Prostate Cancer-12

The Difference Between Evaluation of Bone Status Using QCT Versus DEXA

Emphasizing the importance of the bone microenvironment in PC appears justified because there is a strong correlation with osteoporosis and osteopenia, as determined by bone mineral density examinations, at the time of diagnosis of PC.

In a report by Smith et al., osteoporosis was present in 63% of men at the time of diagnosis of PC, prior to any therapy. An additional 32% of men, in this same study population, had osteopenia.248 In this landmark paper, the investigators evaluated DEXA bone mineral density testing and compared it to quantitative computerized tomography (QCT) bone mineral density testing in the same patients. A significantly greater percentage of men were found to have osteoporosis using the QCT methodology than the DEXA approach. DEXA bone mineral density evaluation picked up osteoporosis in only 5% of men. Therefore, using QCT technology, abnormalities in bone density were found in 95% of men compared to 34% of men with DEXA.

Studies done by Strum and Scholz have confirmed the results of Smith et al. (see Table 16). We found either osteoporosis (50%) or osteopenia (50%) in 100% of the men we studied with QCT. In the same men, using DEXA, we found only 5% with osteoporosis and 50% with osteopenia.249 A reasonable question is "why are there such differences in the two techniques?" The DEXA scan may read degenerative changes involving bone and joint tissues and calcium deposits within blood vessels as bone density.250-254

DEXA Scanning Underestimates the Occurrence of Osteoporosis in Men with PC

The data from two separate groups evaluating DEXA versus QCT bone mineral density (done at the same time in men with PC) are strikingly alike. The evaluation of bone density with QCT should be a routine tactic in our goal to achieve and maintain bone integrity
A)Clinical Study -Smith et al.248
Osteopenia -DEXA-29%
Osteoporosis -DEXA-5%
Totals-34%

B)Clinical Study-QCT
Osteopenia-QCT-32%
Osteoporosis -63%
Totals-95%

C)Clinical Study-Strum et al.249
Osteopenia-DEXA-50%
Osteoporosis-5%
Totals -55%

D)Clinical Study-QCT
Osteopenia-50%
Osteoporosis-50%
Totals -100%

The T Score Determines Your Status and Risk of Fracture

The definitions used in the bone mineral density reports that are valid for men or women relate to the T scores. These reports are confusing even to radiologists who are experts in this field. The Z score is often relayed to patients and physicians in the radiology report as the final diagnosis or impression. The Z score compares the findings of the bone density exam, be it QCT or DEXA, with an age-matched population. This is of little actual value because what we are doing is comparing possible pathological findings in a patient with known problems with osteoporosis or osteopenia in a general population of similar age. If I were 70 years old, I would not feel reassured that I am like most other 70-year-olds (who may also have osteoporosis or osteopenia) and therefore I am considered to be normal. I want my bone density to be compared to that of someone with healthy bone tissue that is not likely to fracture, or to release BDGF (bone derived growth factors), which may initiate prostate cancer, stimulate its growth, or have a permissive action on bone metastases.

Therefore, it is the T score that is, or should be, the benchmark in bone mineral density (BMD) evaluations. The T score is based on World Health Organization (WHO) population studies that indicate how your bone density compares to that of a healthy 30- to 35-year-old (woman). There have been no T score determinations set up for men. If the BMD is exactly 1 standard deviation below that which is considered to be normal bone density for a 30- to 35-year-old woman, the patient's T score is minus (-) 1.0. If the BMD is one half of a standard deviation above what is considered normal for a 30- to 35-year-old, the T score is +0.5. More than 1 standard deviation below normal is considered to be the cut-off level to define abnormality. Therefore, if you have a T score of -1.1 or less, you have at least osteopenia. If the T score falls between -1.1 and -2.5, you are still in the range of osteopenia. Once below -2.5, the patient falls into the category of osteoporosis. The fracture risk doubles for each standard deviation below the normal T score.255 Therefore, a person with a T score of -2.0 has twice the chance of fracturing a bone compared to a person with a T score of -1.0.

Osteoporosis is rampant in men newly diagnosed with PC. That is clear from previously cited studies. In light of the knowledge that bone loss occurs during treatment with any therapy that lowers male hormone, the PC patient undergoing almost all forms of ADT is in jeopardy of having abnormal bone density and a serious risk of osteoporosis. Add to this knowledge the fact that bone loss through the process of resorption may be stimulating the PC, and the issue of bone integrity becomes paramount.

In the context of prostate cancer (PC), the bone tissue has to be regarded as a strategic area and must be stabilized, fortified, and brought to the status of a stronghold if we are to optimize our care of the PC patient.


Resources for QCT Testing

Improving bone integrity mandates that we first assess bone integrity status to obtain a baseline. BMD evaluation and the value of the QCT technique has been emphasized in the preceding paragraphs. Since QCT technology is not readily known to most physicians, it is important that patients and partners share these new findings and seek out radiology facilities that have QCT bone densitometry equipment. Two references for sources of QCT testing are Mindways, Inc. and Image Analysis. Telephone numbers and websites for these nationally based organizations are Mindways, (877) 646-3929 (www.qct.com), or Image Analysis, (800) 548-4849 (www.image-analysis.com). For further information on maintaining bone integrity, refer to the protocol Cancer Treatment: The Critical Factors.


Importance of Bone Integrity Extends to Cardiovascular Risk and Possibly Alzheimer's Disease

Studies have shown a relationship of abnormal bone density with an increased risk of cardiovascular disease.256,257 It has been the observation of many that the loss of bone matrix detected by measurements of bone mineral density appears to relate to the deposition of calcium in arteries such as the coronaries, aorta, and femoral arteries. The loss of calcium from the bone matrix is a characteristic finding during excessive bone resorption. Hypothetically, it is reasonable to consider that calcium lost from the bone matrix may be pathologically deposited in blood vessels as well as associated with calcifications elsewhere, such as kidney stones, gall stones, and prostatic calculi. In fact, correlations between osteoporosis and an increased risk for kidney stone development have been reported.

An improvement in bone density with treatments that are designed to prevent kidney stones have likewise been reported.258,259 Studies have shown that bisphosphonate compounds [such as alendronate (Fosamax®)] not only improve bone mineral density but also decrease a substance known as osteopontin, which has been implicated in kidney stone development.260 Other studies have presented this unifying concept and have even linked bone loss and kidney stones with hypertension (high blood pressure).261

A biological marker involved in PC, especially androgen-independent PC, is interleukin-6 (IL-6).262-264 IL-6 is a cell product that stimulates the maturation of osteoclasts, the cells that are major players in the breakdown (resorption) of bone. IL-6 is produced by osteoblasts265 and stimulates the mature osteoclasts to break down bone. IL-6 has been identified as an inflammatory cytokine that is likely to play a major role in Alzheimer's disease (AD). Therefore, the emphasis on bone integrity is of potentially great magnitude. Maintaining bone integrity can now be seen to play a role in the following:

1)Prevention and treatment of osteopenia or osteoporosis
2)Decrease in cardiovascular disease
3)Reduction in kidney stone formation
4)Minimization of release of bone-derived growth factors that can stimulate prostate or breast cancer
5)Prevention of Alzheimer's disease
This again points out that a holistic approach to medicine is vital to our understanding of unifying concepts involved in both health and disease. The hip bone is connected not only to the thigh bone, but also to the heart, kidneys, prostate, breast, and brain.

AD is considered to be an inflammatory disease of the brain associated with the deposition of beta amyloid material. In prior discussions, the importance of the eicosanoid pathways was detailed and the role of the inhibition of AA formation and the prevention of metabolites of AA such as PGE2 and 5-HETE by dietary changes and by the use of EPA and DHA were stressed. COX-2 inhibitors that prevent AA metabolism to PGE2 have been shown to be associated with a decreased incidence of AD. Even nonselective COX-2 inhibitors such as ibuprofen (Motrin) are now shown to have a protective effect against the development of AD.

There are studies that show that all of these pathways are integrated in PC. COX-2 expression and PGE2 secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. An up-regulation of PGE2 by IL-6 in a human cell line of PIN has been demonstrated. PGE2 further stimulates IL-6 soluble receptor release and other complex intracellular functions (gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity).266 These events, induced by PGE2, lead to increased PIN growth. Conversely, the use of a selective COX-2 inhibitor (e.g., Celebrex) decreases cell growth. Moreover, PIN cell growth stimulated by PGE2 was nullified by adding antibodies to IL-6. The authors concluded that increased expression of COX-2/PGE2 contributes to PC development and progression via activation of the IL-6 signaling pathway. Refer to the following sections in the protocol entitled Cancer: Gene Therapies, Stem Cells, Telomeres, and Cytokines: Suppressing Pro-Inflammatory Cytokines, Measuring IL-6 Levels (see TNF-a, IL-8, IL-1b), and the Cytokine Panel.

It should therefore come as no surprise to find that a study of animals fed diets varying in the ratio of AA to EPA reported that (1) higher AA-EPA-ratio diets led to findings of increased PGE2 production in the bone; (2) higher PGE2 in the bone was associated with increased bone resorption; and (3) lower AA-EPA ratios (reflecting higher intake of EPA) were associated with bone formation and decreased PGE2 concentrations.201

There is no doubt that the signaling pathways of communication between a PC tumor cell and bone (with osteoblasts and osteoclasts) are multidimensional. A conceptualized graphic of some of these interactions was shown in Figure 1 on page 1390.


Clinical Aspects of Bone Integrity in the Treatment of PC Patients

Many of the salient points relating to the evaluation and treatment of bone integrity can be found in the protocol entitled Osteoporosis. In addition to numerous articles written by me in the PCRI newsletter Insights, there is also a PowerPoint presentation on this subject that can be downloaded without charge. An update on this topic also appears in the Primer (available at www.lefprostate.org). In general, the main issues that still need a greater focus of attention include the following:

Every man with PC and most likely every apparently healthy man aged 45 or over should be evaluated for osteoporosis and osteopenia. (Refer to the Osteoporosis protocol.
Significant bone loss in PC patients is underestimated by the use of DEXA scanning and should be evaluated with QCT bone density study instead.
Bone resorption, and its correction, are easily evaluated by using a sensitive biomarker, as a biological endpoint (BEP), the (runin to text)
the Pyrilinks-D (free deoxypyridinoline or free Dpd). Dpd levels can be obtained from the second urine sample of the patient's day. This test is inexpensive and is an excellent tool to monitor the biological endpoint of bone resorption activity. In men, a normal value for Dpd is less than or equal to 5.4 (nanomoles Dpd/nanomoles creatinine) using the Metra Biosystems assay and up to 6.6 using the assay from Quest Laboratories.

In men, if the free Dpd exceeds the upper limit of normal, it is indicative of excessive bone resorption. This finding may be secondary to underlying PC in the bone or secondary to increased bone resorption due to ADT or illnesses such as diabetes, hyperthyroidism, Paget's disease of the bone, or hyperparathyroidism.

If the Pyrilinks-D level is abnormal, it should be corrected with the use of combination therapy employing a bisphosphonate compound, a calcium-containing bone supplement, and Rocaltrol (synthetic vitamin D). The most active oral bisphosphonates are Fosamax and Actonel. The bone supplement is best taken in the evening between dinner and bedtime. Studies have shown that the administration of calcium in a bone supplement will reduce bone resorption by up to 20%, but only if it is administered in the evening.269 This is apparently due to a circadian rhythm involving bone formation and bone loss.

The use of Rocaltrol (calcitriol or 1,25-dihydroxy vitamin D3) requires a prescription. It is not to be confused with ordinary vitamin D3. There are an increasing number of articles relating to the use of standard dose270 or high dose calcitriol,271 used either alone or with chemotherapy such as Taxotere272 in combination with bisphosphonates to slow the doubling time of PSA and dramatically reduce PSA levels. This holds great promise for the PC survivor.

When bone resorption is halted, and the net effect favors bone formation, it is critical that not only sufficient calcium be available to restore bone density, but also other ingredients necessary for healthy bone formation. These include magnesium, boron, and silica, as well as vitamin K. The nature of the calcium salt used in these preparations is also of major significance, because calcium carbonate is not well absorbed in older patients when gastric HCL production is decreased.

Calcium citrate, bisglycinate, and microfine calcium hydroxyapatite should be used preferentially. Two excellent comprehensive bone supplements include Bone Assure from Life Extension Foundation and Bone Up from Jarrow. It is important for the PPP team to understand the importance of these substances in bone physiology and their interactions with other cellular processes. A detailed description of these issues can be found in the Primer.


10. SUPPORTIVE CARE OF THE PATIENT
Supportive Care Measures

A military campaign is never successful unless the troops are supported in their efforts. Great military strategists win their battles because they realize the value of generous support for their soldiers. This is true in all endeavors; it is critical to invoke this principle in the support of the patient as he faces challenging crossroads in pursuit of quality and quantity of life. This is the essence of outstanding medical care and goes hand-in-hand with the physician-scientist whose prime directive is a strategy of success for the patient with whose life he is entrusted. This is an incredible opportunity for physicians, given the immediate intimacy with patients and their partners facing life-threatening illnesses. But what does supportive care mean?

Supportive care of the patient involves the fine-tuning needed to maximize efficacy while minimizing adverse effects. This is the basis for the concept of Therapeutic Index.

Therapeutic Index (TI) = Benefits of Therapy ÷ Adverse Effects of Therapy

Supportive care of the patient must be a conscious up-front concern with every aspect of the physician/patient encounter. The list below details some of the main supportive care issues that the PC patient may encounter. This is not an exhaustive list because an itemization of every supportive care measure (SCM) would involve numerous pages of text.