NOEI Therapeutic Options for the Treatment of Osteoporosis

Presented by The Johns Hopkins University School of Medicine in collaboration with the National Osteoporosis Foundation.

Developed through a strategic educational facilitation by Medikly, LLC.

Supported by an educational grant from Lilly USA, LLC, and Amgen Inc.

PODCAST TRANSCRIPT:

THERAPEUTIC OPTIONS FOR THE TREATMENT OF OSTEOPOROSIS

Suzanne Jan de Beur, MD

I think the key when you are considering pharmacotherapy is making sure you are treating a high-risk

patient. It has come to light over the last several years that some of the therapies we use for

osteoporosis have some significant side effects. They are also outstanding fracture reducers, so we do

not want throw the baby out with the bath water, but we do want to make sure we are treating people

at high risk of fracture. Because age is such a driver of fracture risk, many times just looking at the T score

on a DXA report does not give us the whole picture. So for example, you may be seeing a 50-year-old

woman with no other risk factors, but with a T score of -2.4 at her hip and you may feel the urge to treat

this woman. But when you put her true fracture risk and you calculate it on a FRAX calculator, she does

not meet treatment thresholds based on the National Osteoporosis Foundation criteria. However, you

take an 80-year-old woman who may have a T score of -1.4 at her hip, but no other risk factors, you put

her in the FRAX calculator and she would meet the treatment threshold, so just by looking at a DXA scan

you would probably feel less comfortable treating the 80-year-old and more comfortable treating the 50-

year-old, but in fact the 80-year-old’s risk of fracture is quite a bit higher than the 50-year-old’s. The key

to pharmacotherapy is treating that high-risk patient.

So who are high risk and how can we tell? Well as I alluded to in my earlier comments, FRAX is a tool that

is web based that has been developed by the World Health Organization that uses a number of different

parameters to assess a patient's fracture risk: the age, the gender, personal history of fracture, family

history of hip fracture, glucocorticoid use, current smoking, alcohol intake, the bone density in the

femoral neck, history of rheumatoid arthritis – and calculate the 10-year probability of either a major

osteoporotic fracture or a hip fracture. If the 10-year probability of a major osteoporotic fracture

exceeds 20% or the 10-year probability of a hip fracture exceeds 3%, the recommendation is the patient

would benefit from treatment. So, as I said the T score does not give the whole story in many people, so I

really recommend using the FRAX risk assessment as a way to identify the high-risk patients.

I think right now our problem is that we are treating too many young women and not treating enough

older women. In addition, we are not really recognizing those people that fracture are, our high-risk

patients and those are the people that are screaming for treatment. We need to prevent another fracture

in these individuals to prevent premature mortality. So, I use FRAX as a way to predict fracture risk and

to select patients for treatment. I think anybody who has low bone density or actually anybody who

really wants to build their peak bone mass really should be getting enough calcium, vitamin D, and

weight-bearing exercise as I talked about earlier. But when more than that is required when you have a

high-risk patient that needs treatment, let us talk about the different treatment options.




There are two classes of treatments; they are the antiresorptives, which are treatments that focus on the

osteoclast. The osteoclast is the cell that breaks down bone. And what antiresorptive treatments do, in

one way or another, they inhibit the osteoclasts’ ability to break down bone. The other classes of

medications are called anabolic agents and these are agents that focus on the osteoblast, which are the

cells that build up bone. They stimulate osteoblasts to make bone. There is one agent in that category

and that is teriparatide. In the antiresorptive category there are the bisphosphonates, there is

denosumab, there is estrogen, there is selective estrogen receptor modulators, raloxifine, and there is

calcitonin. Really, I think that the mainstays of osteoporosis therapy are the bisphosphonates. They are

the most frequently prescribed pharmacotherapy and they have been out on the market for many years.

There are several of these; alendronate, risedronate, ibandronate, and zoledronic acid are the ones

available in United States, and they are very effective at reducing fracture. For example, the absolute

reduction in fracture is about a 1000 fractures per 100,000 patient-years of exposure. This is similar to

say HMG-CoA reductase Inhibitors or statins in lowering the risk of cardiovascular disease, very potent

reducers of fracture.

However, there are a number of limitations of using these medications. One is that they are very poorly

absorbed in the GI tract, so they may cause GI upset and this may limit their usefulness. In addition,

anyone who malabsorbs anything – someone with celiac disease or gastric bypass or people with Crohn's

disease – this may not be an effective mode of giving the bisphosphonate. There is an IV preparation of

bisphosphonate, zoledronic acid that can be helpful in this regard. Zoledronic acid does have some of its

own side effects, which include flu-like symptoms that you can have in up to 30% to 40% of patients the

first time they get the drug. So when I am talking to my patients in the exam room and we are talking

about the different therapies, say they have a lot of GI side effects to oral bisphosphonates and we have

decided going to go with IV bisphosphonates or zoledronic acid. I say, listen "I want you to know that

30% of people can get these flu-like illnesses and it can be incapacitating for a few days. So if in the next

three or four days, you have a project due at work, you have to be on your A-game, your granddaughter

is getting married, your 50th wedding anniversary, whatever is important to you in the next 3 days, if that

cannot be missed, I want to know about it because it is optional when we give this medication and I don't

want you to miss something important because you had a side effect to this medication”. I should say of

the oral bisphosphonates, all of them except for ibandronate have fracture reduction at both the hip and

the spine. Ibandronate only has fracture reduction that is seen in a prospective clinical trial in the spine,

so you should be aware of that. I don't typically use ibandronate in someone who is at high risk of hip

fracture.

Now, with bisphosphonates, we have heard a lot about longer term effects and generally I don't like to

use bisphosphonates beyond 10 years. There are a couple of side effects that are related to the dosing

and the length of exposure. So, for example osteonecrosis of the jaw is something that has arisen over

the last couple of years that has been shown to be dose related to long-term bisphosphonate. Now, it is

not a definite association, but it does seem to be a risk factor for development of osteonecrosis of the

jaw, high doses that we usually use when we are treating breast cancer metastasis. So for example, that

has a frequency or incidence of about 20 to 30 per 100,000 patient-years of exposure – a whole

magnitude less of frequency, very rare occurrence compared to the fracture efficacy. But, if you don't

have a patient that’s at high risk of fracture, you are exposing them to the possible adverse risks of the

medication. Again, it is really critical to pick that high risk patient so the benefits definitely outweigh the

risks. The other side effect that we have been hearing about is an association with atypical fractures of




the femur. Again, we are not sure if this is associated, but it appears that longer-term bisphosphonate

use may be a risk factor.

Again a very rare occurrence, incidence here is about 60 per 100,000 person-years of exposure. Again, if

the benefit is not clear then there is amplification of the risks.

Let’s talk about other antiresorptive therapies. So we talked about bisphosphonates. What about

selective estrogen receptor modulators? These are compounds, and the one in this class is raloxifine,

that act like estrogen at the bone, but do not have the adverse effects of estrogen either in causing

endometrial proliferation or in increasing breast cancer risk. So you don't have to give this with

progesterone. In fact, they have used it in some breast cancer prevention trials and shown some efficacy.

So there is not the concern here with the breast cancer or the endometrial proliferation. It does have the

same proclotting effects that estrogen has, so this needs to be kept in mind when you are thinking about

putting your patient on this medication. This medication, this antiresorptive, primarily reduces vertebral

fractures. There is not good hip fracture data; there is approximately 30% to 50% reduction in vertebral

fractures. In addition to its clotting effects similar to estrogen, it does not treat hot flashes. Estrogen

treats hot flashes, but raloxifene does not treat hot flashes and it may exacerbate hot flashes. In addition,

there can be leg cramps and fluid retention that sometimes we can also see with estrogen. So raloxifine,

great for that patient with low bone density in the spine, but keep in mind if you have anyone that has

any coagulation difficulties then this is not a good choice.

Estrogen also is well established to reduce fracture at both the vertebral and nonvertebral sites even in

women not classified with osteoporosis. It is not approved for treatment of osteoporosis, but it is

approved for prevention of osteoporosis. It is not recommended for first-line therapy because of the

other adverse effects: the slight increased risk of breast cancer, the risk of endometrial proliferation so

that you have to give it with progesterone, and the risk of thromboembolism. Having said that, if I have a

woman with really debilitating hot flashes who is in the menopausal transition and she is at high risk of

fracture, many time,s I will use estrogen for a short period of time in those individuals because it is a 2-

for-1: it is treating the hot flashes and also treating the low bone density. Now, if she has a family history

or personal history of breast cancer or other risk factors that would modify my use of estrogen, I pay

special attention to that. But sometimes estrogen will help especially in the situation where you have

debilitating hot flashes.

Let’s switch from the antiresorptive therapies, which are working on the osteoclast, to the anabolic

therapy, which is teriparatide. This is human parathyroid hormone. I know many of you are saying “wait

a minute; I thought excessive parathyroid hormone was associated with bone loss?” Well you are right.

However, astute scientists observed that when PTH was given in short pulsatile fashion that it actually

stimulated the osteoblast rather than the osteoclast, and that is exactly the idea behind this anabolic

therapy. You give an injection under the skin of the PTH peptide and it increases your PTH level for a

couple of hours and then it returns to baseline. The short burst of elevated PTH is what causes the

anabolic action, so this is actually a medication that builds bone. It is one that I use in people with severe

osteoporosis or ones that have a failed bisphosphonate therapy, meaning either they lose bone density

on bisphosphonates or they fractured on bisphosphonate. This has shown efficacy at both the hip and

spine, and so I use it in that way. Now teriparatide is not an easy medication to use, but patients tend to

do well. Once they are taught, they tend to do very well. I even had a gentleman who was deathly afraid




of needles and was able to work through his fear and use the very small needle for daily injections of

teriparatide. It is given once a day under the skin. Some drawbacks to it are, if you have had cancer that

has metastasized to the bone or if you have had radiation to your bone or if you are a young person still

growing or have open epiphyses, this would not be an appropriate therapy to you. In addition, patients

with high blood calcium levels or high PTH levels, I do not use this therapy in these individuals because

they will only exacerbate the hypercalcemia and the PTH levels are already high and so you won't get that

pulsatile PTH effect that I spoke about earlier. In addition, teriparatide when it was given at very high

doses to rats, some of the rats developed osteosarcoma, which is a type of bone tumor. For this reason,

any individuals with Paget's disease or have radiation to bone or cancer metastasis to bone, we do not

like to use teriparatide in those individuals because their increased risk of osteosarcoma. What has been

reassuring to me since teriparatide has been on the market, the incidence of osteosarcoma is not

increased over background, so it does not appear that there is an increase in osteosarcoma in those

individuals that use teriparatide.

The last agent that I wanted to talk to you about is a new agent that is out. It is an antiresorptive therapy;

it is called denosumab. It is an antibody that inhibits RANK-ligand. RANK-ligand is an important molecule

on the surface of those osteoclast, those bone cells that breakdown bone. What it does is that it inhibits

the differentiation, so it keeps the osteoclasts in that immature state. It has been found to be effective in

reducing vertebral fractures as well as hip fractures. It has a couple of side effects, just like every other

agent. It is given once every 6 months, so that is great, and it is a subcutaneous injection, they don't have

to self-administer. However, there is increased risk of infection especially skin infections and urinary tract

infections. There also have been reported hypocalcemia in individuals that are predisposed to that. Just

like bisphosphonates, there have been some associated cases of osteonecrosis of the jaw. Denosumab is

a very potent antiresorptive agent because it inhibits osteoclasts, but the advantage is that it does not

accumulate in the bone like bisphosphonates do and it is quickly reversible. The downside to it are that if

you don't keep up your injections there could be a big rebound phenomenon where there would be

increased osteoclasts now differentiating and causing bone resorption. But again it is a very effective

agent. When you are dealing with people that can't tolerate bisphosphonates or need ongoing treatment

beyond 10 years, many times this is a good agent to use. In addition, it is not contraindicated in those

with renal failure, like the bisphosphonates are, so a lot of times a good choice in those patients.

So the good news is, over the last 10 to 15 years, there has been many new osteoporosis therapies

developed that give the physician a wide array to choose from, so you can tailor therapy to your patient.

And there are several new agents coming down the pike, down both on the anabolic side and on the

antiresorptive side. Choosing an osteoporosis medication based on your patient’s history and on your

patient’s profile and their side effects, and getting the right agent for them, is easier than ever given the

wide array of agents available.

Adrienne Berarducci, PhD, ARNP, BC, CCD

One of the most important things in treatment strategies especially with the pharmacotherapeutics in

osteoporosis, is really looking at patient preference. We know that we have a number of different

medications available now by a different route and different dosing schedule for our patients and actually




sitting down with them and looking at what is their history, what are their comorbidities that may affect

how the drug is metabolized and tolerated and again preference of the

patient. All bisphosphonates now are generally given weekly or monthly; and asking the patient what is

their preference when we are prescribing. Would they feel more comfortable taking it weekly? Would

they like to take it monthly? Letting them know that they can change this down the road; giving them

that control over their own healthcare is very important. Same with the IV medication. Some patients

will tell you, and giving them the option of IV bisphosphonate versus oral bisphosphonate, and they will

tell you, I would rather just do it to do it once a year and get it over with. Being very frank with them,

very honest about possible side effects that can occur. Also, when we talk about side effects, let them

know that the side effects do not happen commonly in all patients. Many patients are afraid because of

the things they have seen in the popular media or because they have a friend or family member who had

an untoward effect from a medication. You need to let them know that, for one thing, they are not that

friend or family member, so the drug more than likely will react differently in them. But also that some

of the things in the popular media do not affect the general population of patients with osteopenia and

osteoporosis that are going to be taking these drugs. Being very frank with them about what we know,

what the scientific data tells us. We can talk about things that we can do to minimize those side effects.

We know about flu-like symptoms in patients that take IV bisphosphonates. Let them know that before

they go for the infusion, for a day or two before they have the infusion to take some Tylenol or Advil, a

drug that they can tolerate, one of the two, a day or two ahead a time and take it the day of and possibly

after and to drink plenty of fluids with these medications. If we are very honest and upfront with

patients, they are prepared if they do have a side effect, so that it does not hinder efforts to possibly

treat them with something else later. Again, letting them make their own choices about the type of

medications that they are going to be taking, whether they prefer oral, parenteral, and how often they

want to be taking their medication. It gives patients control and it gives them more faith in us as

healthcare providers that we care enough and are interested in what their desire is.

NOEI Therapeutic Options for the Treatment of Osteoporosis

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Transcript of NOEI Therapeutic Options for the Treatment of Osteoporosis