POSTGRAD. MED. J. (I964), 40, 158

THE STUDY OF OSTEOPOROSISAND OSTEOMALACIA

G. ALAN ROSE, D.M., F.R.I.C.From the Metabolic Unit, Department of Medicine, The General Infirmary at Leeds

ALTHOUGH many articles have appeared in thejournals in recent years on the subjects of osteo-porosis and osteomalacia, our knowledge of thesesubjects continues to be very fragmentary. Inthe case of osteoporosis there has been much con-troversy about the atiology. Some continue toagree with the views of Albright and Reifenstein(I948) that osteoporosis is primarily due toabnormality of the bone matrix, while others havereverted to the earlier view that there is primarilya deficiency of calcium. The pros and cons ofthese -two views have been reviewed recently(Lancet I963) and need not be discussed in detailhere.- Others have considered the aetiology inquite different terms altogether. Thus, Little(I963) concluded, as a result of electron micro-scope studies, that the osteocytes of osteoporoticbone liberated a substance which degraded thematrix following which mineral was removed.

Treatment of OsteoporosisWith the aetiology of osteoporosis in doubt, it

is not surprising that there is also doubt aboutthe best treatment. The sex hormone treatmentof Reifenstein and Albright (I947) now has therespectability of time. There seems to be- no riskof carcinoma induction as was once feared andpatients benefit from it (Henneman and Wallach,1957) ceasing to lose height and to fracture.Positive calcium balances are not always seen,however, and often when seen are only slightin amounts, and the bones do not apparentlyremineralize (Henneman and Wallach, I957;Nicholas and Wilson, 1959). The high calciumintake strongly recommended by Nordin (I962)is said to give the same symptomatic improve-ment and in addition to give strongly positivecalcium balances. Nordin (I962) claimed positivecalcium balances as great as 34 mg./kg. bodyweight (2.4 g. for a 70 kg. man) per day forperiods of time of up to one year. Neverthelessno remineralization of bone has been demon-strated as yet even with this high calcium intakeregime. This is puzzling because if a positivecalcium balance of 2.4 g./day continued for ayear then the total gain by the body would be835 g., an amount which must be visible radio-logically however distributed in the body. Thenormal adult skeleton contains I,000-I400 -g. of

calcium (Albright and Reifenstein, 1948), and areduction of 30% to 50% can generally be detectedby eye on an ordinary X-ray film (Lachman,I955), so that a gain by osteoporotic bone of835 g. could not be missed radiologically howeverdiffusely this gain might be spread through thebones. Nordin himself has expressed somepuzzlement writing (I962) 'It is perhaps sur-prising, even when this insensible loss of calcium'(referring to sweat) 'is taken into account, thatcalcium supplements have not yet produced anyconvincing changes on spinal roentgenogramsapart from some possible hardening of the endplates'. A possible explanation of this discrep-ancy between the radiological and the balancedata is that the high calcium intake magnifies theerrors inherent in the balance technique. Suchseems quite likely when it is recalled that nor-mally 8o% of the ingested calcium appears in thestools, and that this figure becomes even higheron a high calcium intake, and yet complete stoolcollections are extremely difficult. Toilet paperis frequently rejected without analysis, smallquantities of faces may be lost in manipulation,and even in the best-run metabolic units, stoolsmay occasionally be lost without trace.Although sex (and anabolic) hormones and a

high calcium intake probably represent the twotherapies' for' osteoporosis in most commo'n useat the present time, this by no means exhauststhe list of therapies that have been recommended.It was claimed by Shorr and Carter (1952) thatstrontium salts given by mouth led to positivestrontium balances after high calcium intake nolonger gave positive calcium balances. Thistherapy was found to be effective by McCaslinand Jones (1959) but no balance data were givenand the trial appeared to be uncontrolled. Albu-min infusions were recommended by Albright andReifenstein'(1948) for the treatment of idiopathicosteoporosis. Again however this therapy doesnot appear to have been widely adopted. Anderson(I954) found that one patient with idiopathicosteoporosis repeatedly showed a striking' fall inurinary calcium following each- plasma infusion.Three otber patients in the same series howeverfailed to respond (Dent, I955). Sodium fluoridetherapy has recently been advocated for osteo-porosis. by Rich and Ensinck (I96I) who claimed,

copyright. on July 9, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.461.158 on 1 March 1964. D

ownloaded from

March I964 ROSE: The Study of Osteoporosis and Osteomalacia

in a preliminary communication, that good positivecalcium balances could be achieved. Theseresults still await confirmation.

New Methods of StudyIt therefore seemed reasonable to undertake

new balance studies to try and compare theeffectiveness of some of these various therapies inosteoporosis, and this is now in progress in thismetabolic unit. Starting with the proposition thatremineralization of bone is never seen whateverthe therapy, it seemed likely that the changes incalcium balance to be observed might be small,so that a method of improving the accuracy ofmeasurement of faecal calcium was required toavoid the possible errors discussed above. Twonew methods have therefore been investigated.Firstly, the continuous chromium marking ofstools of Whitby and Lang (I960) has been used.Rose (I964) has shown that the chromiumsesquioxide follows the calcium and phosphorusin the stools remarkably closely so that losses ofstools on toilet paper or in manipulation, or fromany other cause, can be estimated and allowed forby measuring chromium recovery in the stools.The overall accuracy of the balance is thereforeincreased, and this will be true especially whenftecal calcium is very high as on a high calciumintake. This fact is illustrated in Fig. i whichshows the result of a i2-day balance study on anosteoporotic patient while in the fourth month ofhigh calcium intake therapy. When fecal calciumis not corrected for chromium recovery, sheappears to be in positive calcium balance of about250 mg./day (in the range often claimed byothers). But the chromium recovery was 89%and when allowance is made for the chromiumloss the balance becomes virtually zero. Notethat the chromium correction makes very littledifference to the overall phosphorus balance sincefecal phosphorus is so much less than the faccalcalcium, both relatively and in absolute amounts.The second method of improving measurement

of frecal calcium is by the use of radioactivecalcium. A tracer dose can be given orally andthe recovery in the stools should indicate theextent of absorption of dietary calcium. Bysubtracting calcium absorbed from calcium given,the unabsorbed calcium is derived. Unabsorbedcalcium differs from the faccal calcium by thecalcium secreted into the bowel (but not re-absorbed). If this net secreted calcium is constant,then by assuming this value and knowing absorbedcalcium (from the isotope study) one can calculatethe actual fecal calcium. Others have attemptedthis before (see Eklund, I962) but been unable toget the correlations expected. In conjunctionwith the Department of Medical Physics at

MWISS GWE.VDLINf N. J?eers*

IDI/OPATHI/C OSTfO/ OR s/S

UNCORRECrED FOR CHROMIEUM CORAREcT(0-

p as

G/d.y --I' '

I 0-

C. as

*7 ai 10. 4 . 2 29-4MAY A/NE MAY JUVNE/963 1963

FIG. i.-The calcium and phosphorus balance of anosteoporotic patient in the 4th month ofhigh calciumintake. When the results are uncorrected for f;calchromium recovery, she appears to be in positiveealcium balance of about 250 mg./day, but this iseliminated when the correction for lost chromium(and therefore lost feces) is made.

In this and the other Figs. the balance data areconstructed in the manner of Albright and Reifen-stein (X948). Diet is plotted down from the zeroline. From the diet line, excretion is plotted up, theshaded portion indicating faecal excretion and theclear portion the urinary excretion.

this hospital, this work is being repeated, using47Ca and using values for fical calcium bothwith and without correction for chromiummarker. Results obtained so far show greatlyimproved correlation when correction is madefor chromium marker. These results are not yetcomplete however and will not be discussedfurther here.

Results in OsteoporosisIn this study of osteoporosis now in progress a

repeated finding has been that the faecal calciummay be as high as, or higher than, the calciumintake, even though the intake has been normaland about the same as the patients' normal intakewhen at home. Patients may therefore be innegative calcium balance with an intake of about

copyright. on July 9, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.461.158 on 1 March 1964. D

ownloaded from

ifo POSTGRADUATE MEDICAL JOURNAL March I964

6WENUOLIE -i. -'rS .4.. L N. r..

ID10PAtHIC OST/EOPOASIS srgMOID OSOORsI.

FAECES vi., -zJURINE M. "

0-

co1.0

G/6Ay°S2

0 6 12 IS 24 DOAtS 0 6 12 iS 24

FIG. 2.-Selected balance data from two studies on osteoporotic patients toshow, firstlv that the fiecal calcium may equal or exceed the dietary calcium,even on a normal calcium intake, and secondly that the overall balance isnot improved by lowering the frecal calcium with vitamin D. In each case,the fall in fxcal calcium continued in the following 6-day period despitechanges in therapy.

I g./day and despite a normal or low urinarycalcium, as shown in Fig. 2. Such high fiecalcalcium values have been observed before byothers (Reifenstein and Albright, 1947; Lichwitz,de Seze, Paolaggi, Lanham, Hioco, Miravet andBordier, I962; Heaney, i962) but have not beenstressed, although the observation seems to haveimportant theoretical and practical implications.Two possible explanations for the high frecalcalcium present themselves. Firstly, it might bethat the patient has an inability to absorb dietarycalcium, and this gives rise to calcium deficiencywhich is the cause of the osteoporosis. If thiswere so then administration of vitamin D insufficient dose to overcome the absorption defectshould cure the condition. Fig. 2 shows thatthis does not occur since when the calcium isabsorbed a positive calcium balance is preventedby a matching rise in urinary calcium. Note thatin the case of Stella H. the rise in urinary calciumwas preceded by the fall in fiecal calcium (andthis has been seen in another patient) so that itis most unlikely that the fall in faecal calcium wasdue to the rise in urinary calcium. A secondexplanation for the high faecal calcium thereforeseems more likely, i.e. that the faecal calcium isactually maintained high because the bonescannot utilize the calcium. What the mechanismmight be whereby this is achieved is interestingto consider,' but no suggestions can be offered atthe present time. The practical implication ofthe high frecal calcium concerns evaluation of theosteoporotic patient. Albright and Reifenstein(I948) considered that in post-menopausal osteo-

porosis, the urinary calcium was high during aphase of demineralization of bone, and thatlater a normal or low urinary calcium indicatedthat a new calcium balance had been achieved,and the aim in treatment was to lower the urinarycalcium. This reliance on urinary calcium isclearly unwarranted when the fiecal calcium ishigh, and it may be that in studying the effectof therapy it would be most unwise to ignorethe facal calcium and measure urinary calciumalone.A second way of attempting to increase the

dietary absorption of calcium is to raise thecalcium intake without giving vitamin D. Thishas the advantage that it apparently does notcause the rise in urinary calcium which accom-panies vitamin D therapy (see Fig. 2). Positivecalcium balances have been obtained in thepresent study when the calcium intake has beenraised from I to 3 g./day. But these positivebalances have been observed only in the first I2to i8 days of the treatment, and when patientshave been sent out on the therapy and then beenbrought back for further balance study some 3 to4 months later the positive balances have nolonger been present. It seems that it has some-times been possible to arrest a negative balance,but never to establish a positive calcium balancefor a long period. As already discussed above,these results are at variance with those of Harrison,Fraser and Mullan (I96I), and of Nordin (I962).At least three explanations are possible to explainthis variance. Firstly, current methods of balancestudy seem to be more accurate than those avail-

copyright. on July 9, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.461.158 on 1 March 1964. D

ownloaded from

March I964 ROSE: The Study of Osteoporosis and Osteomalacia I6I

able previously. Secondly, the calcium tabletsformerly available (lactate or gluconate) wereunpalatable when given in the large doses requiredand it seems likely that some patients would nottake the full dose when sent home. By contrast,the calcium tablets used in this study haveinvariably been the Calcium-Sandoz effervescenttablets which make a pleasant drink whichpatients enjoy, so that it is much more likely thatthey will continue the treatment when at homeand in between balance studies. Thirdly, we mustnot overlook the possibility that osteoporosis isnot a single condition, and the paqtients studiedin the present limited series may not have thesame disease as those studied by others.The evidence obtained so far in the present

study is that no method of treatment used (highcalcium intake, sex hormones, or fluoride) willput an osteoporotic patient into positive calciumbalance for a prolonged period of time. It hasbeen possible only to arrest a negative calciumbalance. This has been achieved both with highcalcium intake and by hormonal therapy, butfluoride therapy has as yet proved very ineffective.This is apparently a disappointing conclusion atwhich to arrive, but nevertheless it appears to bein accord with radiological evidence. Hennemanand Wallach (I957) stated that 'careful review ofradiographs made with standard technique after5-20 years of estrogen therapy in this series hasfailed to demonstrate a single instance of increasein bone density'. Indeed very few workers haveever claimed to have shown remineralization ofosteoporotic bone. When claims have been made(Martinez and Greenblatt, 1960) the evidencepresented has been very unconvincing. Iannac-cone, Gabrilove, Brahms and Soffer (I960)demonstrated that when the cause of osteoporosisin children was cured by surgical treatment ofCushing's syndrome, and when the new bonegrowth was then normal, even then the oldvertebral bone did not remineralize. It thereforeseems that remineralization of osteoporotic bonemay be impossible, except perhaps in the case ofacute immobilization osteoporosis.

This biochemical and radiological evidenceagainst remineralization in no way gainsays thevalue of the treatment of osteoporosis in prevent-ing further fractures and loss of height, since thearrest of a negative calcium balance may well besufficient to achieve this. It does mean howeverthat claims to have established prolonged andlarge calcium balances should be viewed withsome caution.

OsteomalaciaThe case for further studies of osteomalacia is

a quite different one. Often, when osteomalacia is

treated, large changes in calcium balance can beproduced and this can be done without recourseto a high calcium intake. Classical balance tech-niques were accurate enough to show thesechanges and it seems established that vitaminD-resistant osteomalacia (or rickets) can alwaysbe cured by giving a sufficiently large dose ofvitamin D (with sodium bicarbonate as a secondtherapy if renal tubular acidosis is present). Dentand Harris (I956) however have pointed out thatthe resistance to the vitamin D applies only tothe therapeutic effect and not to the toxic effectsso that the therapeutic range may become verysmall. The therapy is therefore potentiallyhazardous, especially in chronic renal failurewhere hypercalcemia may be especially disastrous(Dent, Harper and Philpot, I96I). Furthermore,the dose of vitamin D which may be needed toproduce the positive calcium balance required tocure a patient may be toxic when the bones arefully recalcified so that the dose must be graduallyand carefully lowered. If another therapy couldbe found which did not have these hazards itwould be very advantageous. Another reasonfor seeking a different form of therapy is thatsometimes the clinical response to vitamin D isunexpectedly slow. Fig. 3 shows the calciumbalance of a patient with type 2 (Dent, I952) renaltubular osteomalacia (hypophosphataemic osteo-malacia plus a renal glycosuria). Vitamin Ddramatically lowered the fecal calcium as wasexpected, but the overall improvement in calciumbalance was very slight because of the rise inurinary calcium to very high levels. This patientwas eventually cured with no other therapy, butit took many months of vitamin D therapy to gethim walking again and heal the Looserzones.

Because of these hazards and difficulties whichcan occur in the treatment with vitamin D, othermethods of treating osteomalacia are under invest-igation in this department. It was claimed byde Toni and Nordio (I959) that rickets, either ofthe classical D-deficient type or with vitaminD-resistance, could be cured by giving intra-muscular injections of ATP without any vitaminD administration. X-rays were shown to supportthis claim but no balance data were shown. Acalcium balance study was therefore carried outin Leeds in which a 7-year-old girl with type I(Dent, I952) renal tubular rickets (hypophos-phataemic rickets) was studied before and duringATP therapy as recommended by de Toni andNordio. No improvement in calcium balancecould be demonstrated after I 2 days of thistherapy and it was therefore abandoned and hasnot been attempted again. The girl subsequentlydid well on the usual vitamin D therapy.

copyright. on July 9, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.461.158 on 1 March 1964. D

ownloaded from

i62 POSTGRADUATE MEDICAL JOURNAL March I964

ARTHUR N typt2 rmwl tNOW-osteniak

400-

Cs 0--

mg/. 400-

.a lo---

d70- -

--

Jwq - ',4.

s2-

p0-

* o-o-I 1 I .1I I I I I I I I I I I I 1 I I I I8 14 20 26 2 S 14' 20 26 1

SEPT /9M0 ocr J

FIG. 3.-The effect of vitamin D on the calcium balanceof an osteomalacic patient. The plasma inorganicphosphate failed to rise to normal levels and thismay be the reason why calcium absorbed from theintestinal canal has not been retained. Renal tubularacidosis was not present.

It was claimed by Fraser, Jaco, Yendt, Munnand Liu (I957) that intravenous phosphate in-fusions sufficient to restore the plasma inorganicphosphate to normal would cure rickets withoutthe use of large doses of vitamin D. Again theevidence was radiological and no balance datawere given. Steendijk (I96I) was able to obtainsimilar results in a single patient, but again nobalance data were given and the possibi-lity ofrearrangement of total body calcium rather thanan increase in total calcium retention was franklyconsidered as a possible explanation.Although phosphate infusions might raise the

plasma inorganic phosphate to normal, it isdifficult to see how they could lower the frcalcalcium, an essential step in the cure of thepatient illustrated in Fig. 3. However, Fig. 3shows that the failure in retention of absorbedcalcium was accompanied by a failure of plasmainorganic phosphate to reach normal levels andit is possible that had the plasma inorganic phos-phate been raised by phosphate infusions at thesame time as vitamin D was administered a veryfavourable calcium balance might have beenestablished. In order to try and evaluate the useof phosphate therapy, balance studies have there-fore been carried out on two further patients withtype I (Dent, I952) renal tubular (hypophos-

phatoemic) rickets and osteomalacia respectively.The patient with rickets was on vitamin Dtherapy throughout in the form of I.25 mg. ofvitamin D2 twice daily. With no other therapy hewas in negative calcium balance of I00-150 mg./day with urinary calcium of about 6oo mg./day; the plasma inorganic phosphate was 2-3mg./ioo ml. Following intravenous infusions of'neutral' sodium phosphate of pH 7.4 for sixdays, the plasma inorganic phosphate rose to3.5-4.0 mg./Ioo ml., the frcal calcium was un-changed, but the calcium balance became positivedue to a fall in urinary calcium to about44o mg.,day. Following this, increasing doses of thesame phosphate mixture were given orally fori8 days during which the plasma phosphate rosesteadily to 5.4 mg./ioo ml. (plasma calciumremaining normal); the urinary calcium fell to100 mg./24 hours, but the fecal calcium rosefrom 450-750 mg./24 hours, thus achieving apositive balance of I00 mg./24 hours. It seemedfrom this study that a rise in plasma phosphatewould lower the urinary calcium, but either thisrise itself did not affect faecal calcium if the loadwas given intravenously, or else raised the fiecalcalcium if given orally. The patient with theosteomalacia was studied first with no therapywhen the frcal calcium was equal to the (normal)dietary intake and the urinary calcium about90 mg./24 hours. Following intravenous phos-phate for five days the plasma phosphate rosefrom 2.2-4.4 mg./Ioo ml. and the urinarycalcium fell to about 30 mg./24 hours. Thefiecal calcium was unaffected however so thatthe intravenous phosphate therapy alone seemedincapable of producing a positive calcium balance.In the next i2 days the plasma inorganic phos-phate was maintained at 2.9 mg./ioo ml. bygiving the phosphate load orally. There was' asmall rise in facal calcium which offset the con-tinued lowered urinary calcium. In the next i2days no phosphate supplement was given, butvitamin D3 (8 mg./day) was given. This wasfollowed by a fall in plasma inorganic phosphateback to about 2.2 mg./ioo ml. and the effect onthe calcium balance was as in periods 3 and 4 ofFig. 3, the rise in urinary calcium being slightlygreater than the fall in frecal calcium. In thenext I2 days oral phosphate therapy and thevitamin D3 were given together. The plasmainorganic phosphate rose to 4.0 mg./ioo ml.,the fiecal calcium continued to fall, but theurinary calcium now fell to I50-200 mg./24 hoursand a positive calcium balance of 400 mg. /24hours was achieved. This treatment was con-tinued as an out-patient and she made a rapidclinical recovery. These results are consistentwith the observations both of Frame and Smith

copyright. on July 9, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.461.158 on 1 March 1964. D

ownloaded from

March 1964 ROSE: The Study of Osteoporosis and Osteomalacia 163

(1958) that oral phosphate therapy increased thepositive calcium balance of a boy with vitaminD-resistant rickets who was already on vitaminD therapy, and with those of Frame, Smith,Fleming and Manson (I963) that oral phosphatealone did not improve the calcium balance of awoman with D-resistant osteomalacia. Theyshow that while phosphate therapy alone canlower the urinary calcium, this cannot replacevitamin D which is required to promote absorp-tion of dietary calcium.

SummaryRadiological evidence strongly suggests that

osteoporosis (with the possible exception of acuteimmobilization osteoporosis) may be an irrever-sible condition. The changes therefore to beexpected in calcium balance when an osteoporotic

is treated are small compared with those oftenseen in osteomalacia. Methods of obtaining moreaccurate calcium balances are needed to showthese small changes, especially when a highcalcium intake is used. The method of continuousmarking of stools with chromium sesquioxideseems to provide just such a method. Using thismethod, it has so far proved impossible to obtainprolonged large positive calcium balances inosteoporosis on either high calcium intake,anabolic hormones, or sodium fluoride.Two alternative therapies to vitamin D have

been explored for use in vitamin D-resistantosteomalacia. ATP has been found to be ineffective.Intravenous phosphate alone has been ineffectivein producing positive calcium balances, but iseffective as a complement to vitamin D undercertain conditions.

REFERENCESALBRIGHT, F., and REIFENSTEIN, E. C. (1948): The Parathyroid Glands and Metabolic Bone Disease. Baltimore: Williams

& Wilkins.ANDERSON, J. (1954): Idiopathic Osteoporosis-Symptomatic Relief by Plasma Infusions, Proc. roy. Soc. Med., 47, 509.DENT, C. E. (1952): Rickets and Osteomalacia from Renal Tubule Defects, J. Bone Jt Surg., 34B, 266.

(I955): Idiopathic Osteoporosis, Proc. roy. Soc. Med., 48, 574., and HARRIS, H. (1956): Hereditary Forms of Rickets and Osteomalacia, J. Bone Jt Surg., 38B, 204.,HARPER, C. M., and PHILPOT, G. R. (1961): The Treatment of Renal Glomerular Osteodystrophy, Quart. J.Med., 30, I.

DE TONI, E., and NORDIO, S. (1959): The Relationship Between Calcium-phosphorus Metabolism, the 'Krebs Cycle'and Steroid Metabolism, Arch. Dis. Childh., 34, 371.EKLUND, S. (1962): Medical Uses of Ca47. Technical Report Series No. io of the International Atomic Energy Agency,Vienna.FRAME, B., and SMITH, R. W. (1958): Phosphate Diabetes. A Case Study of Osteomalacia, Amer. J. Med., 25, 771.--, --, FLEMING, J. L., and MANSON, G. (1963): Oral Phosphates in Vitamin-D-refractory Rickets and

Osteomalacia, Amer. J. Dis. Child., Io6, 147.FRASER, D., JACO, N. T., YENDT, E. R., MUNN, J. D., and LIu, E. (1957): The Induction of In Vitro and In Vivo

Calcification in Bones of Children Suffering from Vitamin-D-resistant Rickets Without Recourse to Large Dosesof Vitamin-D, Ibid., 93, 84.

HARRISON, M., FRASER, R., and MULLAN, B. (I96I): Calcium Metabolism in Osteoporosis, Lancet, i, 1015.HEANEY, R. P. (1962): Radiocalcium Metabolism in Diffuse Osteoporosis in Man, Amer. J. Med., 33, i88.HENNEMAN, P. H., and WALLACH, S. (1957): Review of Prolonged Use of Estrogens and Androgens in Post-menopausaland Senile Osteoporosis, Arch. intern. Med., 100, 715.IANNACCONE, A., GABRILOVE, J. L., BRAHMS, S. A., and SOFFER, L. J. (I960): Osteoporosis in Cushing's Syndrome,Ann. intern. Med., 52, 570.LACHMAN, E. (1955): Osteoporosis: The Potentialities and Limitations of its Roentgenologic Diagnosis, Amer. J. Roent-

genol., 74, 712.Lancet (1963): Mineral or Matrix?, i, 538.LICHWITZ, A., DE SEZE, S., PAOLAGGI, J. B., LANHAM, C., HIoco, D., MIRAVET, I., and BORDIER, PH. (1962): L'osteoporoseIdiopathique de l'homme, Sem. Hop. Paris, 38, 252.LITTLE, K. (1963): Bone Resorption and Osteoporosis, Lancet, ii, 752.MARTINEZ, O. M., and GREENBLATT, R. B. (I960): The Role of Corticoids in Osteoporosis, Geriatrics, I5, 555.MCCASLIN, F. E., and JONES, J. M. (1959): The Effect of Strontium Lactate in the Treatment of Osteoporosis, Proc.

Mayo Clin., 34, 329.NICHOLAS, J. A., and WILSON, P. D. (1959): Diagnosis and Treatment of Osteoporosis, J. Amer. med. Ass., 171, 2279.NORDIN, B. E. C. (1962): Calcium Balance and Calcium Requirement in Spinal Osteoporosis, Amer. J. Clin. Nutr.,10, 384.REIFENSTEIN, E. C., and ALBRIGHT, F. (1947): The Metabolic Effect of Steroid Hormones in Osteoporosis, J. Clin.Invest., 26, 24.RICH, C., and ENSINCK, J. (I961): Effect of Sodium Fluoride on Calcium Metabolism ofHuman Beings, Nature, 191, I85.ROSE, G. A. (I964): Experiences with the Use of Interrupted Carmine Red and Continuous Chromium SesquioxideMarking of Human Fmeces with reference to Calcium, Phosphorus and Magnesium, Gut, in press.SHORR, E., and CARTER, A. C. (I952): The Usefulness of Strontium as an Adjuvant to Calcium in the Remineralizationof the Skeleton in Man, Bull. Hosp. Jt Dis. (N. Y.), 13, 59.STEENDIJK, R. (1961): The Effect of a Continuous Intravenous Infusion of Inorganic Phosphate on the Rachitic Lesions

in Cystinosis, Arch. Dis. Childh., 36, 321.WHITBY, L. G., and LANG, D. (I960): Experience with the Chromic Oxide Method of Fecal Marking in Metabolic

Balance Investigations on Humans, J. clin. Invest., 39, 854.

copyright. on July 9, 2020 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.40.461.158 on 1 March 1964. D

ownloaded from