CA2199250A1 - Estrogens and parathyroid hormone for treating osteoporosis - Google Patents

Abstract

The present invention provides methods of treating a human or other animal subject having a bone metabolism disorder, consisting essentially of the steps of: (a) administering to said subject a safe and effective amount of an antiresorptive compound, during a period of greater than about 6 months; (b) administering to said subject a safe and effective amount of a parathyroid hormone, during a period of from about 3 to about 12 months.

Description

~ wo 96107416 9 ~ ~ ~ o PCT/IJS95111386 ESTROGENS AND PARATHYROID HORMONE FOR
T~EATING OSTEOPOROSIS

BACKGROUND OF T~ INVENTION
This invention relates to methods of increasing bone mass in humans and other anim~1C i.e., for the trç~tnle~t of osteoporosis and related bone metabolic disorders. In particular, this invention relates to such methods of tre~tment by the a~lministration of an estrogen compound and parathyroid hormone.
The most common metabolic bone disorder is osteoporosis. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. In general, there are two types of osteoporosis- primary and secondary. "Secondary osteoporosis" is the result of an idçntifi~le disease process or agent. However, approximately 90% of all osteoporosis cases is "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, age-assoeiated osteoporosis (a~fPcring a majorit~ of mdividuaTs~ o~ver the age of 70 to 80), and idiopathic osteoporosis a~ecting middle-aged and younger men and women.
For some osteoporotic individuals the loss of bone tissue is sufficiently great so as to cause ,~,~ç1.~ 1 failure of the bone structure. Bone fractures oflcen occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
The mec~ -;cl~l of bone loss in osteoporotics is believed to involve an imb~l~nce in the process of "bone remodeling". Bone remodeling occurs throughout life, renewing the skeleton and l..~ the strength of bone. This remodeling involves the erosion and filling of discrete sites on the surface of bones, by an olga~ed group of cells called llbasic multicell~ r unitsll or l'BMUs".
BMUs primarily consist of "osteoclasts", "osteoblasts", and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an "activated"
BMU by an osteocl~ct forming a resorption cavity. This cavity is then filled with - t bone by osteoblasts.
Normally, in adults, the remodeling cycle results in a small deficit in bone, due to incomplete filling of the bone resorption cavity. Thus, even in healthy adults, age-related bone loss occurs. However, in many people, particularly in post-menopausal osteoporolics, there is an increase in the number of BMUs that WO 96/07416 0 2 ~ 9 9 2 ~ O PCT/US95/11386 ~

are activated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.
Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency.
Many compositions and methods are described in the medical literature for the "treatment" of osteoporosis. Many of these compositions and methods attempt to either slow the loss of bone or to produce a net gain in bone mass. See, for example, R. C. Haynes, Jr. et al., "Agents affecting Calcification", The Pharmacolo~ical Basis of Therapeutics. 7th Edition (A. G. Gilman, L. S. Goodman et al., Editors, 1985); G. D. Whedon et al., "An Analysis of Current Concepts and Research Interest in Osteoporosis", Current Advances in Skeletogenesis (A. Ornoyet al., Editors, 1985); and W. A. Peck, et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation.
Among the tre~tnlentc for osteoporosis s~lg~ested in the literature is the ~minictration of bisphosphonates or other bone-active phosphonates. See, for example, Storm et al., "Effect of Intermittent Cyclical Etidronate Therapy on Bone Mineralization and Fracture Rate in Women with Post-Menopausal Osteoporosis", 322 New Fn~l~ntl Journal of Medicine 1265 (1990); and Watts et al., "Inte~ iLle~"
Cyclical Etidronate Tr~.. l of Post-Menopausal Osteoporosis", 323 New En~land Journal of Medicine 73 (1990). Such tre~tmPntc using a variety of bisphosphonates are desclibed in U.S. Patent 4,761,406, Flora et al., issued August 2, 1988; U.S. Patent 4,812,304, Anderson et al., issued March 14, 1989;
U.S. Patent 4,812,311, Uchtm~n, issued March 14, 1989; and U.S. Patent 4,822,609, Flora, issued April 18, 1989. The use of such phosphonates for the tre?tm~nt of osteoporosis, and other disorders involving abnormal calcium and phosphate metabolism, is also described in U.S. Patent 3,683,080, Francis, issued August8, 1972; U.S. Patent 4,330,537, Francis, issued October28, 1980; U.S.
Patent 4,267,108, Blum et al., issued May 12, 1981; European Patent Publication 298,553, Ebetino, published January 11, 1989; and Francis et al., ''Chemir~l~
Biochemical, and Medicinal Properties of the Diphosphonates", The Role of Phosphonates in Livin~ Systems, Chapter 4 (1983).
~ lminictration of estrogen is also used as a means to prevent osteoporosis in postmenopausal women. This therapy typically involves daily ~lminictration offrom about 0.625 milligrams to about 1.25 milligrams of conjugated estrogens, orequivalent ~mo~lntc of other estrogen hormones. Estrogen may also be used to treat osteoporosis (i.e., actual building of bone in osteoporotics), although this has ~ wo 96/n7416 0 ~ 1 9 9 ~ 5 0 pcl~595/11386 not been fully established. See, for example, Barzel, "Estrogens in the Prevention and Tre~tmPnt of Post-Menopausal Osteoporosis: a Review", 85 Arnerican Journal of Medicine 847 (1988); Barzel, "Estrogen Therapy for Osteoporosis: Is it Effective?", Hospital Practice 95 (1990); Fttin~çr, et al., "Post-Menopausal Bone Loss is Prevented by TrP~tmPnt with Low-Dosage Estrogen with C~lci~m", 106 Annals in Internal Medicine 40 (1987); Lindsay, et al., "The Minimllm Effective Dose of Estrogen for Prevention of Post-Menopausal Bone Loss", 63 Obstetrics and Gynecolo~y 759 (1984); "Eserogen", Drug Illro~ Lion 1765 (1990); and World Patent Publication 92 1447~, McOsker, published September 3, 1992.
Furthermore, the use of estrogen has been associated with certain side effects, such as uterine bleeding. See, Rudy, "Honnone Replacement Therapy - How to Select the Best Preparation and Regimen," 88 Post~raduate Medicine 1~7 (1990).
Parathyroid horrnone has also been suggested as a therapy for osteoporosis. Treatments using parathyroid hormone are disclosed in the following references: Hefti, et al., "Increase of Whole-Body C~ m and Skeletal Mass in Normal and Osteoporotic Adult Rats Treated with Parathyroid Horrnone", 62 Clin. Sci. 389-396 (1982); Hock, et al., "Resorption Is Not Fc.sçnti~l for the Stimulation of Bone Growth by hPTH-(1-34) in Rats In Vivo", 4(3) Jnl. of Bone and Mineral Res. 449~58 (1989); German Patent Pl-blic~tion DE 39 35 738, Forssman, published May 8, 1991; U.S. Patent 4,698,328, Neer, et al., issued October 6, 1987; U.S. Patent 4,833,125, Neer, et al., issued May 23, 1989; U.S.
Patent 5,118,667, Adams et al., issued June 2, 1992; World Patent Publication 9311786, Geddes and Boyce, published June 24, 1993; U.S. Patent 4,822,609, Flora, issued April 18, 1989; U.S. Patent 4,812,304, Anderson, et al., issued March 14,1989; German Patent Publication DE 32 43 358, Hesch, published May 24, 1984;
Hesch, et al., "Results of a Stirlnlll~ting Therapy of Low Bone Metabolism in Osteoporosis with (1-38h PTH and Diphosphonate EHDP" 66(19) Klin. Wschr.
976-984 (Oct 1988); German Patent Publication DE 32 43 358, Hesch, published May 24, 1984; Delling, et al., "Morphologic Study of Pelvic Crest Spongiosa in Patients with Osteoporosis during ADFR Therapy with Parathyroid Hormone and Diphosphonates", 128(1) Z. Orthop. 1-5 (1990) (he~e;lianer "Delling, et al."); and Delmas, et al., "The In Vivo Anabolic Effect of hPTH-(1-34) Is Blunted When Bone Resorption Is Blocked By A Bisphosphonate" 6(1) J. Bone Mineral Res.
S136 (#214) (Aug. 1991).
Applicant has found, surprisingly, that the a~iminictration of parathyroid hollllone after ~ in;~l.aLion of an estrogen compound provides benefits not recognized in the art. Accordingly, the methods of this invention provide effective wo 96/07416 ~ 3 Q ~ 5 0 PCT/US95/11386 methods of preventing and treating osteoporosis, with improved efficacy and reduced side effects compared to methods among those known in the art.
SUMMARY OF T~; INVEN~ION
The present invention provides methods of treating a human or other animal subject having a bone metabolism disorder, consisting ecsentiAlly of the steps of:
(a) Arlminictering to said subject a safe and effective amount of an estrogen compound, during a period of greater than about 6 months;
(b) administering to said subject a safe and effective amount of a parathyroid hormone, during a period of from about 3 to about 12 months.
DESCRIPTION OF THE INVENl ION
The methods of the present invention comprise the ~minictration of an estrogen compound and parathyroid hormone compound to a human or other animal subject. Specific compounds and compositions to be used in these processes must, accordingly, be pharm~ceutically-acceptable. As used herein, such a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commencurate with a reasonable benefit/risk ratio.

Estrogen Compounds:
The methods of this invention comprise ~lminctration of an estrogen compounds. As .t;f~,.ed to herein, an "estrogen compound" refers to naturally occurring hormones, synthetic steroidal compounds, and non-steroidal compounds, and conjugates, metabolites and derivatives thereof, which having estrogenic activity. Naturally-occurring estrogen compounds are steroids which contain a cyclopentanoperhydrophenall..el-e ring system. Such naturally-occurring estrogencompounds are obtained from p,~.,a"l mares' urine or p-epared synthetically, using methot1c well-known in the art. See: "Estrogens", Drug Illrullll~lion 1765(1990); and Rudy, "Hormone ReplAcpm~nt Therapy - How to Select the Best P.epa-alion and Regimen," 88 Postgraduate Medicine 157 (1990); and C.
Chli.ctiAncen et al., "Estrogens, Bone Loss and Prevention," 1 Osteoporosis Int. 7 (1990); all of which are incorporated by ,e~ere"~e herein.
Estrogen compounds useful in the metho-~c of this invention include, for example, estradiol, estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethinyl estradiol, polyestradiol phosphate, e~L-upipale, diethylstilbestrol, dienestrol, chlololl;Anise~-, and m--ixtures thereof. A plefe--ed estrogen horrnone WO 96/07416 PCT/US9~i/11386 ~ 9 ~ ~ 0 useful herein is "conjugated estrogen", which is a mixture of sodium salts of the water-soluble sulfate esters of estrone and equilin. Such conjugated estrogens may also contain other estrogenic substances found in pregnant mares' urine, such as17-a-dihydroequiline, 17-a-estradiol, equilenin, and 17-a-dihydroequilenin.
Also useful in the methods of this invention are the antiestrogen compounds. As referred to herein, an "antiestrogen compound" is a compound which has the estrogen agonist activity of inhibition of bone resorption, but which has estrogen antagonist activity on other tissues, notably breast and uterus.
Antiestrogens may be steroids or non-steroids. Steroidal antiestrogens are exemplified by tamoxifen and related compounds. Many compounds that have been discovered for reasons of other activities, such as anti-progesterones or anti-androgens, are also antiestrogens useful in the methods of this invention. Non-steroidal antiestrogens also include, for example, raloxifene, and related compounds disclosed in U.S. Patent 4,418,068, issued November 29, 1983 (incorporated by reference herein).

Parathyroid Hormone The methods ofthis inven~ion also co~ lise ~riminictration of a parathyroid hormone. As rer~ d to herein, "parathyroid hormone" refers to the naturally occurring human parathyroid hormone, synthetic analogs thereof, parathyroid hormone and parathyroid hormone fr~mPntc m~nuf~cSl~red by lecolllbinallL DNA
technology, and parathyroid hormone fr~ mPntc and parathyroid hormone fragment analogs. Parathyroid hormone useful in the methods of this invention inrllldPc, for example hPTH (1-38), hPTH (1-34), hPTH (1-37), hPTH (2-34), and hPTH (2-38). Detailed descriptions of the types of parathyroid hormones available and methods for m~nllf~ctllring parathyroid hormone are disclosed in the following references, all incorporated by ~ ere.lce herein, U.S. Patent 4,105,602, Colescott, et al., issued August 8, 1978; U.S. Patent 4,698,328, Neer, et al., issued October 6, 1987; U.S. Patent 4,833,1Z5, Neer, et al., issued May 23, 1987;
DE 32 43 358, Hesch, publication date May 24, 1984; and DE 39 35 738, FOI~ AnI1~ et al., publication date May 8, 1991.

Methods of Tltall"e"l This invention provides methods for treating a human or other animal subject having a bone metabolism disorder, consisting esse~ ly of the steps of:

WO 96/07416 PCT/US95/11386 ~

2 ~ 0 6 (a) administering to said subject a safe and effective amount of an antiresorptive compound, during a period of from about 2 weeks to about 6 months;
(b) aAminictering to said subject a safe and effective amount of a parathyroid hormone, during a period of from about 3 to about 12 months.
Preferably, in step (a), said antiresorptive compound is ~clminictered for greater than about 8 months. Also preferably, in step (b), said parathyroid hormone is ~Aminictered for from about 4 months to about 8 months, more preferably for about 6 months. Preferably steps (a) and (b) are repeated from 1 to 5 times (i.e, so the entire method comprises performance of each step, in sequence, 2 to 6 times).
The estrogen compound and parathyroid hormone are aAminictçred in a "safe and effective amount", which, as referred to herein, is the quantity of a material which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commenC--rate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the trç~tment the nature of concurrent therapy (if any), and the specific formulations employed.
The specific amount and dosage regi,..en of a particular estrogen compound ~(lminictered during the methods of this invention is a function of thepotency of the compound, as well as other factors. ~lere.~bly, the antiresorptive compound is ~ministçred in amountc and in regirnenC recognized in the art of useful for l,eaLing osteoporosis in accordance with sound medical practice.
Potency of an estrogen compound can be eA~,essed in terms of its "LED"
or "least effective dose", which is the minim~lm dose of compound that is effective, by itself, to cause a si~nific~nt inhibition of bone resorption. ~ler~ bly, in the methods ofthis invention, the a"lirtjo,~ e compound is adminictçred at a level of at least about 0.8 LED of the compound, more plere,ably from about .8 LED t about 5 LED, more preferably from about .8 to about 3 LED.
The specific LEDs of a given estrogen compound will vary depending upon its çh~mic~l composition, and method of ~A,..;.~ lion (i.e., oral or pare.,le-~l).
The lower the LED, the more potent the compound. Generally, it is desirable to minicter higher potency estrogen compounds in lower doses and on a fewer number of days in the period of ll~ ,l Likewise, the higher the LED, the less potent the compound. Accoldi"gly, then, in general, it is desirable to aAminictçr a ~ WO96/07416 ~a~2~0 PCT/US9~iJ11386 lower potency estrogen compound in higher doses and on a greater number of days in the period of treatment.
The LED of the estrogen hormone is that level of the horrnone which, by itself, is effective to prevent bone loss in subjects having osteoporosis. That level is generally recognized to be about 0.625 mg per day of conjugated estrogen or an equivalent dose of other estrogen hormones (for example, 2~ mg per day of ethinyl estradiol; or 2 mg per day of 17-b-estradiol). Conjugated estrogen is plc~rably ~lminietered at a level of from about 0.3 mg to about 1.25 mg per day, pl~;rt l~ly about 0.63 mg per day. See, Barzel, "Estrogens in the Prevention and Tre~tm~nt of Post-Menopausal Osteoporosis: a Review", 85 American Journal of Medicine 847 (1988); Lindsay, et al., "The Minimum Effective Dose of Estrogen for Prevention of Post-Menopausal ~one Loss", 63 Obstetrics and Gynecologv 759 (1984); Genant et al., "Effect of Estrone Sulfate on Postmenopausal Bone Loss", 76 Obstetrics and Gynecolo~y 529 (1990); all of which are incorporated by reference herein.
Pa~ oid horrnone is routinely dosed in International Units (IU). In the methods ofthis invention, parathyroid hormone is plefelably a~lministered at levels of from about 100 to about 700 IU per day, more preferably from about 200 to about 600 IU per day, more preferably from about 400 to about 500 IU per day.
During the ~ ..e.~ period of step (a), the estrogen compound can be ~minietered daily, or in a cyclical fashion. During l:he ~r~ le ~I period of step (b), the parathyroid hormone must be given at least one day every seven days of everythirty(30)-days. Preferably, the parath,vroid hormone is ~minietered at least about SO% of the days during the periodl of step (b).
The methorls of this invention comprise lre~ e~.~ of o~L~opo~osis at all stages of the disorder. Since osteoporosis is an ongoing process of bone loss, rather than a disorder having a discrete be~;nl.;--~ or end-point, 'ltr~tmpntll~ as refe..ed to herein, con~iete of any method which stops, slows, or reverses the process of bone loss which occurs in osteopolusis.
Preferred methods of this invention comprise lle~ t of osteoporosis in subjects who have already lost skeletal mass (herein referred to as "establishedo~,oporosis"). Such methods of this invention for the tre~tment of established osteoporosis p-erel~bly cG-..~,lise a~imini~tering the actives for a period of time s--ffirient to achieve an increase in the net skeletal mass of said subject. Theincrease in mass may be in cortical bone, trabecular bone, or both. Preferably, the net skeletal mass is h.l,.edsed by at least about 5% per year, preferably by at least about 10% per year.

WO 96/07416 ~ 9 ~ ~ ~ PCT/US95/11386 The specific period of time sufficient to achieve an increase in the net skeletal mass of the subject may depend on a variety of factors. Such factors include, for example, the specific actives employed, the amount of actives mini~tered, the age and sex of the subject, the specific disorder to be treated,concomitant therapies employed (if any), the general physical health of the subject (including the presence of other disorders), the extent of bone loss in the individual, and the nutritional habits of the individual.
The therapeutic regimen ~Itili7ing the methods of this invention are preferably continued for at least about twelve months. Of course, a therapeutic regimen may be continued indefinitely, according to sound medical practice.
Preferably the subject is treated until a net skeletal mass is obtained commensurate with reduced fracture risk as ~csec~ed by the patient's physician.
Also, preferably, the subject is a~lministered nutritional and other therapeutic agents to aid in the increase of bone mass. Such optional agents include, for example, Vitamin D and calcium.
In the methods of this invention, "arlmini~t~ring" refers to any method which, in sound medical practice, delivers the actives used in this invention to the subject to be treated in such a manner so as to be effective in the building of bone.
The actives may be ~minictered by any of a variety of known methods of a~lminictration, e.g., orally, dermatomucosally (for example, dermally, sublingually, intranasally, and rectally), parenterally (for example, by subcutaneous injection, intr~mllcc~ r injection, intra-articular injection, intravenous injection), and by inhalation. Thus, specific modes of ~ L~lion include, but are not limited to, for example, oral, transdermal, mucQs~l sublingual, intr~m~ccul~r, intravenous, in~ape~iloneal, subcutaneous ~ e~ on~ and topical application.
A p,t;rt:"ed method for the Lle~ .l of osteoporosis in~ ies an initial diagnostic step, to determine the presence of the disorder. Thus, a prc:r~lred method of this invention co,u~.,ises the steps of p~çulllung a ~ia~nostic on a human subject for the detection of osteoporosis and, upon obtaining a positive result from said diagnostic, ~mini~tering the actives according to the methods of this invention. For such methods for l,~..-e,-~ of postmenopausal female subjects prior to significant bone loss, said initial di~gnostic step comprises pe~rulllun~ a diagnostic for d~tell-linillg menopause. Such methods are well known in the art,and include, for example, determination of the bone mass and rate of bone remodeling. The rate of bone remodeling can be dete..--h,cd by measurement of biochemical n.~,ke,s. See, Hui, et al., "The Contribution of Bone Loss to wo 96/07416 PCT/US95/11386 ~ 2 ~

Postmenopausal Osteoporosis," l Osteoporosis Int. 30 (1990), incorporated by reference herein.
Suitable diagnostics for the detection of established osteoporosis are also well known in the art. Such methods include the measurement of the radiodensity of skeletal radiographs, qll~nti~tive computerized tomography, single energy photon absorptiometry, dual-energy photon absorptiometry, dual energy X-ray absorptiometry, and ql-An~ ;ve digital radiography. Di~nostic techniques among those useful herein are described in W. A. Peck et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Founrl~tion (incorporated by reference herein).

Dosa~e Forms: --The estrogen compound and parathyroid hormone may be a-~mini.ctered in any of a variety of pharmaceutically-acceptable compositions. Such compositions may comprise an active and a pharmzlceutic~lly-acceptable carrier.
Pharm~re~lt;c~lly-acceptable carriers include solid or liquid filler diluents orencapsul~tin~ sub~ cec~ and mixtures thereof, that are suitable for ~minictration to a human or lower animal. The term "compatible", as used herein, means that the components of the pharm~ce~lti~l composition are capable of being cG....~ gled with the actives, and with each other, in a manner such that there is no interaction which would s~lbst~nti~lly reduce the pharm~e~ltic~l efficacy of the pharm~ceutiç~l composition under ordinary use situations. Pharm~ceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for ~ ;c~ on to the human or lower animal being treated.
Some e.~l,ples of the sulslaices which can serve as pharmAçe-ltic~l carriers are: sugars, such as lactose, glucose and sucrose; ~La,.illes, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tr~g~r~nth malt; gelatin; talc; stearic acid; m~necillm stearate; vegetable oils, such as peanut oil, co~lonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, m~nnitol, and polyethylene glycol; agar;
alginic acid; pyrogen-free water; isotonic saline; phosphate buffer solutions;
wetting agents and lubricants such as sodium lauryl sulfate; coloring agents;
flavoring agents; and preservatives. Other col~lpalible pharm~ce~ltic~l additives and actives may be included in the pharm~ce~tically-acceptable carrier for use in the compositions of the present invention.

WO 96/07416 PCT/US95/11386 ~
0 2~ 2 5 lo The choice of a pharrn~ce~ltically-acceptable carrier to be used in conjunction with the active is determined by the way the active is to be a~mini~tered If the active is to be injected, the prerelled pharm~ceutical carrier is sterile water, physiological saline, or mixtures thereof. The pH of such parenteral composition is preferably adjusted to about 7.4. Suitable pharm~ceutic~lly-acceptable carriers for topical application include those known in the art for use in creams, gels, tapes, patches, and similar topical delivery means.
The pharm~ceutically-acceptable carrier employed in conjunction with the actives is used at a concentration sufficient to provide a practical size to dosage relationship. The pharrn~ceutically-acceptable carriers, in total, may comprise from about 0.1% to about 99.9% by weight of the pharm~ceutical compositions of the present invention, preferably from about 5% to about 80%, and most preferably from about 10% to about 50%.
A plcrelled method of a~minictering bisphosphonates is orally, in a unit-dosage form (i.e., a dosage forrn co..l~inil~g an amount of active suitable for a~mini~tration in one single dose, accolding to sound medical practice). P,erGlred unit dosage forms for bisphosphonate include tablets, capsules, suspensions, andsolutions, colllpl;S;ng a safe and effective amount of active. Pharrn~ceutir~lly-acceptable carriers suitable for the prepal~ion of unit dosage forms for oral admini~tration are well known in the art. Their selection will depend on secondary considerations like taste, cost, shelf stability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art. Preferably, oral unit dosage forms of the bone-active phosphonate comprise from about 0.0005 mgP/kg oral per day to about 1.0 mgP/kg oral per day ofthe phosphonate.
A p,erG--ed method of a(~ministering parathyroid hormone is via subcutaneous injection in a unit dosage form. P.erGllGd unit dosage forms for injection include sterile solutions of water, physiological saline, or mixtures thereo The pH of said solutions should be adjusted to about 7.4. Preferably, unit dosage forms of parathyroid hormone comprise from about 4 IU to about 15 IU
per kg per day.
Other pl erGl I ed dose forms for parathyroid horrnone include nasal, trandsermal, rectal, sublin~l, and oral. Plcrcllcd oral forrns inrlude, for eA~ )le, liposomes, lipid emulsions, and proteinaceous cages.

~ Wo 96/07~16 3 ~ ~ ~ 9 2 ~ ~ PcT~rJsg~ 386 Kits:
This invention also provides kits for conveniently and effectively implementing the methods of this invention. Such kits comprise one or more unit doses of estrogen compound, one or more unit doses of parathyroid hormone, and a means for facilitating compli~nce with methods of this invention. Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropliate active in the correct dosage in the correct manner. The compliance means of such kits incllldes any means which f~ilit~tes all~ninict~ring the actives according to a method of this invention. Such compliance means in~ des instructions, p~c~in~, and dispensing means, and combinations thereof.
Examples of pa~ ging and dispensing means are well known in the art, incl~ldin~
those described in U.S. Patents 4,761,406, Flora et al., issued August 2, 1988; and U.S. Patent 4,812,31 1, Uchtman, issued March 14, 1989 and U.S. 4,833,12~, Neer et al., issued May 23, 1989, all incorporated by reference herein.
The following non-limiting examples illustrate the compositions, processes and uses of the present invention.

An Asian female human patient weighing app.o~Lin.alely 62 kg and diagnosed with postmenopausal osteoporosis is treated by a method of this invention. Specifically, for a period of eight months, the patient is ~-lminiet~red the bisphosphonate, 2-(3-pyridyl)- 1 -hydroxyelhalle- 1,1 -bisphosphonic acid. The patient is orally a~iminictçred one ~:ablet per day, with each tablet CG..~,.ini.~g 0.002 mgP/kg per day of the bisphosphonate. The estrogen l,. ~ is discontinued Then, for the next six months, the patient is ~dminietered parathyroid hormone (human synthetic fragment 1-34, or h PTH 1-34). The hormone is subcl~t~neol-ely ~rlministered at a dose of 13 IU/kg via insulin syringe to the anterior thigh for five days out of every week during the six-month period.
A biopsy of iliac crest bone is taken and reveals an increase in mean wall thickness of the remodeling units (BMU) co.--ph-ed to her baseline biopsy. The activation frequency and depth of resorption cavities on cancellous, cortical and endocortical surfaces are not eiEnific~ntly increased above the values observed at b~seline Bone mineral density is measured, intlic~ting an increase of 11%.

A human Ca-lc~ci~n female patient weighing approkin-alely 60 kg and t1i~gnosed with po~ll"enopa.lsal osteoporosis is treated by a method of this W096/07'116 ~ 9~5 12 PCT/[~S9S/11386 invention. Specifically, the patient is administered conjugated estrogen for a period of one year. The estrogen is ~lmini~tçred via a transdermal patch, delivering estrogen at a level of 0.625 mg per day. A~er the one year month period, the estrogen ariminictration is discontin~ed However, the patient is then also ~tlmini~tered parathyroid hormone (human synthetic fragment 1-34, or h PTH 1-34) for six months, as a daily nasal spray delivering 5 IU/kg.
A blood sample is then obtained and analyzed for the bone specific marker, osteocalcin, and bone-derived and total alkaline phosphatase. Osteocalcin valuesare increased by 57% and both bone and total alkaline phosphatase are slightly elevated co."pa.ed to preL~ ",ent values. Base mineral density is measured, indicating an increase of 10%.

Claims (4)

WHAT IS CLAIMED IS:

1. A method of treating a human or other animal subject having a bone metabolism disorder, consisting essentially of the steps of:
(a) administering to said subject a safe and effective amount of an estrogen compound, during a period of greater than about 6 months.
(b) administering to said subject a safe and effective amount of a parathyroid hormone, during a period of from about 3 to 12 months.

2 A method of treating a human or other animal subject, according to Claim 1, wherein, in step (b), said parathyroid hormone is administered for about 6 months.

3. A method of treating a human or other animal subject, according to Claim 1, wherein said steps (a) and (b) are repeated from 1 to 6 times.

4. A method of treating a human or other animal subject, according to Claim 2, wherein said estrogen compound is a conjugated estrogen and is administered at a level of from about 0.3 mg to about 1.25 mg per day.