By Stephen B. Strum, M.D.
Reprinted from PCRI Insights January, 1999 vol. 2, no. 1
Much of this issue of Insights is devoted to an in-depth discussion of bone integrity. Why so much emphasis on bone? Every so often I come across a topic in PC that rivets my attention. Bone integrity and the factors that relate to growth of PC in bone, why PC spreads to bone, the nature of bone pain from PC and the issue of prevention of bone metastases by changing the micro-environment are important pieces in the puzzle of what we need to solve about PC. Bear with me and read through this issue.
In the last issue of Insights, we discussed three concepts relating to bone integrity:
- Bone Formation
- Bone Resorption
- Bone Density
We used the analogy of the bone as a bank account with bone density being the balance, and formation and resorption being deposits and withdrawals, respectively.
When excessive bone resorption persists, a loss in bone mass results. If unchecked, it eventually leads to osteoporosis. Osteoporosis is a critical health issue in the United States; 1 of 2 women and 1 of 8 men older than 50 years of age are expected to have bone fractures. The cost of osteoporotic related illness in the United States is $38 million dollars a day or $14 billion dollars each year. The ratio of bone fractures for men becomes significantly higher when men are subjected to castration since the abrupt decrease in androgens is analogous to what women experience at menopause at the time of abrupt decrease in estrogens. Male menopause is induced by androgen deprivation therapy (ADT), be it from surgical castration, the use of an LHRH agonist like Lupron® or Zoladex®, or sequential androgen blockade (SAB) using an anti-androgen (Casodex®, Eulexin®, or Nilandron®) with a 5 alpha reductase inhibitor (Proscar®).
ADT is an abrupt event. It results in more osteoporosis and related fractures than that observed during natural male menopause. Male menopause induced by castration, from any cause, is an accelerated, compressed, and intensified menopause in contrast to natural menopause, where a gradual loss of androgens occurs over decades.
In men with prostate cancer undergoing ADT, bone resorption begins immediately. This has been documented in publications looking at the alterations of bone architecture as a result of orchiectomy1-5 as well as a side effect of LHRH agonist therapy.6-8
Orchiectomy Causes More Bone Loss Than LHRH Agonists
Compared to orchiectomy, there is a preferential preservation of bone mineralization and less loss of bone osteoid with the use of LHRH agonists. When orchiectomy is performed, the body reacts to the loss of testosterone by stimulating the pituitary to release LH and FSH. The high levels of FSH and LH are also associated with increased levels of ACTH (adrenocorticotrophic hormone) produced by the pituitary with consequent increased levels of cortisol. It is the increased cortisol levels that suppress the osteoblast (the cell that lays down osteoid to initiate new bone formation). These changes do not occur with LHRH agonist therapy or with treatments involving estrogens. LH and FSH production are decreased by these agents, and there is no reflex stimulation of the pituitary gland.9
The Osteoclast Is The Mediator of Bone Resorption
|ADT: androgen deprivation therapy is any treatment that decreases the availability of male hormone (androgens) to the prostate cancer cell population. This can occur by decreasing Testosterone (T), by removing the testicles surgically by orchiectomy, or by the use of LHRH agonists such as Lupron®, Zoladex® or Triptorelin®. It can also be accomplished by the use of anti-androgens such as Eulexin®, Casodex® or Nilandron®, either alone or in combination with Proscar®. Other agents such as Nizoral®, DES® are also examples of ADT, with additional anti-tumor effects not mediated by androgen deprivation.
ACTH: adrenocorticotrophic hormone
ATF: amino terminal fragment (highly active part of uPA molecule)
EGF: epidermal growth factor
|FSH: follicle stimulating hormone
HMW-uPA: high molecular weight uPA
IGF-1: insulin growth factor 1
IGFBPs: insulin growth factor binding proteins
IL-1: interleukin 1
IL-6: interleukin 6
IL1R and IL6R: receptors for IL-1 and IL-6
LH: luteinizing hormone
MMP-2: matrix metalloprotease 2
PDGF: platelet-derived growth factor
PTHrP: parathormone related protein
Resorption: act of removal by absorption
RH: releasing hormone
TGF-b: transforming growth factor beta
TNF-a: tumor necrosis factor-alpha
uPA: urokinase plasminogen activator
Tumor cells try to survive by producing cell products that stimulate the cell’s own growth (autocrine loops) or by elaborating proteins or enzymes that affect nearby cells (paracrine loops). For example, uPA (urokinase plasminogen activator) is a key substance made by the tumor cell that is able to self-stimulate both the tumor cell (autocrine loop) and the nearby osteoblast (paracrine loop). PTHrP, elaborated by neuroendocrine cells that make CGA (chromogranin A), is involved with uPA in similar activities.
The uPA also cleaves IGFBPs (insulin growth factor binding proteins) to release IGFs that not only stimulate osteoblast growth, (which in turn makes more IGF-1), but also allows the IGF-1 to turn on uPA production within the tumor cell (paracrine loop). Other interactions are discussed in the following scenario.
A possible scenario: Osteoblastic growth utilizes calcium and causes a drop in serum calcium stimulating osteoclastic bone resorption to lyse (dissolve) bone to maintain serum calcium. This is accompanied by an increase in parathormone (PTH) and vitamin D levels which are also trying to maintain calcium homeostasis. The osteoclastic activity releases bone-derived growth factors such as insulin growth factor-1 (IGF-1) and transforming growth factor beta (TGF-beta). These in turn stimulate the tumor cell population to grow and release PTHrP and uPA. The uPA cleaves insulin growth factor binding proteins 1 & 2 (IGF BPs 1-2) to release IGF-1 and IGF-2. The uPA and the IGFs as well as interleukin- 1 (IL-1) also stimulate the osteoblasts to produce IL-6. IL-6 stimulates activity of mature osteoclasts as well as osteoclast precursor cells which have been shown to have IL-6 receptors (IL-6R).
The tumor cell within the bone also produces TGF-b which stimulates release of PTHrP and matrix metalloprotease 2 (MMP-2), the latter of which dissolves collagen1. MMP-2 also cleaves a less active form of uPA (HMW-uPA) into a more active form (ATF) which in turn stimulates osteoblast growth. The tumor cell also has receptors for IGF-1 which in turn stimulates production of uPA, as mentioned previously.
What Are The Implications For Treatment?
The tumor cells survival mechanisms are elaborate. However, as these mechanisms become better understood, they give us new opportunities to block the action of cytokines, proteins and enzymes. Agouron® 3340, for example, is an investigational agent that blocks MMP-2 (as well as MMP- 3, 9 and 13).
There are other autocrine loops and paracrine loops of importance that are not shown in Figure 2 due to lack of space. PC cell lines express cytokine factors and their receptors for GM-CSF, M-CSF, SCF and G-CSF (autocrine loops).22 These factors are also commonly found in the bone marrow (paracrine loops). Perhaps sampling the marrow of high-risk patients using micrometastatic assay approaches as is being done by Impath Labs, and evaluating positive assays by incubating them with these various growth factors would give us ways to manipulate tumor growth as well as to caution us on the use of various growth factors in certain patient subsets.
Endothelin-1® (ET-1) is another PC cell product that stimulates osteoblastic growth and may also mediate the pain associated with bone metastases by virtue of its potent vasoconstrictor properties. High affinity ET-1 receptors were found on osteoblasts and ET-1 increased alkaline phosphatase activity during new bone formation in vivo. Moreover, 58% of men with advanced PC had significantly higher levels of ET-1 than the control group.23
The Role Of Bisphosphonates
Discuss these findings with your doctor and show him the references relating to articles in this exciting field. Determine your bone status with a bone mineral density (BMD) assessment along with a first or second voided urine specimen for Pyrilinks-D®. The latter test is one of the measurements of bone breakdown that is increased with excessive bone resorption. Excessive resorption may result from ADT, PC in the bone, the use of steroids or from other factors mentioned in the first issue of Insights. Since this a critical issue in the prevention and treatment of bone metastases, a discussion of bone integrity evaluation and management is warranted.
Evaluation of Bone Integrity & Management
Excessive bone resorption can occur as part of aging, or it can be secondary to medical diseases e.g. diabetes, alcoholism, hyperthyroidism, hyperparathyroidism, breast and prostate cancers, or the use of medications such as steroids and dilantin. We suggest your bone integrity status be evaluated with a baseline bone mineral density (BMD) to determine your bone mass and also with a first or second morning urine to measure the collagen breakdown product deoxypyridinolium (Dpd) which is commercially available as Pyrilinks-D® (Figure 4).
If either or both of these are abnormal, it would be good medicine to correct this by stopping excessive bone resorption and aiding bone formation. How do you do this?
How To Prevent Excessive Bone Resorption
Calcium supplements help make healthy bone and stop resorption. BPs drive calcium into the bone. If no calcium supplement is given or if calcium is not present during these times, hypocalcemia occurs and poor quality bone is formed. Therefore, when using BPs, start calcium supplements a day or two before initiating BP therapy. Use calcium citrate for better absorption. Calcium by itself has been shown to reduce bone resorption. This is especially true if calcium is administered in the evening, ideally before sleep. Due to the large size of the calcium supplements, we suggest you take 500 mg with dinner and 500 mg at bedtime. Blumsohn et al have described the circadian rhythm of calcium absorption as shown below.
- Nocturnal increase in parathormone (PTH)
- Peak Excretion of Dpd & Ntx at 0300–0700
- Calcium taken in evening suppresses nocturnal increase in PTH
- Calcium supplements taken in evening suppresses daily excretion of Dpd by 20%, Ntx by 18%.
Citrical® by Mission Pharmaceuticals or Calcium Citrate® by Solgar are two excellent brands of calcium citrate. If your diet is high in calcium, decrease the calcium supplements accordingly and work with your doctor to optimize calcium administration.
Synthetic Vitamin D
Not to be confused with ordinary Vitamin D3, synthetic Vitamin D (1,25 DihydroxyCholecalciferol), has many interesting properties for PC. In a recent issue of The Prostate Forum, an excellent newsletter published by Snuffy Myers MD and his staff, Vitamin D was reviewed. In the area of bone integrity, synthetic Vitamin D (Rocaltrol® or Calcitriol®), can be used to enhance calcium absorption from the gastrointestinal tract. Rocaltrol® also has antiproliferative36-39 and anti-angiogenesis effects40-41 on prostate cancer growth and is able to slow the rate of PSA rise in patients with early recurrent PC.42 The limiting factor in this study was the finding of increased urinary excretion of calcium. We would speculate that the administration of calcium at night, as well as the use of BPs to drive calcium into bone formation, would decrease these findings and allow for higher doses of Rocaltrol®. Rocaltrol® should also be given at bedtime to decrease urinary calcium excretion.
It appears that calcium and Vitamin D have a circadian rhythm which obviously affects their biologic function. Perhaps bone formation and resorption occur mostly at night or in the early hours of the morning. This may be the reason for the complaint of growing pains of teenagers occurring at night, and the need to check the Pyrilinks-D® test with a first or second morning voided urine specimen.
For patients with prostate cancer with evidence of bone metastases detected by bone scan or by bone marrow examination using a monoclonal antibody to detect micro-metastatic disease (Impath), we suggest the use of pamidronate (Aredia®). This is given intravenously. We like to give the first dose at 30 mg over 1.5 hours to minimize the chance of an acute phase response (APR). The APR is usually associated with fever within 28-36 hours of the initial exposure to the ABP. The APR is felt to be due to a first-time reaction of the amino BPs with macrophage-like cells resulting in the release of interleukin-1 (IL-1).33 Since we have seen two patients in consultation with kidney damage after a high first dose of Aredia®, we routinely give the first dose at 30 mg and then increase to 60-90 mg every two weeks thereafter.
Serum calcium levels should be watched and the patient encouraged to take calcium supplements as discussed previously. In patients without bone metastases, the use of alendronate (Fosamax®) is encouraged. Since Fosamax® is poorly absorbed in the small intestine it should be given one hour before breakfast and taken only with water. The patient is advised not to lie down after taking Fosamax®. If symptoms of gastrointestinal upset such as belching and burping or discomfort in the stomach region occur, Fosamax® should be stopped and the physician notified.
A key paper on the use of bisphosphonates to reduce new metastases to bone, liver and lung as well as to prolong survival in women with breast cancer was recently published in the New England Journal of Medicine.34 Breast cancer and prostate cancer have strong similarities sufficient to warrant extrapolating data from the breast cancer literature and seeing if such approaches are effective in prostate cancer. In this study, the bisphosphonate used was oral Clodronate® at a dose of 400 mg four times per day. The patients studied included 302 women with breast cancer with tumor cells in the bone marrow. Patients were randomized to Clodronate® (157) versus control (145). Patients in both groups received standard surgical, hormonal and chemotherapy treatments. The results are shown in Table 2 below.
During the median observation period of 36 months, distant metastases (bone or visceral) were detected in 21 women in the Clodronate® group as contrasted to 42 women in the control group. In this study, all women had evidence of bone marrow metastases using immuno-histochemical staining of bone marrow aspirates. Details are shown in the table. The results of this paper should prompt a similar study in prostate cancer.
An alternative agent to be used is (Miacalcin®) nasal spray. Miacalcin® is a derivative of salmon calcitonin. Miacalcin® will reduce bone resorption due to prostate cancer,35 but there are not as many papers on the use of Miacalcin® in regard to bone physiology of PC as there are dealing with the bisphosphonates. Randomized studies should be done since Miacalcin® is so much easier to take than Fosamax®. Miacalcin® is dosed as one spray in one nostril per day with the right and left nostrils alternated to prevent nasal irritation. We have seen just one allergic reaction to Miacalcin® occurring in a patient with a history of fish allergy.
Bone Integrity – Concluding Remarks
In my opinion, the institution of bone integrity measures as detailed in this issue of Insights should be a routine part of the management of the PC patient. This is true not only to prevent bone metastases, but also to maintain the structural integrity of the bone to avoid fractures and bone pain.
We will continue to watch the literature on bone integrity in PC since it represents an avenue to increased supportive care of the patient and insights into better tumor control.
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2. Eriksson S, Eriksson A, Stege R, et al: Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcif Tissue Int 57:97-99, 1995.
3. McGrath SA, Diamond T: Osteoporosis as a complication of orchiectomy in 2 elderly men with prostatic cancer. J Urol 154:535-536, 1995.
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