|
Further Discussions on the Use of Fosamax for
Osteoporosis
My
April 2008 newsletter carried an article, Patients
Commonly Receive Misinformation on Osteoporosis
Treatments by Gillian Sanson who is a woman's health
educator and researcher in Auckland, New Zealand and the
author of several books, including The Myth of
Osteoporosis. I would like to continue this
discussion beginning with a response from Jerry
Donnelly, D.M.D of a men`s osteoporosis support group,
maleosteoporosis.org. Following Dr. Donnelly’s concerns
is a reply from Ms. Sanson. For my thoughts on this
subject see my
Hot Topics on osteoporosis:
May
1, 2008
Dr.
McDougall,
I'm
disappointed in the information in the latest newsletter
regarding osteoporosis and Gillian Sanson's letter you
printed. Osteoporosis, and bisphosphonates for its
treatment, is a complex medical problem often fraught
with misinformation that doesn't make it easier for
people to sort facts from fiction. Sanson's article,
which could have been good, adds more misinformation.
I'm particularly bothered by her cherry picking a few
articles, particularly older ones, and then selecting
sentences here and there to present her case without
also covering other facts presented in the articles, or
elsewhere. I do agree on all but one topic, which I'll
discuss below, regarding what she says in the last
segment about
over-treating individuals who don't have frank
osteoporosis, but that seems to get lost because of the
faultiness of other information in the letter.
It is
very confusing to say, "They [bisphosphonates] do not
re-build bone, . . ." Exactly what do they do then?
They certainly allow the body to rebuild bone, while not
doing it themselves, but what is the difference? If my
T-score was -2.5 (I had lost 25% of my bone density)
when I first started taking Fosamax and it is now
normal, is she saying there is no new bone?
Bisphosphonates work because they prevent the breakdown
of bone by interfering with osteoclasts. They have no
effect on osteoblasts which continue to build bone.
This gives a net effect of increased bone build up
compared to pretreatment levels because the body can
form more bone. If this is not rebuilding bone, what is
it?
To say
the anti-fracture benefit is minimal and then cite an
eight- and a ten-year old study is not good science.
There are too many subsequent studies showing the
benefit of bisphosphonates on fracture reduction for me
to cite. But I will give you two that show rather
effectively that, not only do the bisphosphonates reduce
fracture risk, they do it in proportion to how well the
individuals adhere to the prescribed bisphosphonate
dosing regimen. [To see any studies I cite, go to
PubMed and paste in the numeric portion of the PMID] See
PMID: 17999022 for a study by Rabenda V and others in
Osteoporosis International in November 2007. In summary
this study showed that individuals who took their
medications as they were expected to had a 60% reduction
in fracture risk compared to those who did not follow
dosing regimens and didn't properly take their
medications. Note that the poorest compliance was
among women taking the 5-mg daily alendronate and that
greater compliance occurred when the 70-mg once-weekly
dosing was used. Note also that the two studies Sanson
cites regarding fracture efficacy were done when the
only dose available was 5-mg daily. Even so this dosage
was shown to be effective in preventing fractures,
particularly in individuals with true osteoporosis, as
would be expected.
Another study showing the effectiveness of fracture
reduction when patients complied with recommended dosing
levels was done by Siris ES and others in Mayo Clin Proc
in 2006, PMID: 16901023. They found significantly fewer
fractures at 24 months when compliance rates were above
50%, and particularly when 75% or greater. Note that in
some studies compliance rates have been shown to be
approximately 39%.
Once
again for her citation on fracture reduction she recites
the 12-year-old article by Black DM and others while
ignoring 12 years of other articles on this topic. I'm
sure she is aware of this, but her readers may not be.
Any medication taken for osteoporosis is going to have a
limited fracture reduction ability. If an individual
with, e.g., 25% reduction in bone mineral density (BMD)
never falls, that person will most likely never
fracture. Those who will, however, expect to benefit
are those who have regained BMD and who also happen to
fall. If there were a way to know in advance exactly
who would fall and who wouldn't fall we'd never need
medications except for those with the most severe BMD
loss. Unfortunately, no one has figured out how to
predict falls yet, so we have to give the medications to
all those at risk to prevent fractures in the few who do
fall.
The
information Sanson provides regarding brittle bones is
extremely weak. The article that Dr. Ott writes her
editorial about cited 9 older individuals, 3 of whom
were also on estrogen and 2 of whom were on
glucocorticoids. Considering the millions of
individuals who have taken Fosamax, I certainly don't
find these numbers alarming, and don't think any good
scientist would pay them much heed without further
evidence of the microfracturing problem. Additionally
she cites an article regarding beagle dogs in which the
authors note, "The doses of these bisphosphonates were
six times the clinical doses approved for treatment of
osteoporosis in humans." To cite that article and not
mention that these animals were given six times the
normal human dose is quite deceptive.
To
cite a lawsuit in progress with absolutely no scientific
evidence for any of the statements by the plaintiff is
also deceptive. I'm taking Fosamax and noticed that my
food didn't taste as good today, can I sue Merck and
blame Fosamax and have that cited as a side effect of
Fosamax? Come on!
Sanson
states that there is only one long-term study on
bisphosphonates, but this is incorrect. There is also a
7-year study for risedronate. See PMID: 15455188 for
the study by Mellstrom DD and others in Calcif Tissue
Int in 2004.
In her
final sentence she mentions regular exercise and
appropriate diet to maintain bone health. I'm a vegan
now and follow your plan as much as I can. I was also
mostly vegetarian when I was diagnosed with osteoporosis
and I was active duty Army doing a regular exercise
regimen of aerobic and nonaerobic exercise for the
previous twenty years which didn't protect me from
osteoporosis. I'm aware of no clinical trial showing
that any diet and exercise regimen is effective in
treating, especially postmenopausal osteoporosis, or any
other form of osteoporosis either.
Sanson
is bothered by what she considers as too great an
emphasis on the positive for bisphosphonates and not
enough emphasis on the negative. She, in my opinion,
suffers from having the exact opposite overemphasis on
the negative aspect of bisphosphonates without giving
them enough credit for their beneficial actions.
Reality is somewhere between these two levels, and that
is what I think your readers should know.
Bisphosphonates are certainly not the ideal medication
that I would suggest for anyone with osteoporosis, but
there are few alternatives at this point especially for
men, and there were none in 1995 when I was diagnosed
with osteoporosis. The Sanson letter never mentions men
who comprise about 20% of those with osteoporosis, and
she suggests no real options that have been shown
effective in controlled clinical trials at regaining BMD
for individuals with osteoporosis. To criticize that
which has been shown effective at treating osteoporosis,
albeit with some side effects, and offer no proven
alternative to regain lost BMD, is not doing your
readers a service. I've suffered vertebral compression
fractures before I started Fosamax with none since. I
also don't want more, or worse, a hip fracture. Thus
I'm forced to stay with Fosamax, its side effects
notwithstanding, until someone provides me with a safer
clinically proven alternative to retain my currently
normal BMD. I suspect many other men and women are in
the same category.
Regards,
Jerry
Donnelly, D.M.D (Doctor of Dental Medicine?)
www.maleosteoporosis.org |
|
Reply fom Gillian
Sanson
May 4, 2008
Dear Dr Donelly
I appreciate the
comments raised in your email of May 1st. It
is the lack of information and widespread misinformation
about osteoporosis diagnosis, prevention and treatment
that concerns me also. However, rather than being
polemic as you suggest, I believe I offer an
evidence-based perspective that goes some way to redress
the imbalance of information generated by an uncritical
media, commercial influence in the reporting of clinical
trials, and direct-to-consumer advertising of
pharmaceuticals – all of which could be accused of
‘cherry-picking’ the research and selectively educating
the public.
In my experience,
consumers and doctors like to know as much as possible
about potential benefits, side-effects and risks of
treatments in order to better consider the pros and cons
of embarking on treatment. It is also very helpful to
understand medical concepts like numbers needed to
treat, and the difference between relative and absolute
risk in order to fully understand the effectiveness or
otherwise of a treatment.
My letter published in
the recent McDougall Newsletter addresses the issues
raised by Dr Komaroff in his ‘By the Way Doctor’ column
in the Harvard Health Letter in February this year. He
was responding to questions about the safety of long
term bisphosphonate use – more than 10 years - and about
concerns that long term use could result in weaker bones
and diseases in the jaw. In that context I referred to
the lack of long term evidence, and to accumulating
anecdotal and medical evidence that the drugs could be
associated with increased risk for fracture. The reason
I mentioned the woman taking legal action as a result of
her fractures was that it made news at the time I was
penning my reply and had relevance at that moment. No
doubt you are also aware of the study by
Odvina et al. which reports nine patients
who had been taking alendronate (Fosamax) for 3 to
8 years and presented with unusual fractures with
delayed healing. Although nothing is proved by this, the
cases are important because they provide more
clues about the potential adverse effects of
bisphosphonates and their action of suppressing bone
formation - something that we will not fully know the
repercussions of for many years to come. The recent
evidence for jaw necrosis and other bone necrosis
associated with oral bisphosphonate use must serve as a
warning that these are drugs with the potential for
serious harm.
Obviously there is a
distinction between osteoporosis prevention and the
treatment of established osteoporosis. My letter did not
cover the controversial issue of the diagnosis of
pre-osteoporosis or osteopenia based on bone mineral
density (BMD) alone, and the associated widespread
prescribing of potent drugs to healthy individuals to
reverse normal age-related bone loss. It did however
acknowledge there is the potential for benefit from
bisphosphonates in ‘high risk’ individuals, but observed
that even then, the majority who take the drug will not
benefit from it. Impressive sounding relative risk
reduction percentages can be very misleading and mask
the much smaller reductions in absolute risk. Even ‘high
risk’ women and men are at low absolute risk for
fracture and if fully informed may choose not to take
medication for the small absolute risk reduction it
offers.
Unfortunately, an
increase in bone density does not necessarily equate
with fracture prevention. Although you maintain it is
not ‘good science’, the Phase III Fracture Intervention
Trial (FIT) of 1996 and 1998 I refer to remains the
largest randomised controlled trial (RCT) on alendronate
(Fosamax) to date, and its two branches are still
considered the definitive trials to this day – just as
the similar size and vintage VERT and HIP studies remain
the original and most cited trials of risedronate (Actonel).
There is in fact no better science to be found on these
drugs. In recent years there has been considerable
re-analysis of data from these original trials.
The
new 2008 Cochrane reports on both
alendronate and
risedronate are meta-analyses of all randomized
controlled trials from 1966 to 2007. They therefore
offer the most useful evidence on fracture outcomes to
date. Their findings reflect almost exactly the same
small fracture risk reductions as those reported in the
early big trials mentioned above. They conclude that for
5 mg of risedronate daily there were no statistically
significant reductions in the primary prevention of
vertebral and non-vertebral fractures. A statistically
significant benefit in the secondary prevention of
vertebral, non-vertebral and hip fractures was observed,
but not for the wrist. For alendronate, at 10 mg a day,
the outcome was similar, except that for primary
prevention there was a clinically important reduction in
vertebral fractures. Of note, the absolute risk
reduction for secondary prevention of hip fractures was
only 1 percent. This is the same as the outcome from the
FIT trial.
You are right to point
out that I made an error when I overlooked the 2 year
extension of the risedronate trial which does offer data
up to 7 years. However the 2 year extension was not
placebo controlled and involved only 164 women. The fact
remains that we do not have evidence from large
long-term placebo controlled trials and the long term
effects of bisphosphonates remain unknown. Meantime vast
numbers of people continue to take these drugs which
accumulate in the body and have an indefinite half life.
It is my hope that as consumers we have learned from the
mistakes of the past – in particular the prescribing of
HRT to millions of women for over more than 4 decades
when there was no evidence from large long-term placebo
controlled trials determining short or long term
safety. As a consequence generations of healthy women
were put at increased risk for heart disease, blood
clots, stroke, and breast cancer.
Unfortunately,
bisphosphonates do not rebuild bone. They are not
anabolic – i.e. they don’t build up bone tissue,
replace, or rebuild damaged trabecular bone. They do, in
most cases, increase BMD, thus DEXA scans will show an
increase in mineral density or quantity. Just how this
impacts on bone quality long term is still not clear.
Increased mineralization appears to increase the risk
for more brittle bone. For an excellent explanation of
the action of bisphosphonates, I refer you to Dr. Susan
Ott’s 2005 article
‘Long-Term Safety of Bisphosphonates’ published in
the journal of Clinical Endocrinology and Metabolism:
‘The amino-bisphosphonates
strongly inhibit osteoclastic bone resorption.
During normal bone remodeling, osteoblastic bone
formation follows resorption and occurs within the
eroded cavities, so inhibition of bone
resorption also results in inhibition of bone
formation. Bone biopsy studies using double tetracycline
labels show that the bone-forming surface is
suppressed by 60–90% with usual doses of the
bisphosphonates. These drugs are certainly
not anabolic! [her exclamation, my bolding] The
volume of bone does not increase. The bone
density as measured by dual-energy x-ray absorptiometry,
however, does increase. This is because the bone
is no longer remodeling, and so there is not
much new bone. The older bone is denser than
the newer bone; there is less water and more
mineral in the bone, and the radiographic techniques
thus measure the higher density. Osteoporotic
bone is generally undermineralized, so some
increase in mineralization (or hardening of the bone)
may improve the bone strength.’
Bipshosphonates are
becoming easier to take, with once-a month and
once-a-year doses now available. We don’t have any
evidence from clinical trials to reassure us that the
side-effects with higher doses are not greater.
Susan Ott warns: ‘The bisphosphonates in doses used
today suppress bone formation to a greater
extent than the other antiresorbing medications,
so it is possible that microdamage accumulation
would develop after 15 or 20 yr—just about
the time between menopause and the usual
onset of osteoporotic fractures. Certainly this
is an issue that requires long-term, carefully
designed research.’
The official in the FDA
who recently raised the alert regarding the joint bone
and muscle pain side-effect is concerned that this
effect may be more apparent now because it is associated
with the much higher doses. I am contacted almost daily
by women who have taken Fosamax or Actonel, and are now
suffering from crippling chronic pain. Some are even
confined to wheel chairs and unable to manage the
simplest of daily tasks. Most question why they were not
warned of the potential for this serious side-effect. I
worry that these women represent the tip of the
ice-berg. How many out there are experiencing severe
pain that is attributed by their doctor to
osteoarthritis or even osteoporosis rather than the
bisphosphonate?
Regular exercise and
appropriate diet is a commonsense recommendation for
prevention of osteoporosis and a host of age-related
conditions. With respect, I did not make claims in my
letter that there are clinical trials showing that
either of these modalities will successfully treat
established osteoporosis.
I am not an
osteoporosis expert. I am a women’s health educator and
a health care consumer with a family history of
osteoporosis who is looking for answers. Bisphosphonates
are one of the few pharmaceutical options available to
people at this time. I would be delighted if they were
safe and effective treatments. It is up to each
individual to determine whether the benefit of taking
these drugs outweighs the risk in their situation. I
don’t claim to have answers, but I do think we are owed
accurate information in our search for them.
Best wishes,
Gillian Sanson
www.gilliansanson.com
www.gilliansanson.wordpress.com
|
