Health Matters 1 - John Dwyer 16.12.2002

Osteoporosis Androgen Deprivation Therapy and Bisphosphonates

Many of our members are, or have been, treated with androgen deprivation therapy (ADT) either by injection of "zoladex", or similar agent or by orchiectomy.

A very cursory examination of peer reviewed literature reveals the considerable interest in this field. A very large number of papers or reviews have appeared within the past two years.

It is clear that ADT can result in a loss in bone mineral density (BMD) and, in some cases, to osteoporosis. Reviews of the literature up to 2002 are published by M.R. Smith (1) and by M.A. Moyad (2). Both authors discuss the causes and diagnosis of osteoporosis with the former concentrating more on medical treatment and the latter on complementary treatment. This present note summarises the features from these reviews that seem most relevant to our members, and adds points from other sources which may help to clarify the discussion.

Factors enhancing osteoporosis are included in Table 1, which also suggests some complementary treatments (2). The message is that patients guided towards long term

ADT should seek advice on their risk of osteoporosis. Ideally, a measurement of bone mineral density (BMD) should be made at the commencement of ADT and followed by a second measurement six or twelve months into treatment. Although BMD can be measured by a simple (for the patient) non- invasive procedure it is not readily available. Using the definitions accepted by the World Health Organisation (WHO), loss in BMD is reported to the patient as a negative number which refers to the decrease in bone density measured in standard deviations (a measure of variation in results) from the mean bone density for young adults. Table 2 gives the recommendations of WHO. For each unit change in the reported value (one standard deviation) there is a loss in bone mineral density of around 12%. Moreover, the probability of fracture doubles for each unit decrease; and is increased by a factor of seven for patients with previous fractures (3). According to M.G. Oefelein (4) patients with prostate cancer treated with ADT are at risk of skeletal fracture and risk increases with duration of therapy. Slim white males with a body mass index less than 25 kg/m. are at most risk. The same author also suggests that skeletal fracture may be a negative predictor of survival (5). However, it is possible to exaggerate risk of fracture, because base level probabilities are small (3). B.J. Kiratli, compared, over a 10 year period, prostate cancer patients given ADT with patients not treated in this way. He observed a greater loss in MBD for patients treated with ADT, and reported some benefit from intermittent ADT in the later years of treatment (6).

As discussed previously, in a paper by Roy Nixon (7), bone, which consists of a matrix of collagen fibres impregnated with a complex form of an inorganic salt (calciumhydroxyapatite), is continuously being remodelled by a process involving both bone resorption (dissolution of bone) and bone formation. The resorption of bone involves the participation of osteoclasts (generated in bone marrow) which are cells that move to injury sites and erode bone. By- products from this process can be detected in the urine and blood stream of patients (8). Bone formation (building) is the function of osteoblasts which are generated in the blood and migrate to regions where bone has been eroded by osteoclasts. The overall bone remodelling process (1) (3) involves the participation of both male and female hormones.

Clearly, loss in bone mineral density will arise when the rate of bone dissolution exceeds that of bone accumulation. This latter process is influenced strongly by the concentration of serum (extra- cellular) calcium and the active form of vitamin D (Table1). Vitamin D is generated in the body from a form of cholesterol (7- dehydrocholesterol) by the action of sunlight on the skin, followed by a further reaction in the liver to produce 25- hydroxyl vitamin D 3 , which in turn is converted within the kidneys to 1, 25- dihydroxyvitamin D 3 , often written as 1, 25 (OH) 2 D 3 . In these formulae, OH is the chemical symbol for a hydroxy group (an oxygen atom linked to a single hydrogen atom) and the numbers 1, 25 relate to the particular carbon atoms to which the hydroxyls are attached. The 1, 25 (OH) 2 D 3 is reported to be 100 times more potent than 25 (OH) 2 D 3 and is sold commercially as calcitriol. It is suggested that 1, 25 (OH) 2 D 3 can also exert anti tumour activity (9).

The normal dietary intake of calcium for patients at risk of osteoporosis involves 1200 to 1500 mg per day along with a daily supplement of 400 IU of vitamin D 3 . However, a diet rich in calcium has been associated with an increased risk of prostate cancer (10), and more recently (11) this diet is alleged to increase the progression of regional/distant disease (metastasis). (Paradoxically, increased concentrations of calcium within prostate cancer cells are lethal, and calcium is a proposed target for prostate cancer treatment (12)). Complete agreement on the role of dietary factors is, as always, difficult to establish but there is clearly a concern in regard to patients on ADT who are at risk of osteoporosis, and this is reflected in the suggestions made in Table 1 where increased levels of vitamin D 3 are proposed. S. Strumm (8) also recommends that patients on ADT take a calcium citrate supplement, and Moyad (2) suggests that calcium citrate malate be used. These forms of calcium can be taken at any time whereas the carbonate should be taken with meals to improve absorption.

It is important that patients having ADT are assisted, in consultation with their medical advisors, to find an appropriate balance of calcium and vitamin D .

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Loss of Bone Mineral Density and Bisphosphonates During ADT

Loss of BMD during ADT can be prevented or much reduced by injesting compounds with the generic name "Bisphosphonates". The chemical replacement of an oxygen atom (O) linking two phosphorous (P) atoms, in biphosphates, by a carbon atom (C) permits the formation of a family of fairly simple but highly effective compounds. The list in the note by Roy Nixon (7) includes clodronate, pamidronate (Aredia), alendronate (Fosamax) and the more recently developed zoledronate (Zometa), with relative potencies of 1,100,1000. Zoledronates (and ibandronates) must be taken intravenously.

These materials can alter the balance between bone resorption and bone generation. By inhibiting the potency of osteoclastic activity in bone resorption they can limit further erosion of bone and can, in some cases, result in an increase of perhaps 6% in BMD (3). A mechanism for the role of bisphosphonates in bone restructuring has been proposed by H. Fleisch (13), summarised by S. Strumm (8), and discussed recently by L Widler et al. (14). According to Virtanen et al. (15) the overall mechanism involving bisphosphonates is still under investigation.

In conclusion, it seems advisable that men commencing prolonged treatment by ADT should discuss the possibility of monitoring changes in BMD, and the advantages and disadvantages of treatment by bisphosphonates. In this context it appears that intravenous injection of the amino-bisphosphonates, in low doses, is well tolerated (16) but those orally delivered can be aggressive within the stomach (8).

These matters should be discussed by patients and their medical advisor(s), and it should be understood that there is little or no information on any problems that might arise from the long-term use of bisphosphonates.

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Bisphosphonates and Treatment for Bone Metastasis

Metastasis to bone is a major cause of morbidity in cancer of the prostate (CaP), so that avoidance of skeletal complications arising from metastasis, and if possible limiting the progression of metastatic disease is, consequently, of considerable interest to patients. In the review by Smith (1) the results of a randomised study involving 47 men are discussed. It is concluded that intravenous pamidronate is an effective treatment for osteporosis.

A recent paper by F.S.Saad et al. (17) describes a "Randomised, Placebo-Controlled Trial of Zoledronic Acid (Zometa) in Patients with Hormone Refractory Prostate Carcinoma". In this study the patients (214) receiving zoledronate (4mg every three weeks) reported 33% skeletal events, whereas those patients (208) who were given a placebo reported 44%. Moreover the median time to the first skeletal- related effect was considerably shorter for the placebo group. However, the authors do not report a significant difference, between the two groups, with regard to disease progression. At the dose of 4 mg every three weeks zoledronate was well tolerated but at twice this dose there was evidence of deterioration in renal function.

In an earlier paper, F. Fulfaro et al. review results of a phase III trial on the role of bis phosphonates in the treatment of metastatic bone disease (18). This investigation was based on the analysis of data from the Medline and Cancer Lit. Database (Jan. 1984- 1998) and, consequently, was not a designed trial. The conclusions from this study, which examined the administration of clodronate (orally) and pamidronate (intravenously), agreed with those by Saad et al. (17) with regard to the achievement of pain relief by the administration of bisphosphonate and in the delayed onset of skeletal complications, but also claimed that intravenous pamidronate can slow down the progression of the disease. M. Fassnacht et al. (19) also suggest that bisphosphonates can influence tumour progression. Additionally, the study of three cell lines, produced from cells taken from metastic sites in (a) lymph nodes (b) bone and (c) brain, provides in-vitro evidence that bis-phosphonates can reduce cell growth (20).

Summarising

Results so far suggest that bisphosphonates are effective in: -

• Preventing Osteoporosis
• Delaying the onset of Skeletal Complications
• Providing Pain Relief in Bone Metastases

At this time, although there is both in-vivo and in-vitro evidence that bisphosphonates can decrease the progression of bone metastatic prostate cancer the evidence does not, currently, appear to be conclusive.

TABLE 1
COMPLIMENTARY THERAPIES TO REDUCE THE RISK OF OSTEOPOROSIS IN MEN RECEIVING HORMONE SUPPRESSION*

* Modified from reference 2

TABLE 2
WORLD HEALTH ORGANISATION DEFINITION OF OSTEOPOROSIS

REFERENCES

1. M.R. Smith, Urology 60 (Suppl 3A): 79-86, 2002
2. M. A. Moyad, Urology 59 (Suppl 4A): 34-40, 2002
3. M. Davies, Private Communication, October, 2002
4. M. G. Oefelein, et al. J.Urology 166 (5): 1724-1728, 2002
5. M.G. Oefelein, et al. J. Urology 168 (3): 1005-1007, 2002
6. B. J. Kiratli, et al. Urology, 57 (1): 127-132, 2001
7. Roy Nixon, "Bone Integrity" Oct. 2001
8. S. B. Strumm, Proc. PCIR US- TOO Conf. Los Angeles , 2000
9. S.Y. James, et al. J Steroid Biochemistry and Molecular Biology 58 (4): 395-401, 1996
10. E. Giovannucci, et al. Cancer Research 58: 442-447, 1998
11. A.R. Kristal et al. Cancer Epidemiology Biomarkers and Prevention 11 (8): 718-725, 2002
12. V. J. Tapia-Vieyra, Archives of Medical Research, 32:175-184, 2001
13. H. Fleisch, J. Endocrinology Metab. 19: 80-100, 1998
14. L. Widler, et al. J. Medical Chemistry, 45 (17): 3721- 3738, 2002
15. S. S Virtanen, et al. Cancer Research, 62 (9): 2708-2714, 2002
16. M.R. Smith, N.England J. Med. 345: 948-955, 2001
17. F. Saad et al. Cancer Institute 94: 1458-1488, 2002
18. F. Fulfaro, Pain 78 (3): 157-169, 1998
19. M. Fassnacht, et al. J. Endocrinology, 174 (3): 509-516, 2000
20. M.V. Lee Cancer Research 61 (6): 2602-2608, 2002

NOTE. John Dwyer is not medically qualified. This article is for information and is not to be considered as medical advice.

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