Urologic Oncology: Seminars and Original Investigations 21 (2003) 380 –383
`
`Seminar article
`Risk factors for male osteoporosis
`
`Francisco A. Conde, R.N., Ph.D.a, William J. Aronson, M.D.b,*
`a Department of Nursing, West Los Angeles-VA Healthcare Center, Los Angeles, CA, USA
`b Department of Urology, UCLA School of Medicine, Los Angeles, CA, USA
`
`Abstract
`
`Hypogonadism from long-term androgen deprivation therapy (ADT), either by bilateral orchiectomy or administration of gonadotropin-
`releasing hormone (GnRH) agonists, causes significant and accelerated bone loss that may increase the risk of bone fractures in men
`with prostate cancer. Recent reports, as well as new data from our institution, have shown a high prevalence of pre-existing osteopenia
`and osteoporosis in men with prostate cancer before receiving ADT, and this is of great concern because of the risk of further bone
`loss during ADT. Data from these studies suggest the urgent need for clinical guidelines for screening, prevention, and treatment of
`these cases. This article reviews the prevalence and risk factors associated with osteoporosis in men and addresses risk factors in men with
`prostate cancer not
`receiving ADT. Considerations for
`the patient selection and timing of bone densitometry will also be
`discussed. © 2003 Elsevier Inc. All rights reserved.
`
`Keywords: Androgen deprivation therapy; Prostate cancer; Osteoporosis; Orchiectomy; Gonadotropin-releasing hormone agonists
`
`Introduction
`
`Definition of osteoporosis
`
`Androgen deprivation therapy (ADT), either by bilateral
`orchiectomy or administration of gonadotropin-releasing
`hormone (GnRH) agonists, remains the mainstay of therapy
`for patients with advanced prostate cancer. Its use is rapidly
`increasing with the inclusion of patients with prostate spe-
`cific antigen (PSA) recurrence or biochemical relapse fol-
`lowing definitive therapy for primary treatment of locally
`advanced prostate cancer. With more aggressive PSA
`screening, many men initiating ADT are younger and
`asymptomatic, and are now faced with the long-term use of
`ADT. Retrospective and prospective studies have consis-
`tently shown that hypogonadism from ADT results in sig-
`nificant bone loss and higher incidence of bone fractures in
`men with prostate cancer than seen in controls [1–9]. Fur-
`ther, reports have also shown a high prevalence of pre-
`existing osteopenia and osteoporosis in men with prostate
`cancer before receiving ADT [5,7,8].
`
`* Corresponding author. Tel.: ⫹1-310-268-3446; Fax: ⫹1-310-268-
`4858.
`E-mail address: waronson@ucla.edu (W.J. Aronson).
`
`1078-1439/$ – see front matter © 2003 Elsevier Inc. All rights reserved.
`doi:10.1016/S1078-1439(03)00109-1
`
`Osteoporosis is a disease characterized by low bone
`mineral density (BMD) resulting in increased susceptibility
`to bone fractures [10]. Osteoporosis is responsible for more
`than 1.5 million fractures that occur in the United States
`each year. Over 250,000 fractures involve the hip, and it is
`estimated that 20 percent of men with osteoporotic hip
`fractures will die within one year from a complication of the
`injury [11]. Osteoporotic fractures are expected to rise dra-
`matically over the next 50 years as the population continues
`to age and life expectancy increases [12].
`The burden of osteoporosis is largely because of hip and
`vertebral fractures [13]. In 1990, an estimated 30% of 1.7
`million hip fractures occurred in men worldwide [14]. Men
`have a higher mortality after hip fracture than do women
`[14]. Osteoporosis can often cause pain, diminished quality
`of life, decreased physical mobility and independence, in-
`ability to work, and increased burden on caregivers who
`must care for the patient with fracture. Furthermore, in
`1995, the National Osteoporosis Foundation estimated that
`direct care of patients in the United States with osteoporosis
`to be $10 to 20 billion annually.
`Studies have shown that reduction in BMD is the most
`important predictor of osteoporotic fractures in both men
`and women [15,16]. Accordingly, the World Health Orga-
`nization has defined normal, osteopenia, osteoporosis, and
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`F.A. Conde, W.J. Aronson / Urologic Oncology: Seminars and Original Investigations 21 (2003) 380 –383
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`381
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`established osteoporosis in women based on BMD as com-
`pared to young adult mean values [17]. Normal BMD is
`defined as T-score value ⬎ ⫺1 standard deviation (SD),
`osteopenia as T-score between ⫺1 and ⫺2.5 SD, osteopo-
`rosis as T-score ⬍ ⫺2.5 SD, and established osteoporosis as
`T-score ⬍ ⫺2.5 SD below the young adult mean value in
`the presence of one or more fractures. While these defini-
`tions are based on women, they are also used to diagnose
`osteopenia and osteoporosis in men.
`
`Risk factors for osteoporosis in men
`
`Hypogonadism is a well-established risk factor of osteo-
`porosis in men [18]. Other risk factors include aging, eth-
`nicity, smoking, excessive alcohol consumption, deficiency
`in dietary calcium intake, physical inactivity or sedentary
`lifestyle, low body mass index (BMI), certain diseases, and
`medications, particularly chronic use of glucocorticoid
`agents.
`
`Aging
`
`During childhood and adolescence, more bone is formed
`than resorbed. Peak bone mass is reached in the twenties
`and is maintained up to the age of 40 for both men and
`women. After age 40, bone mass begins to decrease at the
`rate of about 0.4 to 1.3% per year in the peripheral skeleton
`of men and women up to age 80. By the age of 80, it is
`estimated that bone mass declines to half its maximum
`value [19].
`Age-related reductions in the number of Leydig cells and
`testosterone levels are associated with bone loss in elderly
`men [14]. An estimated 5-fold increased risk of hip fractures
`was seen among elderly men with age-related hypogonad-
`ism [20]. Among elderly men admitted for spinal osteopo-
`rosis, approximately 5% of the cases were a result of hy-
`pogonadism [21].
`
`Ethnicity
`
`On the average, African-Americans have approximately
`10% greater BMD than Whites in the United States [22].
`Asians have lower BMD when compared with Caucasians.
`However, after controlling for body size, these differences
`are reduced, and the variability of BMD within each race is
`much greater than the differences between races [23].
`
`Smoking
`
`Although the exact mechanism is not clearly understood,
`cigarette smoking is a risk factor for osteoporosis. Vogel
`and colleagues (1997) examined bone density and bone loss
`rates among 1303 Japanese-American men who were cur-
`rent cigarette smokers, past smokers, and nonsmokers [24].
`Results indicated that compared with never smokers, cur-
`
`rent and past smokers had significantly less bone density,
`especially in the cancellous calcaneus and trabecular distal
`radius. Also, the magnitude of the smoking effect was
`strongly associated with the duration of smoking. These
`findings were consistent with the Rotterdam study in which
`a statistically significant higher rate of bone loss was seen in
`both elderly men and women who currently smoked ciga-
`rettes [16].
`
`Alcohol consumption
`
`Moderate alcohol intake is associated with lower risk of
`fracture [25]. However, excessive alcohol consumption is
`associated with low BMD and increased fracture risk among
`men and women. Possible mechanisms include impaired
`calcium metabolism secondary to liver disease and in-
`creased risk for falls because of poor balance [15].
`
`Dietary calcium level
`
`Adequate intake of calcium is necessary for achieving
`optimal peak bone mass during development and maintain-
`ing calcium homeostasis [15,18]. Calcium deficiency in-
`creases bone resorption and is a common cause of acceler-
`ated bone loss in the elderly. In a population-based study
`involving 1,856 elderly men in Rotterdam, Netherlands be-
`tween 1990 through 1995, after adjusting for age, BMI,
`lower limb disability, energy intake, cigarette smoking, and
`alcohol consumption, higher calcium intake was associated
`with lower rates of bone loss in men (P ⫽ 0.04) [16].
`Both American men and women consume less than 800
`mg of calcium per day [26]. Currently, the National Institute
`of Health recommends for men over the age of 63 years old
`to have a calcium intake of 1500 mg/day to prevent osteo-
`porosis [27]. This calcium requirement can be achieved by
`the addition of calcium supplements (such calcium carbon-
`ate, calcium citrate, and calcium phosphate) with dietary
`calcium intake. In a 3 year prospective, randomized, double-
`blind trial, daily intake of 500 mg of calcium with 700 IU of
`vitamin D supplements has been shown to significantly
`increase BMD and reduce the incidence of fractures as
`compared to placebo in both elderly men and women aged
`65 years or older [28].
`
`Physical activity
`
`Physical activity plays an important role in achieving
`peak bone mass during adolescence and is positively asso-
`ciated with BMD in adult males [18,29]. Nguyen et al. [18]
`examined the efficacy of multiple risk factors for osteopo-
`rotic fractures in 820 men aged 60 years or older. They
`found that higher physical activity was protective against
`fracture risk. Similar results were reported by Kujala et al.
`[30] and Kanis et al. [31]. Physical exercise, particularly
`weight bearing exercise, may prevent fractures from falls
`[32]. While the exact exercise prescription for both men and
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`F.A. Conde, W.J. Aronson / Urologic Oncology: Seminars and Original Investigations 21 (2003) 380 –383
`
`women is currently unknown, benefits of exercise include
`increasing bone density, muscle strength, balance, and co-
`ordination.
`
`BMI
`
`BMI is positively related to BMD [33]. Studies have
`shown that lower BMI scores were associated with BMD
`loss [16,34,35]. As well, increasing BMI is associated with
`a reduced risk of fracture in men [25,36]. Studies also
`suggest that obesity is associated with increased BMD and
`may decrease incidence of fracture in men.
`
`Diseases and medications
`
`Diseases, such as chronic renal failure, hyperparathy-
`roidism, hyperthyroidism, rheumatoid arthritis, chronic ob-
`structive pulmonary disease (COPD), and functional loss
`associated with central nervous system disorders, are known
`to cause osteoporosis in men [18]. Glucocorticosteroids are
`extensively used by elderly as anti-inflammatory agents for
`treatment of acute and chronic asthma, chronic lung disease,
`and rheumatoid arthritis [37]. These medications, however,
`causes bone (particularly trabecular bone) loss through sup-
`pression of osteoblastic activity and inhibition of intestinal
`calcium absorption. Also, corticosteroid-related hypocalce-
`mia directly stimulates PTH secretion, causing increased
`osteoclastic bone resorption. Risk factors associated with
`steroid-induced osteoporosis include total cumulative dose,
`daily dose of glucocoticoid, and duration of therapy [38].
`Among 161 ambulatory patients with rheumatic disease
`treated with long-term prednisone, patients who were
`treated with a cumulative dose of less than 10 g of pred-
`nisone had an estimated 23% incidence of osteopenia and
`22% incidence of fracture. Those who received 10 to 30 g
`had a 40% incidence of osteopenia and 33% incidence of
`fracture. Furthermore, patients who received over 30 g had
`78% incidence of osteopenia and of those, 53% had radio-
`graphic evidence of fracture [39].
`Histologic examination of bone among patients treated
`with long-term glucocorticoid therapy revealed an estimated
`20% trabecular volume loss after 5 to 7 months of therapy.
`Also, 63% of individuals who received an average of 5
`years of varying doses of glucocorticoid agents suffered
`significant bone loss [40].
`
`Prevalence of osteopenia and osteoporosis before ADT
`
`A number of studies have reported a high prevalence of
`osteopenia and osteoporosis in men before receiving ADT
`or on watchful waiting for their prostate cancer. The pres-
`ence of osteopenia and osteoporosis before receiving ADT
`is of great concern because of the expected bone loss during
`long-term ADT, and therefore, these men may be at greater
`risk for developing osteoporotic fracture. Data on the factors
`
`associated with osteopenia and osteoporosis before ADT are
`limited and have not been well established. In a sample of
`12 men (mean age of 78) with advanced prostate cancer,
`Diamond et al. [8] found 75% had osteoporosis in the
`lumbar spine and 33% had osteoporosis in the femoral neck
`before receiving ADT. Wei et al. [7] studied 8 men (median
`age ⫽ 76) with prostate cancer who were not on ADT and
`found 38% with osteopenia and 25% with osteoporosis.
`Risk factors for osteoporosis such as age, ethnicity, physical
`activity, smoking, alcohol consumption, and calcium levels
`were examined, but no significant differences were found
`between the ADT and no ADT groups [7]. Recently, in a
`sample of 35 men with a median age of 75, Berruti et al. [5]
`reported pre-existing osteopenia and osteoporosis in the
`lumbar spine (46% and 14%, respectively), and at the hip
`(40% and 4%, respectively). As well, no significant associ-
`ations were found among age, physical activity, alcohol and
`caffeine consumption, calcium intake, and smoking habits
`with changes in BMD using univariate and multivariate
`regression analysis [5]. In our institution, we studied BMD
`of 34 men (mean age ⫽ 69) with nonmetastatic prostate
`cancer who have not received ADT, and we found 73.5%
`had osteopenia (55.9%) or osteoporosis (17.6%) of the lum-
`bar spine and/or femur. In our sample, older age and lower
`BMI were factors significantly associated with bone loss in
`the lumbar spine and femur of these men.
`
`When and for whom should bone mineral density be
`performed?
`
`Currently, it remains unclear if and when bone densi-
`tometry should be obtained in men before, or while receiv-
`ing ADT. For patients about to begin ADT, the urologist or
`caregiver needs to assess the risk factors for osteoporosis
`before initiating therapy. Given that ADT is known to cause
`a progressive decline in BMD and because osteoporosis is
`easier to prevent than to treat, men with significant risk
`factors should undergo BMD studies at baseline. Whether
`all men with prostate cancer should undergo BMD studies at
`baseline remains unclear. Our present practice is to only
`obtain baseline bone density studies in men with risk fac-
`tors, and to wait 2 years while on ADT before obtaining
`bone density studies in men without risk factors given that
`men have a 30 percent higher peak bone mass than women
`[11,41]. At issue is whether merely the diagnosis of prostate
`cancer increases the risk for bone loss, and given the high
`incidence of low bone density in men with prostate cancer
`before receiving ADT [5,7,8], whether all these patients
`should have baseline bone density testing. Larger prospec-
`tive studies will be required to resolve this issue.
`
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