Hormone-Refractory Prostate Cancer

or Castrate-Resistant Prostate Cancer

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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)
 

 
 

 

This information related to HRPCa, AIPC, and/or CRPC is provided for educational purposes only and does not replace or amend professional medical advice. Unless otherwise stated and credited, the content of this website is by and the opinion of and copyright © 2001-2013 Howard Hansen and/or HRPCa Association, Inc.  All Rights Reserved.  Our policy regarding privacy, right to reprint and contact information are at About Us. We are a 501(c)(3) not-for-profit public charity.