This is Mayo Clinic Docs, a curated

weekly podcast for physicians

and health care providers.

I'm your host, Darrell Chukotka, a

general internist at the Mayo Clinic

in Rochester, Minnesota.

Musculoskeletal pain is extremely

common, especially as our patients

become older.

Those of us who have a primary care

practice commonly see patients

with tenderness, injury or

inflammation, meniscal terrors

and osteoarthritis.

Unfortunately, our treatment options

have been limited and may include

watchful waiting, hoping for

improvement.

Anti-inflammatory medications,

steroid injections or

physical therapy

when severe.

Some patients benefit from joint

replacements.

However, until our patient reaches

the time to consider joint

replacement, our efforts to

help our patients often leave much

to be desired.

A relatively new treatment approach

has appeared in the past decade

musculoskeletal and regenerative

medicine.

But does the research back up

the numerous claims of benefit?

We're going to get the true current

and future potential of regenerative

medicine for musculoskeletal

problems from Dr. Shane Shapiro,

a sports medicine physician in the

Department of Orthopedics at the

Mayo Clinic.

Shane, welcome.

Thank you. Thank you for having me.

Well, let's talk about this

interesting problem

in musculoskeletal medicine.

What challenges do you see

for the current standard of care

medical approaches that?

May not completely address

our patients care.

Well, you certainly highlighted part

of that in your introduction there

very nicely.

Most of what we're treating on a

regular basis are chronic

degenerative conditions.

A great example of the challenge

in in treating those chronic

degenerate conditions like

take

osteoarthritis, for example, is

that our initial management of

knee arthritis

symptoms utilizes

that conservatives care that

you mentioned and those treatments

are actually quite good.

But the long term efficacy of those

treatments is somewhat poor.

And so things

like NSAIDs,

physical therapy, steroid

injections, they can

become ineffective

over time and then in

late stage arthritis.

As you mentioned, arthroplasty may

be considered for patients with

severe pain and disability,

and these surgeries also have

excellent outcomes.

However, a treatment gap exists

for those patients that do have

symptomatic knee arthritis

that are unresponsive

to

conservative care, but not yet

ready to undergo

or not an appropriate candidate for

more invasive surgical procedures

like arthroplasty.

And as a result, millions

of patients may linger

in what we're

calling the arthritis

treatment gap, which

that treatment gap can extend

20 years through the majority

of the younger osteoarthritis

patients adult life.

So if you do develop symptoms

in your early

40s, you could spend

decades with those symptoms until

you're a more appropriate candidate

for arthroplasty.

And this protracted

period will include debilitating

pain, reduced quality

of life and significant financial

burden sometimes, too.

So as a result, there's a great

need for safe, effective

and cost effective treatment options

for patients

with moderate to

severe osteoarthritis

and something that will

enjoy high patient

acceptance. That's that's what we're

on the hunt for.

Yeah, as you mentioned, it's those

patients with the moderate severity

of problems. That's the issue.

You know, we've got the and my

practice has been mostly middle aged

men and arthritis

of the hip and the knee.

We've got non-steroidal which,

you know, I hate using long term.

They have so many potential adverse

effects. You know, steroid

injections work for a limited amount

of time and some.

But until they're ready for a joint

replacement, I mean, these are age

related changes that they

just are going to be with them for

years.

Well, what

what types of

regenerative products or therapies

are you currently using?

So you can optimize these patient

outcomes.

So we'd like to consider this broad

class of everything that we're

working on in regenerative medicine

as regenerative therapies, but not

all regenerative therapies

truly regenerate tissue.

Some of them are going to treat the

symptoms and

manage pain while hopefully

improving that quality of life.

And so in order

to optimize the patient's care.

We're talking about what we like to

now call first generation

Ortho Biologics.

So the use of biologically active

agents

for orthopedic disease

platelet rich

plasma was our first experience

with an injectable treatment made

from the patient's own cells.

And we originally

trialled this to treat tendon

off of these like lateral

epic delights.

And we

have over 15 years of experience

with this product and have now been

able to adapt formulations

of PRP to be used

intra

articulately to treat

osteoarthritis.

And so

there are now over 10 randomized

controlled trials conducted over

the last decade,

providing

evidence that PRP does improve

the symptoms of osteoarthritis

and in a superior fashion to

some of those

conservative standard

of care treatments by

comparison.

So we make

PRP from centrifugation

of of whole blood.

We're able to separate out

the major components of that blood

and isolate the platelet

fraction, which contains

a large quantity of the body's

growth factors.

And as

enthusiasm for stem cells

grew, we began

to hypothesize that we

could perform a similar process

to bone marrow,

which would not

only isolate the same

desirable growth factors that

the platelet rich plasma

has, but now also a

cellular layer that contains

the additional therapeutic

potential of

the stem cell. Now that was some

years ago that we hypothesized

that and our understanding

of that product, which we

now call

black or bone marrow

aspiration and concentration.

Our understanding has evolved, and

most of us in the field think

this is just a heterogeneous

product consisting of

numerous biologically active

molecules, but

fortunately precious few actual

stem cells.

So the studies have not yet been

able to elucidate whether or not

the stem cell

as has been popularized, whether

or not that's the true therapeutic

agent in

Barmak, or whether it's

just this whole therapeutic

soup

of growth

factors, so to speak,

that provides

the patient with a more favorable

environment in the

degenerated joint.

And finally, there's some slightly

newer procedures

that also involved minimal

manipulation of a patient's

own fat tissue to

create an injectable

therapeutic, which

has also

demonstrated some nice outcomes

in managing arthritic pain

and also even some early success

in rotator cuff disorders.

So, you know, those

three products

made from blood, one made from bone

marrow and then one made from the

patient's own fat.

These are the foundational products

of our novel Ortho

Biologic

Toolkit, but

we still have a long way to go

to to be utilizing these

on a regular basis.

There's still much that we have to

learn about them.

Mm-Hmm.

Well, I would say the majority

of patients that I

have with

these joint pain have osteoarthritis

and often of the knee and

they're often most interested in.

They have questions for me about

stem cell injections

for knee osteoarthritis.

They've heard of, heard of it being

available. They may have had friends

who have had it.

Do we have good evidence that

this benefits patients?

Well, the

evidence is growing, I think is the

fairest way to put it.

And what we have evidence

for is the safety of this

product. The patient's own bone

marrow harvested in in,

concentrated and returned back

in the need to try and improve

the environment inside the knee.

And good clinical trials

have been performed.

We conducted one of those trials

at Mayo Clinic Florida campus

and we like our outcomes.

We had a nice responder rate

of over about 75 percent

and patients did very

well for

a year or sometimes two years.

And a number of my patients,

even five years down the road, are

still doing quite well with that

product.

Still very small number of

patients. And we we haven't really

yet had the opportunity to stratify

patients on the severity

of their disease.

And so you and I mentioned

that. Treatment gap for younger

patients with osteoarthritis

and when they osteoarthritis is

mild to moderate, most conservative

treatment options are going to work

reasonably well, whether it is

conventional standard of care or

whether it's

a stem

cell injection.

And, you know, and

that means almost any

treatment that we

choose, we should

be able to help them with with their

symptoms.

And then as we mentioned, four

more severe cases, you're going to

start talking to patients about

knee replacement surgery.

But for patients that don't

want that

and yet still have severe disease,

that's really

where we

still have not yet

been able to truly

realize the

potential

to regenerate

cartilage. Yet in a severely

arthritic disease,

so patients

know they have

joint tissues that have

deteriorated, that includes

cartilage and bone deterioration.

And when that happens, their desire

and reasonably so is to find

a way to reverse this

and regrow

the degenerated cartilage.

It's unfortunately a way too

simplistic biologic

approach, and we just can't do

that yet. STEM cells can't do that

yet.

So utilizing any

medical therapy, let alone

stem cell stem cell therapy,

is only going to provide symptom

management at best

for a defined period of time right

now.

And definitive management are

what we would call a cure

for osteoarthritis in severe

cases still requires a joint

replacement surgery.

So this is the unfortunate nature

of arthritic disease once it's

reached a certain severity.

But one of the conversations we have

with patients, and I'm sure you

can relate to this is, well,

there are a lot of diseases that we

are able to manage chronically

over time without surgery.

And the big examples that I use

for our patients are conditions like

hypertension and hyperlipidemia,

both of

which we don't

cure those either, and oftentimes

have

to

Medicaid patients with

a pill

that will lower the

cholesterol or lower the blood

pressure. And then most patients

don't think they have high blood

pressure anymore.

But of course, you take that

antihypertensive away from the

patients and up goes the blood

pressure again.

Osteoarthritis can really be the

same way we can create

therapeutic partnerships with our

patients to manage their symptoms.

Sometimes with standard of care,

sometimes with regenerative

therapies, and patients can really

do well for quite a long time

once they're recognizing

that we are doing

something

to to manage

the condition, even if we haven't

yet been able to reverse it or cure

it.

And I think, as you said, most

of the patients who are looking at

these procedures are older patients

and they're used to chronic disease.

As you mentioned, hypertension,

hyperlipidemia, osteoporosis.

So they're not used to cures.

They are very comfortable with

management. So I think they

understand this.

Now you mentioned safety a little

while ago.

I've had a fair number

of patients who have had either

platelet rich plasma injections or

stem cell injections.

I don't recall any who have had

any complications from that.

I suppose you're injecting,

you know, if you're putting a needle

in a joint space with the potential

for infection is always there.

But are there adverse effects

to these procedures that patients

could experience?

Well, that's a great question, and,

you know, we certainly think that

sell products that are manufactured

and processed in an appropriate

manner.

As you have mentioned, they appear

overwhelmingly safe.

You know, from from the patient

returned back to the patient.

We're not seeing

much in the way of complications

from those

procedures like PRP or

like back.

And where we are

seeing problems is on

occasion with applications of

cell therapy outside

a practitioner's particular area of

expertise or possibly

utilizing products

that haven't been packaged,

transported, preserved or

even

approved in the

appropriate manner.

And so there are numerous

reports and in both the

press, as well as the scientific

literature of real harm

that has come to patients from

inappropriately performed stem cell

procedures. And in our orthopedic

practice, we have had to treat

some patients who've had infections

as a result of a contaminated

stem cell product.

Really devastating

consequences.

So it's important

to recognize that the cell

therapies are considered drugs and

thus under the regulatory purview

of the Food and Drug Administration.

And there's a process by which

the FDA approves novel

biologic therapies.

And no off the shelf

stem cell products have yet

been approved for use in this

country to treat orthopedic

conditions. So the only approvals

are stem cells to be used in stem

cell transplants to

treat hematologic

malignancies.

Now, contrast that

with what we are now using those

first generation worth of biologic

therapies.

These are

cell therapies manufactured from

patient's own cells

and

tissues that are minimally

processed and in most

cases, just concentrated and

then given directly

back to the patient

within

the same procedure encounter.

And so those same patient,

same procedure therapies,

those are

allowed by the FDA under

the practice of medicine and have

overwhelmingly been shown to be

safe for patients to treat

orthopedic conditions.

Mm-Hmm.

You know, I've seen multiple

ads for small

clinics that do nothing but

inject PRP,

a stem cell

for almost any type of

musculoskeletal pain.

Are they?

Are they legitimate?

Are they ahead of the research

in terms of what they're doing?

What have they done harm to

the to the reputation of

true musculoskeletal regenerative

medicine?

Well, I don't know if it's

actually harming the reputation of

musculoskeletal regenerative

medicine as much as it is making

it more challenging for patients

to find good solutions to their

orthopedic problems.

We want to

be able to discuss

validated regenerative therapies

with patients.

The platform driving not only

the hope, but also the hype of

regenerative medicine is the stem

cell. And my biggest concern

with

the explosion

of the popularity of stem cells

is the number of practices

that now offer treatments, sometimes

for conditions

that haven't been

validated by clinical science just

yet. And as a result,

there is a significant amount

of misinformation that can be

circulating around the field about

what stem cells can do and what they

can't do when it comes to treating

orthopedic conditions.

So that's really where

counseling patients appropriately

about the reality of

their condition and also

the validity of the scientific

validity of treatments that we have

available to us

right now in 2020 2021.

That's what

makes

those counseling

discussions so important.

Well, what do you see for the

future? What's on the horizon

for regenerative medicine in

musculoskeletal disease?

Well, you know, as

I mentioned,

we are just starting to scratch

the surface with these what

we're calling the first generation

Ortho Biologics, and

we're already looking to how

we can improve upon them.

Mayo Clinic and Mayo Clinic Center

for Regenerative Medicine is heavily

invested in advancing the science

of not only bio

manufacturing of cells

at a large scale, but also in

getting the next

generation of therapies

into clinical trials so that we can

test them.

And one terrific example of this

is an orthopedic procedure

that combines a patient's own

deteriorated cartilage cells that

we can sort of trim out

through an arthroscopic surgery

and then we can

recycle those

deteriorated cartilage cells

and mix them in the operating

room with stem cells from a

from a cell line that are that are

manufactured and expanded

in a lab. And that mixture of the

patient's own cartilage cells

mixed with stem

cells can then be implanted

into the knee in a single

surgery. And this is

already in clinical trials, and it's

a really interesting

second generation therapy,

if

you will, that

builds upon the treatments

that we currently have available to

us. And then we're currently using.

So moving along with

what we've learned from,

from good clinical trials and from

treating patients already

with

how we can make those products

better is what will come

next for patients.

I think one of the major obstacles

the patient needs to overcome in

getting one of these treatments is

the cost and the fact

that insurance companies generally

don't cover this.

How close are we to have

insurance companies covering some of

these procedures? You mentioned that

PRP is getting some pretty good data

showing the effectiveness of it.

You see that on the horizon.

Well, we've seen some very limited

coverage thus far

in those particular procedures.

Like you mentioned, PRP.

There is some insurance coverage,

and it's only because

after 10 years of good clinical

trials, we've been able to

to validate PRP,

especially in its in its use,

almost as a standard of care

for treating osteoarthritis, at

least as good as anything else.

And so when you present

regulators and insurers

with the data to

support its use, then you'll

you'll see more widespread

acceptance. And one

of the things that we need

to do in order to make that happen

is standardize our approach.

Make sure that the way I manufacture

PRP is the way others in the field

are manufacturing PRP.

And then when it becomes a much

more standardized operating

procedure, then you'll

see more widespread acceptance.

Additionally, we're starting to see

some large employers directly

contract with providers

to provide or the biologic

treatments to their patients

as an alternative to surgical

intervention. So a lot

of employers who

would like to keep keep patients

working and not have to necessarily

have the downtime for a surgery.

These are again nice ways that

we can manage certain conditions

in the right patient population.

And so I think when

we narrow down our protocols better

and and find out who the right

patients are that we should be

treating.

Start to see more widespread

insurance adoption.

OK, well, let's

let's conclude by asking you to

summarise what we've discussed maybe

in two or three take-home

points regarding musculoskeletal

regenerative medicine.

Sure. So number one,

the best treatment for any patients.

Orthopedic problem

is never going to be a one size fits

all approach and

is best achieved through

a shared decision making

by the patient and their their

provider.

Number two, we have some exciting

new or the biologic approaches to

offer patients for their orthopedic

conditions.

Not everybody will be best served

by a novel regenerative therapy,

but we're happy to have that

discussion with patients to arrive

at what the best treatment option

is for them.

And the best choice for any patient

is to seek the care of

an expert in their particular

condition. And then maybe that

expert also has some additional

experience with regenerative

medicine that they can that they can

share with the

patient, and that will always serve

the patient well.

We've been discussing

musculoskeletal regenerative

medicine with Dr. Shane Shapiro,

a sports medicine physician at the

Mayo Clinic in Jacksonville,

Florida.

Shane, thank you so much for sharing

your insights with us today.

It's my pleasure. I appreciate you

having me.

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