WEBVTT

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*This machine-generated transcript may have errors. If remediation or a manually-generated transcript is needed, please contact NLM Support at https://support.nlm.nih.gov.*

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It is a great pleasure to introduce to you

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today.

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Professor Russell fraser.

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Professor Russell fraser is professor of

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endocrinology and metabolism as the

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Royal postgraduate Medical school at London.

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The contribution of Professor Russell fraser to

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the field of endocrinology is well known to

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most of you definitely.

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He is the most outstanding endocrinologist

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of our time.

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I would like to ask dr russell fraser

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now to talk to you about the

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treatment of some of the metabolic bone

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disease.

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Professor fraser.

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Okay.

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Mhm.

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It's fixed.

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Goes over the end there.

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That's right

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Professor Simon,

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ladies and gentlemen it's a great pleasure to be

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here to talk with you at the M.

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D.

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Anderson Hospital.

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And my subject as he's

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mentioned is the metabolic

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treatment of bone disease or the

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treatment of metabolic bone disease.

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Not the metabolic treatments of

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other types of bone disease.

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Nowadays we have more

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than one form of bone disease for

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which there is available and metabolic treatment

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and I'm going to refer briefly

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23 of these to

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the treatment of bone disease of a hyper parathyroid

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ism.

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Now it's true that mostly the patient with hyper

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parathyroid is um comes to

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treatment at an earlier stage before there is

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severe bone disease.

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Nevertheless in the old days and

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sometimes still we encounter severe bone

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disease dependent on hyper parole authorities.

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Um and it can be a problem

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merely to operate and remove the parathyroid

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after which there can be quite a

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stormy convalescence unless the bone disease is

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pre treated then of course we have the

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problem of postmenopausal or it

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generate osteoporosis which is usually

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postmenopausal is still quite a

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therapeutic problem.

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We have some long term follow up studies

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indicating the value of certain

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forms of treatment for this disease.

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And then Paget's disease is now

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recognizably a metabolic bone disease.

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Although it's patchy,

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it is rather widely

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disseminated in the severe cases and

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response to metabolic treatment with either

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calcitonin or die phosphor Nate.

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And I want to refer a little to this.

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Most of the experience I'll be

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recording and showing you

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relates to patients in London.

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But as some of you know,

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I've just recently been nine months in new Zealand

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and some of the patients will come from there.

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You could have the first rail

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and the slides.

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That's that.

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Yes.

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We selected for

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patients for for the

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assessment of the treatment.

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As you will see patients with

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osteoporosis.

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This refers to the osteoporosis which is the most

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difficult problem.

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And we've examined the effectiveness of a

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combination of a high calcium diet

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and anabolic and estrogenic

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steroids.

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As you'll see in a little bit later.

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That's the plan of treatment which

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we have assessed over long

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periods of time minimum of six months.

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The patients selected for this trial of course had to be

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very classical osteoporotic subjects.

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If we were going to assess the treatment and here

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you will see the criteria we

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had available for all of

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them.

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Before making that diagnosis at least one

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pathological vertebral fracture.

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That is the only final proof that they're

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very crushable bones.

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Elliott crest biopsy compatible.

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No evidence of Austria Malaysia,

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either on bone histology or on

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biochemistry or X ray and no

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past history of these diseases.

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Which might make a complicating picture.

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Now that group of patients is the group

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on which we have studied the

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problem of treating osteoporosis

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in the case of

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the other two diseases.

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It's more straightforward how we select the group.

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The first thing I would like

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to refer to is the usefulness of small doses of

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vitamin D.

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In treating hyper parathyroid bone

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disease.

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And I think it could well apply to

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osteoporosis as well.

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The small doses of vitamin D.

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But we haven't actually assessed that by the long

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term trial that this sort of thing

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demands.

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Right,

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that's upside down.

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Oh no.

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Uh here we have an example

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of a patient presenting to us

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with bone disease of an obscure type.

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

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level in the normal range but serum

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phosphorus low.

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And the bone disease was classically hyper

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parathyroid bone disease.

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With this small dose of vitamin D.

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You will see that the phosphate came up into the

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normal range or near the normal

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range.

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While the calcium became

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obviously raised only after a

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prolonged period of treatment with this and

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eventually parathyroid tumor was

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removed and the patient's bone disease

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cause no problems at the time of that removal.

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Next.

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Please.

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This type of patient of

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course is picked out as being hyper

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parathyroid bone disease very much

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by the high levels of alkaline phosphate days.

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These as you'll see king armstrong

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units and a very high level

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although the serum calcium was normal and the

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serum phosphate was low.

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So some patients of osteoporosis

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may of course be

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confused with the hyper parathyroid bone

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disease,

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but usually the X rays are pretty characteristic.

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The important thing is that the associated vitamin D.

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Deficiency uh needs

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correcting to eliminate most of the bone

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disease.

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And I don't need to remind you of the

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importance of the kidney

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in inducing the

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formation of the active form of vitamin

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D.

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From the absorbed vitamin D.

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Transformed first in the liver and how high

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calcium levels of hyper parathyroid is.

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Um and perhaps the parathyroid hormone itself

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impair this production.

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And that of course is how these patients get

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some vitamin D.

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Deficiency unless they've got a high intake

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perhaps in this part of the country,

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it's not so unusual to have a high intake

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and therefore bone disease is less common

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problem here we have

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a number of points that

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bear on this vitamin D.

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Deficiency,

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commonly found in hyper parrot

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primary hyper parathyroid isM.

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The patients with bone disease in

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hot sunny climates

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don't tend to have much

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bone disease and it tends to occur

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anyhow in the winter and spring months in

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other parts.

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

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calcium level and the para thor main level especially

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in the patients with bone disease.

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

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calcium IQ hyper parathyroid ISM

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with classical X

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ray findings which may seem a bit mysterious

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unless you think of the concurrent vitamin D.

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Deficiency and

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the high sensitivity of the bone uptake

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of traces is a very important diagnostic clue in

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these patients.

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Here we have a bone biopsy of such a

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patient here under

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calcified bone part

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here the wide Osteo Oid seem and we should

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expect to see here the classification front

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if there was normal classification going on.

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But in this patient therefore we have

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histological evidence of osteo

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Malaysia.

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And here's the bone biopsy taken later

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from the same patient showing much

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thinner Osteo Oid seem lot of

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new calcium laid down.

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And here you see the calcification front

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now has been restored as

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further confirmatory evidence.

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Now I'd just like to illustrate with one other

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patient and we have more than one where in

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the same way there was a combination

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of normal calc mia with

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severe bone disease due to hyper parathyroid

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ISM and treatment with small doses of vitamin

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D.

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Led to a very satisfactory remission

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diagnostic aspects of it deserve a little

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emphasis too of course.

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Before we looked carefully it was

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a puzzle to many why she could have how she could

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have hyper parathyroid is um with a normal

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serum calcium.

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Note the phosphate is low and also the

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clue from the high alkaline phosphate days

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and for that matter the high chloride

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level para thor mon essay,

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as you'll see 10 times normal

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confirming the suspicion of hyper

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parathyroid is.

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Um here we have

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a similar sequence of this serum

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calcium and the serum phosphate in this

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patient who incidentally received little

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phosphate in the later phase.

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Along here the small doses of vitamin D.

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U.

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C.

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Well under 1000 international units.

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

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bringing the calcium into the super

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normal ranges and then carrying on along

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

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normally,

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she was ready for para thyroidectomy

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here.

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The alkaline phosphate is showing the striking

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remission in her bone disease and in

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the austin Malaysian aspects of it,

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in parallel with what we've seen

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about serum calcium levels.

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Now we made some measurements of her bone disease at the

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same time.

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Here we see,

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measured by a method will

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illustrate a little later the bone

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density of her ulna.

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The mean density at the middle of the

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ulna from the distal to the mid shaft

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and right at the beginning here you see these two

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levels which are quite low

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conforming with her severe bone disease

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and then notice how considerable

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improvement has occurred,

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Bone density approximately

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doubling during the period of

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therapy.

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So not only did she lose her weakness and her

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pains and the radiological signs,

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but the bone clearly became thicker,

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perhaps not so easy to see here.

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But we can see here the

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comparison between the I think this is the

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before vitamin D.

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Therapy and here later noticed

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considerable thickening out and

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improving of the osteo

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plastic cyst here and

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of the sub curiosity a Lear asians the

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bone disease really began

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remitting And then

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finally just to conform

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uh confirm the response

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is 7.38 g of

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parathyroid tumor removed quite a sizable

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tumor uh confirming that she

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dearly did have hyper parasite is um chief cell

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adenoma and what I want to

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emphasize quite uneventful

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postoperative course after this pre

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operative drug preparation

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of her severe bone disease which

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really had become obscured because of its

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severity because of the severity of the vitamin

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D.

13:29.180 --> 13:29.900
Deficiency.

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Now,

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as I've indicated

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the usefulness of vitamin D.

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And that small dosage in

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correcting latent or suspect

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unsuspected vitamin D

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deficiency may be very important in other metabolic

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bone disease as well,

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notably in osteoporosis can't do

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harm from over dosage and can make sure we

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don't overlook vitamin D.

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Deficiency.

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And furthermore as we'll see it can improve

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absorption of calcium which is an important

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thing to do in patients with

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osteoporosis

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here,

14:11.150 --> 14:13.950
we just summarizing the aspects of

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bone disease in hyper parathyroid is

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um it's probably a feature that we

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see it all severely only when the

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patient has as well as

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hyperthyroidism,

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VITAMIN D deficiency,

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it's a combined its effect and

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effect of the combined disorder.

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Now,

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

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osteoporosis.

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As I mentioned,

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we were rather careful to choose classical cases

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of osteoporosis who had

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had a fracture and other evidence pointing in that

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direction.

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We divided these into two categories.

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Typical and atypical,

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The typical ones,

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of course being post menopausal females or

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males over 60,

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while the atypical ones had various

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other precipitating components in

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their disease,

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hipaa mails or post

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pregnancy,

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osteoporotic and so on.

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Uh in fact the results which

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we will be showing separately

15:25.100 --> 15:27.650
were not different between these two groups.

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Now the treatment which

15:35.790 --> 15:37.260
we have used,

15:37.260 --> 15:39.860
as you will see has three components in it.

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High calcium diet

15:43.150 --> 15:45.530
attained by giving

15:45.660 --> 15:48.640
supplementary calcium tablets to the

15:48.640 --> 15:51.330
dose of two million equivalents per kilo a day,

15:52.240 --> 15:54.610
which means about two g of calc,

15:54.610 --> 15:57.120
2 to 3 g of calcium per

15:57.120 --> 15:57.650
day,

15:59.040 --> 16:01.300
excessive doses may of course produce

16:01.300 --> 16:04.050
diarrhea but that is inadequate

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dose to give high calcium intake.

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Now,

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one regime which we

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associated with this was

16:13.030 --> 16:15.970
an injection of what's really

16:15.970 --> 16:18.800
a testosterone depot containing

16:18.810 --> 16:20.000
also estradiol.

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That's estrogen plus testosterone a

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small Those of estrogen lasting a

16:25.470 --> 16:27.910
month four mg by intravascular

16:27.910 --> 16:30.690
injection and 65 mg

16:30.700 --> 16:33.260
of the testosterone over that

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period which has the advantage of

16:35.710 --> 16:38.060
minimizing any hazards

16:38.290 --> 16:39.260
of

16:40.840 --> 16:42.880
bleeding from the uterus.

16:43.220 --> 16:45.420
It is not a problem if these

16:45.430 --> 16:47.970
balanced steroids are used

16:49.260 --> 16:51.860
and also of course helping the bones a little too.

16:52.340 --> 16:54.620
An alternative treatment

16:54.850 --> 16:57.380
was an anabolic steroid,

16:57.380 --> 16:58.530
not testosterone,

16:58.940 --> 17:01.070
which proved approximately equivalent

17:01.840 --> 17:03.070
in its effect,

17:03.440 --> 17:06.050
along with the same dose of estrogen.

17:06.840 --> 17:09.820
Those are the three treatments which we

17:09.820 --> 17:10.760
were comparing.

17:12.040 --> 17:15.030
And we compared them in programs which

17:15.030 --> 17:17.860
were approximately six months

17:17.870 --> 17:20.350
for each program on the trial entry.

17:20.740 --> 17:22.220
We first of all

17:23.640 --> 17:24.500
balance them,

17:24.510 --> 17:27.450
did tests on them both on their

17:27.450 --> 17:30.360
home diet and and then immediately after putting onto a

17:30.360 --> 17:33.350
high calcium diet And then

17:33.350 --> 17:35.930
again after they had been on the high

17:35.930 --> 17:38.390
calcium intake for a period 3-6

17:38.390 --> 17:38.950
months,

17:39.260 --> 17:40.960
could they sustain the effects?

17:41.740 --> 17:44.510
And then adding one of the

17:44.510 --> 17:47.320
anabolic steroid programs

17:47.640 --> 17:50.210
whether the testosterone or the other anabolic

17:50.210 --> 17:53.180
steroid and estrogen and then adding

17:53.180 --> 17:53.880
the other one,

17:53.890 --> 17:55.690
randomizing the order of these.

17:55.960 --> 17:58.800
And finally coming back to the high calcium.

17:58.800 --> 17:59.200
Only.

18:00.440 --> 18:03.190
I should say that through

18:03.190 --> 18:04.850
these various regimes,

18:05.240 --> 18:07.920
We had three main methods of

18:07.920 --> 18:08.610
assessment.

18:08.670 --> 18:09.950
On the one hand,

18:10.200 --> 18:11.490
the calcium balance.

18:11.590 --> 18:13.950
Could we attain a positive calcium balance

18:14.740 --> 18:17.670
and keep it secondly,

18:18.340 --> 18:20.570
the measurement of bone density was

18:20.570 --> 18:23.460
the thickness of

18:23.470 --> 18:24.960
the ulna bone

18:25.440 --> 18:28.210
uh showing improvement over the

18:28.210 --> 18:29.930
control procedures

18:31.140 --> 18:33.810
difficult to induce new

18:33.810 --> 18:36.770
bone to such an extent that they get thicker bone.

18:36.780 --> 18:39.690
But was the deterioration

18:39.690 --> 18:42.230
in bone density that normally occurs in

18:42.230 --> 18:45.080
postmenopausal subjects less

18:45.090 --> 18:48.050
than it was without

18:48.060 --> 18:48.760
the program.

18:49.740 --> 18:52.490
And then finally the incidents of fractures,

18:52.730 --> 18:55.730
did they fracture less frequently than they had

18:55.730 --> 18:56.460
done before.

19:00.840 --> 19:01.510
First of all,

19:01.510 --> 19:04.140
the balance data that we used

19:04.150 --> 19:06.960
standard program with a low

19:07.840 --> 19:10.440
intake of calcium in the diet

19:10.940 --> 19:13.520
using chromium markers to make sure the

19:13.520 --> 19:16.210
fecal collections and

19:16.220 --> 19:18.620
vehicle collections and of course daily urine

19:18.940 --> 19:21.480
measuring as you will see particularly the calcium,

19:21.480 --> 19:24.360
but also nitrogen and phosphorus.

19:26.440 --> 19:28.450
Now this rather complex chat

19:28.840 --> 19:31.460
summarizes a series of the

19:31.460 --> 19:32.460
balanced data.

19:32.940 --> 19:35.720
And if I draw your attention to the scale at the left

19:35.720 --> 19:36.150
here,

19:36.380 --> 19:38.260
you will see that normal balance,

19:38.270 --> 19:40.460
neither positive nor negative is there.

19:41.140 --> 19:44.030
And at that situation we're looking at the

19:44.030 --> 19:46.900
first one of the tests when they're on

19:46.900 --> 19:49.720
their home intake of calcium and they're not

19:49.720 --> 19:51.460
having any of our treatment.

19:51.940 --> 19:54.540
And you'll see that a large proportion of them

19:54.550 --> 19:56.750
were below this

19:56.760 --> 19:59.460
level of equal elevation.

20:00.010 --> 20:01.780
Mostly in negative balance.

20:02.340 --> 20:04.670
The distinction between typical and atypical

20:04.670 --> 20:07.540
osteoporosis is the two types of dots.

20:07.860 --> 20:08.590
But as you'll see,

20:08.590 --> 20:10.050
the results are equivalent.

20:10.840 --> 20:11.260
Now.

20:11.260 --> 20:13.850
When they go onto the high calcium diet,

20:13.850 --> 20:16.570
they get a positive balance and here you see the mean

20:16.570 --> 20:18.800
levels right over to here.

20:18.810 --> 20:21.680
When they're on a sustained high calcium intake

20:21.690 --> 20:24.230
all the way through to here they

20:24.240 --> 20:26.460
remain in a positive balance.

20:27.240 --> 20:30.180
And when they go from merely

20:30.180 --> 20:32.640
having a high calcium to adding

20:32.640 --> 20:33.360
primordial,

20:33.940 --> 20:36.380
there isn't much difference in

20:36.380 --> 20:38.770
the degree of positive balance.

20:39.720 --> 20:40.730
And then finally,

20:40.740 --> 20:43.320
when they come off this program

20:43.390 --> 20:45.970
you will see the balance is just

20:45.980 --> 20:46.690
neutral.

20:46.700 --> 20:49.450
So sustaining the high calcium diet

20:49.940 --> 20:52.910
can be achieved over what amounts

20:52.910 --> 20:54.520
to approximately two years.

20:54.580 --> 20:57.480
And then after the series of these studies

20:57.510 --> 21:00.420
they were randomized onto the high calcium

21:00.430 --> 21:02.660
only or the high calcium plus

21:02.660 --> 21:03.600
steroids.

21:03.610 --> 21:05.860
To compare their bone measurements

21:09.740 --> 21:12.360
here we see really

21:13.640 --> 21:16.060
similar data relating this time

21:16.540 --> 21:18.550
to the net absorption of calcium.

21:19.230 --> 21:22.190
I think you will agree that the charting here looks very

21:22.190 --> 21:22.860
equivalent.

21:23.640 --> 21:26.290
Uh and it tells us

21:26.520 --> 21:29.040
that the previous positive balance which was

21:29.040 --> 21:32.040
induced had been attained by

21:32.040 --> 21:34.790
means of increasing the absorption of calcium not by

21:34.790 --> 21:36.410
altering the urinary loss.

21:36.840 --> 21:39.670
I haven't brought the slide to show you but there

21:39.670 --> 21:42.650
was a similar slide showing that the urinary calcium loss

21:42.650 --> 21:44.060
didn't change all through.

21:45.140 --> 21:47.560
So we have

21:48.940 --> 21:51.320
a little confirmatory evidence there

21:51.790 --> 21:54.340
that it might be useful to

21:54.340 --> 21:56.930
supplement this increased absorption even a bit

21:56.930 --> 21:59.800
further by adding the small dose of

21:59.800 --> 22:00.560
vitamin D.

22:01.220 --> 22:04.050
At least it was increased absorption of calcium

22:04.360 --> 22:07.220
that caused the

22:07.220 --> 22:09.310
alteration in the calcium balance.

22:10.140 --> 22:13.130
That of course doesn't prove that the bones were any better for

22:13.130 --> 22:15.450
the patient any less fracturing ble.

22:16.240 --> 22:19.060
And now we must move to evidence about that.

22:20.240 --> 22:21.980
This is the chart

22:22.370 --> 22:24.350
showing the

22:24.830 --> 22:27.310
data of the measurement

22:27.320 --> 22:30.220
of the bone

22:30.220 --> 22:32.960
density and I think the

22:32.960 --> 22:34.800
immediately following chat

22:35.540 --> 22:37.130
illustrates how we did it.

22:37.490 --> 22:40.440
But we'll come back to showing you the

22:40.440 --> 22:41.930
method of measurement shortly.

22:42.010 --> 22:44.110
What I draw your attention to.

22:44.180 --> 22:47.030
Is it over this time scale of months.

22:47.030 --> 22:49.070
Going up to a five or six year period.

22:49.070 --> 22:49.850
With some of them.

22:50.340 --> 22:53.000
We have measurements of

22:53.000 --> 22:55.810
the bone density in the forearm bone

22:55.810 --> 22:58.730
using it as an index and you'll see

22:58.980 --> 23:01.940
that the density is steadily declining as it does

23:01.940 --> 23:03.050
in normal subjects.

23:03.680 --> 23:06.570
But of course it is at a lower level than normal

23:06.570 --> 23:09.330
subjects is steadily declining

23:09.340 --> 23:10.300
in the group.

23:10.320 --> 23:13.200
When we have observed data on over

23:13.210 --> 23:14.110
no treatment,

23:14.110 --> 23:16.750
neither high calcium nor the

23:16.760 --> 23:17.560
steroids,

23:18.340 --> 23:20.770
this group only got the high calcium

23:21.220 --> 23:23.960
and you can distinguish them from these symbols here,

23:24.840 --> 23:27.560
the hollow lines is

23:27.560 --> 23:30.140
slightly slower,

23:30.140 --> 23:32.620
perhaps than the No treatment though when

23:32.620 --> 23:34.850
statistical measurements are checked,

23:34.860 --> 23:36.560
it's not significantly different.

23:37.340 --> 23:37.950
However,

23:37.960 --> 23:40.460
when we look at those who are having the full program,

23:41.000 --> 23:43.950
the anabolic and estrogenic steroids as well as

23:43.950 --> 23:45.200
the high calcium diet,

23:45.640 --> 23:48.580
you will see that there appears to be a real improvement in

23:48.580 --> 23:50.690
the bone density generate.

23:50.810 --> 23:53.760
There is not the normal expectation of a steady

23:53.760 --> 23:55.460
decline over the years.

23:55.940 --> 23:58.600
And we submit that this is very important

23:58.600 --> 24:01.480
evidence that the osteoporotic

24:01.480 --> 24:03.170
bone is improving.

24:05.040 --> 24:05.430
Now,

24:05.430 --> 24:08.360
I'd just like to show you how the measurements were made

24:08.940 --> 24:09.210
here.

24:09.210 --> 24:11.800
You'll see the patient sitting with his

24:11.810 --> 24:14.090
arm hanging down into

24:14.090 --> 24:16.030
a perspex

24:16.640 --> 24:19.290
vessel squared vessel containing

24:19.290 --> 24:21.260
water so that the

24:21.840 --> 24:24.740
density other than the bone is

24:24.740 --> 24:27.740
standardized hanging down beside his hand,

24:27.740 --> 24:29.000
you perhaps can't appreciate.

24:29.000 --> 24:31.850
It is a little alum in ium wedge step

24:31.850 --> 24:32.300
wedge,

24:32.510 --> 24:34.950
which serves as the reference standard.

24:38.030 --> 24:40.450
And then this is the type of picture that is

24:40.460 --> 24:41.500
photographed.

24:42.140 --> 24:44.960
And here you will see the ulna bone and

24:44.960 --> 24:47.740
what is done when the standardized

24:47.750 --> 24:48.950
picture is taken.

24:49.740 --> 24:52.650
And it was taken as you noticed on that

24:52.660 --> 24:55.490
previous photo with the patient some distance

24:55.490 --> 24:58.320
from the X ray machine and the film some

24:58.320 --> 25:00.260
distance from the patient's arm,

25:00.270 --> 25:01.800
so that we didn't get scattered.

25:03.540 --> 25:06.000
The scanner goes up the mid shaft

25:06.000 --> 25:08.420
here and millimeter by millimeter.

25:08.450 --> 25:10.860
We make a comparison with the density

25:10.880 --> 25:13.460
standardized off this aluminum wedge

25:13.840 --> 25:16.370
and that enables us to get to chart as

25:16.370 --> 25:19.090
illustrated here the mean

25:19.100 --> 25:20.970
concentration of bone mineral,

25:20.980 --> 25:23.490
although it might have been expressed in

25:23.500 --> 25:25.430
milligrams of aluminum per

25:25.440 --> 25:27.320
cubic centimeter.

25:27.410 --> 25:29.900
It is expressed here in terms

25:30.020 --> 25:31.960
of calcium mineral.

25:32.940 --> 25:35.720
And you'll see as you go

25:35.730 --> 25:38.030
upwards towards the mid shaft there

25:38.030 --> 25:40.190
steadily increasing density.

25:40.200 --> 25:42.380
Shown in a normal subject.

25:42.390 --> 25:44.460
That's just illustrating the method.

25:47.110 --> 25:47.950
And

25:50.140 --> 25:52.590
when we were looking at the data from our

25:52.590 --> 25:53.300
patients,

25:53.320 --> 25:55.920
what we looked at was the mean of all these

25:55.920 --> 25:58.770
values from the distal to the mid shaft and taking a mean

25:58.770 --> 26:01.280
figure which in this patient would be around

26:01.280 --> 26:04.180
here and you'll notice that that's approximately twice the

26:04.180 --> 26:05.880
value in that case,

26:06.160 --> 26:09.140
in that normal subject of what our patients were

26:09.140 --> 26:09.670
showing.

26:10.440 --> 26:13.190
So this is useful

26:13.190 --> 26:15.980
radiological check on the bone

26:15.990 --> 26:16.860
density.

26:18.140 --> 26:20.990
This gives data rather closely

26:20.990 --> 26:23.200
similar to the Cameron machine.

26:23.230 --> 26:25.930
As long as the details of the

26:25.930 --> 26:28.480
precision and steady working of either

26:28.480 --> 26:31.160
machine is carefully attended to.

26:31.640 --> 26:31.850
Okay.

26:34.140 --> 26:36.320
And as you'll see summarized here,

26:36.600 --> 26:39.510
we feel this data

26:39.610 --> 26:42.270
produces strong evidence

26:42.640 --> 26:45.420
that the program I've

26:45.420 --> 26:48.160
just outlined can attain a

26:48.170 --> 26:51.110
positive calcium balance in the patients for

26:51.110 --> 26:54.110
a prolonged period of time if both

26:54.110 --> 26:56.260
components of the treatment are used.

26:57.240 --> 26:59.870
And it also results

26:59.870 --> 27:02.860
in not only a lessening of the

27:02.860 --> 27:04.680
decline in bone density.

27:04.750 --> 27:06.980
That normally happens with age

27:07.000 --> 27:09.770
but appears to on average

27:09.780 --> 27:12.270
even induce some improvement in that

27:12.270 --> 27:12.860
measurement.

27:13.910 --> 27:16.880
The third criterion which we are still collecting

27:16.880 --> 27:19.680
data on on these subjects is

27:19.910 --> 27:22.070
the matter of the frequency of fractures.

27:22.420 --> 27:25.170
I haven't shown you a slide of that because they're not

27:25.170 --> 27:26.560
statistically different yet.

27:27.040 --> 27:29.940
But there are hardly any fractures in

27:29.940 --> 27:31.580
the patients under treatment.

27:32.040 --> 27:34.800
And of course we're waiting to accumulate

27:34.800 --> 27:37.570
longer periods of time so that we can

27:37.570 --> 27:40.500
make a standard comparison

27:40.500 --> 27:43.320
with the control subjects and the subjects

27:43.320 --> 27:45.770
before they had the treatment.

27:47.940 --> 27:48.450
I haven't,

27:48.450 --> 27:50.660
as you'll note referred in any way to

27:50.750 --> 27:53.570
fluoride largely because we

27:53.570 --> 27:56.280
haven't made any measurements of the effectiveness of

27:56.280 --> 27:56.910
fluoride.

27:58.400 --> 28:00.850
Though I might say we have rather strong

28:00.850 --> 28:02.900
instincts against trying it.

28:03.540 --> 28:06.490
And we submit that there isn't really any

28:06.490 --> 28:08.980
very good evidence that it is helpful.

28:09.350 --> 28:12.110
The only evidence available is

28:12.110 --> 28:14.790
histological showing the distribution of

28:14.790 --> 28:16.350
types of cell in the bone.

28:16.940 --> 28:19.860
And what of course we want to know is does

28:19.860 --> 28:22.720
the balance between bone formation

28:22.720 --> 28:25.560
and bone reabsorption change as regards

28:25.560 --> 28:26.100
rates.

28:26.460 --> 28:29.270
Not as regards of numbers of cells to be seen.

28:30.040 --> 28:31.520
And it's a treatment of course

28:31.790 --> 28:34.470
that destroys activities of

28:34.470 --> 28:36.750
enzymes and can only

28:36.910 --> 28:39.410
be used or is only recommended

28:39.420 --> 28:41.950
when you are having a balancing

28:42.400 --> 28:45.200
dose of high dose of vitamin D.

28:45.330 --> 28:48.010
Which seems to us not a very satisfactory

28:48.010 --> 28:48.670
program.

28:52.320 --> 28:55.060
Now the third metabolic bone

28:55.060 --> 28:56.900
disease that we encounter

28:57.550 --> 29:00.210
uh and of course which is a very common bone

29:00.210 --> 29:01.410
disease pageants

29:03.030 --> 29:05.670
one which now

29:06.840 --> 29:09.760
and for many decades has been thought of as a

29:09.760 --> 29:12.340
metabolic bone disease because of its

29:12.350 --> 29:15.260
although because it is patchy we may

29:15.300 --> 29:17.460
not suspect that

29:17.840 --> 29:20.830
this seems to be true of course of many metabolic

29:20.830 --> 29:21.770
bone diseases.

29:24.740 --> 29:26.700
Here we have a typical subject

29:27.110 --> 29:30.090
with the bones

29:30.580 --> 29:32.760
showing their softness and collapsing

29:33.240 --> 29:35.360
and being the subject of fracture.

29:35.840 --> 29:38.840
And of course the patients getting quite

29:38.840 --> 29:40.240
a lot of bone pain.

29:41.030 --> 29:43.220
Uh it is

29:43.230 --> 29:45.270
now well

29:45.650 --> 29:48.550
established that this can be influenced both by

29:48.550 --> 29:51.170
calcitonin and by di phosphate.

29:51.820 --> 29:54.580
And I'd like to discuss a little bit some of our

29:54.580 --> 29:55.590
results with this.

29:57.740 --> 29:59.590
Uh here you can

29:59.600 --> 30:02.430
recognize the dry radiate

30:02.430 --> 30:03.940
pelvis and the

30:03.950 --> 30:06.650
excessive of course

30:07.170 --> 30:10.000
enlargement of the bone typical of pageants of that

30:10.010 --> 30:12.880
patient better to

30:12.880 --> 30:13.390
treat them.

30:13.390 --> 30:13.940
Of course,

30:13.940 --> 30:16.790
a bit earlier rather than at the

30:16.790 --> 30:18.520
stage that lady had reached.

30:19.840 --> 30:21.340
An important component.

30:21.340 --> 30:23.710
Of course in treating Paget's disease

30:24.080 --> 30:26.990
is to assess whether the pain

30:27.170 --> 30:29.860
that the patient is apt to

30:31.240 --> 30:34.140
come to the doctor about really is bone pain

30:34.140 --> 30:36.970
because quite often they do get joint pain

30:37.250 --> 30:39.880
and the pain may have nothing to do with their bones.

30:40.060 --> 30:42.160
Even if they've got Paget's disease.

30:42.540 --> 30:45.390
And I think we're all familiar with these various

30:45.390 --> 30:48.190
criteria as able

30:48.190 --> 30:50.770
to indicate that the bone is

30:50.770 --> 30:53.640
characteristically bone the pain is

30:53.640 --> 30:54.430
characteristically.

30:54.430 --> 30:57.310
Bone pain will shortly see

30:57.310 --> 31:00.290
some assessments made of the effectiveness of the

31:00.290 --> 31:03.060
treatments on bone pain in these

31:03.060 --> 31:03.600
patients.

31:04.240 --> 31:07.210
And when we have been assessing it

31:07.210 --> 31:10.040
that way subjective though it may be it has

31:10.040 --> 31:10.740
related of course,

31:10.740 --> 31:11.670
to bone pain.

31:13.640 --> 31:16.490
But we're fortunate in this disease and having

31:16.500 --> 31:19.350
other criteria which are biochemical

31:19.410 --> 31:21.990
and which can enable us to

31:21.990 --> 31:24.920
assess the progress or changes in the bone disease,

31:25.250 --> 31:26.930
the serum alkaline phosphates.

31:26.930 --> 31:29.660
Here we have a bunch of patients with Paget's disease

31:30.040 --> 31:31.790
and you will recognize

31:32.340 --> 31:35.000
that these are all

31:35.170 --> 31:36.830
raised the level.

31:36.830 --> 31:39.770
These are international units in this slide and

31:39.770 --> 31:42.710
these are new Zealand patients here we have the

31:42.710 --> 31:43.790
acid phosphate days.

31:43.790 --> 31:44.850
Also abnormal.

31:45.080 --> 31:47.970
Though not so useful because

31:47.970 --> 31:49.420
the values are so much lower.

31:50.140 --> 31:52.690
It's sufficient to look at the alkaline fast for days.

31:53.100 --> 31:55.840
The urinary hydroxy polling is another very good

31:55.840 --> 31:56.530
criterion.

31:56.530 --> 31:57.030
Both of them,

31:57.030 --> 31:59.620
of course reflectors of rapid

31:59.630 --> 32:02.500
bone turnover and we'll look at

32:02.510 --> 32:05.140
the results of treatment in the

32:05.140 --> 32:07.640
respect of both these gray.

32:07.640 --> 32:10.350
Both these biochemical route area as well as pain.

32:10.940 --> 32:13.250
Just remind you that they do really

32:13.420 --> 32:16.150
correlate when you compare these two

32:16.150 --> 32:19.060
indices when measured on the same subject.

32:22.240 --> 32:24.170
It is of course the case

32:24.170 --> 32:26.820
that the amount of the skeleton

32:26.820 --> 32:27.460
involved,

32:27.940 --> 32:30.880
maybe quite small in perhaps the majority of

32:30.880 --> 32:31.560
the patients.

32:31.720 --> 32:34.490
But sometimes it really does go up to a

32:34.490 --> 32:35.940
very high percentage.

32:35.940 --> 32:38.100
These are assessments made

32:38.100 --> 32:40.810
off skeletal surveys

32:41.150 --> 32:43.950
and showing the extensiveness of the

32:43.950 --> 32:45.980
bone involvement in some subjects.

32:47.940 --> 32:50.890
And of course just remind you the

32:50.890 --> 32:53.200
commonness of different sites,

32:53.210 --> 32:56.180
the pelvis and the Femara

32:56.190 --> 32:58.350
being the most common of course.

32:58.740 --> 33:01.070
Uh So all these other sites

33:01.080 --> 33:03.920
being quite reasonably frequent.

33:03.920 --> 33:06.640
Till you come to the bottom of the list though no

33:06.640 --> 33:09.560
area apparently being quite immune.

33:12.940 --> 33:13.310
Well,

33:13.310 --> 33:14.930
calcitonin of course,

33:15.110 --> 33:17.770
whose molecule is illustrated here

33:18.140 --> 33:20.550
is available as

33:20.550 --> 33:22.090
porcine calcitonin,

33:22.090 --> 33:25.060
as salmon calcitonin and as human calcitonin.

33:25.830 --> 33:27.940
And here you see in red,

33:27.940 --> 33:30.730
the number of mono acids that

33:30.730 --> 33:33.190
differ between human and

33:33.190 --> 33:35.450
porcine and of course there are

33:35.450 --> 33:38.360
differences also between human and salmon.

33:39.140 --> 33:41.830
And on General Principles one would feel

33:42.180 --> 33:44.760
that the human one is the better one to

33:44.760 --> 33:45.350
use.

33:45.840 --> 33:48.560
Perhaps mostly because of the

33:48.940 --> 33:51.910
greater likelihood of

33:51.910 --> 33:54.890
antibody problems when using

33:54.900 --> 33:55.950
other than human,

33:56.120 --> 33:58.820
which is of course synthetically produced

33:58.820 --> 33:59.270
human.

34:00.940 --> 34:03.750
The all of them

34:03.750 --> 34:06.250
seem to produce a little bit of side effect

34:06.250 --> 34:09.180
flushing but perhaps that's not

34:09.180 --> 34:10.020
too serious.

34:10.740 --> 34:13.670
Here we are seeing a comparison in the potency

34:13.670 --> 34:16.560
between three micrograms of human

34:16.940 --> 34:19.470
and 10 times as much of

34:19.470 --> 34:22.370
porcine and you'll see that even with

34:22.370 --> 34:24.220
this tenfold advantage,

34:24.300 --> 34:27.280
the porcine doesn't drop the plasma

34:27.290 --> 34:29.060
calcium as much.

34:31.040 --> 34:31.980
On the other hand,

34:31.980 --> 34:34.700
when we compare the same dose of human with a

34:34.700 --> 34:37.540
10th of that dose of salmon.

34:37.890 --> 34:40.410
You will see that we get a bigger effect and a more

34:40.410 --> 34:42.060
lasting effect from the salmon,

34:43.040 --> 34:45.710
it is of course possible to use

34:45.710 --> 34:48.050
salmon On a three times a week

34:48.050 --> 34:50.820
basis or even twice a week

34:50.830 --> 34:51.420
basis,

34:52.040 --> 34:54.730
whereas the others are

34:54.730 --> 34:57.630
usually necessary daily injections

34:58.440 --> 35:00.360
If one wants to get a good dividend.

35:02.640 --> 35:02.820
Yeah.

35:03.640 --> 35:05.860
Now some of the evidences of effect

35:06.440 --> 35:08.530
Bone uptake of calcium,

35:08.530 --> 35:10.830
45 bone

35:10.830 --> 35:13.710
turnover is a good index to

35:13.710 --> 35:14.190
look at.

35:14.190 --> 35:16.960
And here we're looking at a subject who

35:16.960 --> 35:19.400
had a normal left leg and

35:19.400 --> 35:22.190
had Paget's disease in the right

35:22.200 --> 35:22.640
tibia.

35:23.240 --> 35:26.130
And we're looking first of all at

35:26.140 --> 35:29.040
the uptake before any treatment

35:29.100 --> 35:31.420
and then three months after the treatment with

35:31.420 --> 35:32.190
calcitonin.

35:32.190 --> 35:33.330
Human calcitonin.

35:33.520 --> 35:35.840
And you see the drop towards the normal,

35:36.170 --> 35:38.970
not influencing the situation in the left

35:38.970 --> 35:39.620
leg,

35:39.630 --> 35:42.450
but strikingly in the bone disease.

35:42.460 --> 35:43.010
And of course,

35:43.010 --> 35:45.760
even feeling the temperature shows the

35:45.760 --> 35:46.640
same effect,

35:46.990 --> 35:49.360
it does seem to slow down the turnover.

35:50.240 --> 35:52.090
And here we have a young boy

35:52.090 --> 35:55.060
with not blue psychotics who

35:55.060 --> 35:57.920
had a disease very like Paget's disease in

35:57.920 --> 35:59.060
his early youth,

35:59.540 --> 36:02.360
uh characterized by very high

36:02.360 --> 36:05.220
levels of alkaline phosphate and many

36:05.220 --> 36:08.140
fractures of the bones came for treatment at the

36:08.140 --> 36:09.100
age of five,

36:09.110 --> 36:10.550
as far as we were concerned.

36:11.030 --> 36:13.850
And you will see the drop in his alkaline

36:13.850 --> 36:16.810
phosphate days with his first three months of

36:16.810 --> 36:17.450
treatment.

36:19.230 --> 36:21.740
And you'll see here is urinary

36:21.740 --> 36:23.890
hydroxy pralines during the

36:23.890 --> 36:24.830
calcitonin.

36:25.000 --> 36:27.820
Also dropping down into the upper

36:27.820 --> 36:28.950
normal ranges.

36:31.120 --> 36:33.970
And here an example of his

36:34.260 --> 36:36.790
X rays showing

36:36.790 --> 36:39.650
the typical findings

36:39.650 --> 36:41.350
are Paget's disease.

36:41.350 --> 36:44.220
Or very similar findings to those of

36:44.220 --> 36:45.130
pageants disease,

36:45.130 --> 36:47.390
irregular uh

36:47.400 --> 36:50.270
widening and speculation up and

36:50.270 --> 36:51.250
down the shaft.

36:53.930 --> 36:55.690
And then by now,

36:55.700 --> 36:58.660
after I think only five months we see

36:58.660 --> 37:01.630
a considerable remodeling has occurred and the

37:01.630 --> 37:04.630
bone is much nearer to

37:04.630 --> 37:05.980
our ideas of normal,

37:06.050 --> 37:06.760
though of course,

37:06.770 --> 37:08.450
only a little way in that direction.

37:09.130 --> 37:11.860
We have in London been looking

37:12.070 --> 37:14.960
more extensively at the changes in X

37:14.960 --> 37:17.410
rays on these patients or

37:17.420 --> 37:19.710
also on bone scans

37:20.310 --> 37:23.280
and do find we

37:23.280 --> 37:26.170
can record improvement in the

37:26.180 --> 37:28.660
bone scans though it needs fairly complex

37:28.660 --> 37:31.620
analysis of the bone scans to establish it.

37:32.130 --> 37:34.670
One has to standardize the

37:34.740 --> 37:37.710
density of the uptake against a soft

37:37.710 --> 37:40.350
tissue area and watch for the

37:40.350 --> 37:42.050
changes in this ratio.

37:43.130 --> 37:45.570
It is of course much more difficult to get

37:45.580 --> 37:47.290
changes in the X ray

37:47.300 --> 37:49.910
recognizable than in the biochemical

37:49.910 --> 37:52.810
parameters though it is

37:52.840 --> 37:54.950
evident that you can show these.

37:58.230 --> 38:00.970
Now I thought we should have

38:00.970 --> 38:03.070
seen a slide showing the drop in the

38:03.070 --> 38:06.070
hydroxy praline and in the alkaline

38:06.070 --> 38:06.810
phosphates.

38:06.810 --> 38:08.840
But we may have missed that by mistake.

38:09.710 --> 38:09.990
Now,

38:09.990 --> 38:12.810
I'd like to turn over to

38:12.810 --> 38:14.950
looking at di phosphate

38:15.620 --> 38:16.910
and while we're doing that,

38:16.910 --> 38:19.270
we'll also see a little bit of effect of

38:19.280 --> 38:21.530
calcitonin in comparison.

38:22.620 --> 38:25.600
This undoubtedly is an effective agent

38:25.870 --> 38:28.450
on many of the features

38:28.460 --> 38:30.330
of Paget's disease,

38:30.630 --> 38:33.470
but it is not without

38:33.470 --> 38:34.030
hazard.

38:34.620 --> 38:37.420
The major hazard being the

38:37.420 --> 38:39.740
liability to induce osteo

38:39.740 --> 38:42.740
Malaysia or Western perhaps.

38:43.120 --> 38:46.110
And he asked in Malaysia present and

38:46.110 --> 38:48.450
thereby produce a risk of

38:48.450 --> 38:49.180
fracture.

38:49.190 --> 38:52.040
An increased risk of fracture is undoubtedly one of its

38:52.040 --> 38:52.640
hazards.

38:52.680 --> 38:55.420
And I think studies still progressing

38:55.430 --> 38:58.420
trying to define whether associated

38:58.420 --> 38:59.230
vitamin D.

38:59.240 --> 39:01.960
Or more reduced dosage

39:01.970 --> 39:03.340
can eliminate this.

39:05.320 --> 39:08.070
Here we have some

39:08.070 --> 39:10.260
data comparing the

39:10.270 --> 39:12.560
patients as regards the pain

39:14.920 --> 39:17.270
and other clinical criteria,

39:17.270 --> 39:18.660
but it's mostly the pain

39:19.290 --> 39:22.040
during patients who

39:22.420 --> 39:23.500
for six months,

39:23.510 --> 39:26.220
as you will see received a therapy and for six

39:26.220 --> 39:28.140
months were observed following it.

39:28.720 --> 39:31.330
It was randomized as you'll see between taking

39:31.330 --> 39:33.680
placebo first and taking di

39:33.680 --> 39:34.870
phosphate first.

39:35.400 --> 39:38.350
I think you'll recognize that there isn't really very much

39:38.350 --> 39:40.030
difference in the change of the pain.

39:40.620 --> 39:43.530
one has to be very careful in using pain

39:44.010 --> 39:46.590
to assess changes in bone disease.

39:51.020 --> 39:51.700
However,

39:51.710 --> 39:53.070
here we have another page.

39:53.080 --> 39:55.940
Another slide main

39:55.950 --> 39:56.650
again,

39:56.660 --> 39:59.480
assessed in terms of the pain of the disease

39:59.490 --> 40:01.260
or rather the improvement in it.

40:02.110 --> 40:04.530
Notice that the dotted line representing

40:04.530 --> 40:06.170
calcitonin shows,

40:06.170 --> 40:09.120
I think a much brisker improvement and more

40:09.120 --> 40:11.990
extensive improvement in the period of

40:11.990 --> 40:14.230
taking the therapy following which

40:14.350 --> 40:17.330
the patient breaks away from control

40:17.340 --> 40:18.130
much quicker.

40:18.710 --> 40:20.890
Whereas if you look at the diff oxygenates,

40:21.120 --> 40:23.630
they'd have some improvement during the therapy

40:24.010 --> 40:25.250
and even towards the end,

40:25.250 --> 40:28.120
I would begin a little bit to decline with the new

40:28.120 --> 40:30.610
pain really of the austin

40:30.610 --> 40:31.390
Malaysia,

40:31.400 --> 40:34.050
but it stays much more effectively

40:34.050 --> 40:34.670
afterwards.

40:34.670 --> 40:36.940
It has a much more prolonged effect

40:37.410 --> 40:40.330
and perhaps some combination of the two

40:40.540 --> 40:43.420
might be a useful way for long term

40:43.420 --> 40:44.030
management.

40:45.510 --> 40:45.930
Mhm.

40:46.810 --> 40:49.620
Uh here we're looking at biochemical parameters

40:49.620 --> 40:50.280
this time,

40:50.330 --> 40:52.820
hydroxy prowling as an index of the

40:52.820 --> 40:55.790
turnover and the controls of course

40:55.790 --> 40:57.140
show very little change.

40:57.610 --> 40:58.520
Calcitonin.

40:58.520 --> 41:01.450
Here was porcine calcitonin and there

41:01.450 --> 41:02.790
was indeed an improvement,

41:02.790 --> 41:05.520
though not as effective as we might have liked

41:05.970 --> 41:07.470
and a remission.

41:08.210 --> 41:10.140
But look at the bisphosphonates.

41:10.150 --> 41:13.150
It produces a striking effect and it

41:13.150 --> 41:15.440
retains it for quite a long time afterwards.

41:19.110 --> 41:20.350
That's really,

41:20.350 --> 41:21.720
if you like the same chat.

41:21.970 --> 41:24.740
This time we're looking at the alkaline phosphate days

41:25.080 --> 41:27.030
and the same groups of patients.

41:29.310 --> 41:30.010
Now,

41:30.010 --> 41:30.760
finally,

41:30.770 --> 41:33.330
I would like just

41:33.340 --> 41:36.330
to show you

41:36.710 --> 41:38.720
a little data about some of the

41:38.720 --> 41:40.270
cardiovascular effects.

41:40.810 --> 41:43.050
One of the features of

41:43.050 --> 41:44.910
severe Paget's disease,

41:44.910 --> 41:47.700
which was recognized a good many years ago

41:47.700 --> 41:50.450
by Dr Harris in

41:50.460 --> 41:52.850
London is that they may

41:52.850 --> 41:55.840
have heart failure of a

41:55.850 --> 41:57.730
hipaa dynamic type.

42:00.000 --> 42:02.230
And amongst a group of patients

42:02.760 --> 42:04.320
studied in Auckland.

42:04.760 --> 42:07.670
This set of data with cardiac

42:07.670 --> 42:08.430
index,

42:08.920 --> 42:11.820
namely the cardiac output measurement on the

42:11.830 --> 42:13.930
dye procedure um

42:14.420 --> 42:16.820
measured pre

42:16.820 --> 42:18.620
treatment in these subjects.

42:18.870 --> 42:21.680
And notice reading it by age against this

42:21.680 --> 42:22.680
normal range,

42:22.830 --> 42:25.010
A very large proportion of them

42:25.020 --> 42:27.570
have abnormal

42:27.570 --> 42:30.060
high cardiac index outputs

42:31.100 --> 42:34.040
and of course in this age

42:34.040 --> 42:36.200
range where Paget's disease is common.

42:37.210 --> 42:39.320
This can be an important handicap

42:41.300 --> 42:44.110
and here you see one of the patients

42:44.120 --> 42:47.020
showing perhaps the more striking effects

42:47.500 --> 42:49.580
in terms of cardiac volume

42:49.730 --> 42:52.300
here perhaps rather dilated heart.

42:52.540 --> 42:55.420
But here a strikingly changed

42:55.420 --> 42:56.920
heart in this respect.

42:57.400 --> 42:59.970
There has been noted in their

42:59.980 --> 43:00.600
measurements,

43:01.280 --> 43:03.720
an improvement in those patients who have

43:04.200 --> 43:06.340
abnormal cardiac indexes

43:07.430 --> 43:09.730
when the pageant is under control.

43:11.500 --> 43:12.520
As you will see,

43:12.520 --> 43:15.350
it's quite possible to control Paget's

43:15.350 --> 43:18.190
disease by for a while or many of the

43:18.190 --> 43:21.010
manifestations of it by the

43:21.010 --> 43:23.620
use of either of these drugs.

43:24.430 --> 43:27.020
But perhaps the perfect

43:27.030 --> 43:29.820
treatment hasn't yet been evolved.

43:30.500 --> 43:32.970
We have the injection

43:33.060 --> 43:35.140
disadvantage in

43:35.140 --> 43:37.800
calcitonin but we do seem to be able

43:37.800 --> 43:39.920
to bring all

43:40.120 --> 43:43.090
degrees of active pageants under control with

43:43.090 --> 43:43.330
it.

43:44.500 --> 43:47.020
And in the case of the dye phosphor Nate,

43:47.400 --> 43:50.010
we unfortunately have the hazard

43:50.400 --> 43:53.010
of inducing Austria Malaysia,

43:54.180 --> 43:57.170
which may be something that can be controlled by

43:57.170 --> 43:59.230
the supplementary vitamin D.

43:59.700 --> 44:02.330
Or by alternating the treatment with

44:02.340 --> 44:03.190
calcitonin.

44:03.240 --> 44:05.900
And we're looking into these

44:05.900 --> 44:08.360
aspects of it in London and

44:08.370 --> 44:09.950
Auckland and elsewhere.

44:10.360 --> 44:12.910
And I hope that will become

44:12.910 --> 44:14.050
clarified later.

44:14.190 --> 44:16.900
But it is a very important thing for the patient

44:16.910 --> 44:19.730
with Paget's disease that

44:19.880 --> 44:22.330
some metabolic treatment is now

44:22.330 --> 44:24.060
available for this.

44:24.070 --> 44:26.720
Rather common and rather disabling

44:26.720 --> 44:27.300
disease.

44:28.090 --> 44:28.600
Thank you.

44:30.990 --> 44:31.380
Yeah.

44:33.090 --> 44:33.490
Mhm.

44:39.190 --> 44:40.110
Thank you very much