BONE
INTEGRITY
A Critical Issue for Advanced Prostate Cancer
NOTE:
Consult your doctor on Bone Integrity Management. The following was
written by a patient with HRPC who was diagnosed with moderate osteoporosis
after 18 months on hormone therapy, but he is not a medical doctor.
Topic
Index
Introduction
What
Is Bone Integrity And Why Is It So Important?
Who
Should Be Concerned With It?
Tests
To Check Bone Integrity And Osteoporosis
What
Can Be Done To Prevent Osteoporosis?
What Can Be Done To Restore/maintain Bone Health - bisphosphonates?
Other
Compounds For Correcting Bone Loss
What
Are Side Effects Of The Medication?
Are
There Other Concerns With These Medications?
References
Additional
Websites Related To Bone Integrity/Osteoporosis
Glossary
Introduction
The
importance of maintaining bone integrity for advanced prostate cancer
patients cannot be over emphasized. Men who are on hormone therapy,
which suppresses male androgens (e.g., testosterone), are in danger
of not maintaining their bone integrity. This can result in developing
osteopenia and osteoporosis (low, lower bone mineral density) and thus
a higher probability of bone fractures and perhaps a higher susceptibility
to bone metastases. Many urologists and oncologists are lacking a working
knowledge of this area of prostate cancer management. This may be due
to the fact that osteoporosis (a result of not maintaining bone
integrity) is primarily diagnosed and treated by endocrinologists and
rheumatologists. In light of this, patients have to be pro-active in
maintaining their bone integrity.
What
Is Bone Integrity And Why Is It So Important?
Bones
provide structure to the body and in the case of prostate cancer, bone
provides a favored location for the systemic spread of prostate cancer.
The
standard treatment for prostate cancer that has spread beyond the prostate
itself (hence systemic) is to remove male androgens via surgical or
chemical castration. This results in the same loss of bone mass that
women experience post-menopause, but at a much younger age than normally
seen in men.
In
fact, men not on hormone therapy also develop osteoporosis –
one fifth of hip fractures occur in men and men show the same exponential
increase in hip fractures with age as is seen in women. In men, the
rise occurs about 10 years later than in women (for men not on hormone
therapy). Vertebral fracture prevalence in men is close to that in women.
Who
Should Be Concerned With It?
Men
with prostate cancer who are being treated with androgen deprivation
therapy, such as LHRH agonists (e.g., Lupron and Zoladex) either alone
or in combination with drugs which suppress the androgen precursors
produced by the adrenal glands such as ketoconazole (Nizoral), should
be concerned. Glucocorticoids (e.g., hydrocortisone, prednisone) can
also cause bone loss.
Anti-androgens
such as flutamide or casodex and 5-alpha reductase inhibitors such as
proscar may also contribute to bone degradation, but since they do not
of themselves reduce testosterone, this seems unlikely -- as long as
they are used without LHRH agonists. ASCO 2002
abstract 783 (Sieber PR, et al) found that for bicalutamide(Casodex)
monotherapy, bone mineral density is maintained. Specifically, 150mg
Casodex was compared to medical castration. BMD was maintained for
those on Casodex, but the medically castrated group had a 4-5% loss of
BMD during the two years of observation. Lastly, DES, a
synthetic estrogen compound, supports bone density via estrogen.
Once
on androgen deprivation therapy, changes leading to osteoporosis occur
immediately at a cellular level, according to Strum, but may take months
or years to show up as actual changes in bone density, clinical symptoms
of bone pain or bone fracture. One estimate for the rate of bone loss
is 5-10% in the first year alone (note that for women, each 10% decrease
doubles their risk of fractures.)
Prostate
cancer bone metastases usually cause bone to become much more dense.
Calcium and phosphate are deposited in the region surrounding the tumor
cells (see Prostate Forum, 9/96). The calcium can be taken from bone
structures elsewhere and deposited at the metastatic site. Blood levels
of calcium drop. Thus, you can effectively have thinning of the bones
due to the prostate cancer and at the same time have androgen deprivation
therapy also reducing the BMD which may lead to fractures.
Tests
To Check Bone Integrity And Osteoporosis
DEXA.
Dual energy x-ray absorptiometry of the hip, femoral neck and lumbar
spine. For this test, you lie on a table and the x-ray camera scans
the areas being evaluated. It is fast, totally easy and results are
available shortly after taking the test. Don’t wear anything metal,
however (metal fly zipper is OK). This test will give you your current
bone bank (now you have xx bone material per unit volume). The result
of the DEXA test are reported as a T score and a Z score. Be sure to
use the T-score which references the average peak bone mass for normal
adult women. The more negative this number (in terms of standard deviations),
the more osteoporosis you have. For each standard deviation loss in
bone density, the risk of fracture doubles.
QCT.
Quantitative Computed tomography. Some physicians prefer to use
the QCT scan instead of he DEXA scan since a DEXA scan can be falsely
affected by arthritis and/or calcifications in blood vessels(osteoarthritis
develops in the posterior spinous elements after age 55.) For example, DEXA might show a normal
T-score(> -1.0) while QCT shows a T-score of less than -2.5 which would
indicate osteoporosis.
The
websites for two commercial providers of QCT are: Mindays
www.qct.com or Image Analysis
www.image-analysis.com
A recent
paper by Smith MR, McGovern FJ, Fallon MA, Schoenfeld D, Kantoff PW,
Finkelstein JS, “Low bone mineral density in hormone-naive men with
prostate carcinoma,” Cancer 2001 Jun 15;91(12):2238-45 illustrates the
DEXA/QCT difference. They found that 2 of 41 men (5%) had T scores <
-2.5 by DEXA, but in the SAME men, 26 of 41 men (63%) had T scores <
-2.5 by QCT.
Dpd
or deoxypyridinoline. This is a measure of the collagen breakdown product
deoxypyridinoline
which is available commercially as Metra Dpd(formerly Pyrilinks-D), see
http://www.quidel.com/libraries/pkginserts/BH/8007_metra_dpd.pdf
.
This is a bone breakdown product resulting from osteoclastic degradation
of bone. Osteoclasts are the cells that remove bone (osteoblasts are
cells that add to bone). The normal value in men is up to 5.4. Your
doctor can arrange for this test. You just provide a small amount of
urine (2ml) taken as the 1st or 2nd morning urine
(before 10AM).
If Dpd is greater than 5.4, it usually indicates excess bone degradation
which should be corrected.
NTx (N-Telopeptide.) The Osteomark
urinary NTx test is another breakdown
product test that is available (http://www.ostex.com).
An elevated Dpd or NTx might be brought within the normal range by the
use of a bisphosphonate(see below), calcitriol(synthetic vitamin D) and
calcium supplementation. Urinary NTx is a marker of osteoclastic
activity (bone resorption or breakdown.)
24-Hour
Urine. For this test, you collect your urine output over a 24 hour
period and this must also be kept refrigerated. This can be a lot of
urine! The interest here is to find out how much Calcium is being excreted
through your kidneys and too high a level indicates increased risk for
forming kidney stones. The normal amount is up to 250 mg/24 hours of
Ca++.
"Spot
Urine". A small sample of urine is collected and urinary
calcium and urinary creatinine are measured. The ratio of urinary
calcium to urinary creatinine should be less than 35% in order to
prevent kidney stones. For example, if urinary calcium = 16.3 mg/dl and
urinary creatinine = 77.9 mg/dl, then the ratio is .21 or 21%.
Calcium
in the blood (serum calcium). This must be monitored on a regular
basis. It may be necessary to decrease the amount of calcium in your
diet and/or what you are taking as supplements, if you are also taking
Rocaltrol/calcitriol. There is an incredible balance between the amount of calcium,
the amount of Rocaltrol/calcitriol and the bisphosphonate dose that requires careful
monitoring by your physician.
Alkaline
Phosphatase, serum Bone-specific alkaline phosphatase (BAP.) When
alkaline phosphatase is measured, it is actually the sum of the
bone-specific and liver-specific components (isoenzymes.) BAP can indicate excess osteoblastic cell activity which
may indicate bone metastases. Metra Systems, Inc., says that Bone Alkaline
Phosphatase is an osteoblast membrane-bound molecule which is involved
in bone formation. Levels of this enzyme are thought to be indicative
of the activity of osteoblasts.
Another description of AlkPhos is
that it is an enzyme that is found on the surface of osteoblasts(the
cells that build bone) and as such is used as a serum marker of
increased osteoblast activity. Since bone is being added at
prostate cancer bone metastases, an increased alkaline phosphatase can mean increased
bone met formation. A recent paper by MR Smith et al in Urology
discussed BAP and NTx in their role as predictors of skeletal
complications in HRPC patients (MR Smith, et al, Urology 70: 315-319,
2007.) Their conclusion was that elevated baseline levels of BAP are
associated with a greater risk of adverse skeletal outcomes - events
such as shorter time to radiotherapy or shorter time to first pathologic
fracture. NTx was also found to be of value in monitoring patients
on bisphosphonates.
What
Can Be Done To Prevent Osteoporosis?
For
men without advanced prostate cancer (i.e., not on hormone therapy)
normal androgens and estrogen are usually present in quantities sufficient
to prevent osteoporosis. Additionally, since weight bearing exercise
stimulates bone growth (see Prostate Forum, 11/98), exercise (walking,
aerobics, weight bearing or muscle building exercises) should be a standard
part of a prevention program. Calcium supplements and vitamin D are
the remaining items.
Once on androgen deprivation therapy (surgical or chemical), Strum and
Myers and others recommend bisphosphonates such as Fosamax, Actonel, Aredia
or Zometa along with
Rocaltrol (calcitriol,
1,25 dihydroxy Vit D3), calcium (from calcium citrate) 500-1000mg/day
and exercise as defined above.
Strum
also feels that oral fluoride is a key substance that will make more
bone and harder bone.
Yet another option is to avoid
gonadotropin-releasing hormone agonists (e.g., Lupron, Zoladex) and use
Bicalutamide monotherapy (Casodex). A recent paper discusses bone
turnover during Bicalutamide monotherapy(Smith MR et al, Urology 61:
127-131, 2003). They found
| Treatment |
Testosterone |
Estradiol |
Deoxypyridinoline N-telopeptide
serum
osteocalcin |
| Hormone Naive |
<
Bicalutamide
397 ng/dL |
<
Bicalutamide
27 pg/mL |
Similar to Bicalutamide |
| Bicalutamide |
> GHRH
678 ng/dL |
> GHRH
50 pg/mL |
Similar to Naive |
| GHRH |
<
Bicalutamide and naive
14 ng/dL |
<
Bicalutamide and naive
7 pg/mL |
Highest |
| Conclusion: bicalutamide
monotherapy may maintain bone mineral density and prevent fractures. |
Still another option is to use estrogen patches as the
hormone therapy instead of the GHRH agonists. This might avoid the
use of bisphosphonates, but that is not proven.
What
Can Be Done To Restore and Maintain Bone Health?
Vitamin D, Calcium and bisphosphonates.
As
noted above, the combination of a bisphosphonate such as Fosamax,
Actonel, Aredia or Zometa, synthetic vitamin D in the form of Rocaltrol/calcitriol and calcium supplementation
in the form of calcium citrate are what Strum and Myers generally recommend.
Also recommended is an exercise program (gradually built up) and possibly
an oral fluoride. Detailed information is given in the PCRI Insights
and Prostate Forum newsletters referenced below. Various bisphosphonates
are listed below for reference.
Note:
rocaltrol/calcitriol is a prescription item and is
1,25 dihydroxy Vit D3 and is not to be confused with the normal,
over-the-counter vitamin D3. Myers(Prostate Forum, Vol. 7, No. 1,
November 2002,page 6) says "Fosamax and the other bisphosphonates do not
work well in the absence of adequate calcitriol. And further,
"...this agent can improve the effectiveness of bisphosphonates."
The Prostate Forum of May 2005 (Vol. 9, no. 2) "Vitamin D and Prostate
Cancer" provides updated information on how much vitamin D is needed.
The newsletter covers more than just the application to bone integrity.
Myers suggests 2000 IU vitamin D3 might be appropriate and that levels
of calcitriol should be kept at levels above 40pg/ml. See also the
Vitamin D Council's website.
A series of slides showing the flow of vitamin D is found at
Vitamin D and Bone Health. This is a presentation by David
Hanley, MD.
Bisphosphonates.
Bisphosphonates are effective for maintaining bone integrity and can
result in some increase in bone mineral density. All of the
bisphosphonates listed are on the market, either in the USA or
elsewhere. Their approved use varies.
Aspects of the clinical use of bisphosphonates that
are well established are:
-
Palliative treatment of bone pain due to metastatic disease.
-
Treatment
for malignancy-associated hypercalcemia.
-
Treatment
of skeletal disorders such as osteoporosis, Paget’s disease, multiple
myeloma and breast cancer bone metastases and for
Zometa, treatment of
bone metastases.
Aspects
that are Less Well Established or Speculative.
-
Prevention of bone metastases in prostate cancer(however, read the
page on Zometa to find out about the results of clinical trials with
prostate cancer.)
-
A survival benefit.
-
The blocking of tumor cell mitosis and
stimulation of tumor-cell apoptosis.
Other
Compounds For Correcting Bone Loss or
Maintaining BMD.
Ipriflavone,
a synthetic soy derivative (see PCRI Insights, December 1999, pp.1-5,
9).
Raloxifene
(Evista), a new drug for women suffering osteoporosis. Evista is also
being tested in men who have started hormone therapy(Dana Farber Cancer
Institute) and is also being tested as an anti-prostate cancer treatment
for hormone refractory men.
Miacalcin,
a nose spray (see caution below).
What
Are Side Effects Of The Medication?
Stephen
Strum, M.D. has indicated that the initial dosing with Pamidronate should
only be with 30 mg over 1.5 hours to minimize the chance of an acute
phase response. It can be given at 60-90 mg over 1.5 hours every two
weeks thereafter. Once a month is adequate for osteoporosis treatment.
For pain management, higher doses and more frequent dosings may be required.
This must be worked out with your doctor (see PCRI Insights, January
1999, p. 5.)
Fosamax
dosing directions should be followed very carefully. Fosamax, is poorly
absorbed and must be taken on an empty stomach with water only, ideally
2 hours before breakfast for maximum absorption, but can be taken as
short as 30 minutes before eating. In other words, take upon rising
from a good nights sleep, with about 8 oz. of water, then wait 30 minutes
to 2 hours before having breakfast (1 hour is a good compromise). After
taking Fosamax, one must remain in an upright position (sitting, standing,
but not lying down horizontally). Actonel has similar requirements.
Zometa has a requirement for
monitoring serum creatinine before administering Zometa to ensure that
the kidneys are not deteriorating. See the prescribing information for
more information, www.zometa.com (go
to the USA site from here.)
In general, consult the full
prescribing information for details.
Are
There Other Concerns With These Medications?
Miacalcin
is a brand name for a calcitonin product. It is not as potent in stopping
bone resorption (destruction) as most of the newer bisphosphonates –
being far weaker than Fosamax. Dr. Myers has raised a concern related
to the finding of calcitonin receptors on CaP cells - the worry is that
this might promote their growth in humans with CaP on Miacalcin. Dr.
Strum, however, says, "I have not seen anything to suggest that
this is true in the patients we have on Miacalcin. However, these are
small numbers of patients and larger observations are needed one way
or another. Reference: G.V. Shah et al, "Calcitonin Stimulates
Growth of Human Prostate Cancer Cells Through Receptor-mediated Increase
in Cyclic Adenosine 3’, 5’- Monophosphates and Cytoplasmic Calcium Transients,"
Endocrinology 134 596-602, 1994. Myers recommends Fosamax or Aredia
instead of myacalcin.
References
The
PCRI Insights newsletter, mostly written by Stephen Strum, MD, is available
online. It is written in PDF format and requires Adobe Acrobat 3.0 or
newer to download/view. The website for the Prostate Cancer Research
Institute is http://www.prostate-cancer.org/
and from there click on the "Insights" tab.
1.
PCRI Insights Newsletter (New Developments in Prostate Cancer Treatment)
October 1998, vol. 1, no. 1, pp. 7.
2.
PCRI Insights Newsletter (New Developments in Prostate Cancer Treatment)
January 1999, vol. 2, no. 1, pp. 1-6.
3.
PCRI Insights Newsletter (New Developments in Prostate Cancer Treatment)
May 1999, vol. 2, no. 2, pp. 8-9.
4.
PCRI Insights Newsletter (New Developments in Prostate Cancer Treatment)
July 1999, vol. 2, no. 3, pp. 14-15.
5.
PCRI Insights Newsletter (New Developments in Prostate Cancer Treatment)
December 1999, vol. 2, no. 4, pp. 1-4.
Prostate
Forum Newsletter, written by Charles Myers, M.D., is available at the
following website (at which you can order both the newsletter and back
issues.):
http://www.prostateforum.com.
6.
Prostate Forum, September 1996, Prostate cancer and your bones. Use
of vitamin D, calcium, exercise and Fosamax.
7.
Prostate Forum, July 1998 - Important update on vitamin D.
8.
Prostate Forum, November 1998 - Problems with falls and balance. Principles
of exercise.
Other
References Related to the Impact of Androgen Deprivation Therapy on
Bone Mineral Density
Harry W. Daniell*; Stephen R. Dunn; David W. Ferguson; Gregory Lomas†;
Ziad Niazi; P. Tryg Stratte, Progressive Osteoporosis During Androgen
Deprivation Therapy For Prostate Cancer, The Journal Of Urology 2000;163:181.
Smith MR, McGovern FJ, Zietman AL,
Fallon MA, Hayden DL, Schoenfeld DA, Kantoff PW, Finkelstein JS, "Pamidronate
to prevent bone loss during androgen-deprivation therapy for prostate
cancer," N Engl J Med 2001 Sep 27;345(13):948-55.
Smith MR, McGovern FJ, Fallon MA, Schoenfeld D, Kantoff PW,
Finkelstein JS, “Low bone mineral density in hormone-naive men with
prostate carcinoma,” Cancer 2001 Jun 15;91(12):2238-45. In
this paper they reference 5 papers that document the bone loss due to
androgen deprivation therapy ranges from 4-13%/year and this is on top
of already pre-existing bone loss.
Additional
Websites Related To Bone Integrity/Osteoporosis
The National Osteoporosis
Foundation,
http://www.nof.org
A site maintained by Susan Ott,
M.D., University of Washington, Dept. of Medicine,
http://courses.washington.edu/bonephys/
Glossary
BMD – Bone Mineral Density
DES – diethylstilbestrol, a
synthetic estrogen
DEXA – Dual Energy X-Ray
Absorptiometry
Dpd – deoxypyridinoline (Metra Dpd);
a bone resorption marker reflecting breakdown of bone collagen
LHRH – luteinizing
hormone-releasing hormone; a hormone from the hypothalamus that
interacts with the LHRH receptor in the pituitary to release LH
Modeling and remodeling -
osteoclasts remove bone; the osteoblasts fill in the hole(s). Thus, new
bone is formed on a regular basis(in the absence of bisphosphonates.)
This is the process in adults - no change in bone shape or size occurs.
The amount removed equals the amount deposited. In osteoporosis, more
bone is destroyed than deposited. With bone metastases, bone may
be removed(osteolysis) excessively or excessive bone can be added as in
prostate cancer.
Osteoblasts – bone-forming cells
derived from precursor cells in the blood. They migrate to areas where
bone has been eroded by osteoclasts and lay down collagen and minerals
in the cavities
Osteoclasts – specialized bone
cells which erode mineralized bone by secreting acids and lysosomal
enzymes. They are attracted to bone injury sites. Osteoclasts are
responsible for bone resorption which is the normal process of the
breakdown of bone. Bone resorption triggers bone formation which is done
by the osteoblasts -- a coupled process.
Osteolysis - The dissolution, or
disintegration, of bone.
Osteopenia – Low bone mass or 1-2.5
standard deviations below normal
Osteoporosis – Lower bone mass than
osteopenia or > 2.5 standard deviations below normal.
PC-SPES – a mixture of eight herbs
used in the treatment of prostate cancer(no longer available.)
Author: Howard Hansen (last updated
7 November 2007)
