Equal Time for the Older Male

**sub**Andropause: Fact or Fiction? **endsub** Panayiotis D. Tsitouras, MD, Associate Professor of Medicine and Geriatrics, and Director, Sexual Performance Assessment and Rehabilitation Clinic, Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, began by noting that the term andropause—made up of two Greek words andras (male) and pause (finish)—does not translate into the most optimistic depiction of hormonal changes that take place in aging males. Dr. Tsitouras focused  on the impact of age-associated declines in androgen on men’s health, compared with the impact of age-associated declines in estrogen on women’s health. According to Dr. Tsitouras, “testosterone does decline with advancing age, but in most people who are healthy enough, it remains within the normal range.” Unlike the abrupt declines in estrogen that inevitably occur in menopausal women, testosterone levels in males decline gradually, beginning at age 20 and continuing to age 90. Increases in the incidence of hypogonadism generally correspond to the gradual decreases in the levels of testosterone, both total and bioavailable. Chronically ill nursing home residents are known to have lower levels of testosterone and bioavailable testosterone than the elderly living in communities; acute illness is also known to lower testosterone levels. Therefore, it is not surprising that men with medical problems show higher rates of hypogonadism than their healthier peers. What are some of the signs of hypogonadism? “I can tell you that is not predictable,” stated Dr. Tsitouras. A survey designed by Morley and colleagues1 at St. Louis University School of Medicine, called the Androgen Deficiency in Adult Males (ADAM) Questionnaire, has been used in screening for hypogonadism (Table). It is composed of 10 questions that relate to the individual’s sex drive, mood, energy level, and physical function. Burns and acute trauma have emerged as catalysts for reduction in testosterone levels. General anesthesia has also become associated with lowered testosterone for a period of at least several days following the procedure. However, whereas the level of testosterone may irreversibly drop in one patient, it may revert to its normal level in another, Dr. Tsitouras reported. The implications of testosterone deficiency are increased body fat mass, decreased muscle and bone mass, predisposal to osteoporosis, and decline in libido along with erectile function. Generally, a testosterone level below the normal range is accompanied by decreased sexual activity. According to the Food and Drug Administration, approximately 5 million older men in the United States have hypogonadism (ie, testosterone levels below 300 ng/dL), and unfortunately only 5% of them are being treated. In administering testosterone replacement therapy, the expectation and hope is to reverse the effects of testosterone deficiency, improving the patient’s health and quality of life. Two major risks are known, or suspected, to be associated with testosterone replacement therapy: prostate cancer and male breast cancer. Addressing the risk of prostate cancer, Dr. Tsitouras said, “Unless the prostate-specific antigen (PSA) is grossly increased and/or biopsy proves prostate cancer, mild enlargement or a suspicion of a miniscule cancer in the prostate is not a contraindication for treatment with testosterone.” In the speaker’s experience, the incidence or prevalence of prostate cancer has not increased with initiating testosterone replacement therapy. Studies have shown that castrating men with in situ prostate cancer has no long-term impact, and therefore urologists and oncologists reserve chemical and surgical castration for cases of metastatic prostate cancer. Testosterone replacement therapy is available in four different forms, one of which—oral tablets—causes serious damage to the liver and should therefore be avoided. The other three forms of treatment that can be considered are intramuscular injections (optimal dose, 200 mg every two weeks); transdermal patches (applied to the scrotum or nonscrotal areas); and transdermal gel. According to Dr. Tsitouras, the ideal but most expensive choice is the gel, followed by the patches. The injections are the last choice of therapy, although they are the most affordable. The speaker briefly discussed growth hormone secretion in aging males. It seems that there is a direct relationship between the levels of testosterone and the growth hormone secreted (as indicated by IgF1 levels), but it is observed only with low testosterone levels, below 1.8 ng/mL. “This is something we are going to look into more,” he said. “To summarize and clarify some points, testosterone deficiency in elderly males should be treated,” stated the speaker. However, it does not have to be treated exclusively with testosterone. “Testosterone replacement therapy can be combined with other treatments, appropriate in a given case,” he concluded. Reference 1. Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49(9):1239-1242.

**sub**Pathophysiology, Evaluation, and Management of Male Osteoporosis**endsub** Eric S. Orwoll, MD, FACP, Director, Bone and Mineral Clinic and Densitometry Services, Professor of Medicine, and Attending Physician, Oregon Health Sciences University, Portland, began by pointing out that osteoporosis has been labeled a female postmenopausal disease due to its increased prevalence among postmenopausal women, especially compared with that among men. Most research on the management of osteoporosis has therefore focused on women, neglecting the threat the disease poses to elderly men. “One of the points that I want to make is that osteoporosis is clearly common in men,” said Dr. Orwoll. Examining the incidence of fracture relative to age in both sexes revealed that five- to 10-year delays in fracture increase in men and their shorter life spans account for the major part of the difference between men’s and women’s incidence of fracture. “An Australian observational longitudinal study1 estimated that lifetime fracture risk—any fracture—for males at age 60 was 29%,” recited Dr. Orwoll: a significant number that nears one-third of males 60 years of age or older. Regarding vertebral fractures, initially the prevalence of vertebral deformities in elderly men was thought to be a result of their risk-incurring behavior, such as “being up on the roof with a six-pack, or riding a motorcycle, or some other foolish activity,” said Dr. Orwoll. However, studies have clearly demonstrated that men (like women) with vertebral deformities have lower bone densities. In both sexes, skeletal fragility is thought to contribute to the condition of vertebral deformity, and vertebral deformity is known to increase the risk of fracture in both men and women. Currently in the United States, 20-25% of elderly men have sustained hip fractures. This number is expected to rise in the next few decades as the population continues to age. “So we’re all going to have to know more about taking care of hip fractures in men,” stated Dr. Orwoll. Understanding the causes of hip fracture in the elderly would obviously help prevent them, but unfortunately, at present, this understanding does not go beyond supposing that the incidence of hip fracture is a product of one’s living environment. Other cultures’ statistics validate such an assumption. The Asian statistics, for instance, show much lower fracture risk in both sexes, and the female-to-male ratio is reversed, whereas European studies reveal a male-to-female ratio of 2:3. Men experience a significant age-related bone loss similar to that in women (although in women it is still greater due to the postmenopausal loss they sustain). Risk factors for low bone mineral density (BMD) are also very similar in men and women. For men, they include age, muscle weakness, fracture history, low body mass index, weight loss, corticosteroid use, smoking, calcium insufficiency, alcoholism, and physical inactivity. “I want to emphasize,” stressed Dr. Orwoll, “that we need to identify men at risk before we undertake preventive and therapeutic strategies.” One of the problems in managing osteoporosis in elderly men is that, while it has become conventional to conduct bone density testing in most menopausal women, no testing guidelines have been established for testing in men. “Should all men at the age of 70 or 75 years undergo bone density testing?” challenged Dr. Orwoll. “There are no cost-effective data.” Contrary to women, a relationship between BMD and fracture risk in men has not yet been firmly established. Controversy still surrounds the question of whether to use male or female bone mineral density ranges as a reference, although using the female range grossly underestimates the risk of osteoporosis in men. Dr. Orwoll believes that “a much more reasonable number of men will be identified if the male reference range is used in testing.” Developing a preventive approach to osteoporosis requires understanding its causes. According to Dr. Orwoll, “the rule of thumb is that secondary causes are present in about a half to two-thirds of men.” These causes include glucocorticoid excess (most common), alcohol abuse, hypogonadism, and miscellaneous causes such as renal disease, malabsorption, and multiple sclerosis. Treating these secondary causes is an integral part of osteoporosis management. For example, testosterone replacement therapy is effective treatment in hypo?gonadal men, and bisphosphonates in glucocorticoid-treated patients. “Testosterone, or I should say sex steroids, are clearly important for skeletal metabolism in men, but there are some major unknowns associated with using it in a practical setting,” said Dr. Orwoll. For instance, it is not clear what the threshold level of treatment is, at what testosterone level replacement therapy should commence, or how testosterone therapy affects fracture risk. It appears that both androgens and estrogens are effective in controlling bone mass, but this will take further studies to affirm. As for calcium and vitamin D supplementation, Dr. Orwoll believes that all men who present with low bone density should receive these supplements; he suggested treating men with bone density T scores below -2. He added, “I would be more aggressive [in administering supplements] in the presence of prevalent fractures, which expose men to the risk of subsequent fractures. I would be more aggressive with advancing age.” Apart from pharmacologic agents, avoiding high-risk behaviors such as smoking and consuming alcohol in excess, staying active, and taking measures to prevent falls are important in the treatment of osteoporosis. To preview therapies that may become available in the future, Dr. Orwoll mentioned selective androgen receptor modulators (SARMs), which, in animals, have been shown to have positive effects on muscle mass, sexual function, and bone density, without causing harm to the prostate or lipids. The selective estrogen receptor modulators (SERMs) have also been found in animals to lower cholesterol and prevent bone loss, and they seem to exhibit no negative effects on the prostate. Both the SERMs and the SARMs are potentially highly effective regimens in treating osteoporosis and need to be tested in humans. Dr. Orwoll concluded, “Strategies for identifying men at risk of osteoporosis have been developed, but they are not widely used.” The awareness of osteoporosis as a common and personally devastating disease in men needs to be increased in light of the expected rise in the number of fractures sustained by men. Reference 1. Jones G, Nguyen T, Sambrook PN, et al. Symptomatic fracture incidence in elderly men and women: The Dubbo Osteoporosis Epidemiology Study (DOES). Osteoporos Int 1994;4(5):277-282.

**sub**Evaluation and Management of Glucocorticoid-Induced Osteoporosis **endsub** “To this day, the most potent anti-inflammatories that we have are corticosteroids,” began Stanley B. Cohen, MD, Director of the Arthritis Division at Health South Rehabilitation and the Osteoporosis Center, Baylor Irving Healthcare System, Dallas, TX, and Clinical Associate Professor, Internal Medicine, University of  Texas Southwestern Medical Center at Dallas. This explains why as many as 1.5 to 2 million people in the United States are currently receiving chronic long-term corticosteroid therapy, in spite of the risk of developing glucocorticoid-induced osteoporosis—one of its major side effects. Corticosteroids (CS) are predominantly prescribed for patients with rheumatoid arthritis, polymyalgia rheumatica, asthma, chronic obstructive pulmonary disease, or inflammatory bowel disease. The associated side effects include inhibition of bone growth, osteonecrosis, and delayed union of fracture; skin thinning; hypertension; diabetes mellitus; cataracts and glaucoma; neuropsychiatric effects; and infections. “Corticosteroids are an acute toxin to the bone,” continued Dr. Cohen. It has been shown that discontinuation of CS results in some recovery of  BMD, although the BMD level prior to therapy may never be restored. It has also been demonstrated that the amount of bone loss is proportional to the dose of steroids administered, as well as the length of time over which they were administered (although there is a less obvious relationship here). It is now known that doses as small as 2.5 mg/day of prednisone may increase the risk of hip fracture by almost 70%.1 As with BMD, the risk of hip fracture decreases with discontinuation of CS. In identifying patients at the highest risk for corticosteroid-induced osteoporosis, Dr. Cohen said, “High doses of CS affect all patients, regardless of age, sex, or race.” The effect of low doses on fracture incidence may relate to presteroid BMD and concomitant diseases. In general, older adults are at greater risk of fracture due to their lower baseline BMD, and younger adults have a more rapid rate of bone loss. The trabecular bone is predominantly affected by CS, and consequently a great number of fractures are vertebral, rib, and pelvic. “The good news is that we rheumatologists have become aware of osteoporosis through our experience in managing steroid complications. Our colleagues in family practice and, to a lesser degree, in general internal medicine, neurology, and nephrology may not as clearly understand the damage that steroids can cause to the bone. With meetings such as this, we’re hoping to spread the word on how necessary it is to manage patients with glucocorticoid-induced osteoporosis,” stated the speaker. Management of the disease involves both prevention and treatment. Dr. Cohen mentioned that baseline testing has been previously recommended in patients who are started on long-term CS therapy with prednisone doses greater than 7.5 mg/day for a period of six months or more. Recent results from randomized controlled trials (RCTs) suggest that these recommendations need to be modified by adjusting the dose threshold of prednisone to 5 mg/day, and the time threshold to a period of three months or more. Under both guidelines, serial BMD measurements are recommended yearly for the duration of treatment. Prevention applies to those patients who recently began to receive CS, while treatment applies to those already on chronic CS—most of them with low bone density and some instances of fracture. Lifestyle modifications are an integral part of both prevention and treatment. Using lower doses of CS whenever possible is an obvious and effective prevention method. Other methods include using preparations with a smaller potential effect on the bone, but these are unavailable in the United States. Calcium/vitamin D administration prevents bone loss but not fractures (calcium at 1500 mg/day is necessary, as suggested for all patients on CS; vitamin D should be supplemented at up to 400-800 IU/day). Hormone replacement therapy appears to be an effective treatment in improving BMD in patients on chronic CS, but no fracture data are available from RCTs to assess its true benefit. Calcitonin, due to modest effect on BMD in RCTs, is not considered a choice for first-line therapy. Bisphosphonates, on the other hand, have been demonstrated to reduce bone loss and, in addition, the risk of fracture. Etidronate, alendronate, and risedronate have been shown to be efficacious in patients who are either initiating or undergoing long-term treatment with CS. While etidronate and alendronate are known to reduce fracture risk in postmenopausal women, risedronate reduces the risk in both men and postmenopausal women. Bisphosphonates have thus become the choice for first-line therapy in patients with glucocorticoid-induced osteoporosis. “The new guidelines,” concluded Dr. Cohen, “recommend that patients initiating on corticosteroids of doses greater than 5 mg/day be treated with bisphosphonate. In patients on long-term corticosteroids, with BMD greater than 1SD below young normal, the recommendation for treatment is also bisphosphonate therapy.” Reference 1. Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral cortico?steroids and risk of fractures. J Bone Miner Res 2000;15(6): 993-1000.