Posted @ 8/30/2012 10:42 AM by Dr David Feinstein | Files in VitD,Osteoporosis,FRAX Score
Osteoporosis
is a common skeletal disease in older populations, which leads to
about two million fractures annually in the US. It is a silent
disorder, characterized by decreased bone strength, predisposing to
an increased risk of fracture. Bone strength reflects two major
features, bone density and bone quality. Bone quality includes such
factors as the health of the collagen component of bone, and the
architecture of bone. Bone quality however, cannot practically be
quantified. For now, measurement of bone density remains the primary
technique for measuring bone strength and monitoring the treatment
for osteoporosis.
Bone densitometry is the tool used to
measure bone density. The device measures the bone density in the
lower spine (T1-T4) and in the hip (the entire or total hip and the
femoral neck portion of the hip). A measurement called the T Score
compares an individual’s bone mineral density (BMD) with the
mean value for a young normal person. The difference is expressed in
how many standard deviations (a statistical term) an individual’s
bone density measurement is from the young normal mean. A normal
bone density is defined as a standard deviation from the mean of up
to -1. Osteopenia is thought to be present when an individual’s
BMD is between -1 and -2.5 standard deviations below the mean.
Osteoporosis is present when the patient’s bone density is
less than -2.5 standard deviations below the mean. The more negative
the standard deviation is, the more severe the osteoporosis.
About
80% of patients with osteoporosis are women. Most of them are post-
menopausal. Menopause is when acceleration of bone loss occurs. At
age fifty, the lifetime risk of developing fractures is about 39%
for white women, and 13% for white men. While white women are most
often affected, women of all races are at risk. By age sixty, half
of all women have osteopenia or osteoporosis.
More women
have osteoporotic fractures than new strokes, heart attacks, and
invasive breast cancer combined. Hip fractures are the most serious.
The mortality during the first year after a hip fracture is greater
than 30% for men, and 17% for women. Vertebral (spine) fractures
cause 70,000 hospital admissions annually and commonly cause chronic
pain and deformity. Fractures of the forearm generate 530,000 office
visits annually in the US. Because the incidence of osteoporotic
fractures increases with age, the number of such fractures is
expected to dramatically increase as our population ages.
Bone
is a living tissue. Parts of bone are continuously removed and
replaced with new bone. This process of bone removal and bone
replacement is called the bone remodeling. The entire skeleton, by
this process, is replaced every three years. At any one time, there
may be a million excavation sites going on somewhere in your
skeleton. The body identifies a weak area of bone (microscopic
stress fracture or injury), and recruits a particular cell called an
osteoclast, to attach itself to bone and resorb a localized area of
bone (acid released by the osteoclast digests the bone). After this
phase is completed, another type of cell called an osteoblast is
recruited to the excavation site, and this cell lays down collagen,
which then calcifies, and fills in new bone what had been removed.
In younger life, the entire process of bone remodeling is complete
and the amount of bone laid down is equal to the bone removed. The
bone density of the skeleton therefore remains stable. After
menopause however, and the withdrawal of estrogen, the process of
bone remodeling becomes accelerated and incomplete. The amount of
bone deposited in a bone remodeling cycle is less than the amount of
bone that was resorbed. Because this is taking place in a million
sites all over the skeleton, the end result is that there is a
progressive loss of bone, which results in a decrease of the BMD.
We now know that estrogen deficiency causes the release of
an excessive amount of a substance called RANK Ligand from bone.
RANK Ligand combines with its receptor (recognition site) on
osteoclast precursors (cells that will evolve into osteoclasts) and
on osteoclasts to cause them to become more numerous and more
aggressive. The hungry osteoclasts excavate larger and deeper areas
of bone. This can lead to the destruction of the architecture of
bone, making it more difficult for the osteoblast to adhere itself
to the area of excavation and to replace that which was removed.
Estrogen replacement at the time of menopause can reduce the
rate of bone loss (by reducing the rate of RANK Ligand released from
bone. Estrogen though, is no longer routinely prescribed to women at
the time of menopause because of other effects of estrogen that can
have a negative effect on health. These include such consequences as
a slight increase in the incidence of blood clotting, breast cancer
and possibly heart disease. The decision to give estrogen at the
time of menopause requires a balanced decision weighing risk and
benefit and is strongly affected by the patient’s degree of
vasomotor symptoms such as hot flashes.
The primary
identifiable cause for osteoporosis is (other than genes), estrogen
deficiency. Other so called secondary causes for bone loss however,
may be present and should be considered.
Vitamin D Deficiency
Vitamin D is required to adequately absorb calcium from the gut. Vitamin D can be made in the skin as a consequence of sun exposure; however current use of sunscreens has reduced the amount of Vitamin D that is naturally synthesized. The current recommendation for Vitamin D intake is between 1000 and 2000 units daily. Vitamin D levels can be measured and the ideal blood level is a value greater than 30. If patients are severely deficient in Vitamin D, then much larger doses of Vitamin D can be used such as 50,000 units weekly for three months.
Inadequate calcium intake in the diet
Calcium is found primarily in dairy products, green leafy vegetables and sardines. A diet devoid of dairy products usually contains about 300 mg. of calcium. The current recommendation for calcium intake is about 1200 mg. per day between diet and supplements. Each dairy product contains about 300 mg. of calcium. If a patient consumes two different dairy products per day, he or she would probably need a supplement of about 500 mg. of calcium per day. Too much of a good thing can cause problems. Diets that are extremely high in calcium could predispose to kidney stones and possibly calcification of blood vessels. Calcium carbonate is less expensive however acid-blocking drugs used to treat reflux and gastritis can interfere with its absorption. Calcium citrate (Citracal) can be adequately absorbed even when used concomitantly with acid blocking medications. Probably no more than 500 mg. of calcium should be taken at any one time.
Smoking
If there were not enough reasons before, not to smoke, this is one more.
Excess alcohol
The definition of excess alcohol is 3 or more units of alcohol per day, beer, spirits or wine.
Prolonged periods of inactivity
This can occur following a stroke, or orthopedic surgery. Astronauts who spend long periods of time in space are faced with accelerated loss of bone as a consequence of being weightless.
Use of certain drugs
Prolonged use of steroids, overtreatment with thyroid hormone, and anticonvulsant medications are all associated with accelerated bone loss.
Certain Diseases
Rheumatoid arthritis, hyperparathyroidism, and cancer particularly myeloma.
Poor nutrition especially during adolescence
This can result in inadequate bone being laid down during adolescence, which results in a decrease in the peak bone mass which is the maximum bone that a person will ever have. Therefore when bone loss occurs with aging, the point at which it begins is at a lower point than average.
Eating Disorders or excess thinness
Can
lead to menstrual irregularity or amenorrhea (no period). The
mechanism is low body fat composition that alters pituitary function
leading to estrogen deficiency.
When a patient is being
evaluated for osteoporosis these secondary causes of bone loss
should be considered and corrected if possible.
In
addition to prescribing an adequate amount of calcium and Vitamin D,
and weight bearing exercises such as walking, jogging and rowing,
your doctor may choose to treat with a medication. Oral
bisphosphonates are currently the most common therapy for
osteoporosis. The three most utilized are Fosamax
(alendronate), Actinol
(risedronate), and Boniva
(ibandronate). They have all
been shown to reduce vertebral fractures. It is unknown however,
whether they are equally effective in reducing nonvertebral
fractures. This class of drugs also includes Reclast (zolendronic
acid), which is a once a year drug given over a thirty minute IV
Infusion. All these medications work because they share two
properties, (1) bind to bone and (2) inhibit a key osteoclast enzyme
(framesyl pyrophosphate synthase). After absorption the drug is
deposited on the surface of bone where it is then ingested by
osteoclasts. Osteoclast activity is then reduced leading to
decreased bone resorption. This class of drugs is poorly absorbed in
the GI Tract, with less than 1% of the dose actually absorbed. The
drugs are usually given on an empty stomach, washed down and out of
the esophagus with a full glass of water, and patients are advised
not to have any other food or drink for 30-60 minutes. This is
because food or drink other than water will reduce further the
absorption of what is already a poorly absorbed medication.
Following ingestion, the patient should remain upright for at least
the next hour, to reduce the chance of the medication getting back
into the esophagus where it can cause irritation. Actinol
(risedronate) has recently become available in an enteric-coated
preparation called Atelvia
that eliminates the waiting time
to eat or drink. This could lead to improved compliance and
absorption. Studies have shown that patients for one reason or
another, are not particularly good at taking oral bisphosphonates
and apparently these drugs don’t work if they are not taken as
prescribed.
Prolia
(denosumab) is a new medication
that is a subcutaneous injection that is given every six months. The
drug is classified as a monoclonal antibody. It is directed at RANK
Ligand that is overexpressed following menopause. The binding of
Prolia to RANK Ligand reduces the availability of RANK Ligand to
bind with RANK on preosteoclasts and osteoclasts. This results in
fewer osteoclasts formation and lesser aggressive osteoclasts. This
in turn leads to decreased bone resorption. Prolia is somewhat more
powerful in inhibiting bone resorption than the oral
bisphosphonates. Subcutaneous injections of Prolia avoid the GI
Tract and therefore can be better tolerated by some people who have
GI complaints while on an oral bisphosphonate. Prolia has been
associated with an increased incidence of reoccurrence of chronic
skin conditions such as eczema and there has been a slightly higher
incidence of skin infections reported.
All the drugs so far
mentioned interfere with osteoclast function (bone resorption), but
there is one FDA approved drug that can activate bone formation by
stimulating osteoblast activity. This drug is Forteo
(teriparatide), which is
considered to be an anabolic drug and not an anti-resorptive drug.
Forteo is a form of parathyroid hormone (PTH). Persistent exposure
to PTH as occurs in patients who have hyperparathyroidism, usually
have accelerated rates of bone loss, but when the same hormone is
given intermittently such as daily subcutaneous injections, the
result is a paradoxical response with stimulation of osteoblasts to
lay down more bone. This drug has been approved for use for a
maximum of two years. This is because in rats, Forteo has been shown
to cause a form of bone cancer called osteosarcoma. This
complication has not been shown to occur in humans. Treatment has
been limited to patients with more extreme forms of osteoporosis.
This includes patients who have had multiple previous fractures or
who have failed to respond to oral bisphosphonates. After completing
a course of therapy with Forteo, it needs to be followed by a
bisphosphonate or Prolia in order to maintain the improvement that
was achieved while taking Forteo.
All of the antiresorptive
drugs, including bisphosphates and Prolia, have been associated with
a small risk of a condition called osteonecrosis of the jaw (ONJ).
This can occur spontaneously but it is far more likely to occur
associated with a tooth extraction. The end result is a local
infection and delayed healing of the bone. The chance of developing
this problem is much increased if the patient has also been on drugs
that affect the immune system such as steroids or chemotherapy.
Stopping oral bisphosphonates before the procedure is not likely to
be helpful because of the very long half-life of bisphosphonates in
bone. Before starting any form of antiresorptive treatment, patients
should complete any dental work that is necessary.
An even
rarer problem with antiresorptive drugs is atypical
fractures, which
mean fractures that occur in bones or parts of bones where
osteoporotic fractures rarely occur. This has been attributed to
extreme over-suppression of bone turnover. Fear of this complication
is exaggerated, and the benefits of these drugs are far outweighed
by the 50% reduction that occurs in osteoporotic fractures in such
locations as spine, hip, wrist, pelvis, clavicle and humerus.
Different dosing regimens, including drug holidays from
bisphosphonates, are being evaluated to reduce further this rare
complication, but there are no studies available yet to make a firm
recommendation. Some individuals may have been given bisphosphonates
inappropriately (when they were not indicated) and it is with these
patients that I am most likely to recommend a drug holiday by
stopping the medication.
Drug
therapy is indicated in patients who:
1)
have already had an osteoporotic fracture (each fracture increases
the likelihood of subsequent fractures).
2) have a T Score
in the spine or the hip of less than -2.5 standard deviations from
the mean of a young normal population.
3) have a T Score of
-1.5 to -2.5 (osteopenia) and who have other factors that would
increase their chance of having a fracture such as a strong family
history of osteoporosis, tendency to fall, certain drugs, rheumatoid
arthritis.
The decision to treat osteoporosis can be
clear-cut or it can be questionable. In order to help make that
decision, a scoring system has been devised called the FRAX Score,
the score. This scoring system utilizes the bone mineral density
(BMD) in the femoral neck of the hip and other identifiable risk
factors that predispose to fractures. The FRAX
Score estimates
what a patients’ probability is of having a fracture in the
hip or any major osteoporotic fracture over the next ten years. If
the probability of a hip fracture is estimated to be greater than or
equal to 3%, or the probability of any major osteoporotic fracture
is greater than or equal to 20%, then the evidence would favor
intervention with a medication such as a bisphosphonate. The FRAX
calculator can be found on the internet at www.shef.ac.uk/frax/
Because osteoporosis can be a silent disease, compliance is
a huge problem and patients, unfortunately, are inconsistent in
taking their medications. Generic preparations of Actonel and
Fosamax are available although these drugs should be equivalent to
the branded preparations. This may not in fact, be the case. The
reason for the difference could be related to a high incidence of GI
problems with these generic drugs and therefore compliance. It is
also possible that the generic drugs have reduced bioavailability
compared to the branded drugs and at least one study showed a 40-50%
lower BMD increase when generic compounds were used.
Other
treatments such as plant phytoestrogens
have not been adequately
evaluated to support their use. Fluoride,
which has been helpful in preventing tooth decay, may also be
helpful to improve bone density but the effect can vary with the
dose and can, in fact, have a paradoxical effect on bone to increase
fracture rate. Currently no FDA approved preparation of fluoride is
available. Strontium,
which is available in Europe and seems to have an anabolic effect on
bone, is not available in the US. Calcitonin
(myacalcin) has a relatively
weak effect on bone and should be considered only if all other drugs
cannot be tolerated. Evista, which has both antiestrogen and
estrogen like properties, has been shown to maintain bone density.
Evista has also been shown to reduce the incidence of estrogen
dependent breast cancer. Evista has been used to treat osteopenia
and milder forms of osteoporosis.
Bone
density testing should
be done in all women 65 years and older. Bone density testing could
be done between menopause and age 65 if patients have risk factors
that put them at higher risk of developing osteoporosis. These
include a strong family history of osteoporosis, rheumatoid
arthritis, prolonged use of steroids. Bone density testing can be
done every two to five years if a normal bone density has been
documented. Bone density can be done yearly if a patient has been
started on a medical treatment in order to assess response to
treatment.
For a drug to be effective, bone density does not
necessarily need to increase. If patients maintain their bone
density, the fracture reduction is quite similar to patients whose
bone density increases. The purpose of repeat bone density
measurements is therefore not necessarily to document the increase
of bone density but rather to identify patients whose bone density
decline during treatment. A decline in bone density might imply
noncompliance with the treatment or unrecognized secondary causes of
bone loss such as Vitamin D deficiency or hyperparathyroidism. If no
secondary cause can be found, then a switch to a more potent
treatment or a referral to a physician who specializes in
osteoporosis management is advised.
Fractures tend to occur
when people fall down. Therefore steps to avoid falls are essential.
People are most likely to fall at night on the way to the bathroom.
Modifications in the bathroom such as the addition of handrails
could prevent falls. Patients who are highly likely to fall could
wear hip protectors, which are pads that go over the hips and can be
purchased over the internet.
Osteoporosis is a common medical problem that can lead to fractures which can be life changing and life threatening. Osteoporosis can be accurately diagnosed and under current treatments can reduce the incidence of fracture by about 50% or more. The goal is to try to prevent osteoporosis through better nutrition during adolescence and then through adult life. We want to make sure that patients who are at risk of fractures get the medications that they can afford, tolerate and continue to take.
David Feinstein, MD FRCP(C), FACP, FACP