**5.2 Diagnosis of osteoporosis**

Current guidelines recommend assessment of bone mineral density (BMD) previous to ADT and yearly thereafter (53) with dual-energy x-ray absorptiometry (DXA) which is considered the standard method to measure BMD (54). International Society for Clinical Densitometry (ISCD) recommends that central skeleton sites (lumbar spine, total hip and femoral neck) are the most appropriate locations to asses BMD (55).

Diagnosis of osteoporosis can than be made according to WHO classification: if T- score is less than 2,5 of standard deviation. Values between (-) 1 and (-) 2.5 SD (standard deviation) is defined as osteopenia. T - score stands for the number of standard deviations (SD) from the density of young healthy individuals of the same sex (39).(Table 1)

To improve the identification of patients at highest risk of fracture, WHO has developed an algorithm to predict fractures - FRAX ™ http://www.shef.ac.uk/FRAX/

According to European Association of Urology (EAU) guidelines, a precise evaluation of BMD should be performed by dual X-ray absorptiometry before starting long-term ADT. An initial low BMD (T-score below 2.5, or below 1 if other risk factors are present) indicates a high risk of subsequent non-metastatic fracture, suggesting the need for early use of preventive bisphosphonate therapy (56).


Table 1.

#### **5.3 ADT, prostate cancer (PCa) and clinical aspects of bone disease**

At presence, significant amount of data report that ADT is associated with the loss of BMD in a time-dependent manner (57-59) which leads into increased fracture risk (60). Skeletal fractures negatively correlate with overall survival in men with PCa (61) and maintaining skeletal health is crucial for QoL and survival (62).

Treatment of complications of pathological fractures is complicated and expensive (63). Moreover, the typical feature of PCa is the ability to metastasize into bone in more than 80 % of cases (64). Most bone lesions in PCa are osteoblastic in nature (65). However, studies

Androgen Deprivation Therapy for Prostate Cancer 343

*Bisphosphonates* are one of the most potent inhibitors of bone resorption. The effect on the reduction of osteoporotic fractures has been demonstrated for treatment with alendronate, risedronate, ibandronate, etidronate and zoledronic acid. The effectiveness in reducing vertebral and nonvertebral fractures were confirmed by many studies (73, 74, 75). The optimal regimen for zoledronic acid is unclear, because one study recommends treatment every 3 weeks (76), while another trial has produced similar results with an annual injection (77), and finally, another study reports that single infusion of zoledronic acid in patients receiving ADT reduces bone mineral loss and maintains BMD at least for 12 months during

One of the most important and serious adverse effect of bisphoshonate administration is jaw necrosis (79) The initial BMD could be used to guide the choice of regimen (80).Thus, a 3 month injection might be given in osteoporotic patients, for whom a yearly injection is likely

*Denosumab* is a fully human monoclonal antibody against RANKL (see above). In the largest, well conducted study to date, denosumab was associated with 5.6% increase in the lumbar BMD versus 1% decrease in the placebo arm. There were also significant BMD increases at the total hip, femoral neck and distal third of the radius. 60 mg was delivered subcutaneously every 6 months, was not associated with any significant toxicity, or delayed

It is known that during certain developmental stages- especially during the first years of life, during adolescence, girls surpass in boys several verbal skills. Males excel after about the tenth year of life in non-verbal skills in adulthood, especially in spatial orientation and

Evidence of a link between sex hormones and spatial abilities came from studies of individuals with Turner syndrome (XO karyotype, no gonadal hormones) or testicular feminization syndrome- (XY karyotype, the tissues are refractory to normal levels of TST). These patients have female external genitalia, they are raised as girls. In these patients verbal skills surpass their spatial abilities, which is a typical pattern of cognitive abilities of

Studies on men with idiopathic or acquired hypogonadotrophic hypogonadism confirm the importance of TST for spatial abilities. Short-term androgen supplementation did not restore spatial function, suggesting that low levels of sex hormones during the intrauterine and

Direct sex hormones manipulation supports the conclusion that androgens play an important role in cognition. The first experiments with direct hormonal manipulation can be traced back to 1941 when Simonson et al. (85) published their experiment using methyl TST that was administered to eunuchoids, castrated males, and elderly men. The result was an improved ability to perceive the flicker (critical flicker frequency), a measure of attention

Androgen therapy was also administered to female to male transsexuals in high doses as a preparation before gender reassignment. Their spatial skills have significantly improved,

For ethical reasons, nowadays the manipulation of gonadal hormones is restricted to patients in clinical studies. Thus, the last such study was conducted in 1971. Klaiber et al. (88) studied the effect of infused TST on mental abilities in healthy male students. After a 4-

ADT (78).

to provide insufficient protection (56).

healing in vertebral fractures (81).

manipulation (82).

women (83).

**6. Androgens and cognitive functions** 

neonatal period have a lifelong impact (84).

while verbal skills declined considerably (87).

and alertness, as long as the androgen treatment lasted (86).

show that osteoblastic lesions in PCa have excessive bone growth, but on the other hand also simultaneously increased osteolysis (66). The new bone formed by tumor stimulated osteoblast is weak and poorly mineralized and subsequent osteopenia leads into increased osteolysis - result to the creation of bone matrix with seriously compromised integrity. The risk of developing bone complications is therefore increased.

Treatment of PCa does not focus on skeletal complications that may arise from bone metastases. The main symptom of bone metastases is severe bone pain, which often requires strong narcotic therapy or palliative radiation therapy. Other complications include spinal cord compression and pathological fractures, which may require surgery. These skeletal complications have a negative effect on QoL (65).

Data from a double-blind, placebo-controlled studies show that approximately half of patients treated with ADT had one or more events associated with the skeleton. Most of these events required palliative radiotherapy, or were pathological fractures (67). Skeletal complications are also associated with significant financial expenditure. A recent analysis of the costs of health insurance in the U.S. since 1994 until 2002 revealed that the total cost to treat patient with PCa who had skeletal event were 20 000 dollars higher than in patient who did not experience skeletal event (68).

Interestingly, it has been reported that hormone naive patients with advanced PCa have lower baseline BMD than healthy control, and relatively high prevalence of osteopenia and osteoporosis (69, 70). The largest study that investigated the association of BMD measures with PCa risk in older men enrolled was the Osteoporotic Fractures in Men Study (MrOS) (71).

MrOS was prospective study conducted on 4597 men with mean follow up 5.2 years, which evaluated the association of BMD and incidental PCa in a cohort of older men with no history of PCa. Unexpectedly, the authors found that higher total body BMD was significantly related to reduced risk for PCa. This result was "unexpected" because authors presumed that the higher levels of androgens lead into higher prevalence of PCa, which positively correlates with BMD. Additionally, total body BMD was inversely associated with the development of high-grade, but not low-grade disease. A similar but weaker association was observed for total hip BMD with high-grade PCa. This study confirms the association, although still not elucidated, between low BMD and PCa.

#### **5.4 Treatment of ADT induced osteoporosis**

*Lifestyle changes:* Immobilization is an important cause of bone loss. Immobile patients lose bone mass more rapidly than mobile patients. Regular daily activities, overcoming gravity, walking, and exercise have a positive impact on bone density: it stimulates osteoblasts to produce new bone and inhibits osteoclasts, thereby decreasing resorption of bone. It also improves physical coordination (prevention of falls). Cessation of smoking, decreased alcohol consumption and normalization of body mass index (BMI) helps to maintain BMD (72).

*Ca supplementation:* The ideal is to ensure that the amount of calcium is taken in the normal diet. If the patient is unable to take the recommended amount of calcium in the diet (lactose intolerance, hyperlipoproteinemia, etc) it is recommended for calcium supplementation (1000mg – 1500 mg daily) (72).

*Vitamin D:* Supplementation of vitamin D is recommended when its deficiency can be assumed or proven. The recommended daily dose is 400-800 IU (10-20 mg).

show that osteoblastic lesions in PCa have excessive bone growth, but on the other hand also simultaneously increased osteolysis (66). The new bone formed by tumor stimulated osteoblast is weak and poorly mineralized and subsequent osteopenia leads into increased osteolysis - result to the creation of bone matrix with seriously compromised integrity. The

Treatment of PCa does not focus on skeletal complications that may arise from bone metastases. The main symptom of bone metastases is severe bone pain, which often requires strong narcotic therapy or palliative radiation therapy. Other complications include spinal cord compression and pathological fractures, which may require surgery. These skeletal

Data from a double-blind, placebo-controlled studies show that approximately half of patients treated with ADT had one or more events associated with the skeleton. Most of these events required palliative radiotherapy, or were pathological fractures (67). Skeletal complications are also associated with significant financial expenditure. A recent analysis of the costs of health insurance in the U.S. since 1994 until 2002 revealed that the total cost to treat patient with PCa who had skeletal event were 20 000 dollars higher than in patient

Interestingly, it has been reported that hormone naive patients with advanced PCa have lower baseline BMD than healthy control, and relatively high prevalence of osteopenia and osteoporosis (69, 70). The largest study that investigated the association of BMD measures with PCa risk in older men enrolled was the Osteoporotic Fractures in Men

MrOS was prospective study conducted on 4597 men with mean follow up 5.2 years, which evaluated the association of BMD and incidental PCa in a cohort of older men with no history of PCa. Unexpectedly, the authors found that higher total body BMD was significantly related to reduced risk for PCa. This result was "unexpected" because authors presumed that the higher levels of androgens lead into higher prevalence of PCa, which positively correlates with BMD. Additionally, total body BMD was inversely associated with the development of high-grade, but not low-grade disease. A similar but weaker association was observed for total hip BMD with high-grade PCa. This study

confirms the association, although still not elucidated, between low BMD and PCa.

*Lifestyle changes:* Immobilization is an important cause of bone loss. Immobile patients lose bone mass more rapidly than mobile patients. Regular daily activities, overcoming gravity, walking, and exercise have a positive impact on bone density: it stimulates osteoblasts to produce new bone and inhibits osteoclasts, thereby decreasing resorption of bone. It also improves physical coordination (prevention of falls). Cessation of smoking, decreased alcohol consumption and normalization of body mass index (BMI) helps to

*Ca supplementation:* The ideal is to ensure that the amount of calcium is taken in the normal diet. If the patient is unable to take the recommended amount of calcium in the diet (lactose intolerance, hyperlipoproteinemia, etc) it is recommended for calcium

*Vitamin D:* Supplementation of vitamin D is recommended when its deficiency can be

assumed or proven. The recommended daily dose is 400-800 IU (10-20 mg).

risk of developing bone complications is therefore increased.

complications have a negative effect on QoL (65).

who did not experience skeletal event (68).

**5.4 Treatment of ADT induced osteoporosis** 

supplementation (1000mg – 1500 mg daily) (72).

Study (MrOS) (71).

maintain BMD (72).

*Bisphosphonates* are one of the most potent inhibitors of bone resorption. The effect on the reduction of osteoporotic fractures has been demonstrated for treatment with alendronate, risedronate, ibandronate, etidronate and zoledronic acid. The effectiveness in reducing vertebral and nonvertebral fractures were confirmed by many studies (73, 74, 75). The optimal regimen for zoledronic acid is unclear, because one study recommends treatment every 3 weeks (76), while another trial has produced similar results with an annual injection (77), and finally, another study reports that single infusion of zoledronic acid in patients receiving ADT reduces bone mineral loss and maintains BMD at least for 12 months during ADT (78).

One of the most important and serious adverse effect of bisphoshonate administration is jaw necrosis (79) The initial BMD could be used to guide the choice of regimen (80).Thus, a 3 month injection might be given in osteoporotic patients, for whom a yearly injection is likely to provide insufficient protection (56).

*Denosumab* is a fully human monoclonal antibody against RANKL (see above). In the largest, well conducted study to date, denosumab was associated with 5.6% increase in the lumbar BMD versus 1% decrease in the placebo arm. There were also significant BMD increases at the total hip, femoral neck and distal third of the radius. 60 mg was delivered subcutaneously every 6 months, was not associated with any significant toxicity, or delayed healing in vertebral fractures (81).
