WO1997012620A1 - Method and composition for treatment of osteoporosis - Google Patents

Abstract

The combination of the following active agents for treating osteoporosis: (a) a pharmacologically-acceptable alkalinizing potassium salt which produces hydroxyl ions and is thereby capable of reducing the acidity of tissue fluids or urine and which is selected from the group consisting of potassium bicarbonate and potassium salts of carboxylic acids which are metabolized to bicarbonate and thus alkalinize in vivo; and (b) a bisphosphonate which is effective as an antiresorptive agent for bone in the treatment of osteoporosis; the active ingredients being administered in amounts effective to treat osteoporosis without adversely affecting bone and acid-base homeostatis.

Description

METHOD AND COMPOSITION FOR TREATMENT OF OSTEOPOROSIS

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit under 35 USC § 119(e) of U.S. Provisional Application No. 60/005,397, filed October 6, 1995, which is incorporated herein by reference.

FIELD OF THE INVENTION 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 bisphosphonate.

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. En l. J. Med. (1986), 314:1676; Rusbach et al., in: Textbook of Endocrinology, Ed(s) Williams, (1981), p. 922; Riggs, in: Cecil Textbook of Medicine, Ed(ε) Wyngaarden et al., (1985), p. 1456; Riggs et al. , Am. J. Med. , (1983) , 75:899.

It has been estimated that about 25 million Americans have some form of osteoporosis. The disease occurs most frequently in postmenopausal white women and in the elderly of both sexes. Cummings et al., Epidemiol . , Rev.

7:178-208. About 20 of women in the United States suffer one or more osteoporotic fractures by age 65, and as many as 40% sustain fractures after age 65. National Research Council (U.S.) Committee on Diet and Health, "Diet and Health: Implications for Reducing Chronic Disease Risk", Chapter 23, Osteoporosis, page 615. It has previously been proposed to treat osteoporosis with anabolic agents which stimulate bone formation, e.g., fluoride, parathyroid hormone and anabolic steroids, or with antiresorptive agents which decrease bone resorption. The latter, including estrogen for hormone replacement therapy, calcitonin, calcium supplements with or without vitamin D, and bisphosphonates, are more widely used in the management of osteoporosis. Francis, Curr. Therap. Res. 1995; Vol. 56, No. 9:831-851. At the present time, treatment with estrogen is the therapy of choice in early post enopausal women since it slows if not halts bone loss and reduces the risk of fractures. Hormone replacement therapy is, however, controversial, because of its association with increased risk of breast cancer. In recent years there have been a number of proposals to utilize bisphosphonates in the treatment of osteoporosis. After deposition in bone the bisphosphonates inhibit osteoclastic activity, thereby decreasing bone resorption. One of the bisphosphonates, alendronate, has quite recently been approved for use in the treatment of osteoporosis in the United States.

Inhibition of bone resorption by bisphosphonate administration not only restricts the mobilization of the inorganic cation, calcium, from bone but also restricts mobilization of the inorganic anions — carbonate, bicarbonate, phosphate, and the like — that accompany calcium. Those anions supply base equivalents to the systemic circulation, which react with acids in the circulation, in effect titrating those acids and reducing the acidity of the blood and extracellular fluid. Normally, base released from bone in the process of bone resorption titrates a fraction of the net amount of acid produced endogenously by metabolism of the foodstuffs in ordinary diets. By reducing the fraction of the daily net endogenous acid production that is neutralized by base released from bone, bisphosphonates, through their potent effect to reduce bone resorption, tend to increase the acidity of blood and lower the plasma bicarbonate concentration. In so doing, the administration of bisphosphonates may worsen the low level chronic metabolic acidosis normally present in otherwise healthy persons as a consequence of the endogenous generation of acid from acid precursors in excess of base precursors in ordinary diets.

This undesirable side-effect of bisphosphonates is of particular concern in individuals over 60, who constitute the major target group for bisphosphonate treatment. The reason for this concern is that with advancing age the functional capacity of the kidney normally progressively declines. With declining kidney function, the ability of the kidney to excrete its normal fraction of the endogenous acid load is compromised, which increases the demand on bone to maintain blood pH and plasma bicarbonate homeostasis. But because biphosphonates compromise the ability of bone to mobilize base, bisphosphonate treatment in such older subjects may exaggerate the severity of the metabolic acidosis that normally occurs with aging. Frassetto and Sebastian, J. Gerontol. (1996), 51A:B91. Exacerbation by bisphosphonates of the normally present, low-grade, diet-induced metabolic acidosis may have deleterious effects on the kidney. Acidosis reduces the kidney's production of the calcium-solubilizing substance, citrate, Gordon, J. Clin. Invest. (1963), 42:137, and thereby fosters deposition of calcium salts within the kidney, which creates structural damage to the kidney. Ibid. Conversely, acidosis increases the kidney's production of ammonia, which damages the kidney by inciting inflammation and chemical injury to the kidney cells. Nath et al., Am. J. Kidney Pis. (1991) 17:654. Acidosis also adversely affects the kidney by causing an abnormally high concentration of chloride in the serum (hyperchloremia) . Hyperchloremia induces constriction of renal blood vessels, reducing the supply of nutrients and inducing the release of toxic chemicals. Wilcox, J. Clin. Invest. (1983), 71:726; Wilcox et al., Kidney Int. (1985), 28:43; Quilley et al. , Br. J. Pharmacol. (1983), 108:106. Likewise, exacerbation by bisphosphonates of the normally present, low-grade, diet-induced metabolic acidosis may have deleterious effects on the skeletal muscle. It has been demonstrated that diet-induced low-level metabolic acidosis induces wasting of nitrogen in the urine, a condition that over a long term (e.g., months or years) may result in loss of muscle mass, the major source of nitrogen in the body, and consequently, in muscle weakness. Accordingly, bisphosphonate administration in the long-term may be deleterious to muscle, reducing its mass and strength.

While the bisphosphonates decrease bone resorption, they also substantially decrease bone formation because resorption and formation of bone are normally coupled. Consequently, the rate of bone turnover decreases, i.e., bone remodelling rates decrease. Ibid, p. 833. A reduced remodeling rate restricts the repair of normally occurring microfractures which, in the long term, may weaken bone. Moreover, the bisphosphonates may not uniformly saturate sites in the bone. Bisphosphonate-free sites will then be subjected to increased demands, such as that of releasing skeletal base to neutralize the acids normally produced from metabolism. Over time, that could lead to skeletal instability.

In addition, at greater than recommended doses, bisphosphonates tend to inhibit mineralization of newly formed bone, and may thereby weaken bone. Safety of bisphosphonates is thus subject to compromise by misplaced patient zeal and physician error. Even at recommended doses, prolonged use (e.g., greater than 10 years) conceivably will have a similar anti-mineralization effect. It has also been proposed to administer alkalinizing potassium salts, e.g., potassium bicarbonate, in the treatment of osteoporosis. Morris et al., U.S. Patent No. 5,171,583, issued December 15, 1992 and incorporated herein by reference. It is believed that the administration of such salts at a dosage sufficient to neutralize endogenous acid minimizes the mobilization of skeletal calcium salts and thus improves calcium and phosphorus balance and reduces bone resorption, and, moreover, increases the rate of bone formation. Sebastian et al., N. En l . J. Med. (1994) 330:1776-81.

It is among the objects of the present invention to provide an improved method and composition for the treatment of osteoporosis by the concurrent administration of both a bisphosphonate antiresorptive agent and an alkalinizing potassium salt. Such method makes use of the anti-resorptive properties of each such agent, overcoming the potential side effects of the bisphosphonates related to restriction of skeletal base mobilization, and by allowing reduced dosage of bisphosphonates, mitigating the potential adverse effects of bisphosphonates related to reduced bone turnover and impaired mineralization, to provide an improved modality for the treatment of osteoporotic conditions.

SUMMARY OF THE INVENTION The present invention involves a novel method for ameliorating or preventing osteoporosis in humans afflicted with or predisposed to osteoporosis, which comprises administering the combination of 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 consisting of potassium bicarbonate and potassium salts of carboxylic acids which are metabolized to bicarbonate, and thus alkalinize, in vivo; and

(b) a bisphosphonate effective as a potent antiresorptive agent for bone in the treatment of osteoporosis; the active ingredients being administered in amounts effective to treat osteoporosis without adversely affecting bone and acid-base homeostasis. The present invention provides a more effective treatment for osteoporosis than treatments with bisphosphonates alone. It is believed that the combined treatment with potassium bicarbonate or other alkalinizing potassium salt maintains extracellular pH and plasma bicarbonate concentration, notwithstanding impaired skeletal base mobilization caused by a bisphosphonate, and thus both inhibits bone resorption and stimulates bone formation.

It has been demonstrated that correction of diet- induced metabolic acidosis by chronic administration of potassium bicarbonate reverses the nitrogen wasting which, as noted above, may result over the long term in muscle weakness. Frassetto et al., J. Am. Soc. Nephrol. (1995), 6:308. These findings are consistent with the observation that the more severe forms of chronic metabolic acidosis associated with prolonged fasting and chronic renal insufficiency enhances protein breakdown, nitrogen wasting, and loss of muscle by an alkali-reversible mechanism. Hannaford et al., Am. J. Phvsiol. (1982), 243-.E251-E256; Mitch et al. , Am. J. Kidnev Dis. (1993), 21:91-95; Greiber et al. , Miner. Electrolyte Metab. (1992), 18:233-236; May et al., Miner. Electrolyte Metab. (1992), 18:245-249; Williams et al., Clin. Sci. (1991), 80:457-462; Gougeon-Reyburn et al., Metabolism (1989), 38:1222-1230; Papadoyannakis et al., Am. J. Clin. Nutr. (1984), 40:423-627. The co-administration of potassium bicarbonate sufficient to offset the acidosis-producing effect of the bisphosphonates may thus prevent the potential long term deleterious effect of the bisphosphonates on muscle mass and strength. It will, however, be understood that the foregoing hypotheses are illustrative only and are not intended to restrict the scope of the method and composition of the present invention, other than as set forth in the claims appended hereto. DETAILED DESCRIPTION OF THE INVENTION The two active therapeutic agents co-administered in accordance with the invention, i.e., (a) the pharmacologically acceptable alkalinizing potassium salt and (b) a bisphosphonate which is a potent inhibitor of bone resorption, may be administered as separate dosage forms on different schedules. Such is preferred since the alkalinizing potassium salts are desirably administered with food to reduce gastrointestinal irritation, whereas the bisphosphonates are conventionally administered during fasting periods well in advance of meals because they are poorly absorbed from the intestine and exhibit reduced absorption in the presence of food. It will, however, be understood that alternatively, the alkalinizing potassium salt and the bisphosphonate may be administered in a unitary dosage form designed to facilitate administration of the alkalinizing potassium salt without risk of G.I. irritation (see, for example, those dosage forms described in co-pending Marder et al. Application Serial No. 08/472,693, filed June 6, 1995), incorporated herein by reference.

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 used herein, the term "normal recommended dose" when used to refer to bisphosphonate, means an amount of bisphosphonate which, when administered to a human being subject to osteoporosis is effective in accomplishing one or more of the three outcomes described in the previous paragraph. Such effects may be gauged by one or more of the following chemical markers of bone resorption or formation in humans:

(a) reduction of the urinary hydroxyproline excretion rate. (The urinary hydroxyproline excretion rate is widely used as a marker for bone resorption. Klein 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., Clin. Chim. Acta.. 1987, 297-306); (b) reduction of urinary collagen excretion, i.e., pyridinoline and deoxy-pyridinoline, crosslink excretion rate. (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 Clinical Investigation (1991), 21:310- 315) ;

(c) increase of calcium and phosphorus balances, i.e., making them less negative or more positive. (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, are another reflection of bone resorption/formation (these balances are positive when the total excretion is less than the dietary intake.)); and (d) increase in serum osteocalcin concentration.

(Serum concentrations of osteocalcin serve as a biochemical marker of the rate of bone formation. 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 rate of bone formation increases, and decreases when the rate of bone formation decreases. Brown, et al., The Lancet. May 19, 1984, p. 1091, "Serum Bone GLA-Protein: A Specific Marker For Bone Formation in Postmenopausal Osteoporosis".)

The alkalinizing potassium salts which may be employed in accordance with 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 Berge et al., J. Pharmaceut. Sci. (1977) 66:1, which is incorporated herein by reference. 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 osteoporosis 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 of formulation.

The alkalinizing potassium salts which may be thus administered are preferably selected from the group consisting of potassium bicarbonate (KHC0₃) and pharmacologically acceptable, non-toxic potassium salts of carboxylic acids such as potassium gluconate (CgH_j^KOγ) and potassium citrate (C_€H₅K₃0₇) which are metabolized to potassium bicarbonate in vivo. 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 in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 16th Ed., 1982, which is incorporated herein by reference.

As used herein, the term "bisphosphonate" refers to salts or esters of bisphosphonic acid (which is an analog of pyrophosphoric acid, containing a central carbon atom rather than an oxygen atom) . The bisphosphonates may have simple alkyl or halide side chains, amino side chains, or cyclic side chains. Bisphosphonates which decrease bone resorption and are useful in the practice of the present invention are disclosed, for example, in U.S. Patents Nos. 4,732,998;

4,870,063; 5,130,304; 5,366,965; 5,431,920 and 5,438,048, each of which is incorporated herein by reference. 10

Preferred bisphosphonates useful in the practice of this invention are non-toxic salts or esters of bisphosphonic acids of the formula:

wherein :

R is methyl , amino, -chlorophenyl thio

(— S— f Cl) or 3-pyridinyl );

R' is hydroxy, chloro or hydrogen; and n is an integer of from 0 to 3.

Particularly preferred bisphosphonates which have been found to be high potency antiresorptive agents include etidronate [ (1-hydroxyethylidene) bisphosphonate], alendronate [ (4-amino-l-hydroxybutylidene) bisphosphonate], pamidronate [ (3-amino-l-hydroxypropylidene) bisphosphonate], clodronate [ (dichloromethylene) bisphosphonate], tiludronate [([(4- chlorophenyl) thio] -methylene) bisphosphonate] and risedronate [ (l-hydroxy-2- [3-pyridinyl] -ethylidene) bisphosphonate] . The resorptive characteristics of the foregoing bisphosphonates are described in the aforesaid Francis Review in Curr. Therap. Res., September 1995. The preparation, isolation, and purification of the foregoing bisphosphonates are well known to those skilled in the art. Descriptions of how to prepare the respective bisphosphonates are disclosed in the foregoing patents; see also the literature references for etidronic acid, alendronic acid, pamidronic acid and clodronic acid in the Merck Index, 11th Ed., 1989. Those descriptions for preparing the respective bisphosphonic acids and their corresponding salts and esters are incorporated herein by reference.

Administration of the pharmacologically acceptable alkalinizing potassium salt and the bisphosphonate active agents in accordance with 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. For the alkalinizing potassium salt, these methods include oral, parenteral, and other modes of systemic administration. Different alkalinizing potassium salts may be admixed and simultaneously administered, or benefit may be gained in some instances by their separate, sequential administration. For the bisphosphonate, these methods include oral, parenteral, transdermal, and other modes of systemic administration.

Depending on the intended mode, the alkalinizing potassium salt may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, capsules, pills, powders, solutions, suspensions, or the like, preferably in unit-dosage forms suitable for administration of relatively precise dosages. Similarly, the bisphosphonate may be incorporated in a solid tablet, capsule or pill, preferably in unit-dosage forms suitable for administration of relatively precise dosages. If desired, the unit dosage forms may also contain other active ingredients, or 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 the pharmaceutical art; see, for example, the aforesaid Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 16th Ed., 1982. The alkalinizing potassium salt agent, e.g., bicarbonate, may be provided as a dietary supplement supplied as pills, as granules or powder applied directly to foodstuffs, or dissolved in drinking water, as a convenient means of administration.

Preferably, the alkalinizing potassium salt and bisphosphonate are administered in separate dosage forms. The two drugs may thus be administered on the same schedule or on different schedules in accordance with the normal modes of administration thereof.

Alternatively, the alkalinizing potassium salt and bisphosphonate active agents may be combined in a unitary dosage form, e.g., in a tablet, capsule or pill designed to minimize if not prevent G.I. irritation by the potassium salt, thus obviating the need for their separate administration. See the aforesaid co-pending application Serial No. 08/472,693. 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 agents used in accordance with the present invention, preferably about 70-90%.

The bisphosphonate may be administered in differing amounts, and with or without cyclical dosing schedules, depending upon the particular bisphosphonate administered. For example, the preferred bisphosphonates may be administered in amounts varying from about 5 mg./day (risedronate), to 10 mg./day (alendronate), to 100 mg./day (tiludronate) , to 150 mg./day (pamidronate) to 400 mg./day (etidronate or clodronate) , amounts which have been utilized in resorption studies reported in the literature (see Francis, supra, at p. 839) .

The alkalinizing potassium salt, on the other hand, should be administered in relatively high amounts, an effective dose of potassium bicarbonate, for example, being in the range of from about 30-300 mmoles (3-30 grams) per day, preferably about 60-90 mmoles per day.

As indicated above, concurrent administration of the two active agents in accordance with this invention is effective to treat osteoporosis without adverse effect on bone and acid-base homeostasis. In particular, such administration may increase the efficacy of the bisphosphonate by at least about 25%, and as much as about 200% or more, relative to administration of such agent alone.

The bisphosphonate(s) and alkalinizing potassium salt(s) may be continuously administered on a daily basis or instead, may be administered on a cyclical basis, e.g., 14 days on, and 14 days off. It will also be appreciated by those having skill in the art that in addition to administering the active ingredients as described herein, it may be desirable to supplement the patient's calcium intake, if necessary, to maintain it at 1500 mg or more of calcium per day.

The following examples illustrate some particularly preferred, non-limiting embodiments of the present invention.

EXAMPLE 1 In one protocol which may be utilized in accordance with the invention employing separate bisphosphonate and alkalinizing potassium salt dosage forms, a tablet containing 10 mg. of alendronate sodium is administered to a patient one hour before breakfast and two tablets each containing 1.5 g. (15 mmoles) of potassium bicarbonate are administered to the patient concurrent with each of breakfast and dinner (equivalent to 6 grams or 60 mmoles of potassium bicarbonate per day) . This protocol is maintained for an extended period for chronic treatment of osteoporosis. EXAMPLE 2

In a second, alternative protocol in accordance with the invention, two tablets each containing 2.5 mg. of alendronate sodium and 1.5 g. of potassium bicarbonate (in a form designed to minimize G.I. irritation, e.g., as microcapsules coated as described in the aforesaid U.S. patent application Serial No. 08/472,693), are administered one hour before breakfast, and two tablets containing only potassium bicarbonate (in an amount of 1.5 g. each) are administered to patients with dinner.

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 associated with the potent bisphosphonate antiresorptive agents.

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 the appended claims.

Claims

WE CLAIM :

l. A combination of two drugs for treating osteoporotic disease in a human being subject thereto, which comprises (a) a pharmacologically acceptable alkalinizing potassium salt capable of reducing the acidity of tissue fluids or urine, said alkalinizing potassium salt being selected from the group consisting of potassium bicarbonate and potassium salts of carboxylic acids which alkalinize in vivo; and (b) a bisphosphonate effective as an antiresorptive agent for bone in the treatment of osteoporosis; the active ingredients being administered in amounts effective to treat osteoporosis without adversely affecting bone and acid-base homeostasis.

2. The combination of claim 1, wherein the biophosphonate comprises a pharmaceutically acceptable salt or ester of a compound having the following formula:

wherein: R is methyl, amino, 4-chlorophenyl thio

(— S— f Cl) or 3-p ridir.yl );

R' is hydroxy, chloro or hydrogen; and n is an integer of from 0 to 3.

3. The combination of claim 1, wherein the alkalinizing potassium salt is present in an amount of 3-30 grams per day, and the bisphosphonate is present in an amount of 5-400 mgs. per day.

4. The combination of claim 1, wherein the alkalinizing potassium salt and the bisphosphonate are incorporated in separate dosage forms.

5. The combination of claim 1, wherein the alkalinizing potassium salt and the bisphosphonate are incorporated in a unitary dosage form.

6. The combination of claim 1, wherein the alkalinizing potassium salt is potassium bicarbonate.

7. The combination of claim 1, wherein the alkalinizing potassium salt is a pharmacologically acceptable, non-toxic potassium salt which is metabolized to potassium bicarbonate in vivo.

8. A method for treating osteoporotic disease in a human being subject thereto, which comprises administering the combination of the following active ingredients: (a) a pharmacologically acceptable alkalinizing potassium salt capable of reducing the acidity of tissue fluids or urine, said alkalinizing potassium salt being selected from the group consisting of potassium bicarbonate and potassium salts of carboxylic acids which alkalinize in vivo, and (b) a bisphosphonate which is effective as an antiresorptive agent for bone in the treatment of osteoporosis; the active ingredients being administered in amounts effective to treat osteoporosis without adversely affecting bone and acid-base homeostasis.

9. The method of claim 8, wherein the bisphosphonate is a pharmaceutically acceptable salt or ester of a compound having the following formula:

wherein : R is methyl, amino, -chlorophenyl thio

(— S— f λ Cl) or 3-pyridinyl (— CH₂— < ).

R' is hydroxy, chloro or hydrogen; and n is an integer of from 0 to 3.

10. The method of claim 8, wherein the alkalinizing potassium salt is administered in an amount of 3- 30 grams per day, and the bisphosphonate is administered in an amount of 5-400 mgs. per day.

11. The method of claim 8, wherein the alkalinizing potassium salt and the bisphosphonate are administered in separate dosage forms.

12. The method of claim 8, wherein the alkalinizing potassium salt and the bisphosphonate are administered in a unitary dosage form.

13. The method of claim 8, wherein the alkalinizing potassium salt is potassium bicarbonate.

14. The method of claim 8, wherein the alkalinizing potassium salt is a pharmacologically acceptable, non-toxic potassium salt which is metabolized to potassium bicarbonate in vivo.