CA1330308C - Composition and method for treating osteoporosis in humans - Google Patents

Abstract

ABSTRACT

A medicament for therapeutic treatment of osteoporosis in humans which comprises, in unit dosage form, a combination of calcium carbonate and sodium monofluorophosphate in proportions sufficient to limit medication to from about one to not more than four unit dosages per day, the amount by weight of the calcium carbonate being at least 8 times the weight of the sodium monofluorophosphate.

Description

'.2 ~ ~ 3303~8 3 BACK~ROUND OF THE INVENTION

~ ~his invention is dire~ted to the therapeutic trsatment ¦ of osteoporosis in humans, especially females over the age of 50, and to the development of a medicament to provide a mox~
j effective treatment at lower dosage rates or frequency and with fewer side effects.
~3 It is known that sodium ~luoride ~NaF) is useful in the treatment of osteoporosis, having been ~ound most effective in combination with calcium carbonate and estrogen ~Riggs ~t al, "E~fect of the fluoride/calcium regiment on vertebral ~racture occurrence in postmenopausal osteoporosis", New ~ngland Journal J of Medicine, 1982, 306:446-450~. As disclosed by Rig~s et al., calcium may be administered in amounts of from about 800 mg.
per day up to about 3,000 mg. per day. A range o~ about 1,000 3 to 1,500 mg. per day of calcium is co~monly recommended, corresponding to 2,500 to 3,750 mg. of calcium carbonate per j day. However, it has been conceded that sodium fluoride does `I not offer satisfactory results, whether administered alone or with calcium carbonate, in part because of its relatively high toxicity and is tendency to form precipitates with som~ metal ions, especially calcium. Ericsson in "Monofluorophosphate Physiology: General Considerations", Caries Res. 17 (Suppl. 1):
46-55 (1983), concluded from earlier investigations that some ! advantages could be obtained in terms of fluoride absorption by j the body if sodium monofluorophosphate (MFP) were to be used in '~ place of sodium ~luoride (NaF). It was also concluded that ;~ large amounts of calcium carbonate or calcium phosphate in the denti~rice (45-35%) would significantly reduce the fluoride absorption from the MFP. As a result, Ericsson recommended ~` providing the calcium from a Ca-rich food, e.g. milk, or ~lse adm~nistering calcium in the form of one of its complexin salts, e.g. calcium citrate or calcium gluconate.
. . .
The use of Ca-complex salts has the disadvantage of - requiring much greater amounts of these salts due to their ~ lower content of Ca, as compared to calcium carbonate.
'., ,~

~ ~3~

It is an object of the.present invention to provide an improved medicament which combine~ a supply o~ Ca/F in amounts suffici nt to treat~osteoporosis on a daily basis but in unit dosage amounts which keep ~he number of daily dosages to not more than four, preferably not more than three, and especlally as low as only once to twice per day. Such limited dosages are highly desirable to permit easier self-administration of the medicine as well as better supervised administration.

SUMM~RY OF THE INVENTION

It has now been ~ound, in accordance with the preset invention, that one achievss a very satisfactory and improYed medicament for treating osteoporosis in humans by combining, ln unit dosage form, both calcium carbonate and sodium monofluorophosphate (MFP) in proportions su~icient to limit medication to from one to not more than ~our times per day, the amount by weight of the calcium carbonate being at least 8 times that o~ the sodium monofluorophosphateO It i5 generally desirable to use proportions which limit medication to not more than three times per day, and when using the medicament of the present invention in an especially preferred method of treatment, medication can be limited to only onc~ or twice per day.
Surprisingly, proportions of 8 times or more o~ calcium carbonate to sodium mono~luorophosphate still permit large amounts of fluoride to be absorbed and maintained in the blood stream at le~els considered appropriate ~or ef~ective treatment. In general, the weight ratio o~ the two components CaC03:MFP is at least 8~1 up to as high as 50.1 per unlt dose.
A more suitable range is about 8.5:~ to 25:1, or more narrowly, about 10:1 to 18:1. Especially preferred is the range o~ about 12:1 to 16:1.

~3303~8 It is important to appreciste that ~he invention does not residQ
~n selecting the amount of calc~um to bs taXen on a dally basl~ for the treatment o~ osteoporosis, slnce thl~ can bs varied to any extent deemed appropr~ata by the admlnl~terlng physlc1sn~ Tha normal amount o~ dsily ~ntake o calclum carbonate or treating osteoporosis haY been well establSshed a~ be~ng~l,000 mlll~grams dally under the U.S. Recommenaed Da-ly Allowance ~V.S. RDA), but ln the trsatment of osteoporosls, th~ phy~clan may vary thls amount o~
calc~um carbonate based upon acceptea practlca and the proYen efEectiveness of a particular mealcament.
For example, lt hss been reporta~ by Rl$gs et al, New England Journal of Uedlcine, 306:446-450 ~l982), that calcium carbonats has been adm~nist~rad in wi~ely varylng amounta a8 low as 800 mg. per day up to 88 hi~h 88 3,000 m~. per tay. While it 1~ unllkely that thls toasge range would be axceeted ln pract~ce, it 18 qulte conceivaSle thst even lower dosagss would bs prascrlbed ln ssme ~nstances or that much high~r dosa~e~ could be adopted ln cartaln cases .
Attention is also directed to Lon~, "The Es3ent1-al Guide ko Prescr~ptlon Dru$s l987", Harper ~ Row, Publlshar3, N.Y. (l987), pp.210-213, snd especially pa3e 211, where the recommended dally dosages of calclum carbonate ran~e from as llttle a~ 360 m~. ~or 1nfants aged 6 months or 1Q88 and as much as 1500 mg. for females after 50 years of age (where o~teoporosis become~ a s~gnl~lcant problem). Thus, one skllle~ ln the art can reatily ~elect the effectlve dslly dosage of calcium when ta~en as calcium carbonatQ, dependlng upo~ the psrt1cular purpose for whlch this compound 1 admlnistered.
As stated above, the ~i~niSicance o~ the ~rasent lnvention 18 not dependent on the dally dosage of calcium carbonate, but rather on the surprisin~ dlscovery that calcium carbonate ~8 Sar more ; affect~ve than coult be ~xpected when specif~cslly comb1ned wlth sodium monoSluorophosphste 1n a woight ratio of CaC03 o~ at lea~t 8 tlmes up to about S0 tlmes tho wel~ht of the fluor~ne component, most preferably in the weight ratio of CaC03:~FP of about 12:1 to 16:1. At these prescribed proportiona, lt becomes pos~ble to l~mlt any conventlonally prescr~bed calclum ~osago to not more than four daily unit dosage~, often only one or two da~ly unlt do~ag~.
~orsovar, the use of ~od~um monoPluorophssphat~ tUFP) ln such relatlvely low proport~ons haa baen ~ound to be surprlsingly ef~ectlve ln lmprov1n~ the lov~l of fluor~ds ln tha bo~y an~ al~o in reducin~ the amount of calcium carbonate re~uire~ on a daily basis ln the treatm~nt o~ 08t80poro~18. The compo~itlon oP the lnvant~on - o~fsrs a slgn1f1cant ant unexpa¢tcd lmprovemant 1n the upt~ke of calclum by the patient's bone structure ove~ a period of time.

-- :~3~3~
,.
DETAILED DESCRIPTION OF THE INVENTION

The medicament compositlon of the {nvention i~ formulated in a conventional manner to provide a unit dosage form suitable for . ~. oral ingestion by humans, I.e. in tablet and pr~ferably capsule : ¦form. Magnesium stearate i8 used as an ~n~rt binder in maklng .. ¦tablets, and a conventional gelatin capsuls is the preferred form of administering the active componentsO For the purpose o ¦carrying out long term teits on humans, the follow~ng composit~ons i' ¦ were used in capsule form:
:. I Composition A (Capsule according to th2 invent~on):
I
625.0 mg. Calcium carbonate (250 mg. Ca) l ~derived from oyster ~hell) .l ¦ 45.5 mg. Sodlum monofluorophosphate (6 mg~ F) ¦ 8.5 mg. Magnësium stearate (Tablet5 only) Composition B ~Capsule used for comparison):
625.0 mg. Calcium carbonate ~250 mg. Ca) ~derived from oyster shell) ¦ 13.3 mg. Sodium fluoride ~6 mg. F) j ¦ 7.7 mg. Magnesium stearate (Tablets only) .' ¦Using these composltions, a double blind, placebo controlled, ¦study was made over a one year period, uslng three groups of an ~ ¦equal number of patients each, selected rom women aged 50 to 75 :`` . ¦years. Such te8ts were designed to provide a close comparison between the use o~ sodium monofluorophosphate (MFP) and ~odium . ~ fluoride ~Na~) in combination with a rëlatlve~y large amount o~ ~-calcium carbonate, i.e. a calculated weigh~ ra'cio of CaC03:MFP
, ~ of 13.74:1 for Composition A. The amoun~ of calclum is the ~ame in bo~h Composltion~i A and B.
, ~ _ 4.~

~11 . ' ; ; .

13~3~8 During the first three.months of tests, blood samples were drawn and analyzed to determine the amounts of calcium and fluoride being absorbed, and it was found that the level of fluoride was about twice as high and maintained over a longer period of time when using Composition A (MFP~ as compared to composition B (NaF3. A record was kept of side reactions experienced by each patient. Serum calcium and phosphorous were measured colorimetrically by the methods of Kessler and Wolfman and of Power. Serum fluoride was measured by orion flow through an electrode with the use of TISAB buffer. Serum immunoreactive parathyroid hormone was measured by the use of an an~iserum in a radio-immunoassay that had it~ ma~or determinants directed against the carboxy~terminal region of the parathyroid hormone molecule.
The results most pertinent for the present invention are those which show the difference in absorption rates between the CaC03~MPP combination and the CaC03/NaF combination. These results consistently demonstrated the advantage of using the CaC03/MFP over the CaC03/NaF combination. It was concluded that high weight ratios of CaC03:MFP of more than 8:1, and preferably 12:1 or more, would provide an effective simultaneous administration of both calcium and fluoride in a single tablet or capsule. Moreover, with such proportions, it becomes possible to reduce the number of unit dosages per day down to 1 or 2 as compared to the more usual 4 to 6 dosages previously thought to be needed.
The side effects experienced in the extended tests can be summarized in the manner ~hown by the following Table. ~he control group of patients were given only calcium carbonate as Composition C in the ~ame amount as in the Compositions A and B. Side effects were measured after six months in each case.

' ~

.

~33~8 TABLE

. ISide EffectsCompo~ition A Compo~ ion ~ Composition C
~ .
Incr ~,, I .'.

,1 ¦ General: ~c .l I Diarrhea 0 ~ 5 3 ~ 1 1 / 2 ;~ ¦ Constipat~on 1 / 4 3 ~ 3 / 2¦ Headache 0 / 2 1 / ~ 1 / 1 .
.' 1 Dlzzlness 1 / 3 2 ~ 3 0 /
." ¦ ~ Chest pain 1 / 4 2 / 1 1 / 2 ,~~ I
i' ¦Gastrointestinal:
Heartburn ~ ~ 3 1 / 1 2 /
. l Indigestion 0 / 4 1 / 1 2 / 2 Abdom. Discom~ort 0 / 2 3 / 3 3 /
~l ¦ Nausea 0 / 2 3 / 1 2 / 2 11 l Vomiting 0 / 2 1 / i 1 /
''I

~ ~xtremities:
:1 Muscle cramps1 /~ 3 3 / 6. 2 / 4 ~' Paineul ~olnt~2 / 4 1 / 4 3 / 4 . Weakne3~ 2 / 1 0 / 2 1 /
Back pain 0 / 4 2 / 5 3 / 2 ~! Swollen joints0 ~ 4 1 / 1 2 / 3 ~1 Summary: Com~. A Com~. 3 ~
1' Incr/Decr Incr/Decr Incr/Decr General 3 / 18 11 / 8 . 6 / 8 ~l Gastrointestlnal 0 ~ 3 9 ~ 7 10 / 7 Extrem~tieA 5 / 16 7 / 18 11 / 14 , i ~ '' " ' !'.'"'',~ :
" TOTALS ~ / 47 27 / 33 27 / 29 .~ 240 max. 24Q m~x, 225 max~
I Percentage (~) 3 ~ 20 11 / 14 12 / 13 '~i Note: Compositlon A ~ CaCO3 ~ MFP
Composition B ~ CaCO3 ~ NaF
¦ Co 03itlon ~ ~ CcCO3 only ''' - 6 -`` 1 '"'I .
.1 .

, ...

The results in this Table show a very marked ~uperlorlty when .. ¦calcium carbonate ~caco3) is combined di~ec~ly wi~h sodium ¦ monofluorophosphate (MFP~ i.n a single cap~ul~. Ongoing ~es'cs have ¦confirmed these resul~. Because F from sodium ~luoride ls poorly ¦absorbed when given with calcium carbonate, ~t i~, neces~ary to glve each compound in separa~e capsules or ~able~, io~o in a separate unit dosage form. However, i~ has be~n ~ound that th~
monofluorophosphate ~MFP) does not combin~ w~th th~ calcium o~ the calcium,carbonate to form an lnsoluble preciplta~e, so that the~e two compounds can be administered in unlt do~age ~orm, i.e.
¦together in a single capsule or tablet, ~he~eby en~uring better . ¦pa~ient compliance.
: I ` :~
The Sollowing desc~ibes a ~tudy ~nvolvln~ clinical trlals to determine the efficiency of absorptlon of fluoride as sotlum Sluorids an~ as monoSluorophosphste ~FP) both ln the p~esence of calcium carbonate. A socond ob~ectlve wss to ~lnt out iS the combination of sotium ~luorlde and calcium carbonate or monoSluorophosphate HFP and ealclum carbonate, have any unwantat slde effects compared wlth calclum carbonsta alone, and i~ a comblnation o~ fluorlde and calclum w~ result in an lncrea~e in bone mass, snd whether ~luorlda as sodlum fluo~ide or a~ ~FP is more effectlve.
Patlents wlt~ evidence of sp~nal o~teoporosls were admltted lnto tha study; they were a~Xet to re~pont to a que0tionnalre re~,artln~

~` ' .
, - 7 -,, ~
,, ... ... , .....
`, . .

'f, .' ' ~J' ~3~3~
jo~nt pa~n and swallin~, gastric di~comfort, hair 1038 and ~ome other frequent compla1nts. Patlents were ~lvan calclum carbonate, sodiùm ~luorids and MFP and ~hQ ~tudlas continuad for 12 months during whlch tlme fluorlde absorpt~on wa~ mQ~sured. An snter~or posterior radio~raph of the hand was made in~tlslly snd at 12 month~
to evaluata cortlcal bone mas~. Latersl ra~iographs oS t~s lumbar and thosacic ~pine were used to evaluate the number of fraetu~es . ~
that were present initially and record any subsa~uent fracturas that occurred during the treatmant perlod.
One of the most promisin~ forms of traatment for 08teoporosls i8 à combinatlon of fluoride and calctum. Unwanted slde effaets have frequently been attrlbuted to fluoride, althoush no satlsfactory data have been recordad. Side efSect~ wers monltorea by compsrln~
symptoms, those frequently found ln a populatlon betw~en 50 to 75 years of a~e, beSore an~ after twslve months of madication. S~de effects ln patlents glven NaF were compare~ with patlent~ glven MFP, both ln comblnatlon with caloium carbonats and th~ rasults eompare~
wlth a simllar ~roup of pat~ents ~lven calclum carbonata alone. The present study also allowed a concluslon to be drawn as to the comparative absorption of fluoride a8 the sodium salt (NaF) oomparad with the sodium monofluorophosphate (~FP) form, both aAmin~tered in combination with calcium carbonate. A third ob~ectlve was to compare the change in trabecular and cortlcal bone denslty a~
maasure~ by ~uantitative compute~ tomo~raphy (QCT) of the lower veitebral bo~ies, T12-~4, an~ metacarpal cortlcal thlcXnes~ o~
tha two middle phalan~es on an x-ray of tha hand.
As state~ above, many ~orms of treatment have been usa~ in an att3mpt to increase bone msss and strength ln patlents with osteoporos~s, in order to decresse fracture inc~dence or prevent sny further fractures. Of these most studled, estrogens and a combinatlon of calcium an~ fluori~e hava shown mo~t promise.
Estrogens at doses of 0.6 mg per asy althou~h not at lower do8a~, appear to 810w bone 1088, as ~o calcium supplemsnts. However, in a patlent who has sust3insd a fracture, mersly preventln~ furt~sr bone 1088 will not prev~nt further fractures. Early obssrvatlon on the ~ 8 -~3303~8 effect of fluorlde on bone have been confirmsd by later studles whlch all show that the effsct o~ the element 1Q to st~mulata naw bone formation. If fluoride 15 admlnistered alonQ or ln ~omb~natlon with phosphorus, the long-tarm e~ect i8 one of a d~crease ~n bone , maas snd bone stren~th, apparently resultln~ ~rom a relstlve calcium deficiency due to ths increa~d demand for calcium requlrea to mineralize the new bone. Thls causes the deYelopment o~ sesondary ~yperparathyroidis~ which ~ Pur~har ~timulated i~ phosp~ats i8 given. , , If calc~um is atded to fluoride, ths effQct appQars to be one,o~
a stimulatlon o new bone formation, ~he new bone appears to ba minerallzed and bone re~orption decreased. A comblnatlon o~
~ncreased bone deposition an~ suppression of resorpSlon re~ult~ in an increase in bone mass when the amount of new bone ~o~mad ~xceeds that of bone bain~ resorbet. The ef~ect o~ both ~luorlda ant calclum on bone seam to be dose-related; a 1uor~de level of approximately 48 m~ per tay ~105 m8 ~aF) and 1,500 mg of cal~um ~3,600 m~ of calcium carbonate~ appear to schisvs t~e e~ect oS
raisin~ new bone d~position abovs that of bona ramoved by resorptlon and resultlng in an ~ncresae in bone mas~.
RXPERIHENTAL DESIGN AND ~ETHODS E~PLOYED IN THE STUDY
1. Selection,of Patients:
In tbis study, the a8e o~ the pat~ents wa~ between 50 an~ 75, and limited to wom~n- The p~tients dld not hava evldencs o~ 0~8~0U~
dlseasa other than osteoporoais, and wers not on treatment for oateoporosia with the exceptlon o~ eatro~ens. Patlents wars exclutet 1~ they ha~ chronic liver d~ease, Cu~hing'~ d~s~asn, were receiving antlconvulsant drugs, hat ransl d~aase; o~teomalacia, inSlammatory arthritis, chronic GI dl~order~, severe hyperten~lon or congestive heart fs~lure. A panel 15 was carried out to dsterm1ne eligibility and So~m a base-line blood analysis ~or the study.
Patients who were receivlng estro~ens or calcium ~upplement~ w~ro accepted and remaine~ on their current ho~mone re~,imln, but not on their calcium supplements. Such patlents were randomlr allo'ct0~ to the three treatment groups. ~vitence of oateoporos~s resteg on documented rat~ographic evidence of osteoporosls of one or morq vertebral compresslon fractures.

_ "

~33~3~
The patients were separated randomly into three treatmen~ group~ (A, B, or C). A total of 4 patlents, 15 iA ~wO group3 and 1~ ln th~ third were s~udied ~or a perlod o~ ~ a months.
The study was "doubl~ blind", neither th~ patient nor th~ Investigator~ knew which of the three medicatlon they rece~ved sinee only th~ pharmacist lNas responsibla ~or dispenslng th~ medl-cat~on.

2. Protocol:
When ~ patien~ entered the s~udy, a health history was taken and th~ patl~nt w~s asked to com-plete a questionnaire which ineluded symptoms most ~requently occurr~ng in Q~ slder ~emale population including age of menopause~ ~oint pain, gastrointestinal problems7 diarrhea and a brief dietary summary, the latter being limited ~o whetheP ~he patlen~ Inge~ts dsiry or alcohol products, was a vegetarian or omnivore. Th~ pat~ent wa~ aske~ to s~gn the eonsent form. Flve ml. ot blood was drawn for an initial panel 1~ nnd the patlent wa~ gi~ren an appointment ~or quantitat~ve computed tomography ~QCT) and an x-ray o~ tha hand and splne. The pntierlt was given one months' supply of medicatiort A, B or C and ins~ructed to ~8k~ th~ medleatlon twice a day with meals. After one month the patient was giv~n a further months' ~upply o~ medi~ation and asked to returr~ ln one month. The pati&nts returned to the phsrma~ist ea~h month to plck up one months' supply`o~ capsules and a log was kept in order to evalust~ patlent complian~e. In the twelve-month period only one patien~, ~fter six mon~hs, failed to pick up further supplies of capsules and was lost to ~he study leaving only 14 pat~ents in group C.
After three ~onths five pstients ~rom groups B and C were asked to go to the ~tudy center 6t 8:00 a.m. in a fssting sta~e. Blood was drawn and the patient ~mmediately tool6 two capsules and ste breakfast which hsd to contain st least a glasq o~ or~nge ~uicc and a roll. Blood was drawn again half sn hour, one hour, two hours and four hours after the initial blood drawing.
Serum fluoride was measured in these samples so that 8 comparison could be made between the absorption o~ fluoride from NaF and MFP.
After six months esch patient was sent the questionnaire pertinent ~o the side e~ect of the medication so that an interim comparlson could be made between the threc ~orms o~ medi-cation. The patients completed the same guestlonnaire after twelve mon~h3 on medicatIort and a similar comparison was mad~.
At the end oi the study the spinal and hand x-ray, the QCT of the splne and the panel lS were repeated and fluoride determinatlons made in pa~ients ot group B and t: who were receivlng 1uorlde. rhe ~ood was drawn between seven and nlne hours after ~hs medication had been taken, and three to slx hours after the last meal.
An analysis Or the data was made by compnring data from groups B and C with group A, the group on calcium alone.

3. Medlcatlon-There were three ~orms o~ madications A. .. Caicium O.S gm as CaCo3, tsken twi¢e a day wIth meals~ a ~otal o~ 1.0 gm of calclum per day.
B. ~luorlde and caiclum, 12 m~ ot nuorld~ ~5 Na~ and 0~5 gm oi calcium as C~C:o3 taken twice a dsy with meal~, a total o~ 24 m~ P and 1.0 gm of Ca per day.

., .
... .... .' ,' ~''", ''. .

.' ~' .
.,.
, .

`` ~3303~8 C. Fluoride and Calcium; 12 mg o~ fluoride as sodium mononuorophosphate (MFP~ and 0.5 gm of calcium as CaCo3 tsken twice a day w3th meals9 a total o~ 24 mg of P and 1.~ gm o~ Ca per day.

4. Methodolo~y:
Blood for nuoride analysis was collected ~n speclal fluoride-ree plastie tubesO
Serum nuoride was ~nalyzed by a fluoride specific electrode at the r~ayo ClinicO
-~ Quantitative computed tomography (QCT) has recerltly become an easily avsilable tool for accurate measurements of vertebral trabecular bone. Values as measured by th0 method of Cann 5c Genant (Cann, et al, J.A.M.A. ~980) have shown that a ma30rity o~ women wi~h post-menopausal osteoporosis and spinal fractures have values of QCT that are below ehe mean for àge-matched normal women. lhe data retrieved in the study was used to add to data already available and to compare the e~iect of treatment ~n the three pat~ent groups. A comparison of - the inltial QCT values with dietary history was a~so possible. QCT i3 available at the Santa Rosa Radiology Medical Group Cen~er wi~h a program specifically designed to evaluate ver-tebral cancellous bone, using Tla, Ll, L2, L3 and L4. Metgcarpal cor~i~al thlckness is an est-abllshed method of evaluating cortical bone mass. An x-ray of the hand allowed such evalu-ation.

5. To~icity:
Patients deYeloping severe nausea, GI complaints or 30int symptoms were treated symptomati-cally initially and dropped from tke study if the symptoms persisted.
3 6. Human Sub~ects:
. The patients were bet~een the ages of 50 snd 75, o~ Caucasian background. Forty-five patients with osteoporo~is were s~udled. Thlrty o~ them received either calcium or sodium ~luoride and ;, caleium and ~ifteen received fluoride as mononuorophosphat0~
The initial vertebral x-ray was part Or the patient~ medical history and was used primarily to evaluate the patient's suitability for the study. AD other data was obtained Ior research pur-poses but wes rlso used to elert the pati-nt a:l to sny changss in relr~tlon to osteoporosis.

' ' "~

:
'.

, , -- . ~
~ 3303~8 ` RESULTS
1. Human Sub~ects:
.
-, The mean ~ge of the ~hree groups wa~ slmilar and the proportion o~ women tsking es~rog~n W2S
approximately 25% in each group.
. . .
~ . Tabl~ I .
.

.. . . ..
Ag~ Dis~ibution of Osteoporoti~ Pnffen~;

Age Number In Taldng Number Years S.D.
Ca 15 ~3.3 ~5,~ ~
Ca9 NaF 16 6108 ~7.3 4 C~ MFP 14 64,1 ~7.1 4 2. Serum Chemlstrv:
l parameters in the panel 15 remalned ~;nchanged a~ a result o~ ~reatment except for serum calclum, phosphoru~ and serum aL~aline phosphatase. Serum oslcium ~d phosphoru~ tended to all In tha groups given calcium alon~ whlle serum alkaline phosphatas~ wa~ in¢reased In the calclum and sodlum ~luoride group (p a 0.182) and markedly increased In the group given ~al¢ium ~nd MFP (p = .005 group A and p = .030 group B).

.

~:, .

., .

, .`' ' .

:
Table Il 13 3 0 ~ 0 `
Serum Calcium, pho~phorus and ~calin~ pho3pha~ase in asteoporoti~ patle~

C~ ......... Ca+NaF Ca*MFP
In(tlal 12 mo.Init~l 12 mo. Inlti~l 12 mo.
: ~ Serum Ca mean 9.2 ,8.~ 9.o 8~8 92 897 mg96S.D. 0.3 003 0.3 003 .5 .3 .~ p ~ .0~01 .04~ ,~0~
. .
Serum phosphoru~ 3.8 3.3 3.4 3~,5 3.4 305 mg % S.D. 0.4 0.6 0.3 n.6 .4 .5 p = .Oa6 ,829 . .532 Serum alkalin~
phosphatsse mean ~9 76 ~2 ~6 ~0 ~5 IU/L S.D. 18 1~ 16 20 17 35 . p= .~ag .. .589 .02 . Table m ~` .
C:hange in s~rum~ale~um, pho~phorus and alkallne phosphatas~ 3n osteopoPoti¢ paffents .
Group Ca C~ ~ NaF Ca+ MFP
S Ca mean -.06~* ;-.02 -004 mg/~6 S.D. ~0.4 ~0.3 ~0.4 SP mean 0.5~ -0.1 ~0.1 mg/% S.D. ~0~8 ~0.5 ~0.4 SALE~P mean -3 ~3~ ~25 IUjL S.D. ~ 31 ~ Signif~cantly di~ferent from other two groups P .05 '~ ~ Slgnl~lcantly di~erert ~rom other two group~ P o2 t ~ ~ii,J

3. Fluoride Absorption: 13 3 0 3 0 8 The results o~ the nuoride absorption carried out in tha ten pat~ents In group3 B and C ag~er . I three month~ on treatment were oomQared aY were the serum 1uor~d~ le~els measured at the end o~ twelve months of treatment. The eQrlier study covered a pe~od ~om twelvQ hour~ afte~
tha las~ capsules had been taken to half hour after, un~ our hour3 a~ter9 whlle th~ fluori~e level~ at th~ end o~ twelve month~ ot ~reatmenl: were ~aken seven to nln~ hour3~ stte~ the last caps3~es were ingested. ~luoride absorp~ion from M~P was 5ign~fic3~1y higher a~ all ffme~ than that ~rom Na~. .
:. ..
Table IY

Serum fluoride absorption in osteoporot~e subiect~
in Group B, C:a ~ NaP
and Group C. Ca ~ MP~ af~er 3 month~ o~ t~eatment Hours 0 1/2 1 2 4 Ca + NaF
um mean ~5.4 Y.3 11.5 11.5 9.6 S.D. ~2.8 ~4.4 ~5.9 ~ 4.6 ~:3.2 Ca + ~PP
um mean 10.9 1~.6 22.5 21.6 21.8 S.D. ~206 1 7~9 ~8.3 ~5.8 t 4.4 p = .009 .027 .040 .~14 .001 3l Table V

Serum fluoride leYels In osteoporotlc patient~
~n group B. Ca ~ NaP and group C. Ca + MPP
a~ter 12 month~ of tseatment .
` Hours 7- 9 . . i2 . Ca+ NaF mean 9.1 5,4 S.D. ~ 2.6 ~2.8 Ca + MFP mean 1202 lO.g S.D. 4.1 ~2.6 , p- .027 .00 .~, .

.~

-14- ~

:' ,g'.,". . .

,: .

4, Side Effects: :3 3 3 ~ 3 ~ ~
Some side effects9 such a~ weight loss, fatfgue, sore throat and cough were revlewed but not Included in ~he final presenhtion because they were realized as being symptoms that oceu~ norm-ally. There was no dlfference in these symptoms in the thres groups. The remaining symptoms were divided into t~re~ groups. ~eneral~ whlch included heartburn, hesdache, ~izzlness and chest pain: 'G~strointestinal~ which included diarrhea, constipation, indigestion, abdominal cornfort, nausea and vomiting; and ~Extremeties~ which included muscle cramp~,, painf~d ~oints, weakness, back pain and swo~en ~s~ints. The results ~t six months are ~hown ~n Table ~. The only significant difference was the minimal ~ncrease in gastrointestinal symptoms in group C ¢ompared with groups A Qnd B. The lncrease in extremity si~e ef~ects wa~ also less in this group ~han in the other two but the difference was not so great.
After twelve months on treatment the results o~ the questionnaire were compared wi~h the results of the initial one. There was an 1ncrease in ~he side effects in the C8 and NaP group and also some in the Ca and MFP group (aroup C~. However, in th~ analysis a s~ngle ep~sode ot, for ex~mple, nauseQ, constituted an increase and it is doubtfu~ i~ any gastrointestinsl symptoms were truly related to M~P and six of the eight incidents shown were diarrhea and constipation. In the Ca and NaF group (Group B) the gastrointestinal symptoms were felt to be tru~ side ef~ects since several patients complained during the study of constQnt nausea and abdominal discomfort.
BecQuse there was no drflmatic increase in the side effects seen in the patients given either MFP
and calcium (Group C) or N~ and calcium (Group ~) compared with thos¢ given caleium alono (Group A), a small study was carried out in two patients who were known to demonstrate strong gastrointest{nal reaction to nuoride. Both patients were women aged 63 and 70 respectively and had had osteoporosis and had been on fluoride or approximately onc year~ one on Floricnl and the other on padi~tric fluoride, bo~h taking approximately 20 mg F dailyO 80th had stopped taking fluoride a year ago becaus~ o~ intolerance to it. The patient who had been taking pediatric fluor-ide was given two capsules ot Floricsl~, the addi~ion o~ calcium carbonate in this form of nuoride possibly having a mediating effect on the gastric symptom~ cnused by fluoride alone . However, the patient returned the next day complaining o~ nausea, vomitlng and extreme gastric distress.
Both patients were then given MFP and calcfum and instructed to take two capsules twice a day wlth meals for five days and record any effects they felt to be related to the MFP and cslcium.
Neither patient experienced any symptoms whatsoever.

~ fluoride and calcium t .. ; ~. .
.
. ~,, .
. ~,. .

B YI ~ ~ 3 ~ 3 ~ 8 Ov~rall ~lde ~ffect E~ e Ca only Ca ~ NaF C:a ~ M~P
S~x Month Follow-up Increase Decrease ~Inorease Decreaæ~ ~crease De~rease General 4 7 7 7 8 ~3 ¦ Gastrointestinal 11 11 ... 9 15 1 17 ~ Extremities 11 14 S 23 8 17 i TOTAL 26 32 21 45 lt 47 (number of questions x number of people) ~225 max. 240 max. l9S max~
-; 12% 14% 9% 1 ~% 6~6 24%

Patients were given a questionnaire to fill out and ask to rste a slde e~fect : on a scale o~ 0-4 and whether there was an increase or decrease in that side effect . after taking their medication ~ 3 ' .

`, ' .

"3 .~ .

} - 16 .

T~~ 3 ~

O~rera~l Side ~S~t ~ogiIe !
A .. B C
Twelve Month Ca Qnly Ca ~ Na~ Ca ~ M~P
Follcw-up IncreaseDecreass ~IncreaseD ~orease Increas~Decre~se General 9 5 5 ~ 5 10 Gastrointestinal 11 14 13 ~0 8 16 Extremitiës 10 aû ~9 . 17 13 2Q
TOTAL 3n 39 37 45 26 46 (number o~ questlons x number o~ people) 2a5 maxO 2~0 max. 195 max~
13% 17% 15% ~9% ~3~6 249 t ,-Table vm Side E~fec~ ~ ~ CRll~n Com~

, A B
Ca only Ca ~ NaP Ca ~ MFP
2 constipatlon 3 gastric lrrltstion~ 1 musole ~ramps 2 ~tomaoh gas 2 painful fe~t 1 tlngernails splitt~ng ` 3 nause~
1 vomltlng ~ Pat~nt dropped from study Quantlt~tlve Bone Studles , The quantltatlve computed tomography (QCT) results are shown in Table I~. ~11 three group~
J showed an increase, however, ~he Ca and MP'P tr~ated group w~ the only one k~ which the increase W8S significant. When changes In lndividual QCT values wer~ eomp~ed between groups, '. the C8 and MPP group showed ~ signl~lcant ~ncreas.e ~omQared wlth the group~ on Ca alone and Ca arid N~ ~Table. X).

~ .
,7 ~ . "
: - 17 - :
f. ' ' 1~

(~

T~b~ ~X ~ 3 Q~r Yalue3 Sm~/ce~

. i Ca Ca ~ Na~ Ca ~ D~FP
time Q mean6102 6405 84.7 . S.D. ~1~.8 ~1608 . ~27.3 ! ~ time 12 months mean 6~o3 ~1~9 16179 8.D. ~20.S ~9~5 ~37'4 ' p = o647 o308 ~1~38 ~i TRbl~
Change ~n QCr ~n osteoporoti~ pstients {n groups A., C:a9 8. C:a ~ Na~, CO Ca ~ P

Group Av. 8 A v. C ~ v, C
~, mean ~2.4 ~7.4 ~ ~2.4 ~22.3 ~7.4 ~22.3 .' S.D. ~10.0 ~8.6 ~10.0 ~22.9 ~8.6 ~22.9 p = .148 .008 O034 , :
CONCLUSIONS F~021 STUDY
', The two questions posed in the original cllnical study were lf M~P combined wi~h cslcium would be more effective in inoreasing bone mas~ and would produce ~ewer s~d~ efgects than Na~ aombined wlth calcium. The results a~3wered both questionss Th~ ~uorlde ln MFP is more erfi~iently absorbed than from Na~ and the level In th~ blood appears to be sustalned at a hlgher 18vel ov¢r a tw~lve-hour perlod. It Is not surprising to find ~his reflected In an incresse In ~one mas~ ~ damonstr~ted by the ' QCT flndings. Four patl~nt~ achieved bone mass levels of 135-185 mg/cc whlch are levels found In 30 5 to 40-year-old normal females.
Slde effects were very difficult to evaluate ~nd the somewhat strlct evalu8tlon In wh~ch even a slngie ln~ldent of a symptom was counted a~ sn increase resulted in probably s gre2ter number o~ patlent~
demonstrating side ef~eet~ than l~ more conventlon~l method~ had been used such 8~ notlng lt patlent~
reported sympeoms frequently. The real ~ncrease in sympeoms ln ~he ex~emi~e~ ~n the Ca and M~P
group wa~ probably due to musele crarnps and wesknes~t pos~ibly the resllIt of ~he decrea~e ~n the 3 serym ,calclum In thi~ group.

~` I;

( ~3~30~
No correlatlon was ~ound between the ch8nge In QCT and alkallne phospha~a~e althou~h ~hc tour patients who shoYJed ~he greatest ~esponse In bone mas3 also showed ~he highest alkallne phosph~t~se 3 level st twelve months.

A combination of M~ and cal~ium, in th~ ~orm of ths c~rbong~e, appears ~o be a superior fo~m o~
treatment for os~eoporosis; a~sorption o~ nuoride is greater than from Na~ bone mass is s~gn~f~cantly increased in the majority of patlents an~ side effeets wh}ch woul~ ~allse ~h~ pat~en~ to stop talcing th~
medication seem not to exist.
Absorption o~,fluoride from M~P/Cg show~ a two-~old ~n~rease eomp~Fsd to N~P/Ca. Bone density ! Increases in the three groups:
C:a ~ 2.4%
NaP ~ 7.4%
MFP + 22.3%

. I The invention is ideally directed to a ~lmple method of . ~ treating osteoporosis in human patlents whlch compr~es orally . administering to the patient a single tablet or capsule as a ; ` unitary dosage containing in combination at lea3t eight parts by I weight of calcium carbonate to one part by weigh~ of sod~um monoflurophosphate, up to not more than four capsules or tablets : pee day. Admin1steation of such a unitary dosage is preferably ¦accomplished on oace or not more than t-ice per day.

`

~,............... ...... ,.

.~ :.
~;, . .

~,,'. ..
.' ~ . .
;:, . .

Claims (11)

1. A medicament for therapeutic treatment of osteoporosis in humans which comprises, in unit dosage form, a combination of calcium carbonate and sodium monofluorophosphate in proportions sufficient to limit medication to from about one to not more than four unit dosages per day, the amount by weight of the calcium carbonate being at least 8 times the weight of the sodium monofluorophosphate.

2. A medicament as claimed in Claim 1 wherein the proportions of calcium carbonate and sodium monofluorophosphate are sufficient to limit medication to not more than three unit dosages per day.

3. A medicament as claimed in Claim 1 wherein the proportions of calcium carbonate and sodium monofluorophosphate are sufficient to limit medication to not more than about two unit dosages per day.

4. A medicament as claimed in Claim 1 wherein the weight ratio of calcium carbonate:sodium monofluorophosphate is in a range of about 8:1 to 50:1

5. A medicament as claimed in Claim 4 wherein said weight range is about 8.5:1 to 25:1.

6. A medicament as claimed in Claim 4 wherein said weight range is about 10:1 to 18:1.

7. A medicament as claimed in Claim 4 wherein said weight range is about 12:1 to 16:1.

8. A medicament as claimed in Claim 1 wherein the unit dosage is in the form of an orally administrable tablet.

9. A medicament as claimed in Claim 1 wherein the unit dosage is in the form of an orally administrable capsule.

10. A medicament as claimed in claim 1 containing calcium carbonate in the amount of about 625 milligrams.

11. A medicament as claimed in claim 10 containing sodium monofluorophosphate in an amount of about 6 milligrams.