Feature Article
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Osteoporosis in the Aging Male Dr. Kamel is Assistant Clinical Professor, Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, and Director, Geriatrics and Extended Care Service, St. Joseph’s Mercy Health Center, Hot Springs, AR.
INTRODUCTION Osteoporosis in men is not rare, nor are its related fractures. Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that up to 3-6% (1-2 million) of men have osteoporosis and 28-47% (8-13 million) have osteopenia, when using male cutoffs for bone mineral density (BMD) readings.1 There are several differences in the clinical presentation of osteoporosis between men and women (Table I). Osteoporosis tends to develop later in life in men compared to women. In addition, the incidence of osteoporosis-related fractures is lower in men compared to women. In the U.S., estimates of lifetime fracture risk for Caucasian men range from 13-25% compared to a 50% lifetime fracture risk among Caucasian women.1 Among older adults, the incidence of hip fracture is lower in men (4-5/1000 per year) than in women (8-10/1000 per year).2 However, the mortality attributed to hip fractures is twice as high in men as in women.3 Among men with hip fracture who survive, 80% will not regain their prefracture functional status and up to 50% will be institutionalized.4 Unlike hip fractures, vertebral fractures occur more in middle-aged men than in very old men.4
ETIOLOGY OF MALE OSTEOPOROSIS
There are multiple factors that have been linked to the development of male osteoporosis (Table II). About half of the cases, however, can be attributed to one of three major causes: excessive alcohol consumption, glucocorticoid excess (endogenous or exogenous), and hypogonadism.5 Excessive alcohol consumption is responsible for 15-20% of cases of osteoporosis among men.6 In addition, excessive alcohol use has been linked to increased hip fracture risk.7 Glucocorticoid excess is responsible for another 20% of cases.7 Glucocorticoid-induced bone loss is estimated to affect 30-50% of long-term glucocorticoid users, depending on dose and duration. Recent studies indicate that fracture risk is increased even at low doses of glucocorticoids and that this increased risk is seen soon after the commencement of glucocorticoid therapy. Both increased bone resorption and reduced bone formation contribute to bone loss, which affects cortical and cancellous sites.8 Pathogenesis of this syndrome is multifactorial, and involves decreased calcium absorption from the intestinal mucosa, decreased renal reabsorption of calcium, and impairment of osteoblastic activity.9 Inhibition of the function of osteoblasts is the main mechanism involved. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduced bone formation and strength.10 van Staa and colleagues11 conducted a meta-analysis of 89 papers on the effect of glucocorticoid therapy on bone density and fracture risk and concluded that oral corticosteroid treatment using more than 5 mg (of prednisolone or equivalent) daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture during the treatment period. The risk of fracture was found to increase rapidly after the start of oral corticosteroid therapy (within 3-6 months) and decrease after stopping therapy.11
Hypogonadism (either primary or secondary) has been reported in 15-20% of men with spinal osteoporosis.12 In addition, the prevalence of hypogonadism was reported to be increased fivefold among older men with hip fractures.13 However, serum testosterone levels do not correlate with BMD in eugonadal men.14 Preston and colleagues15 demonstrated greater rates of BMD loss in men receiving androgen deprivation therapy for prostate cancer. There is also evidence that fracture risk increases following bilateral orchiectomy in patients with prostate cancer.16 Other secondary causes for male osteoporosis include primary hyperparathyroidism, excessive thyroid hormone exposure (hyperthyroidism or overtreatment with thyroid hormone), multiple myeloma, anticonvulsants, high-dose chemotherapeutics, immobilization, and gastrointestinal malabsorption.17,18
In up to 50% of cases of male osteoporosis, no cause could be identified and the condition is called idiopathic osteoporosis. Idiopathic osteoporosis in men has been linked to changes in sex steroid secretion, in growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, and in vitamin D-parathyroid hormone 25(OH)D-PTH system.19 Among these possible mechanisms, IGF-1 has received much attention. Several reports have demonstrated age-related reduction in IGF-1 levels and have correlated these reductions with reduced bone density of the spine and forearm in osteoporotic men.20,21 Although IGF-1 levels decline as a function of age, at any age IGF-1 levels are lower than expected in men with osteoporosis. Growth hormone deficiency does not fully explain why men with osteoporosis have low IGF-1 levels because these men respond normally to a GH stimulation test.22 However, it is likely that subtle abnormalities in GH dynamics that involve either pulsatility or circadian rhythm exist. More recently genetic studies indicate a possible genetic association for this observation.23
There have been an increasing number of reports recently to support that bone loss in men may be related to declining levels of estradiol rather than testosterone.19,24,25 Some published reports linked a mutation in the estrogen receptor26 or the aromatase enzyme (aromatase enzyme activity is required for the conversion of androgens to estrogens) to the development of osteoporosis.27,28 Administration of conjugated estrogen resulted in increased bone mass in individuals with aromatase deficiency but not in those with mutation of the estrogen receptor. Such cases suggest that a major part of androgen action on the male skeleton is probably mediated by estrogen.
EVALUATION OF MEN WITH OSTEOPOROSIS
Table III lists some of the laboratory tests that may be helpful in the evaluation of men with osteoporosis. Colon-Emeric and associates29 surveyed 43 U.S. physician-researchers who published on the subject of male osteoporosis in the peer-reviewed literature between the years 1993 and 1997 for osteoporosis evaluation in men. Among respondents, 89% recommended measuring serum testosterone levels; 85% recommended measuring serum calcium; 75% recommended measuring 25-OH D levels; 73% recommended screening for multiple myeloma; and 61% recommended checking serum thyroid-stimulating hormone (TSH) levels. In addition, 92% recommended bone density assessment by dual-energy x-ray absorptiometry.29
Current recommendations for bone density assessments by the National Osteoporosis Foundation does not address men.30 However, more recently the International Society for Clinical Densitometry (ISCD) Position Development Conference that was held in July 2001 indicated that men (regardless of race) with prior fragility fractures or with a condition widely recognized to increase the risk of bone loss and fracture (such as hypogonadism, corticosteroid treatment, hyperparathyroidism, excessive alcohol use, anticonvulsant therapy use, and prior gastrectomy) as well as all men aged 70 years or older should have their BMD assessed.31 According to the World Health Organization guidelines, postmenopausal osteoporosis is diagnosed when BMD is more than 2.5 standard deviation (SD) below the peak bone mass reference standard for young Caucasian women.32 This threshold, however, has not been validated in men. Thus, it is not clear if this threshold can be used to diagnose osteoporosis in men. In addition, there is an ongoing debate on whether it will be best to use gender-specific reference values of bone mass or the female reference values to diagnose osteoporosis in men. When applying male cut-off values to the NHANES III, the prevalence of osteoporosis in elderly men was found to be 3-6% compared to a prevalence of 1-4% when applying female standards.1 The ISCD Position Development Conference that was held in July of 2001 recommended that male osteoporosis should be defined as a BMD T-score of -2.5 or below the normal mean for men.31
Men diagnosed with idiopathic osteoporosis are often symptomatic at presentation with an osteoporosis-related fracture or back pain. This is in contrast to women with idiopathic osteoporosis in whom the diagnosis is often made by BMD measurements in the absence of symptoms.4 In men, it is uncommon to obtain BMD assessments even in the presence of clear-cut risk factors for osteoporosis.18,33,34
TREATMENT OF MEN WITH OSTEOPOROSIS
Therapeutic interventions aimed at preventing bone loss that have been tested in men include calcium and vitamin D supplementation, alendronate, risedronate, testosterone replacement therapy, and PTH (1-34) (teriparatide).
Two published randomized, controlled trials tested the effect of calcium and vitamin D supplementation on bone density and fracture risk in men. In the first trial, calcium and vitamin D supplementation had no effect on bone density in men.35 Men in this trial had a high basal dietary calcium intake (1159 mg/day of elemental calcium). In a more recent study, Dawson-Hughes et al36 randomized 389 community-dwelling elderly (45% men) to receive either 500 mg of elemental calcium plus 700 IU vitamin D3 supplementation or placebo daily and followed them for 3 years. Male subjects in this study who received the calcium and vitamin D supplementation showed significant increase in BMD at the hip, spine, and total body. In addition, serum osteocalcin concentrations were 9% lower in this group by the end of the 3-year follow-up period compared to baseline. Over the 3-year study period, only two men, both in the placebo group, had osteoporotic fractures. A U.S. National Institute of Health Consensus Development Conference panel in 1994 recommended a daily elemental calcium intake of 1000 mg/day for men under age 65 years and 1500 mg/day for men over the age of 65 years.37 The median daily dietary calcium intake for men in the U.S. is 826 mg. The average American diet contains 389 mg calcium per 1000 kcal.38
There is evidence to indicate that testosterone supplementation might have a salutary effect on BMD in men. In one study, 13 hypogonadal elderly men received testosterone enanthate (100 mg/week) for a period of 3 months and had significant decline in urinary excretion of hydroxyproline, a marker of bone resorption, in all subjects.39 One study reported an increase in serum osteocalcin levels in elderly hypogonadal men treated with testosterone for a period of 3 months.40 Another study reported an increase in spinal BMD of 5% and trabecular BMD of 14% in hypogonadal men treated with testosterone.41 Bone-specific alkaline phosphatase and urinary hydroxyproline levels were significantly decreased in this study. Transdermal testosterone was shown to increase BMD in elderly hypogonadal men.42,43 Testosterone has also been shown to reduce the risk of glucocorticoid-induced osteoporosis in men of all ages on long-term prednisone treatment.44 Reid et al44 using a crossover design treated 15 asthmatic men who were on long-term prednisone therapy with testosterone esters by intramuscular injection monthly for 1 year, and after a washout period the groups were then crossed over and studied for another 12 months. Bone density in the lumbar spine increased by 5% during testosterone supplementation (P = 0.005) but did not change during the control period in which subjects received calcium only. Testosterone therapy has been shown to increase hematocrit levels in 25% of subjects.45 Although there is no evidence that links testosterone levels to the development of prostate cancer46 or to benign prostatic hypertrophy (BPH),47 testosterone administration may accelerate the clinical course of prostate cancer, and its use is absolutely contraindicated in individuals with this condition.39 On the other hand, there is no evidence that testosterone therapy accelerated the development of BPH.48 More recently Amory et al49 showed that concomitant administration of finasteride and testosterone appears to attenuate the impact of testosterone therapy on prostate size and prostate-specific antigen, and might reduce the change of BPH in older men on testosterone therapy without significantly impacting the beneficial effect of testosterone therapy on bone.49 Other potential side effects of testosterone therapy include the development of gynecomastia, water retention, and sleep apnea.50,51 There is a need for long-term placebo-controlled trials to examine the effects of testosterone on the incidence of hip fractures, and to better define the risk–benefit ratio of treatment in older men (particularly those with low normal serum testosterone levels) before this treatment can be widely recommended.
Alendronate, a bisphosphonate, is currently the only bisphosphonate approved by the Food and Drug Administration (FDA) in the U.S. for the prevention and treatment of male osteoporosis. This approval was based on a 2-year randomized, double-bind, placebo-controlled trial that enrolled 241 men with osteoporosis across 20 centers in 11 countries.52 Subjects were randomized to receive alendronate 10 mg or placebo daily. All subjects also received 500 mg of elemental calcium and 400 IU of vitamin D. Alendronate resulted in a significant increase in BMD at both the lumbar spine and the hip regions as well as an odds ratio of incident vertebral fractures of 0.1 (95% CI = 0.00,0.88; P = 0.017).52 It is worth noting, however, that fracture incidence was not a prespecified endpoint of this relatively small study. In addition, two methods were used for assessment of vertebral fractures; one showed a reduction with treatment while the other did not.
Risedronate is another bisphosphonate that has been approved by the FDA for prevention and treatment of glucocorticoid-induced osteoporosis (including that which affects men) and is currently being studied to treat idiopathic and hypogonadal osteoporosis in men.53
The osteogenic effect of PTH was initially indicated by Bauer et al54 in 1929, and then clearly demonstrated 3 years later in rats by Selye.55 Kurland et al56 randomly assigned 23 men with idiopathic osteoporosis (30-68 years old) to receive 400 IU of PTH (1-34) (teriparatide) or a vehicle administered daily by subcutaneous injection for 18 months. Teriparatide administration resulted in significant increase in BMD at the lumbar spine and the hip. Orwoll et al57 randomized 437 men with spine or hip BMD more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 mcg or teriparatide 40 mcg for a median duration of 11 months. By the end of the therapy period, the teriparatide group had a 5.9% increase (20-mcg dose) and 9% increase (40-mcg dose) in BMD at the spine, and 1.5% increase (20-mcg dose) and 2.9% increase (40 mcg) in BMD at the femoral neck compared to the placebo group. Adverse events were similar in the placebo and 20-mcg group but more frequent in the 40-mcg group.57 In November 2002, the FDA approved teriparatide (20 mcg daily) for the treatment of male osteoporosis secondary to hypogondism.
The safety of long-term administration of teriparatide has not yet been determined. The use of teriparatide should be reserved for patients with very low BMD and should be used for only a short duration. Patients receiving teriparatide should be carefully monitored for the development of hypercalcemia. Recently, Finkelstein et al58 showed that alendronate impairs the ability of teriparatide to increase BMD at the lumbar spine and the femoral neck in men. This effect is possibly due to an attenuation of teriparatide-induced stimulation of bone formation by alendronate.
CONCLUSION
Osteoporosis in men is not rare nor are its related fractures. There are differences in clinical presentation of osteoporosis between men and women. Fifty percent of cases, however, can be attributed to one of three major causes: excessive alcohol use, glucocorticoid excess (endogenous or exogenous), and hypogonadism. There is an ongoing debate on whether it will be best to use gender-specific reference values of bone mass or the female reference values to diagnose osteoporosis in men. At the present time, only alendronate and teriparatide are currently approved by the FDA for the treatment of male osteoporosis that is idiopathic or due to hypogonadism. Risedronate is approved by the FDA for the treatment of glucocorticoid-induced male osteoporosis and is currently being evaluated for the treatment of idiopathic and hypogonadal osteoporosis in men.
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(Annals of Long-Term Care: Clinical Care and Aging 2004;12[6];40-45) Annals of Long-Term Care - ISSN: 1524-7929 - Volume 12 - Issue 06 - June 2004 |