Francisco Bandeira, Hossein Gharib, Airton Golbert, Luiz Griz and Manuel Faria (eds.)Endocrinology and Diabetes2014A Problem-Oriented Approach10.1007/978-1-4614-8684-8_25
© Springer Science+Business Media New York 2014
25. Osteoporosis in Men
(1)
Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, PH 8W-864, New York, NY 10032, USA
Abstract
Osteoporosis is characterized by bone loss with microarchitectural deterioration, reduced bone strength, and increased risk of fracture (Kanis et al., J Bone Miner Res 9:1137–41, 1994; NIH Consensus Development Panel on Osteoporosis Prevention, South Med J 94:569–73, 2001). It is, in part, a disorder of the aging skeleton and, thus, as the world population ages, it is inevitable that the incidence of this disease will also increase. For example, in the USA during the first quarter of this century, the population greater than 50 years old will increase by 60 % (Day, Population projections of the USA by age, sex, race, and hispanic origin: 1995 to 2050. US Bureau of the Census, Current Population Reports, US Government Printing Office, Washington, DC, P25-1130, 1996; Cummings and Melton, Lancet 359:1761–7, 2002). With that increase in the older population will come a greater incidence of osteoporosis. This disease has traditionally been considered to be a disease of postmenopausal women but men now constitute nearly 1/4 of all osteoporotic patients (Burge et al., J Bone Miner Res 22(3):465–75, 2007; Center et al., JAMA 297:387–94, 2007). Hip fracture, which accounts for at least 1/3 of all fractures in men (Gullberg et al., Osteoporos Int 7:407–13, 1997), is associated with a threefold higher mortality rate in men than in women (Center et al., Lancet 353:878–82, 1999). Data from Trombetti et al. (Osteoporos Int. 13:731–7, 2002) show that more years of life are lost in men than in women after a hip fracture. This may be due, at least in part, to the impression that men are typically older when they sustain a hip fracture and are, therefore, more likely to suffer from serious comorbid events when they fracture. Data from the classic study of Johnell and Kanis (Osteoporos Int 17:1726–33, 2006), however, indicates that worldwide, the peak number of hip fractures occurs at a similar age for men and women, between the ages of 75 and 79.
Moreover, similar to women, the absolute risk of a subsequent fracture in men increases substantially after the first fragility fracture (Center et al., JAMA 297:387–94, 2007). The Australian Dubbo Osteoporosis Study noted that the relative risk of a second fracture after an initial osteoporotic fracture in a cohort of community-dwelling men > 60 years old was 3.47 (CI 95 %: 2.69–4.48) while for women, the relative risk of the second fragility fracture was 1.97 (CI 95 %: 1.71–2.26). Mortality risk was also greater when the second fracture occurred, again with men showing greater mortality [11.3 per 100 person-years (95 % CI, 9.8–13.0)] than women [7.8 per 100 person-years (95 % CI, 7.1–8.5)] (Bliuc et al., JAMA 301:513–21, 2009). The cohort in the ongoing, large epidemiologic study of male skeletal health known as MrOs (The Osteoporotic Fractures in Men Study) included a large international sample of men > 65 years old. In MrOs, the advent of a rib fracture resulted in a twofold increased risk of future rib, hip, or wrist fracture, independent of BMD or other factors (Barrett-Connor et al., BMJ 340: c1069, 2010).
Clinical Case
A 71-year-old male was referred for a diagnostic evaluation of osteoporosis. Although the patient had no complaints, his primary care physician obtained a screening bone density test, in view of his age. There is a strong family history of osteoporosis on his paternal side with his father, aunts, and uncles all affected. He has never had a fracture. He has never had a kidney stone. The patient drinks one glass of wine on average per night, and smokes cigarettes (30 pack-years). There is no history of corticosteroid, thyroid hormone, or antiseizure medication use. His diet is relatively poor in calcium-containing foods but, recently, he has added a calcium supplement with vitamin D to his regimen. His exercise routine, over the past 10 years, consists of swimming and walking three times per week. Recently, he has added weight-bearing exercises to his regimen. There has been no height loss from his peak of 180 cm.
Past medical history: Hypertension, since age 65, is well controlled on angiotensin-converting enzyme therapy.
Personal and social history: Patient is married and has one daughter (50 years old) and one son (45 years old), both of whom are healthy.
Family history: Father died at 92 from an upper respiratory infection. His mother is 95 years old with hypertension and diabetes. He has no siblings. A strong family history for osteoporosis is as noted.
Physical examination: Height, 180 cm; weight, 104 kg; BMI, 32 kg/m2. There was no dorsal or supraclavicular fat pads. Examination of heart, lungs and abdomen was normal. There were no striae. The back was straight, without scoliosis or kyphosis. No physical findings of hypogonadism were detected.
Laboratory results: Calcium, 9.2 mg/dL (nl: 8.9–10.1); phosphorus, 3.4 mg/dL (nl: 2.5–4.5); PTH, 25 pg/mL (nl: 15–65); 25-hydroxyvitamin D, 35 ng/mL (nl: 30–50 ng/mL); alkaline phosphatase activity, 52 IU/L (nl: 33–96); and creatinine, 0.85 mg/dL (nl: 0.76–1.27 mg/dL). The estimated glomerular filtration rate was normal (89 mL/min/1.73 m2). Total testosterone was 528 ng/dL (nl: 260–1,000 ng/dL) with normal FSH and LH levels. Serologies for gluten enteropathy were negative. Liver function was normal. Serum and urine protein electrophoresis were normal. 24-h urine collection for calcium (180 mg/g creatinine) and cortisol (20 μg) was normal.
Bone density results: T-scores at the following sites were as follows: −3.0 (lumbar spine); −2.6 (total hip); −2.5 (femoral neck).
Summary: The patient has several risk factors for osteoporosis, namely, age, family history, and tobacco use. By densitometric criteria with T-scores < −2.5, he has osteoporosis and is a candidate for therapy with pharmacological agents.
Key Points to the Diagnosis of Bone Loss in Men
The information to be presented in this discussion is base upon general and specific review material as described in the abstract [1–12].
Medical History and Physical Examination
A complete review of systems draws attention to potential causes of bone loss by eliciting symptoms such as weight loss, change in body shape, bruising, hair pattern, libido, alcohol intake, smoking, and kidney stones. A medication history focuses upon thyroid hormone, glucocorticoids, and antiseizure medications. The physical examination should always include height so that a comparison can be made with the historical record of peak height. Height loss of more than 5 cm calls for imaging studies [X-ray or vertebral fracture assessment by dual energy X-ray absorptiometry (DXA)] to investigate the possibility of a vertebral fracture. The presence or absence of kyphosis and/or scoliosis should be noted. Mobility and overall frailty are observed. Signs of common secondary causes of osteoporosis are sought: hypogonadism (testicular size, hair pattern), hyperthyroidism (neck exam, reflexes), Cushing’s syndrome (supraclavicular fat pads, skin thickness, striae, proximal muscle weakness), chronic obstructive pulmonary disease (anterior-posterior chest diameter, distant breath sounds), alcoholism (liver size, palmar erythema). Any of these findings can be helpful clues to the differential diagnosis of osteoporosis.
Laboratory Tests
Laboratory tests should include serum calcium, phosphate, albumin, creatinine with estimated glomerular filtration rate, alkaline phosphatase activity, liver and thyroid function tests, 25-hydroxyvitamin D, parathyroid hormone, total testosterone, complete blood count and 24-h urine for calcium excretion. Depending upon the history and the physical examination, additional laboratory tests should be considered (i.e., cortisol, gluten antibodies, tryptase [13]).
Bone Mineral Density (BMD)
The gold standard for the diagnosis of osteoporosis in men and women is the BMD measurement by DXA. Recent guidelines of The Endocrine Society [14] recommend that all men over 70 years old should have a screening BMD test, in agreement with previous recommendations by the International Society of Clinical Densitometry and the National Osteoporosis Foundation in the USA [15]. BMD should also be obtained in men under the age of 70 who have other risk factors for osteoporosis such as excessive alcohol intake, smoking, rheumatoid arthritis, glucocorticoid use (>5 mg prednisone or equivalent for >3 months), use of gonadotropin-releasing hormone agonists, low body weight, chronic obstructive pulmonary disease, hyperparathyroidism, hyperthyroidism, hypogonadism, delayed puberty, or family history of hip fracture [16–19]. Some experts advocate extending this screening window to men with hypercalciuria/nephrolithiasis, and those with a history of constitutionally delayed puberty.
A history of a fragility fracture after the age of 50 is another indication for a BMD test. Vertebral or hip fractures occurring under these circumstances are particularly noteworthy.
A history of a fragility fracture, defined as a fracture occurring spontaneously or after minor trauma (i.e., a fall from a standing height), can be diagnostic of osteoporosis. In this case, a BMD test is performed not to make the diagnosis of osteoporosis but rather to determine the extent of bone loss and its pervasiveness.
BMD of spine and hip are the usual DXA measurement sites. If one of these regions cannot be interpreted (e.g., osteoarthritic changes in the lumbar spine), the forearm at the distal 1/3 radius is recommended. Forearm DXA is also recommended in those with primary hyperparathyroidism, hyperthyroidism, and those on androgen deprivation therapy (ADT) [14]. The diagnosis of osteoporosis is established with a BMD T-score of −2.5 or less (i.e., 2.5 standard deviations below average peak BMD) [20]. There is controversy as to which reference range should be used to calculate T-scores in the male population. The Endocrine Society Guidelines and the International Society of Clinical Densitometry [14, 21] both recommend the male-specific reference range (peak bone mass for 25–30 year-old young men who have achieved peak bone mass) although other groups recommend the female database [22]. The uncertainty over which referent database to use is a result of a differing opinion as to whether absolute fracture risk or relative fracture risk should be used. The argument for using a male referent database for men is that the relationship between BMD and fracture risk is similar among men and women. For every SD unit reduction in BMD by DXA, fracture risk is doubled in men and in women. Therefore, the relative risk using the male referent database is the same for a T-score of −2.5 as it is for a woman whose T-score is −2.5 using a female referent database. Even though relative risk is the same, using the gender-specific referent standard, absolute risk is not. A man’s T-score of −2.5 confers a lower absolute risk of fracture than a woman’s because the risk of fracture is lower in men than in women at any T-score. This latter point has led experts to recommend that the female database be used for both men and women. The absolute risk of fracture is a function of the absolute BMD in g/cm2, not the T-score. If this approach is taken, however, the diagnosis of osteoporosis in men will be made much less frequently and will be inconsistent with epidemiological data on fracture incidence in men. Therefore, utilization of the male database seems to make more sense.
FRAX®
The fracture risk calculation tool FRAX®, approved by the World Health Organization in 2008 (http://www.shef.ac.uk/FRAX/index.jsp), is widely used in many countries throughout the world, including Brazil and other Latin American countries. FRAX® helps to identify those with osteopenia who are at high risk for fracture. FRAX® incorporates established clinical risk factors besides BMD (e.g., height, weight, age, sex, family history of hip fracture, glucocorticoid use, rheumatoid arthritis, alcohol intake, smoking, secondary causes of osteoporosis) and calculates a 10-year probability of hip fracture and major osteoporotic fracture (clinical vertebral, hip, forearm, or humerus). FRAX® is a country-specific algorithm, applicable to men and women [23, 24], with each country setting its threshold for therapeutic intervention according to its own cost effectiveness measures. In the USA, treatment with a pharmacological agent is recommended if the 10-year fracture risk by FRAX® for a major osteoporotic fracture is ≥20 % or for hip fracture is ≥3 %.
Differential Diagnosis of Bone Loss in Men
About 40–50 % of men diagnosed with osteoporosis will be shown, upon further evaluation, to have a secondary cause of bone loss [25]. Excessive alcohol intake, hypogonadism, and glucocorticoid excess are the three most important causes of secondary osteoporosis in men [26]. Other important etiologies to be considered are gastrointestinal disorders (e.g., celiac disease can be subclinical), hypercalciuria, chronic obstructive pulmonary disease, organ transplantation, neuromuscular disorders, systemic illnesses (i.e., multiple myeloma), and medications [27]. In the setting of a fragility fracture, it is necessary to rule out the possibility of a pathologic fracture due, for instance, to a skeletal metastasis (i.e., prostate, lung).
It is not uncommon for there to be no obvious etiology to the osteoporosis, besides aging itself. In men over the age of 70, it is appropriate to use the term age-related osteoporosis. In individuals who are younger, however, aging is an incomplete explanation, particularly in view of the fact that age-related bone loss in men typically does not begin until around the age of 60. For want of a better word, the term used for these individuals is “idiopathic” osteoporosis, and, as noted, is applied often to osteoporotic men in their middle years. The term “idiopathic” does not mean to imply that there is no cause, but merely that a cause is not apparent. Studies of idiopathic osteoporosis have focused upon genetic predispositions [28], polymorphisms of the aromatase gene [29, 30], and deficiencies in the insulin-like growth factor system. Patients with insulin-like growth factor deficiency present with a low bone turnover state, with paucity of osteoblasts and osteoclasts on the bone surface and osteoblast dysfunction with decreased osteocalcin production, associated with low insulin-like growth factor levels [31–33].
Treatment: New and Future Therapies
The Endocrine Society recommends pharmacologic therapy for men who are at high risk for fracture. The indications in men are as follows: the presence of a fragility fracture (clinical or morphometric vertebral or hip); T-score at the lumbar spine, femoral neck, and/or total hip that is ≤−2.5; in the US for those who have a T-score between −1.0 and −2.5 but in whom FRAX calculates a risk for any type of fragility fracture in the next 10 years ≥ 20 %, and for hip fracture is ≥ 3 %; and long term glucocorticoid therapy [14].
Most of the pharmacologic agents that are currently available for men with osteoporosis have been previously tested and approved for women. The studies in men, in general, have not had adequate numbers of patients to ascertain a change in fracture incidence. Rather, other surrogate endpoints such as increases in BMD and changes in bone turnover markers have been used. On the whole, however, even without hard fracture endpoints, it seems that the efficacy of these drugs in men is similar to that in women [14]. Medications available at this time to treat male osteoporosis can be grouped according to their chemical class and function.
Bisphosphonates
The current bisphosphonates approved by the FDA for the treatment of male osteoporosis are alendronate, risedronate, and zoledronic acid [34–42]. These bisphosphonates have been shown to increase BMD and to reduce bone turnover markers in men with osteoporosis. Alendronate and risedronate are oral bisphosphonates, requiring patients to take the drug in the morning, on an empty stomach with plain water and to wait approximately 30 min before eating, drinking, or taking other medications [43]. A new formulation of risedronate (DR 35 mg) can be taken before or after breakfast [44].
Alendronate is given weekly (70 mg) although the daily 10 mg formulation is still available. Both the weekly and the daily formulations increase BMD in men and reduce bone turnover markers. Men with osteoporosis treated for 2 years with daily alendronate 10 mg had a lower fracture incidence and less height reduction compared to those in the placebo group, with BMD increments at the lumbar spine (+7.1 %), femoral neck (+2.5 %), and total body (+2.0 %) compared to baseline values [45]. Similarly, another study showed that treatment with alendronate 10 mg daily for 3 years promotes BMD gains at the lumbar spine (+8.8 %), femoral neck (+4.2 %), and total hip (+3.9 %) [40]. Daily and weekly alendronate was associated with the same increments in BMD [46]. A meta-analysis has provided additional support for the effects of alendronate to reduce vertebral fracture incidence in men [47].
Risedronate is effective in the treatment of primary and secondary causes of bone loss in men [38, 48]. Risedronate is taken either daily (5 mg), weekly (35 mg), or monthly (150 mg), the latter two being the most commonly used regimens. In an open label clinical trial conducted by Ringe et al., daily treatment with risedronate 5 mg for 1 year reduced the incidence of a new vertebral fracture by 60 % compared to placebo which was sustained for the second year of treatment and associated with BMD improvements at the lumbar spine (+6.5 %); femoral neck (+3.2 %), and total hip (+4.4 %) [38, 48]. In a 2-year, randomized, double-blind, placebo-controlled study in men with osteoporosis, Boonen et al. demonstrated that weekly risedronate is as effective as daily risedronate in terms of reductions in bone turnover markers and increases in BMD [49]. There were very few fractures in that study and a difference between placebo and the treatment arms could not be ascertained. In a 2-year open-label extension of this trial, risedronate was associated with further increases in BMD [50]. Risedronate has also been shown to be effective in the treatment of bone loss in men >65 years of age who have sustained a cerebrovascular accident. Although the number of hip fractures was small (10 in the placebo vs. 2 in the risedronate groups), risedronate was associated with a significant reduction in hip fracture incidence [51].
Zoledronic acid is administered intravenously at a dose of 5 mg once yearly for the treatment of osteoporosis. Satisfactory results with this drug were observed in osteoporotic men [39]. Zoledronic acid is as effective as alendronate in increasing BMD and reducing bone turnover markers the men with idiopathic osteoporosis or osteoporosis due to hypogonadism [52]. Moreover, in the treatment and prevention of glucocorticoid-induced osteoporosis, zoledronic acid was superior to risedronate in increasing BMD and reducing bone turnover markers [53]. A double-blind, randomized placebo-controlled registration trial for zoledronic acid, known as The Health Outcomes and Reduced Incidence with Zoledronic Acid Once-Yearly Recurrent Fracture Trial (HORIZON-FT), enrolled men and women with a recent low-trauma hip fracture (within 90 days of surgical repair). Boonen et al. conducted a subset analysis grouping the results by gender [54]. Patients were randomized either to yearly infusion with zoledronic acid or placebo for 24 months, with a mean follow-up of 21 months. In the group treated with zoledronic acid, adjusted BMD increased significantly at the total hip (+3.8 %) and femoral neck (+3.1 %) as compared to the placebo group (p < 0.01 for all comparisons). Increments in BMD in men were similar to the increments in the women, demonstrating clearly that zoledronic acid increases BMD in men with history of a recent hip fracture [54].
Most of the aforementioned studies of bisphosphonates in men have focused upon equivalency data with regard to BMD and bone turnover markers in the intention-to-treat analyses. While these studies have provided some evidence for fracture reduction, there had not been a prospective, randomized, double-blinded, placebo-controlled trial of a bisphosphonate statistically powered to show a reduction in fracture incidence until recently. Boonen et al. conducted such a study in a major clinical 2-year, placebo-controlled trial of 1,199 men, 50–85 years old, with primary or hypogonadism-associated osteoporosis [55]. Zoledronic acid or placebo was administered at baseline and at 1 year. An important feature of this trial is that it was powered to determine a difference in fracture endpoints. The primary endpoint was the percentage of men who sustained 1 or more new morphometric vertebral fractures after 24 months. Overall, patients treated with zoledronic acid had a 67 % reduction in relative fracture risk and a 3.2 % risk reduction in absolute risk (4.9 % vs. 1.6 %; p = 0.0016). Furthermore, the group that received active drug experienced fewer moderate to severe vertebral fractures (p = 0.026) and less height loss (p = 0.0002) in comparison to placebo. Men with osteoporosis due to hypogonadism demonstrated results similar to the group with normal testosterone levels. No difference was seen between serious adverse events in the zoledronic acid and placebo groups [55].
Osteoanabolic Therapy
The two available osteoanabolic treatments for osteoporosis are PTH(1-84), the full length, native molecule, and its foreshortened analogue PTH(1-34), known as teriparatide. Teriparatide is approved worldwide including Europe, Brazil, and the USA for the treatment of men and postmenopausal women with osteoporosis at high risk for fracture and for the treatment of glucocorticoid-induced osteoporosis. PTH(1-84) is approved for the treatment of postmenopausal osteoporosis in a several number of countries, but not in the USA or in Brazil.
Teriparatide is administrated as a daily 20 μg subcutaneous injection for no more than 2 years. Orwoll et al. showed that treatment with teriparatide for 11 months in men with idiopathic osteoporosis or osteoporosis due to hypogonadism increases BMD to virtually the same extent as in women over that same period of time [56]. Participants were followed for 30 months after the drug was discontinued due to early termination of the trial. Over this period of time some received antiresorptive therapy. After discontinuation 18 months later, there was an overall reduction in moderate to severe vertebral fractures when the original teriparatide treatment groups (20 and 40 μg) were compared to the original placebo group [57]. In glucocorticoid-induced osteoporosis, a clinical trial in which men were included showed that teriparatide promotes better BMD outcome and lower vertebral fractures when compared with patients treated with alendronate [58, 59]. As shown in the study of Kaufman et al. [57] as well as other studies, discontinuation of teriparatide therapy is associated with rapid reductions in BMD if a bisphosphonate is not used promptly thereafter [60].
In women who have previously been treated with an antiresorptive drug and sequentially with teriparatide, the actions of teriparatide may be delayed [61]. However effects of prior bisphosphonate therapy are overcome, usually with the first 6 months of PTH treatment. In men, simultaneous therapy with teriparatide and alendronate gave no densitometric advantage over monotherapy with teriparatide alone [62]. Walker et al. have recently reported a randomized, double-blind study to evaluate the combination of teriparatide and risedronate. A total of 29 men, aged 37–81, with low BMD at the spine, hip, or distal radius were enrolled [63]. Patients were randomized to receive risedronate 35 mg weekly plus daily-injected placebo, teriparatide 20 μg subcutaneously daily plus weekly oral placebo, or both risedronate plus teriparatide (combination) for 18 months. BMD gains at the lumbar spine were seen in all three groups (p < 0.05), but there were no between-group differences. However, total hip BMD increased to a greater extent in the combination group (3.86 ± 9.2 %) versus teriparatide (0.29 ± 8.0 %) or risedronate (0.82 ± 8.0 %; p < 0.05 for both). Femoral neck BMD also increased to a greater extent in the combination group (8.45 ± 14.1 %) versus risedronate (0.50 ± 12.2 %; p = 0.002), but was not different from teriparatide alone.
The safety of teriparatide has recently been reviewed with specific reference to reports of osteosarcoma in rats when administered very large doses for a large proportion of a rat’s life [64, 65]. The 10-year history of parathyroid hormone as a treatment for osteoporosis does not provide any evidence that osteosarcoma is a risk when teriparatide or PTH(1-84) is used for the treatment of osteoporosis [66, 67].
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
