It is a great pleasure to introduce to you 

today.

Professor Russell fraser.

Professor Russell fraser is professor of 

endocrinology and metabolism as the 

Royal postgraduate Medical school at London.

The contribution of Professor Russell fraser to 

the field of endocrinology is well known to 

most of you definitely.

He is the most outstanding endocrinologist 

of our time.

I would like to ask dr russell fraser 

now to talk to you about the 

treatment of some of the metabolic bone 

disease.

Professor fraser.

Okay.

Mhm.

It's fixed.

Goes over the end there.

That's right 

Professor Simon,

ladies and gentlemen it's a great pleasure to be 

here to talk with you at the M.

D.

Anderson Hospital.

And my subject as he's 

mentioned is the metabolic 

treatment of bone disease or the 

treatment of metabolic bone disease.

Not the metabolic treatments of 

other types of bone disease.

Nowadays we have more 

than one form of bone disease for 

which there is available and metabolic treatment 

and I'm going to refer briefly 

23 of these to 

the treatment of bone disease of a hyper parathyroid 

ism.

Now it's true that mostly the patient with hyper 

parathyroid is um comes to 

treatment at an earlier stage before there is 

severe bone disease.

Nevertheless in the old days and 

sometimes still we encounter severe bone 

disease dependent on hyper parole authorities.

Um and it can be a problem 

merely to operate and remove the parathyroid 

after which there can be quite a 

stormy convalescence unless the bone disease is 

pre treated then of course we have the 

problem of postmenopausal or it 

generate osteoporosis which is usually 

postmenopausal is still quite a 

therapeutic problem.

We have some long term follow up studies 

indicating the value of certain 

forms of treatment for this disease.

And then Paget's disease is now 

recognizably a metabolic bone disease.

Although it's patchy,

it is rather widely 

disseminated in the severe cases and 

response to metabolic treatment with either 

calcitonin or die phosphor Nate.

And I want to refer a little to this.

Most of the experience I'll be 

recording and showing you 

relates to patients in London.

But as some of you know,

I've just recently been nine months in new Zealand 

and some of the patients will come from there.

You could have the first rail 

and the slides.

That's that.

Yes.

We selected for 

patients for for the 

assessment of the treatment.

As you will see patients with 

osteoporosis.

This refers to the osteoporosis which is the most 

difficult problem.

And we've examined the effectiveness of a 

combination of a high calcium diet 

and anabolic and estrogenic 

steroids.

As you'll see in a little bit later.

That's the plan of treatment which 

we have assessed over long 

periods of time minimum of six months.

The patients selected for this trial of course had to be 

very classical osteoporotic subjects.

If we were going to assess the treatment and here 

you will see the criteria we 

had available for all of 

them.

Before making that diagnosis at least one 

pathological vertebral fracture.

That is the only final proof that they're 

very crushable bones.

Elliott crest biopsy compatible.

No evidence of Austria Malaysia,

either on bone histology or on 

biochemistry or X ray and no 

past history of these diseases.

Which might make a complicating picture.

Now that group of patients is the group 

on which we have studied the 

problem of treating osteoporosis 

in the case of 

the other two diseases.

It's more straightforward how we select the group.

The first thing I would like 

to refer to is the usefulness of small doses of 

vitamin D.

In treating hyper parathyroid bone 

disease.

And I think it could well apply to 

osteoporosis as well.

The small doses of vitamin D.

But we haven't actually assessed that by the long 

term trial that this sort of thing 

demands.

Right,

that's upside down.

Oh no.

Uh here we have an example 

of a patient presenting to us 

with bone disease of an obscure type.

And what we're looking at here is the serum calcium 

level in the normal range but serum 

phosphorus low.

And the bone disease was classically hyper 

parathyroid bone disease.

With this small dose of vitamin D.

You will see that the phosphate came up into the 

normal range or near the normal 

range.

While the calcium became 

obviously raised only after a 

prolonged period of treatment with this and 

eventually parathyroid tumor was 

removed and the patient's bone disease 

cause no problems at the time of that removal.

Next.

Please.

This type of patient of 

course is picked out as being hyper 

parathyroid bone disease very much 

by the high levels of alkaline phosphate days.

These as you'll see king armstrong 

units and a very high level 

although the serum calcium was normal and the 

serum phosphate was low.

So some patients of osteoporosis 

may of course be 

confused with the hyper parathyroid bone 

disease,

but usually the X rays are pretty characteristic.

The important thing is that the associated vitamin D.

Deficiency uh needs 

correcting to eliminate most of the bone 

disease.

And I don't need to remind you of the 

importance of the kidney 

in inducing the 

formation of the active form of vitamin 

D.

From the absorbed vitamin D.

Transformed first in the liver and how high 

calcium levels of hyper parathyroid is.

Um and perhaps the parathyroid hormone itself 

impair this production.

And that of course is how these patients get 

some vitamin D.

Deficiency unless they've got a high intake 

perhaps in this part of the country,

it's not so unusual to have a high intake 

and therefore bone disease is less common 

problem here we have 

a number of points that 

bear on this vitamin D.

Deficiency,

commonly found in hyper parrot 

primary hyper parathyroid isM.

The patients with bone disease in 

hot sunny climates 

don't tend to have much 

bone disease and it tends to occur 

anyhow in the winter and spring months in 

other parts.

And there's often a lack of correlation between the serum 

calcium level and the para thor main level especially 

in the patients with bone disease.

And then as we've just seen you can get normal 

calcium IQ hyper parathyroid ISM 

with classical X 

ray findings which may seem a bit mysterious 

unless you think of the concurrent vitamin D.

Deficiency and 

the high sensitivity of the bone uptake 

of traces is a very important diagnostic clue in 

these patients.

Here we have a bone biopsy of such a 

patient here under 

calcified bone part 

here the wide Osteo Oid seem and we should 

expect to see here the classification front 

if there was normal classification going on.

But in this patient therefore we have 

histological evidence of osteo 

Malaysia.

And here's the bone biopsy taken later 

from the same patient showing much 

thinner Osteo Oid seem lot of 

new calcium laid down.

And here you see the calcification front 

now has been restored as 

further confirmatory evidence.

Now I'd just like to illustrate with one other 

patient and we have more than one where in 

the same way there was a combination 

of normal calc mia with 

severe bone disease due to hyper parathyroid 

ISM and treatment with small doses of vitamin 

D.

Led to a very satisfactory remission 

diagnostic aspects of it deserve a little 

emphasis too of course.

Before we looked carefully it was 

a puzzle to many why she could have how she could 

have hyper parathyroid is um with a normal 

serum calcium.

Note the phosphate is low and also the 

clue from the high alkaline phosphate days 

and for that matter the high chloride 

level para thor mon essay,

as you'll see 10 times normal 

confirming the suspicion of hyper 

parathyroid is.

Um here we have 

a similar sequence of this serum 

calcium and the serum phosphate in this 

patient who incidentally received little 

phosphate in the later phase.

Along here the small doses of vitamin D.

U.

C.

Well under 1000 international units.

She had a bit more because of the severity of her disease,

bringing the calcium into the super 

normal ranges and then carrying on along 

to here as the bone disease healed and she was able to walk 

normally,

she was ready for para thyroidectomy 

here.

The alkaline phosphate is showing the striking 

remission in her bone disease and in 

the austin Malaysian aspects of it,

in parallel with what we've seen 

about serum calcium levels.

Now we made some measurements of her bone disease at the 

same time.

Here we see,

measured by a method will 

illustrate a little later the bone 

density of her ulna.

The mean density at the middle of the 

ulna from the distal to the mid shaft 

and right at the beginning here you see these two 

levels which are quite low 

conforming with her severe bone disease 

and then notice how considerable 

improvement has occurred,

Bone density approximately 

doubling during the period of 

therapy.

So not only did she lose her weakness and her 

pains and the radiological signs,

but the bone clearly became thicker,

perhaps not so easy to see here.

But we can see here the 

comparison between the I think this is the 

before vitamin D.

Therapy and here later noticed 

considerable thickening out and 

improving of the osteo 

plastic cyst here and 

of the sub curiosity a Lear asians the 

bone disease really began 

remitting And then 

finally just to conform 

uh confirm the response 

is 7.38 g of 

parathyroid tumor removed quite a sizable 

tumor uh confirming that she 

dearly did have hyper parasite is um chief cell 

adenoma and what I want to 

emphasize quite uneventful 

postoperative course after this pre 

operative drug preparation 

of her severe bone disease which 

really had become obscured because of its 

severity because of the severity of the vitamin 

D.

Deficiency.

Now,

as I've indicated 

the usefulness of vitamin D.

And that small dosage in 

correcting latent or suspect 

unsuspected vitamin D 

deficiency may be very important in other metabolic 

bone disease as well,

notably in osteoporosis can't do 

harm from over dosage and can make sure we 

don't overlook vitamin D.

Deficiency.

And furthermore as we'll see it can improve 

absorption of calcium which is an important 

thing to do in patients with 

osteoporosis 

here,

we just summarizing the aspects of 

bone disease in hyper parathyroid is 

um it's probably a feature that we 

see it all severely only when the 

patient has as well as 

hyperthyroidism,

VITAMIN D deficiency,

it's a combined its effect and 

effect of the combined disorder.

Now,

we'd like to turn to data on the treatment of 

osteoporosis.

As I mentioned,

we were rather careful to choose classical cases 

of osteoporosis who had 

had a fracture and other evidence pointing in that 

direction.

We divided these into two categories.

Typical and atypical,

The typical ones,

of course being post menopausal females or 

males over 60,

while the atypical ones had various 

other precipitating components in 

their disease,

hipaa mails or post 

pregnancy,

osteoporotic and so on.

Uh in fact the results which 

we will be showing separately 

were not different between these two groups.

Now the treatment which 

we have used,

as you will see has three components in it.

High calcium diet 

attained by giving 

supplementary calcium tablets to the 

dose of two million equivalents per kilo a day,

which means about two g of calc,

2 to 3 g of calcium per 

day,

excessive doses may of course produce 

diarrhea but that is inadequate 

dose to give high calcium intake.

Now,

one regime which we 

associated with this was 

an injection of what's really 

a testosterone depot containing 

also estradiol.

That's estrogen plus testosterone a 

small Those of estrogen lasting a 

month four mg by intravascular 

injection and 65 mg 

of the testosterone over that 

period which has the advantage of 

minimizing any hazards 

of 

bleeding from the uterus.

It is not a problem if these 

balanced steroids are used 

and also of course helping the bones a little too.

An alternative treatment 

was an anabolic steroid,

not testosterone,

which proved approximately equivalent 

in its effect,

along with the same dose of estrogen.

Those are the three treatments which we 

were comparing.

And we compared them in programs which 

were approximately six months 

for each program on the trial entry.

We first of all 

balance them,

did tests on them both on their 

home diet and and then immediately after putting onto a 

high calcium diet And then 

again after they had been on the high 

calcium intake for a period 3-6 

months,

could they sustain the effects?

And then adding one of the 

anabolic steroid programs 

whether the testosterone or the other anabolic 

steroid and estrogen and then adding 

the other one,

randomizing the order of these.

And finally coming back to the high calcium.

Only.

I should say that through 

these various regimes,

We had three main methods of 

assessment.

On the one hand,

the calcium balance.

Could we attain a positive calcium balance 

and keep it secondly,

the measurement of bone density was 

the thickness of 

the ulna bone 

uh showing improvement over the 

control procedures 

difficult to induce new 

bone to such an extent that they get thicker bone.

But was the deterioration 

in bone density that normally occurs in 

postmenopausal subjects less 

than it was without 

the program.

And then finally the incidents of fractures,

did they fracture less frequently than they had 

done before.

First of all,

the balance data that we used 

standard program with a low 

intake of calcium in the diet 

using chromium markers to make sure the 

fecal collections and 

vehicle collections and of course daily urine 

measuring as you will see particularly the calcium,

but also nitrogen and phosphorus.

Now this rather complex chat 

summarizes a series of the 

balanced data.

And if I draw your attention to the scale at the left 

here,

you will see that normal balance,

neither positive nor negative is there.

And at that situation we're looking at the 

first one of the tests when they're on 

their home intake of calcium and they're not 

having any of our treatment.

And you'll see that a large proportion of them 

were below this 

level of equal elevation.

Mostly in negative balance.

The distinction between typical and atypical 

osteoporosis is the two types of dots.

But as you'll see,

the results are equivalent.

Now.

When they go onto the high calcium diet,

they get a positive balance and here you see the mean 

levels right over to here.

When they're on a sustained high calcium intake 

all the way through to here they 

remain in a positive balance.

And when they go from merely 

having a high calcium to adding 

primordial,

there isn't much difference in 

the degree of positive balance.

And then finally,

when they come off this program 

you will see the balance is just 

neutral.

So sustaining the high calcium diet 

can be achieved over what amounts 

to approximately two years.

And then after the series of these studies 

they were randomized onto the high calcium 

only or the high calcium plus 

steroids.

To compare their bone measurements 

here we see really 

similar data relating this time 

to the net absorption of calcium.

I think you will agree that the charting here looks very 

equivalent.

Uh and it tells us 

that the previous positive balance which was 

induced had been attained by 

means of increasing the absorption of calcium not by 

altering the urinary loss.

I haven't brought the slide to show you but there 

was a similar slide showing that the urinary calcium loss 

didn't change all through.

So we have 

a little confirmatory evidence there 

that it might be useful to 

supplement this increased absorption even a bit 

further by adding the small dose of 

vitamin D.

At least it was increased absorption of calcium 

that caused the 

alteration in the calcium balance.

That of course doesn't prove that the bones were any better for 

the patient any less fracturing ble.

And now we must move to evidence about that.

This is the chart 

showing the 

data of the measurement 

of the bone 

density and I think the 

immediately following chat 

illustrates how we did it.

But we'll come back to showing you the 

method of measurement shortly.

What I draw your attention to.

Is it over this time scale of months.

Going up to a five or six year period.

With some of them.

We have measurements of 

the bone density in the forearm bone 

using it as an index and you'll see 

that the density is steadily declining as it does 

in normal subjects.

But of course it is at a lower level than normal 

subjects is steadily declining 

in the group.

When we have observed data on over 

no treatment,

neither high calcium nor the 

steroids,

this group only got the high calcium 

and you can distinguish them from these symbols here,

the hollow lines is 

slightly slower,

perhaps than the No treatment though when 

statistical measurements are checked,

it's not significantly different.

However,

when we look at those who are having the full program,

the anabolic and estrogenic steroids as well as 

the high calcium diet,

you will see that there appears to be a real improvement in 

the bone density generate.

There is not the normal expectation of a steady 

decline over the years.

And we submit that this is very important 

evidence that the osteoporotic 

bone is improving.

Now,

I'd just like to show you how the measurements were made 

here.

You'll see the patient sitting with his 

arm hanging down into 

a perspex 

vessel squared vessel containing 

water so that the 

density other than the bone is 

standardized hanging down beside his hand,

you perhaps can't appreciate.

It is a little alum in ium wedge step 

wedge,

which serves as the reference standard.

And then this is the type of picture that is 

photographed.

And here you will see the ulna bone and 

what is done when the standardized 

picture is taken.

And it was taken as you noticed on that 

previous photo with the patient some distance 

from the X ray machine and the film some 

distance from the patient's arm,

so that we didn't get scattered.

The scanner goes up the mid shaft 

here and millimeter by millimeter.

We make a comparison with the density 

standardized off this aluminum wedge 

and that enables us to get to chart as 

illustrated here the mean 

concentration of bone mineral,

although it might have been expressed in 

milligrams of aluminum per 

cubic centimeter.

It is expressed here in terms 

of calcium mineral.

And you'll see as you go 

upwards towards the mid shaft there 

steadily increasing density.

Shown in a normal subject.

That's just illustrating the method.

And 

when we were looking at the data from our 

patients,

what we looked at was the mean of all these 

values from the distal to the mid shaft and taking a mean 

figure which in this patient would be around 

here and you'll notice that that's approximately twice the 

value in that case,

in that normal subject of what our patients were 

showing.

So this is useful 

radiological check on the bone 

density.

This gives data rather closely 

similar to the Cameron machine.

As long as the details of the 

precision and steady working of either 

machine is carefully attended to.

Okay.

And as you'll see summarized here,

we feel this data 

produces strong evidence 

that the program I've 

just outlined can attain a 

positive calcium balance in the patients for 

a prolonged period of time if both 

components of the treatment are used.

And it also results 

in not only a lessening of the 

decline in bone density.

That normally happens with age 

but appears to on average 

even induce some improvement in that 

measurement.

The third criterion which we are still collecting 

data on on these subjects is 

the matter of the frequency of fractures.

I haven't shown you a slide of that because they're not 

statistically different yet.

But there are hardly any fractures in 

the patients under treatment.

And of course we're waiting to accumulate 

longer periods of time so that we can 

make a standard comparison 

with the control subjects and the subjects 

before they had the treatment.

I haven't,

as you'll note referred in any way to 

fluoride largely because we 

haven't made any measurements of the effectiveness of 

fluoride.

Though I might say we have rather strong 

instincts against trying it.

And we submit that there isn't really any 

very good evidence that it is helpful.

The only evidence available is 

histological showing the distribution of 

types of cell in the bone.

And what of course we want to know is does 

the balance between bone formation 

and bone reabsorption change as regards 

rates.

Not as regards of numbers of cells to be seen.

And it's a treatment of course 

that destroys activities of 

enzymes and can only 

be used or is only recommended 

when you are having a balancing 

dose of high dose of vitamin D.

Which seems to us not a very satisfactory 

program.

Now the third metabolic bone 

disease that we encounter 

uh and of course which is a very common bone 

disease pageants 

one which now 

and for many decades has been thought of as a 

metabolic bone disease because of its 

although because it is patchy we may 

not suspect that 

this seems to be true of course of many metabolic 

bone diseases.

Here we have a typical subject 

with the bones 

showing their softness and collapsing 

and being the subject of fracture.

And of course the patients getting quite 

a lot of bone pain.

Uh it is 

now well 

established that this can be influenced both by 

calcitonin and by di phosphate.

And I'd like to discuss a little bit some of our 

results with this.

Uh here you can 

recognize the dry radiate 

pelvis and the 

excessive of course 

enlargement of the bone typical of pageants of that 

patient better to 

treat them.

Of course,

a bit earlier rather than at the 

stage that lady had reached.

An important component.

Of course in treating Paget's disease 

is to assess whether the pain 

that the patient is apt to 

come to the doctor about really is bone pain 

because quite often they do get joint pain 

and the pain may have nothing to do with their bones.

Even if they've got Paget's disease.

And I think we're all familiar with these various 

criteria as able 

to indicate that the bone is 

characteristically bone the pain is 

characteristically.

Bone pain will shortly see 

some assessments made of the effectiveness of the 

treatments on bone pain in these 

patients.

And when we have been assessing it 

that way subjective though it may be it has 

related of course,

to bone pain.

But we're fortunate in this disease and having 

other criteria which are biochemical 

and which can enable us to 

assess the progress or changes in the bone disease,

the serum alkaline phosphates.

Here we have a bunch of patients with Paget's disease 

and you will recognize 

that these are all 

raised the level.

These are international units in this slide and 

these are new Zealand patients here we have the 

acid phosphate days.

Also abnormal.

Though not so useful because 

the values are so much lower.

It's sufficient to look at the alkaline fast for days.

The urinary hydroxy polling is another very good 

criterion.

Both of them,

of course reflectors of rapid 

bone turnover and we'll look at 

the results of treatment in the 

respect of both these gray.

Both these biochemical route area as well as pain.

Just remind you that they do really 

correlate when you compare these two 

indices when measured on the same subject.

It is of course the case 

that the amount of the skeleton 

involved,

maybe quite small in perhaps the majority of 

the patients.

But sometimes it really does go up to a 

very high percentage.

These are assessments made 

off skeletal surveys 

and showing the extensiveness of the 

bone involvement in some subjects.

And of course just remind you the 

commonness of different sites,

the pelvis and the Femara 

being the most common of course.

Uh So all these other sites 

being quite reasonably frequent.

Till you come to the bottom of the list though no 

area apparently being quite immune.

Well,

calcitonin of course,

whose molecule is illustrated here 

is available as 

porcine calcitonin,

as salmon calcitonin and as human calcitonin.

And here you see in red,

the number of mono acids that 

differ between human and 

porcine and of course there are 

differences also between human and salmon.

And on General Principles one would feel 

that the human one is the better one to 

use.

Perhaps mostly because of the 

greater likelihood of 

antibody problems when using 

other than human,

which is of course synthetically produced 

human.

The all of them 

seem to produce a little bit of side effect 

flushing but perhaps that's not 

too serious.

Here we are seeing a comparison in the potency 

between three micrograms of human 

and 10 times as much of 

porcine and you'll see that even with 

this tenfold advantage,

the porcine doesn't drop the plasma 

calcium as much.

On the other hand,

when we compare the same dose of human with a 

10th of that dose of salmon.

You will see that we get a bigger effect and a more 

lasting effect from the salmon,

it is of course possible to use 

salmon On a three times a week 

basis or even twice a week 

basis,

whereas the others are 

usually necessary daily injections 

If one wants to get a good dividend.

Yeah.

Now some of the evidences of effect 

Bone uptake of calcium,

45 bone 

turnover is a good index to 

look at.

And here we're looking at a subject who 

had a normal left leg and 

had Paget's disease in the right 

tibia.

And we're looking first of all at 

the uptake before any treatment 

and then three months after the treatment with 

calcitonin.

Human calcitonin.

And you see the drop towards the normal,

not influencing the situation in the left 

leg,

but strikingly in the bone disease.

And of course,

even feeling the temperature shows the 

same effect,

it does seem to slow down the turnover.

And here we have a young boy 

with not blue psychotics who 

had a disease very like Paget's disease in 

his early youth,

uh characterized by very high 

levels of alkaline phosphate and many 

fractures of the bones came for treatment at the 

age of five,

as far as we were concerned.

And you will see the drop in his alkaline 

phosphate days with his first three months of 

treatment.

And you'll see here is urinary 

hydroxy pralines during the 

calcitonin.

Also dropping down into the upper 

normal ranges.

And here an example of his 

X rays showing 

the typical findings 

are Paget's disease.

Or very similar findings to those of 

pageants disease,

irregular uh 

widening and speculation up and 

down the shaft.

And then by now,

after I think only five months we see 

a considerable remodeling has occurred and the 

bone is much nearer to 

our ideas of normal,

though of course,

only a little way in that direction.

We have in London been looking 

more extensively at the changes in X 

rays on these patients or 

also on bone scans 

and do find we 

can record improvement in the 

bone scans though it needs fairly complex 

analysis of the bone scans to establish it.

One has to standardize the 

density of the uptake against a soft 

tissue area and watch for the 

changes in this ratio.

It is of course much more difficult to get 

changes in the X ray 

recognizable than in the biochemical 

parameters though it is 

evident that you can show these.

Now I thought we should have 

seen a slide showing the drop in the 

hydroxy praline and in the alkaline 

phosphates.

But we may have missed that by mistake.

Now,

I'd like to turn over to 

looking at di phosphate 

and while we're doing that,

we'll also see a little bit of effect of 

calcitonin in comparison.

This undoubtedly is an effective agent 

on many of the features 

of Paget's disease,

but it is not without 

hazard.

The major hazard being the 

liability to induce osteo 

Malaysia or Western perhaps.

And he asked in Malaysia present and 

thereby produce a risk of 

fracture.

An increased risk of fracture is undoubtedly one of its 

hazards.

And I think studies still progressing 

trying to define whether associated 

vitamin D.

Or more reduced dosage 

can eliminate this.

Here we have some 

data comparing the 

patients as regards the pain 

and other clinical criteria,

but it's mostly the pain 

during patients who 

for six months,

as you will see received a therapy and for six 

months were observed following it.

It was randomized as you'll see between taking 

placebo first and taking di 

phosphate first.

I think you'll recognize that there isn't really very much 

difference in the change of the pain.

one has to be very careful in using pain 

to assess changes in bone disease.

However,

here we have another page.

Another slide main 

again,

assessed in terms of the pain of the disease 

or rather the improvement in it.

Notice that the dotted line representing 

calcitonin shows,

I think a much brisker improvement and more 

extensive improvement in the period of 

taking the therapy following which 

the patient breaks away from control 

much quicker.

Whereas if you look at the diff oxygenates,

they'd have some improvement during the therapy 

and even towards the end,

I would begin a little bit to decline with the new 

pain really of the austin 

Malaysia,

but it stays much more effectively 

afterwards.

It has a much more prolonged effect 

and perhaps some combination of the two 

might be a useful way for long term 

management.

Mhm.

Uh here we're looking at biochemical parameters 

this time,

hydroxy prowling as an index of the 

turnover and the controls of course 

show very little change.

Calcitonin.

Here was porcine calcitonin and there 

was indeed an improvement,

though not as effective as we might have liked 

and a remission.

But look at the bisphosphonates.

It produces a striking effect and it 

retains it for quite a long time afterwards.

That's really,

if you like the same chat.

This time we're looking at the alkaline phosphate days 

and the same groups of patients.

Now,

finally,

I would like just 

to show you 

a little data about some of the 

cardiovascular effects.

One of the features of 

severe Paget's disease,

which was recognized a good many years ago 

by Dr Harris in 

London is that they may 

have heart failure of a 

hipaa dynamic type.

And amongst a group of patients 

studied in Auckland.

This set of data with cardiac 

index,

namely the cardiac output measurement on the 

dye procedure um 

measured pre 

treatment in these subjects.

And notice reading it by age against this 

normal range,

A very large proportion of them 

have abnormal 

high cardiac index outputs 

and of course in this age 

range where Paget's disease is common.

This can be an important handicap 

and here you see one of the patients 

showing perhaps the more striking effects 

in terms of cardiac volume 

here perhaps rather dilated heart.

But here a strikingly changed 

heart in this respect.

There has been noted in their 

measurements,

an improvement in those patients who have 

abnormal cardiac indexes 

when the pageant is under control.

As you will see,

it's quite possible to control Paget's 

disease by for a while or many of the 

manifestations of it by the 

use of either of these drugs.

But perhaps the perfect 

treatment hasn't yet been evolved.

We have the injection 

disadvantage in 

calcitonin but we do seem to be able 

to bring all 

degrees of active pageants under control with 

it.

And in the case of the dye phosphor Nate,

we unfortunately have the hazard 

of inducing Austria Malaysia,

which may be something that can be controlled by 

the supplementary vitamin D.

Or by alternating the treatment with 

calcitonin.

And we're looking into these 

aspects of it in London and 

Auckland and elsewhere.

And I hope that will become 

clarified later.

But it is a very important thing for the patient 

with Paget's disease that 

some metabolic treatment is now 

available for this.

Rather common and rather disabling 

disease.

Thank you.

Yeah.

Mhm.

Thank you very much