OSTEOPOROSIS: Part 2

Question 1

How do we manage patients at risk of fracture?

Answer 1

Low risk
10 year fx risk <10%
Do not treat.
Reassess in 5 years

Moderate risk
10 year fx risk 10 – 20%
Consider treatment based on
additional risk factors
and patient preference

High risk
10 year fx risk >20%
Or
Prior fragility fracture
Or
Multiple fractures

Treat with pharmacologic
therapy

if they’re moderate risks, so that 10-20% risk of fracturing in next ten years. Really it’s based on other, other risk factors they may have. So if they have really strong family history, there’s other situations that you’re concerned about. Maybe they’re getting closer to that 20%, then maybe we should be treating

With low-risk, we may re-assess with bone marrow density. It has five years, but anywhere 3-5 years is fine

Question 2

How do we manage patient at risk of fracture?

Answer 2

What about FRAX?
Recommend treatment if:
Major osteoporotic fracture >20%
Hip fracture >3% (guidelines in U.S., in Canada we
base on major osteoporotic fracture)

Question 3

Osteoporosis Medications

Answer 3

Antiresorptives
n Bisphosphonates
Oral:
alendronate
risedronate
Intravenous
zoledronic acid
n Monoclonal antibody against RANKL
denosumab
n Selective Estrogen Receptor Modulator
(SERM):
raloxifene
n Hormone Therapy (HT)

Anabolic agents
n Parathyroid Hormone (PTH):
teriparatide
n Sclerostin Inhibitor
romosozumab

Nowadays, most of these agents are preventative for all types including vertebral, hip and non vertebral.

raloxifene or SERM has only shown vertebral fracture reduction and it hasn’t shown non vertebral on hip fracture reduction in the studies. It could be other way the studies were done and whatever, but it’s mainly showing vertebral fracture.

Teripareatide did not show hip frac reduction but it;s just the way study was done, it’s still good anabolic agent

Question 4

Studies for osteoporosis

Answer 4

Outcomes:
n Reducing fracture risk
§ Vertebral fractures
§ Relative risk reduction in vertebral fractures by 30 – 70%
depending on study (NNT ~ 12 - 21 in studies)
§ Hip, non-vertebral fractures
§ Relative risk reduction in hip and non-vertebral fractures
depends on agent (range 40 – 50%, NNT ~ 91 - 200 in studies)

higher bone remodeling rate, they’re more, I guess metabolic active then compare to and having trabecular bone

all studies are looking at vertebral fracture reduction as their primary outcome. Usually hip and non vertebral outcome. Non vertebral fractures are secondary outcomes. So much of the studies are powered for that primary outcome for vertebral fractures.

they have to have fracture reduction to be able to get on the market as an agent.

Question 5

Osteoporosis Medications

Answer 5

Antiresorptives
alendronate
risedronate
etidronate* - -
zoledronic acid
denosumab
raloxifene - -
estrogen**
Anabolic
teriparatide -
romosozumab

Nowadays, most of these agents are preventative for all types including vertebral, hip and non vertebral.

raloxifene or SERM has only shown vertebral fracture reduction and it hasn’t shown non vertebral on hip fracture reduction in the studies. It could be other way the studies were done and whatever, but it’s mainly showing vertebral fracture.

Teripareatide did not show hip frac reduction but it;s just the way study was done, it’s still good anabolic agent

Question 6

Antiresorptive Agents MOA

Answer 6

Denosumab
RANK Ligand
Inhibitor

Raloxifene
Estrogen
Reduce RANK
Ligand

Teriparatide
PTH Analog

Bisphosphonates
bind to bone
inhibit osteoclasts

RANK = Receptor activator of nuclear factor-κB
PTH = parathyroid hormone

Bisphos: bind to this hydroxy appetite in the bone. they actually get included when they bind to the part that’s already going through bone resorption, so opening. And then they get included in there. The osteoblasts come along and go over that bone. incorporated into that bone. When the next time that an osteoclast comes along, it starts to break down that bone to get it ready for bone remodeling. But it causes apoptosis,of that osteoclasts.

Denosumab: inhibiting that the rank receptors don’t get activated and therefore the osteoclasts don’t, you don’t see that normal bone resorption with the osteoclasts.

Raloxidene: reduces rank ligand so that the main action is gonna be on preventing bone resorption.

Teriparatide: PTH receptors found on both osteoclasts and osteoblasts. Intermittent administration. Exposure causes increased activity of osteoblasts. Someone who has hyperparathyroidism, e.g. you’re going to see an increase in osteoclasts activity. So terror apartheid favors when you give it in this type, it favors increasing osteoblast activity, bone formation. That’s how it’s an anabolic agent.

Question 7

Considerations with Bisphosphonates

Answer 7

n Bind to areas of active bone remodeling
n Incorporated into bone with bone formation
n Released with bone remodeling
n Different binding affinity:
Zoledronic acid>alendronate>risedronate>etidronate
This concept is important for drug holidays!

Alendronate probably has residing time of about ten years in the bones.

Question 8

Bisphosphonates
products

Answer 8

Oral bisphosphonate*
alendronate Fosamax®, generics
10, 70 mg tabs
70 mg/75 ml solution
Fosavance®
70 mg/2800 IU vitamin D3
70 mg/5600 IU vitamin D3
70 mg weekly

risedronate Actonel®, generics
5 mg, 35 mg or 150 mg tabs
Actonel DR® 35 mg
35 mg weekly
150 mg once a month

IV bisphosphonate
zoledronic acid Aclasta®, generic 5 mg yearly
(15 min infusion)

Question 9

Oral Bisphosphonates
Adverse Effects

Answer 9

GI effects: abdominal pain/distension, dyspepsia
§ Diarrhea
§ Musculoskeletal: muscle, bone, joint aches/pain
Rare: Esophagitis, ulcers – alendronate, note: unclear if
risedronate has same GI issues, however patient counseling
is the same as alendronate

Diarrhea, not too common. It’s usually right in the beginning. They may get a couple of days, but usually not an issue

musculoskeletal types of pain, joint aches, muscle aches that are non-descript. Usually this is after awhile of use. It’s not right away. And if they are going to experience that it might be even a few months after regular use or usually we don’t have to take people off.

esophagitis, so irritation of the esophagus and possibly ulcers as well. More commonly with Alendronate than any of the others, alendronate has an open chain at their final and risideronate has more of a closed chain. It probably doesn’t have the same GI effects, but we recommend the same thing with them.

sitting upright for the first half-hour, these drugs are very poorly absorbed. The poor bioavailability, less than 1% of the drug is absorbed. I usually recommend up to an hour for the once weekly

Question 10

Patient Counseling: Oral
Bisphosphonates

Answer 10

alendronate, risedronate:
n Take on empty stomach with a full glass of plain
water – best in the morning one-half hour (note:
recommend 1 hour for once weekly) before eating
or drinking
n Do not lie down for at least 30 minutes after
taking

Oral bisphosphonates have
poor bioavailability <1%

Question 11

Actonel DR Formulation can be
taken with food (breakfast)

Answer 11

pH-sensitive
enteric coating

Bypasses
esophagus and
stomach and
delays release
until the small
intestine, where
the pH >5.5

Intended to
reduce the
binding of
risedronate with
dietary calcium

This is just information about the DR form which can be taken with food and breakfast. It has a pH sensitive enter coded coating as well as collating agent. It’s going to leave it for you don t have to memorize it or anything like that. But it’s just there to know that there is an agent that can be taken with food

Question 12

IV Bisphosphonate

Answer 12

Zoledronic acid (ZA):
§ 15 minute infusion once a year
Adverse effects
* Acute phase reaction: flu like symptoms 1 – 3 days
after injection (fever, chills, bone pain, etc)* – can
last 3 – 4 days in 10 – 20% patients
* renal impairment
*can administer acetaminophen/ibuprofen or diphenhydramine before infusion
Monitor: calcium, phosphate, sCr/GFR prior to each dose

see a little bit more with the IV than an oral is the renal impairment that it can cause renal impairment. If we use high enough doses of the oral, it could do that as well.

But the IV you get this large dose with IV right into the system. It’s cleared. Both oral and IV are cleared by the kidneys and then the rest is taken up by the bones. So there’s about 50% that’s cleared by the kidneys and then the rest gets taken up by there.
High levels of IV in renal tubule cells can cause apoptosis of those cells, seen more with zoledronic acid

we also look at things like calcium and phosphate because just avoid like hypocalcemia

Question 13

Contraindications with Bisphosphonates

Answer 13

n women of childbearing potential
n alendronate, ?risedronate:
§ Abnormalities of the esophagus
§ Inability to sit/stand upright for
30 minutes
Patients with renal impairment:
-Product monographs recommend
avoid if CrCl <30 ml/min
(risedronate),
CrCl <35 ml/min (alendronate,
zoledronic acid)
-Issue: most landmark trials
excluded patients with renal
impairment.

let’s say they were really kyphotic, right? They’re not gonna be able to sit upright. They can have reflux already, which agent I’m going to choose. I’m not going to choose the Alendronate. I probably would choose residronate over that, knowing that there’s probably a bit better safety if you’re looking at an oral agent,

It’s not shown to be teratogenic and there’s been lots of individuals who’ve, who’ve been of child-bearing potential, who’ve, who’ve actually been on bisphosphonates before. But it’s just, we just avoid just in case,

Question 14

Drug Interactions with Bisphosphonates

Answer 14

Any drug that decrease the bioavailability of oral bisphosphonates:
§ calcium supplements
§ iron supplements
§ laxatives containing magnesium
§ antacid containing magnesium, aluminum or calcium
§ vitamins supplements containing minerals
§ Actonel DR – PPI’s, H2antagonist

Question 15

Bisphosphonate Induced Osteonecrosis of the
Jaw (ONJ)

Answer 15

n What is osteonecrosis of the jaw?
n area of exposed bone in the jaw that does not heal after 8
weeks.
The theory with bisphosphonates:
n Slows bone turnover (bone turnover helps with bone healing)
n Jaw bone not able to heal properly
n More common in cancer patients on high dose IV
bisphosphonates.
n Associated with major dental issues (invasive dental
surgery, gum infections, poor dental hygiene).
n Incidence of ONJ in Canada in patients with
osteoporosis is rare
n ~1 to 69 in 100,000 patient-years

Patients with osteoporosis are greater risk of having a fracture, then getting ONJ.

n Patient education is key!
n Very small risk of ONJ
n Good oral hygiene, regular dental checkups
n Recommend holding bisphosphonate before a major dental
procedure or dental surgery, though not conclusive if it helps

Question 16

Atypical Femoral Fractures (AFF)

Answer 16

n Fractures occurring along the
distal femur:
Ø Subtronchanteric/ diaphyseal
n Occur with little or no trauma
n Approximately 30% are
bilateral.

n Potential mechanism unknown: alteration of normal tissue
repair process from continuous bone suppression.
n Associated with long term bisphosphonate use (>5 – 7 years
of use).
n Incidence is rare: 2 – 78 per 100,000 person-years1
n Patients report prodromal pain in thigh, pelvis or hip2
§ weeks to months before fracture

the bones are not able to have that normal repair process in the area. It’s associated with long-term use. So duration, so more than five to seven years of with the bisphosphonates.

the bones are not able to have that normal repair process in the area. It’s associated with long-term use. So duration, so more than five to seven years of with the bisphosphonates.

we’re counseling patients to look for prodromal pain
it can happen weeks to months before that fracture. What’s good about if they start expressing that to you is we can catch it before it happens. So if we start seeing those little hairline fractures on the x-ray, usually we give anablolic

Question 17

Selective Estrogen Receptor
Modulator (SERMs)

Answer 17

Raloxifene (EvistaR, generic)
Mechanism of action:
n Agonist effect on ER on bone,
lipids
n Antagonist effect on ER on
breast and uterus
n Breast Cancer
n decreases the incidence of
breast cancer

n Adverse effects
n hot flashes
n leg cramps
n Risk of venous thromboembolism
(same incidence as hormone
therapy)

n Contraindications
* pregnant women
* active or past VTE (use same
considerations as for hormone
therapy)

It has antagonists effects on the breast as well as the uterus. So you don’t need preventative progesterone or anything because it has antagonists effects.
be cautious in individuals that are probably closer to the menopause

cramps that can occur. It can occur in up to 3% to 5% of people.Usually when leg cramps happen, we have to stop the drug

Question 18

Menopausal Hormone Therapy (MHT)

Answer 18

n Current Role:
* MHT is an option in those women who also have moderate to severe menopausal symptoms
* Risks and benefits of MHT in the individual patient should be assessed
* Doses of 1 mg estradiol or equivalent is required to reduce fractures.
* Lower doses such as 0.5 mg may help prevent further bone loss

prevent bone loss and also helps with fractures in someone who is still symptomatic having like hot flashes and night sweats or they’re using it for that reason, then this is an okay option to consider and will prevent further bone loss

at least 1 mg of estradiol or 0.625 milligram of conjugated estrogen Or equivalent is required to reduce fractures

it may not help with fractures or we just don’t have the data to say it’s going to help with fractures

Question 19

Denosumab

Answer 19

n Human monoclonal antibody
against RANKL
n Prevents osteoclast activity
and bone resorption
n Prefilled syringes – subcutaneous
n Dose: 60 mg subcutaneous every six months

. It prevents normal activity and bone resorption, they dont work as wll

Question 20

Denosumab
AE

Answer 20

n Musculoskeletal pain
n Rash/eczema
n Infections (i.e. cellulitis)
n Hypocalcemia
Monitor: calcium at baseline and 2 weeks after starting denosumab, or if
signs of hypocalcemia, phosphate, sCr/GFR
Preferred agent in renal impairment – no dosage adjustments (monitor Ca, ↑risk of hypocalcemia)

Pain would be after a few months (q6 months after they might see it after 1st or 2nd inj)

we often get a calcium at baseline before we start prolia
But the only issue is, is that these patients, especially when they get down to less than 15 mils per minute of Cr clearance or GFR increased much more increased risk of hypocalcemia. have to be very careful for calcium levels

Think of it as a very potent antiresorptive. And that’s why you could see reports of AFF as well.

Reports of ONJ and AFF

Patient Assistance Program = Provital Program
Note: increased vertebral fractures upon discontinuation of denosumab, adherence is very important

it’s super important that they get it in six months. Because what happens if they miss? What can occur is they actually see an increase in bone resorption happening where you can see increase in vertebral fractures upon discontinuation. 6months, the max 2 months within that one to two months kind of thing.

Question 21

Teriparatide (ForteoR)

Answer 21

n Recombinant human PTH (1-34)
n Only PTH agent available in Canada.
n Subcutaneous injection (subcutaneous pen)
n Dose: 20 mcg subcutaneous daily
n Length of therapy: 24 months
n Must be refrigerated.

n Side effects:
§ dizziness, postural hypotension hypercalcemia, hypercalcuria, uric acid, muscle cramps
might see some dizziness because of probably postural hypotension. They’re standing up or they might just get dizzy with their standing up. So usually I tell them to get there to do their injection initially at night. And you’re sitting down so you don’t get dizzy and fall because these are often more frail patients.

check calcium because the worry is high calcium levels with parathyroids. So we check for high calcium. It’s not a clinic often it’s not clinically significant with the calcium, we’ll do a baseline and we’ll probably do one and probably just a few months later

would not use if CrCL<30
n Contraindications:
§ Severe renal insufficiency
§ Bone metastases, bone cancer
§ Patient at risk of osteosarcoma
Risk of osteosarcoma with humans has not been shown in humans (study terminated early in the landmark trial because of osteosarcoma in rats)

n Continue with antiresorptive agent after discontinuing (2 years)
n Forteo Customer Care Program
Monitor: calcium at baseline and in one month, PTH, phosphate, sCr/GFR

Question 22

Romosozumab (EvenityR)

Answer 22

n Administration: subcutaneous injection
n Dose: 210 mg subcutaneous once a month (administered as two
consecutive injections with prefilled syringes (105 mg each)
n Duration is 12 months
n Keep in fridge, let stand for 30 min before administration
Monoclonal antibody
against sclerostin

By inhibiting sclerostin, it actually increases osteoblast function and that’s how it causes bone formation. But it can also affect osteoclasts in some way as well.

by inhibiting sclerostin and you can actually see a preventing that osteoclasts, the bone resorption from osteoclasts

It is mainly an anabolic agent because it does more favorably increase bone formation. But it does have that tendency to be dual. And so it may have some antiresorptive effects as well.

But we kept classified as an anabolic agent.

Question 23

Romosozumab AE

Answer 23

§ More common: arthralgia/joint pain, injection site pain/erythema,
nasopharyngitis, headache
§ Rare: hypocalcemia, cardiovascular events (occurred more
frequently than with alendronate, but not in the placebo trials)
n Contraindications: History of MI or stroke
n Neutralizing antibodies have developed but unclear if affects efficacy

Dosage adjustment not required for renal impairment, but need to monitor for hypocalcemia
watch for calcium, so you can see hypocalcemia with this agent as well

for any new drug coming on the market, they have to compare it to Alendronate.
increased incidence of MIs or stroke, which was not seen in the Alendronate group.
But they didn’t show it in the placebo trials. So the question was, is it really happening because of Romo, or is there something with Alendronate that’s providing protection? Its not certain
we always ask, have you had a heart attack, we had a stroke or even cardiovascular disease

Question 24

Therapeutic Options: First Line

Answer 24

alendronate
risedronate
zoledronic acid
denosumab
Therapeutic Options: First Line
Prevention of vertebral, hip
and nonvertebral fractures

Question 25

Therapeutic Options: Other

Answer 25

raloxifene: Prevention of vertebral
fractures only in women

menopausal
hormone therapy: If vasomotor
symptoms in women

Question 26

When would anabolic agents be considered?

Answer 26

n Anabolic agents (ie teriparatide, romosozumab) often
reserved for patients with severe osteoporosis who have not
responded to other therapy
§ Follow with antiresorptive therapy once discontinued

Limited by funding not currently covered by blue cross
reserve these for patients with severe osteoporosis who have not responded to other therapy. So let’s say they’re on something and they continue to fracture or they have major bone loss as well

we follow with antiresorptive, as I mentioned, with Romo, e.g. one year later, we would switch them to one of the antiresorptive two years with teriparatide

some parts of the US, they are using anabolic for some other first-line agents. Get them to build bone. And then you can do an antiresorptive. And so you’re starting off at a much better place than with an antiresorptive. Because antiresorptive will still help build bone, but it’s not doing it directly. It’s preventing that bone resorption and then the bone formation can happen. But if you can target that bone formation first,

Question 27

Glucocorticoid-Induced Osteoporosis (GIOP)

Answer 27

n Consider prevention of GIOP if:
n > 3 months cumulative therapy during the preceding year
n Prednisone equivalent dose of 7.5 mg per day (or 2.5 – 5 mg
if risk factors for osteoporosis)
n Options:
n alendronate, risedronate, zoledronic acid, denosumab
n teriparatide if not respond to other agents

Question 28

Cost Osteoporosis Medications

Answer 28

Agent Approximate
cost/year
alendronate, risedronate ~$480
IV zoledronic acid ~$700
denosumab ~$800
teriparatide ~$12,300
romosozumab ~$7,900

n Alberta Blue Cross will cover:
§ alendronate, risedronate,
etidronate, HT
§ special authorization:
§ Denosumab
§ Zoledronic Acid
§ Raloxifene
n Private plans may cover

Question 29

Monitoring Therapy

Answer 29

n Repeat BMD:
§ Patients on therapy:
§ New therapy – in 2 – 3 years
§ Established therapy – in 3 – 5 years
§ Use same DEXA machine for repeat BMD!
n When to change therapy?
§ if continue to lose bone density
§ side effects
BMD’s can only be ordered every 2 years
in AHS

Question 30

Patients not responding:

Answer 30

n Check 2nd causes:
§ Adherence
§ Vitamin D deficiency
§ If oral bisphosphonate: malabsorption, drug interactions
§ Other diseases/causes (ie Celiac disease)
n Note: Adherence and persistence with osteoporosis medications is
low (adherence – roughly 50 – 60%, persistence - <25%)

Question 31

Poor Adherence Leaves Patients at
Higher Risk of Fracture

Answer 31

50% adherence leaves
patients at approximately
the same fracture risk
as no therapy

50% adherence leaves patients at approximately the same fracture risk is no therapy.

Question 32

What is a drug holiday?

Answer 32

n Stopping the medication for a period of time to allow time
to “reset”
n Drug holidays can be considered for people with low to
moderate risk of fracturing, not with high risk.
n Drug holidays are only with bisphosphonate therapy =
retained in bone for extended time and have ongoing
fracture reduction after discontinuation.
n With other osteoporosis medications will see bone loss as
soon as they are discontinued
n Drug holidays can be considered after continued use of:
§ oral bisphosphonates: 5 years
§ IV bisphosphonates: 3 years
n Duration of drug holiday can vary from 2 – 4 years,
reassess with repeat BMD – start monitoring at 1 – 2
years.