hydroxyproline
excretion rate (measured as described in the Klein, Charles et
al. and Deacon et al. publications described above) by more
than 10%:
(b) a reduction in the urinary collagen crosslink
excretion rate (measured as described in the Robins et al.
publication described above) by more_than 10%; and
(c) an increase in calcium and phosphorus balances
(measured as described in conventional manner), for example,
by as much as 10%, or more.
As can be seen from the foregoing, the combination
drug of the present invention exhibits a synergistic effect in
treating osteoporosis, i.e., the combination of the two drugs
is substantially more effective than the same amount of the
thiazide when independently administered. Most preferably,
the thiazide diuretic ingredient of the combination drug may
be administered in an amount equivalent to the daily oral
CA 02159355 2004-11-30
administration of 3 to 20 mg of hydrochlorothiazide,
appreciably lower than the usual daily oral diuretic dose in
humans. The combination of the present invention
incorporating these lower dosages o! the thfazide is not only
effective in treating osteoporosis, but also significantly
reduces the health risks and side effects associated with
thiazide diuretics at higher doses. It is generally
convenient to supply the foregoing daily dosages in multiple
(e.g., 3 to 5) tablets incorporating the active ingredients in
10 suitable excipients and coated with a suitable sustained
release coating.
The amount of the thiazide diuretic administered in
accordance with the present invention will, of course, be
dependent on the potency of the particular thiazide used and
.the mode of administration. The relative and equivalent
potencies of various thfazide diuretics are well known to
those skilled in the art. (The equivalent daily diuretic
doses of hydrochlorothiazide and other thiaside diuretics are
disclosed in Fried et al., 1986, subra, at pp. 68-?0 and in .
Drug Evaluations Subscription, supra'.)
For example, 500 mg of
chlorothiazide are equivalent to ?5 mg of hydrachlorothiazide
in terms of hypocalciuric potency and ability to treat
osteoporosis. Given the disclosure herein, it will be well
within the ability of one skilled in the art to select a
thiazide diuretic and a dose level equivalent to the dosages
of the particular thiazides described herein.
It will also be appreciated by those having skill in
the art that in addition to administering the combination drug
described herein, it may be desirable to supplement the
patient's calcium intake, if necessary, to maintain it at
about 1500 mg of calcium per day.
The following examples illustrate some particularly
preferred, non-limiting embodiments of the present invention.
EXAMPLE I
A combination drug tablet is prepared containing the
following active ingredients: 3 mg of hydrochlorothiazide and
94/22312 PCT/US94/03403
11
1.5 grams of potassium bicarbonate. Four such tablets are
administered daily, to provide a daily dose of 12 mg of the
hydrochlorothiazide and 6:0 grams (60 milliequivalents) of the
potassium bicarbonate.
EXAMPLE II
A combination drug tablet is prepared containing the
same ingredients as Example I, except that the tablet contains
only 0.75 mg of hydrochlorothiazide. Again, four such tablets
are administered daily for effective treatment of
a0 osteoporosis.
From the foregoing, it will be appreciated that the
present invention provides a novel method and composition
which effectively treats/prevents osteoporosis in human
subjects, with lower health risks and incidence of side
effects than would be associated with thiazide diuretics.
Although the present invention has been described in
some detail by way of illustration and example for purposes of
clarity and understanding, it will be obvious that certain
changes and modifications may be practiced within the scope of
20 the appended claims.
