the treatment regimen of the present invention consists of one or more cycles , whereby each cycle consists of a bone activating period , a bone resorption inhibition period and a rest period . during the bone activating period , bone cells are induced into a synchronized metabolism . during the bone resorption inhibition period , the bone resorption which naturally follows the activation is limited to a minimum by administration of a bone resorption inhibiting polyphosphonate . the rest period allows for natural bone formation to occur . the preferred mode of administration is orally , but other modes of administration include , without limitation , intramuscular , intravenous , intraperitoneal , and subcutaneous administration , as well as topical application . all compounds described herein are administered orally , except where specified otherwise . by &# 34 ; subject afflicted with or at risk to osteoporosis &# 34 ; as used herein is meant a subject diagnosed as suffering from one or more of the various forms of osteoporosis , or a subject belonging to a group known to have a significantly higher than average chance of developing osteoporosis , e . g ., post - menopausal women , men over the age of 65 , and persons being treated with drugs known to cause osteoporosis as a side effect ( such a adrenocorticoid ). by &# 34 ; bone cell activating compound &# 34 ; as used herein is meant a compound which increases the rate of activation of new remodeling units on bone . the concept is described in more detail in frost , clinical orthopedics and related research , 143 , 227 ( 1979 ) and in rasmussen et al ., metabolic bone disease and related research , 2 , 107 ( 1980 ), the disclosures of which are incorporated herein by reference . in most cases this increased rate of activation is initially manifested by an increase in the number of bone resorbing cells and bone resorbing sites . biochemical indicies of skeletal remodeling , such as urinary hydroxyproline levels , are expected to become elevated according to the magnitude of the response to the bone cell activating compound . specific examples of such compounds are parathyroid hormone ( pth ), inorganic phosphate , growth hormone , fluoride , thyroid hormones ( e . g . thyroxine ), certain vitamin d metabolites and prostaglandins . it may be possible to induce bone cell activation by non - chemical means , e . g . a strict , physical exercise regimen , or electrical currents . by &# 34 ; bone cell activating amount &# 34 ; as used herein is meant an amount of the bone cell activating agent sufficient to effect a medically significant increase of the rate of activation of new remodeling units . if inorganic phosphate is used as the bone cell activating compound , the amount is in the range of from about 4 mg / kg / day to about 60 mg / kg / day ( p . o .) of phosphorus , with amounts of from about 30 mg p / kg / day to about 50 mg p / kg / day preferred . daily doses of inorganic phosphate should not exceed about 3 . 6 grams of phosphorous for any subject afflicted with or at risk to osteoporosis because severe diarrhea and gastrointestinal distress is likely to occur for dosages which exceed this amount . bone cell activating amounts of other bone cell activating compounds are as follows : 1 , 25 - dihydroxy vitamin d 3 and other 1 - hydroxy vitamin d metabolites : from about 0 . 001 microgram / kg / day to about 0 . 03 microgram / kg / day ( p . o . ); 25 - hydroxy vitamin d 3 and other 25 - hydroxy vitamin d metabolites ( not including 1 , 25 - dihydroxy vitamin d metabolites ): from about 0 . 1 microgram / kg / day to about 3 microgram / kg / day ( p . o . ); inorganic fluoride ( e . g . sodium fluoride ): from about 0 . 1 mg / kg / day to about 1 . 0 mg / kg / day f per day ( p . o . ); thyroxine : from about 0 . 01 mg / kg / day to about 0 . 5 mg / kg / day ( p . o . ); triiodothyroxine : from about 0 . 1 microgram / kg / day to about 2 . 5 microgram / kg / day per day ( p . o . ); prostaglandin pge 2 : from about 0 . 1 to about 25 mg / kg / day ( p . o . ); parathyroid hormone 1 - 34 : from about 0 . 1 microgram / kg / day to about 3 . 0 microgram / kg / day ( s . c .). by &# 34 ; bone resorption inhibiting polyphosphonate &# 34 ; as used herein is meant a polyphosphonate of the type disclosed in u . s . pat . no . 3 , 683 , 080 , granted aug . 8 , 1972 , francis , the disclosures of which are incorporated herein by reference . the term &# 34 ; phosphonate &# 34 ; includes the phosphonic acids , as well as their pharmaceutically acceptable salts and esters . preferred polyphosphonates are geminal diphosphonates ( also referred to as bis - phosphonates or diphosphonates ). the polyphosphonates may be administered in the form of the acid , or of a soluble alkali metal salt or alkaline earth metal salt . hydrolyzable esters of the polyphosphonates are likewise included . specific examples include ethane - 1 - hydroxy - 1 , 1 - diphosphonic acid , pentane - 1 - hydroxy - 1 , 1 - diphosphonic acid methane diphosphonic acid , methane dichloro diphosphonic acid , methane hydroxy diphosphonic acid , ethane - 1 - amino - 1 , 1 - diphosphonic acid , ethane - 2 - amino - 1 , 1 - diphosphonic acid , propane - 3 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid , propane - n , n - dimethyl - 3 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid , propane - 3 , 3 - dimethyl - 3 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid , phenyl amino methane diphosphonic acid , n , n - dimethylamino methane diphosphonic acid , n ( 2 - hydroxyethyl ) amino methane diphosphonic acid , butane - 4 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid , pentane - 5 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid , hexane - 6 - amino - 1 - hydroxy - 1 , 1 ,- diphosphonic acid , and pharmaceutically acceptable esters and salts thereof . the amount of the polyphosphonate to be used is determined entirely by its potency as a bone resorption inhibiting agent . this potency is determined by means of the thyroparathyroidectomized ( tptx ) rat model described herein and expressed as the lowest effective dose ( led ) of the compound which is defined as the lowest subcutaneously given dose of polyphosphonate , in mg p per kg body weight , which in the tptx rat model results in an inhibiton of the pth - induced rise in serum calcium level . since the amount of polyphosphonate to be administered is dependent on the bone resorption inhibition potency of the compound , the amount to be administered is conveniently expressed as multiples of led . extrapolation of the dosages for polyphosphonates from the tptx rat model to humans is possible based on the observation that oral dosages in humans are proportionally related to the leds for polyphosphonates in the tptx rat model . it is therefore observed that suitable amounts of polyphosphonates for administration in subjects afflicted with or at risk to osteoporosis are from about 0 . 25 × led to about 3 . 3 × led , while amounts of from about 0 . 25 × led to about 2 . 5 × led are preferred , and amounts of from 0 . 50 × led to 2 . 0 × led are most preferred . the leds of a number of polyphosphonates are collected in table i . ranges for the daily administration of some polyphosphonates for subjects afflicted with or at risk to osteoporosis are therefore : ethane - 1 - hydroxy - 1 , 1 - diphosphonic acid : from about 0 . 25 mg p / kg to about 3 . 3 mg p / kg , with from about 0 . 25 mg p / kg to about 2 . 5 mg p / kg preferred ; dichloromethane diphosphonic acid : from about 0 . 12 mg p / kg to about 1 . 67 mg p / kg , with from about 0 . 12 mg p / kg to about 1 . 25 mg p / kg preferred ; propane - 3 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid : from about 0 . 025 mg p / kg to about 0 . 33 mg p / kg , with from about 0 . 025 mg p / kg to about 0 . 25 mg p / kg preferred ; butane - 4 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid : from about 0 . 0025 mg p / kg to about 0 . 033 mg p / kg , with from about 0 . 0025 mg p / kg to about 0 . 025 mg p / kg preferred ; and hexane - 6 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid : from about 0 . 025 mg p / kg to about 0 . 33 mg p / kg , with from about 0 . 025 mg p / kg to about 0 . 25 mg p / kg preferred . an important aspect of the present invention is the discovery that too high a dosage of polyphosphonate is detrimental to net bone formation . in fact , dosages which are routinely prescribed for the treatment of paget &# 39 ; s disease appear on the high side for treatment in the present regimen . generally , polyphosphonate dosage should not exceed about 3 . 3 × led / day , and are preferably below about 2 . 5 × led / day . polyphosphonate dosage below 2 . 0 × led / day are most preferred . another important aspect of the present invention is the discovery that the natural cycle time of bone resorption / formation can be shortened . as disclosed in frost , &# 34 ; treatment of osteoporosis by manipulation of coherent bone cell populations ,&# 34 ; clinical orthopedics and related research , 143 , 227 ( 1979 ), the disclosures of which are incorporated herein by reference , the natural cycle time varies from 3 to 6 months . with the method of the present invention it is possible to reduce the cycle time to about 41 to about 85 days . thus , it is possible to repeat the treatment cycle up to 9 times a year , as distinguished from 2 - 4 times a year based on the natural cycle . the shorter cycle time is believed to result in a faster overall bone build - up . neither bone cell activating compounds nor bone resorption inhibiting polyphosphonate are administered during the rest period . this is not to say that no chemical should be administered to the patient at all during this period . food supplements like calcium and vitamin d ( to be distinguished from bone cell activating metabolites of vitamin d ) can beneficially be administered during this period . to determine the bone resorption inhibition potency of several polyphosphonates , the following animal model was used . in this study 50 male wistar rats weighing approximately 150 - 160 grams were thyroparathyroidectomized surgically by the breeder ( charles river breeding laboratories ®). all rats were double housed on arrival in suspended cages with purina laboratory rodent chow ® and tap water ad libitum . after acclimation to the laboratory environment for 3 - 5 days , the rats were placed on a low calcium , low phophorous ( 0 . 18 %/ 0 . 22 %) diet ( teklad ®) and given 2 % ( w / v ) calcium gluconate supplemented deionized water via water bottles . on day four of low - calcium diet all rats were anesthetized with ketaset ® ( ketamine hydrochloride , 100 mg / ml , bristol myers ), 0 . 10 ml / 100 grams of body weight , weighed and then bled for serum total calcium analysis using flame atomic absorption ( faa ). all rats weighing less than 180 grams were eliminated from the study . animals were then randomized statistically such that the mean total calcium for each group was the same . only rats deemed hypocalcemic ( total calcium ≦ 8 . 0 mg / dl ) were placed in study groups ( 6 animals in each group ). treatments with the various experimental compounds commenced on day 6 and lasted through day 9 of the study ( at 1 : 00 p . m . each day ). dose solutions were prepared to be given at a constant rate of 0 . 2 ml / 100 grams of body weight subcutaneously in the skin flap where the hind leg meets the torso . all rats were weighed and dosed daily . a 25 gauge 5 / 8 &# 34 ; needle was used to administer drug , alternating dose sites daily . on day 9 all rats were fasted in the afternoon at approximately 4 : 00 p . m . on day 10 of study no treatment was given . in the morning a 600 μl sample of whole blood was collected from each rat in microtainer ( b - d # 5060 ) serum separater tubes for serum total calcium ( faa ). two 125 μl samples of heparinized whole blood were also collected to be used for ionized calcium analysis . immediately following blood collection all rats were weighed and injected with bovine parathyroid hormone subcutaneously at a rate of 75 usp units per 100 grams of body weight . blood sampling for total and ionized calcium was repeated three hours post - pth injection . all pre - and post - pth total and ionized calciums were statistically analyzed for significane compared to pth along ( control ) using student &# 39 ; s t - test , analysis of variance , and their non - parametric equivalents . the post minus pre - change and % change were also determined on calcium levels and pre - drug vs post - drug body weights . low calcium and phophorous diets used were prepared by teklad ® test diets ( harlan industries , madison , wis . 53711 ; order # td82195 ) in a pellet form of approximately 0 . 18 % calcium and 0 . 22 % phosphorous . the diets contained all the essential vitamins and minerals required for the rat , with the exception of calcium and phophorous . the calcium and phosphorous levels of the pellets were verified analytically . all dosing solutions of compounds to be tested for bone resorption inhibition potency were adjusted to ph 7 . 4 with sodium hydroxide and prepared in 0 . 9 % saline ( abbott ndc 0074 - 1583 - 03 ), abbott labs , north chicago , il 60064 , usa ). dosing solution concentrations were adjusted to a dosing rate of 0 . 20 ml / 100 grams of body weight . pth was acquired as a powdered bovine extract ( sigma chemical co ., p . o . box 14508 , st . louis , mo ., order # p - 0892 , lot # 72f - 9650 ) at an activity of 138 usp units per mg . pth was prepared in 0 . 9 % saline such that the final concentration was 100 u . s . p ./ ml . all solutions were filtered through a 190 40 whatman filter paper then 0 . 45 μm metricel ® filter . the physiological effect of the pth challenge is a rise in serum calcium level . since the animals were on a low calcium diet , an observed increase in serum calcium level is the result of a resorption of bone material . since polyphosphonates tend to inhibit resorption of bone material , the animals pretreated with polyphosphonate showed a rise in serum calcium level upon pth challenge which was less than that found in control animals which had been treated with saline vehicle instead . the lowest dose at which the polyphosphonate is capable of inhibiting bone resorption , as evidenced by a decreased rise in serum calcium upon pth challenge , is a measure of the bone resorption inhibition potency of the polyphosphonate . where necessary the test was repeated , whereby the animals were administered with 0 . 5 and 0 . 2 × led , in order to refine the determination of led . the led values of some representative diphosphonates are presented in table i . table i______________________________________lowest effective ( antiresorptive ) dose ( led ) values led ( mgcompound * p / kg ) ______________________________________ethane - 1 - hydroxy - 1 , 1 - diphosphonic acid ( ehdp ) 1 . 0dichloromethane diphosphonic acid ( cl . sub . 2 mdp ) 0 . 5propane - 3 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid ( apd ) 0 . 10butane - 4 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid ( abdp ) 0 . 01hexane - 6 - amino - 1 - hydroxy - 1 , 1 - diphosphonic acid ( ahdp ) 0 . 10______________________________________ * all compounds were in aqueous solution , the ph of which had been adjuste to 7 . 4 with naoh . at this ph the diphosphonic acids are present as their disodium salts . patients clinically diagnosed as suffering from osteoporosis are subjected to a treatment regimen according to the present invention as follows . each patient is subjected to from 3 to 8 cycles , each cycle consisting of ( a ) a bone activating period of 3 days during which 2 tablets of phosphate sandoz ™ were administered 3 times daily ( each tablet contains 500 mg of elemental phosphorous ); ( b ) a bone resorption inhibition period of 14 days during which the patients receive 5 mg / kg / day ( corresponding to 1 . 24 mg p / kg / day , or 1 . 24 × led ) of didronel ( norwich eaton pharmaceuticals , norwich , n . y .) divided into 3 doses ( each didronel tablet contains 200 mg of disodium ehdp ); ( c ) a rest period of 45 days during which the patients receive a diet which is verified to contain a minimum of 1 g / day of calcium . the treatment regimen results in an appreciable alleviation of osteoporotic conditions . table ii__________________________________________________________________________ bone resorption inhibition period rest totalbone activating period dose / day period cycledays compound dose / day days compound ( mg p / kg ) days days__________________________________________________________________________1 1 , 25 - vit . d . sup . ( a ) 1 μg 10 cl . sub . 2 mdp 2 . 5 30 413 naf 20 mg 12 apd 0 . 5 40 555 pth 1 - 34 . sup . ( b ) 100 μg 17 ahdp 0 . 03 50 723 pge . sub . 2 . sup . ( c ) 10 mg / kg 15 abdp 0 . 005 60 78__________________________________________________________________________ . sup . ( a ) 1 , 25 dihydroxy vitamin . sup . ( b ) parathyroid hormone 134 . sup . ( c ) prostaglandin e . sub . 2 a treatment regimen consisting of two or more of the above cycles results in an appreciable alleviation of osteoporotic conditions .
a method for treating or preventing osteoporosis is disclosed . bone cells are synchronized during a bone cell activating period ; bone resorption , which normally follows activation , is inhibited using a polyphosphonate ; bone formation is allowed to occur in the rest period during which nutrient supplements may be administered to the patient . the method shortens the natural cycle time of bone formation / resorption , resulting in a faster bone build - up .