Osteoporosis in the aging male
Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. 1 The National Osteoporosis Foundation (NOF) estimates that over 14 million American men had osteoporosis or low bone mass in 2002. 2 One in four men older than 60 years of age will experience a fracture, 3 yet age-related bone loss in men remains under-recognized and undertreated.
Sixteen percent of men older than 50 and 35% men older than 85 fall each year. 4 Hip fractures in men increase mortality by fourfold in the first three months after fracture, 5 and one-year mortality reaches 20%. 6 Epidemiologic surveys consistently show higher mortality in men than women of similar ages after fracture. 7 Among survivors of hip fracture, more than 1 in 4 becomes disabled in the following year, 8 and nearly 1 in 5 will require long-term nursing home care. 9 Care for patients after hip fracture is expensive to society. In the US, direct costs for patients with osteoporotic fractures is estimated at up to $18 billion/year in 2002 dollars. White men account for 18% of these costs, or $3.2 billion annually. 10 Vertebral fractures also increase long-term mortality, 3 , 7 , 11 cause persistent back pain, deformity, functional decline, and diminished quality of life.
Importantly, the prevalence of osteoporosis and osteoporotic fractures are expected to rise as men live longer. The NOF predicts that there will be 20.5 million American men with osteoporosis or low bone mass by 2020. 2 By 2025, annual costs for osteoporosis-related fractures is expected to be $25.3 billion. 2
Identifying men at high risk for osteoporotic fracture
Previous fracture is the strongest predictor of any future fracture. The Osteoporotic Fractures in Men (MrOS) Study 12 followed 5995 men aged 65 and older and showed that men with a history of fracture after 50 years had a twofold increased risk of nonvertebral fracture compared to men without prior fracture. A second important predictor of fracture is advancing age. The Dubbo Study showed that, compared to men aged 70–74 years, men older than 80 years had 28 times as many vertebral fractures, nine times as many hip fractures, and nearly five times as many overall fractures. 13 Third, bone mineral density (BMD) predicts fracture risk. The use of BMD by dual energy X-ray absorptiometry (DEXA) to predict fracture risk is comparable to the use of blood pressure to predict stroke and is substantially better than using serum cholesterol to predict the risk of myocardial infarction. The MrOS investigators 12 also found that tricyclic antidepressant use (hazard ratio [HR] 2.36), the inability to complete a narrow walk trial (HR 1.70), falls in previous year (HR 1.59), and depressed mood (HR 1.72) all increased fracture risk independent of BMD.
Bone quality indicators such as cortical thickness, microarchitecture, turnover, porosity, damage accumulation, and the rate and quality of mineralization are other important predictors of fracture, yet they are difficult to incorporate into clinical practice. 14 Compared to women, men have bones with larger cross-sectional areas, and as men age they tend to preserve trabecular number. Apart from bone density, both of these factors are thought to ameliorate fracture risk.
In addition to age-related bone loss, osteoporosis in men is frequently secondary to other comorbidities such as glucocorticoid use, hypogonadism, vitamin D deficiency, cigarette smoking, heavy alcohol intake, immobility, or inadequate dietary calcium intake. Studies among ambulatory men with osteoporosis indicate that 30%–64% have at least one identifiable risk factor. 15 , 16 The World Health Organization (WHO) has developed the FRAX TM fracture risk assessment tool, a group of country- and ethnicity-specific risk calculators which allow an estimate of fracture risk based on historical and exam findings. 17
Treatment strategies
Traditional nonpharmacologic therapies include treatments intended to increase bone mineral density, prevent falls, and prevent fractures with falls. Several recent papers have reviewed the literature on fall prevention, hip protectors, and calcium and vitamin D supplementation in men. 14 , 18 , 19 Weight bearing exercise can prevent falls 20 and increase BMD. 21 Inadequate dietary calcium and vitamin D intake are risk factors for osteoporosis. The NOF recommends that individuals 50 years old and older consume 1200 mg calcium and 800–1000 IU vitamin D daily. Several studies of calcium and vitamin D supplementation have shown increased BMD, decreased fracture risk, 22 – 24 and even decreased mortality 23 irrespective of baseline 25-hydroxyvitamin D levels. However, another large randomized controlled trial of calcium and vitamin D in secondary prevention of osteoporotic fractures showed no benefit. 25
The NOF recommends drug treatment for men aged 50 and older with prior hip or vertebral fracture, with osteoporosis (T-score ≤ −2.5 at the femoral neck or spine), or with osteopenia (T-score between −1.0 and −2.5 at the femoral neck or spine) and an absolute 10-year risk of hip fracture ≥ 3% or 10-year risk of a major osteoporosis-related fracture ≥ 20% based on the FRAX calculation. 26 Drugs for the treatment of osteoporosis can be classified into antiresorptive or anabolic agents. Antiresorptive agents, or drugs that inhibit osteoclast action, include most of the commonly used therapies in men such as calcitonin, testosterone, and bisphosphonates.
Calcitonin
Trovas and colleagues 27 randomized 28 osteoporotic men to receive daily intranasal calcitonin 200 IU or placebo. At 12 months, the treated group had significantly suppressed markers of bone turnover and greater BMD at the lumbar spine but not hip. Toth and colleagues 28 studied 71 men with idiopathic osteoporosis but no prior fracture. In these men, intranasal calcitonin daily during alternate months for 18 months significantly increased BMD at the spine and hip and decreased vertebral fractures.
Calcitonin is not approved in the US for the treatment of male osteoporosis.
Testosterone
Studies have consistently shown that testosterone replacement improves BMD in hypogonadal men. 29 – 32 Snyder and colleagues 31 randomized 108 men aged over 65 years without osteoporosis to daily testosterone patch or placebo. They found no treatment effect on BMD in the group as a whole or in men with baseline testosterone level >400 ng/dL. Anderson and colleagues 33 studied intramuscular testosterone injections every two weeks in men with osteoporosis and prior vertebral fracture. In this population, the authors found that testosterone therapy suppressed markers of bone turnover and significantly increased lumbar spine BMD.
No studies have assessed the effect of testosterone replacement on fracture risk, and testosterone is not approved in the US for the treatment of osteoporosis.
Teriparatide
Teriparatide (1–34 PTH), stimulates bone formation. Teriparatide has been shown to raise BMD in men at the hip and spine more than alendronate alone, 34 , 35 and it reduces vertebral fractures by 90%. 35
Teriparatide is approved by the US FDA for treatment of osteoporosis in men considered at high risk for fracture.
Bisphosphonates
Bisphosphonates are synthetic pyrophosphate analogues with a P-C-P backbone that is resistant to hydrolysis and two phosphate groups that bind hydroxyapatite with high affinity. The central carbon binds the R1 side chain, often a hydroxyl group, which binds calcium and allows for more stable interaction with the bone matrix. 36 The longer R2 side chain gives each bisphosphonate its characteristic properties and potency. Bisphosphonates can be classified based on the presence or absence of a nitrogen atom in the R2 side chain. The nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) are more potent inhibitors of osteoclast action. 37
Mechanism of action
Bisphosphonates are poorly absorbed through the gut, with less than 1% bioavailability after oral administration. 38 The kidneys excrete approximately 50% of the drug unchanged. 39 The remaining bisphosphonates bind hydroxyapatite crystals on the bone surface with high affinity, where they are internalized by and accumulate in osteoclasts.
Within the osteoclast, the nonnitrogen containing bisphosphonates (etidronate, tiludronate) are incorporated into adenosine triphosphate (ATP). These nascent nonhydrolyzable ATP analogs are toxic to osteoclasts, leading to mitochondrial inhibition and osteoclast apoptosis. 40 The nitrogen-containing bisphosphonates inhibit the enzyme farnesyl pyrophosphate synthase (FPPS) in the HMG-CoA reductase pathway leading to cholesterol synthesis. In addition to cholesterol synthesis, this pathway produces the intermediate metabolites farnesol and gerinylgeranol that are necessary for protein prenylation. Prenylation is the posttranslational attachment of hydrophobic prenyl groups to cytoplasmic proteins to allow binding to the cell membrane. 40 Such modification allows the Ras superfamily of GTPases to exert changes in cytoskeletal function that produce the characteristic osteoclast ruffled border and allow osteoclast attachment to bone. 41 Biopsies of alendronate-treated bone show greater numbers of osteoclasts and abnormal giant, hypernucleated osteoclasts detached from bone. The number of osteoclasts increased with cumulative dose of alendronate, suggesting that the drug may prolong osteoclast survival. 42 Bisphosphonate potency, the ability to inhibit bone resorption in vivo , is directly related to drug ability to inhibit FPPS in vitro . 37 Nitrogen-containing bisphosphonates also inhibit osteoclast precursor differentiation and inhibit osteoblast-mediated osteoclast activation. 38
Evidence of benefit
Pamidronate
Several randomized controlled trials of pamidronate for the treatment of osteoporosis include men. Ryan and colleagues 43 randomized 122 subjects with prior vertebral fracture to oral pamidronate 300 mg/day (group A) for four weeks every 16 weeks, 150 mg/day (group B) for four weeks every eight weeks or placebo (group C). At 2 years, the authors reported significant reductions in serum osteocalcin (29% group A and 33% group B) and urinary deoxypyridinoline (16% group A, 21% group B, p < 0.01 for all comparisons to placebo). They found significant increases in BMD at the spine, hip, and total body (See Table 2 ).
Brumsen and colleagues 44 randomized 101 subjects with prior vertebral fracture to oral pamidronate 150 mg/day or placebo. At three years, the investigators found significant reductions in urinary hydroxyproline and serum alkaline phosphatase and significant increases in BMD at the lumbar spine (See Table 2 ). Men and women had similar increase in BMD in response to pamidronate. There were significantly fewer morphometric vertebral fractures (ARR 22%) in the pamidronate group, and the number needed to treat (NNT) with pamidronate for three years to prevent one vertebral fracture was 5. Six subjects in the placebo group and three pamidronate-treated subjects experienced symptomatic vertebral fractures. Three subjects in the placebo group and one pamidronate-treated subject experienced nonvertebral fractures (ARR 4%). At the end of three years, 53 of the study subjects agreed to participate in an open-label two year extension of the trial. There were equal numbers from the pamidronate and placebo groups, and all subjects received oral pamidronate 150 mg/day. With pamidronate treatment, the differences in urinary hydroxyproline and serum alkaline phosphatase between the initial study groups disappeared. The BMD of the prior placebo group increased to greater extent compared to the prior treatment group such that, at the end of an additional two years there was no significant difference in femoral neck BMD between the groups. The subjects who received pamidronate for five years continued to have a small yet significant greater increase in lumbar spine BMD compared to those subjects who had initially received placebo.
Boutsen and colleagues 45 studied 27 subjects who required initiation of long-term glucocorticoid therapy at a dose of at least 10 mg/day prednisolone for polymyalgia rheumatica (16), inflammatory bowel disease (4), temporal arteritis (3), and rheumatoid arthritis (2). The subjects were randomized to receive a single dose IV pamidronate 90 mg at the start of glucocorticoid therapy (group A); IV pamidronate 90 mg once followed by 30 mg IV pamidronate every three months (group B); and control (group C). Both treatment groups experienced significant decreases in bone-specific alkaline phosphatase, osteocalcin, and C-telopeptide at three months. At 12 months, however, all bone markers of the once-treated group had risen again and only group B observed a sustained decrease in bone resorption. At six and 12 months, there was significantly greater BMD at the lumbar spine, femoral neck, and total hip in both treatment groups compared to control (see Table 2 ). There were no fractures recorded during the 12 month study.
Pamidronate is not approved in the US for the treatment of osteoporosis in men or women.
Alendronate
Alendronate was the first bisphosphonate to be extensively studied in men. In a study by Ho and colleagues, 46 80 subjects with either primary or secondary osteoporosis and prior vertebral fracture received alendronate 10 mg daily. The investigators also followed 43 matched controls. Over 12 months follow-up, the investigators found significantly improved BMD at the lumbar spine and femoral trochanter but not femoral neck (See Table 2 ). Results were similar for women and men.
Orwoll and colleagues 47 randomized 241 men with osteoporosis to 10 mg daily alendronate or placebo. After two years of treatment, the authors observed a significant 59% decrease in urinary N-telopeptide of type I collagen and 38% decrease in bone-specific alkaline phosphatase in the alendronate group. In the alendronate-treated group, bone mineral density at 24 months increased significantly at the lumbar spine, total hip and femoral neck compared to placebo. Quantitative analysis of spine radiographs revealed significantly fewer vertebral fractures in the alendronate group (aldosterone–renin ratio [ARR] 6.3%) but no significant difference in nonvertebral fractures (See Table 2 ).
These findings were confirmed by Ringe and colleagues 48 in an open label study of 134 men with osteoporosis randomized to 10 mg daily alendronate or the vitamin D analog alfacalcidol 1 μg daily. With three years follow-up, they observed significantly greater increases in BMD at the lumbar spine and femoral neck in the alendronate-treated group. The alendronate group had significantly fewer vertebral fractures (ARR 13.9%, p = 0.04) and no difference in nonvertebral fractures (See Table 2 ).
A meta-analysis of the alendronate trials including 375 men 49 concluded that alendronate treatment significantly decreases the risk of vertebral fractures (odds ratio [OR] 0.36) in men with osteoporosis. There were not sufficient data to confirm a significant decrease in nonvertebral fractures.
Alendronate is approved in the US for the treatment of osteoporosis in men.
Risedronate
Ringe and colleagues 50 studied risedronate in 316 men with primary or secondary osteoporosis. Over half of those enrolled had a vertebral fracture prior to the start of the study. Subjects were randomized to risedronate 5 mg daily or control, and all received calcium and vitamin D supplementation. At 12 months, there was a significantly greater improvement in BMD at the lumbar spine, total hip, and femoral neck. At one year, the treated subjects experienced fewer vertebral fractures (ARR 7.6%, p = 0.028), a nonsignificant 42% decrease in nonvertebral fractures, and significantly less back pain than the control group (See Table 2 ).
Boonen and colleagues 51 randomized 284 men with osteoporosis but without prior fracture to weekly risedronate 35 mg or placebo in 2:1 ratio. The risedronate-treated group had significant reductions in the bone turnover markers c-telopeptide, n-telopeptide, and bone-specific alkaline phosphatase at three months, and these effects persisted throughout the two-year study period. The treatment group also experienced significantly greater increases in BMD at the lumbar spine by three months and at the total hip and femoral neck by six months (see Table 2 ). These treatment differences increased throughout the study. The authors noted a nonsignificant trend toward overall fracture reduction, though the study was not powered to detect a difference.
Reid and colleagues 52 studied 184 men enrolled in two RCT receiving daily risedronate 2.5 mg, risedronate 5 mg, or placebo for the prevention or treatment of glucocorticoid-induced osteoporosis (GIO). Prior to enrollment, the subjects had received either <3 months (prevention study) or >6 months (treatment study) chronic oral glucocorticoid therapy of at least 7.5 mg/day prednisone or equivalent, most commonly for rheumatoid arthritis, lung disease, and polymyalgia rheumatica. At one year, the subjects treated with risedronate 5 mg/day experienced 61% decrease in urinary n-telopeptide and 20% reduction in bone-specific alkaline phosphatase. The GIO treatment study group treated with risedronate 5 mg experienced significant increases in BMD at the lumbar spine and femoral neck compared to baseline. In the GIO prevention study, risedronate 5 mg/day prevented the significant loss in BMD at the hip and lumbar spine seen in the placebo group. The authors reported that risedronate 2.5 mg/day produced similar yet smaller effects on BMD. When both risedronate treatment arms from both studies were combined, the authors found a 19% ARR in morphometric vertebral fractures at one year. However, fracture data were reported for only 96 of the 184 enrolled subjects.
Prior stroke is a risk factor for fracture, through immobility decreasing bone mineral density and by gait instability increasing risk for falls. Sato and colleagues 53 studied 280 men 65 years or older after hemiplegic stroke. The subjects were randomized to risedronate 2.5 mg daily or placebo and followed for 18 months. Urinary deoxypyridinoline concentration decreased significantly compared to baseline and compared to placebo within the first six months of risedronate treatment and remained stable thereafter. The authors assessed BMD at the second metacarpal bones on both hemiplegic and unaffected sides. On the hemiplegic side, metacarpal BMD increased 2.5% in the risedronate-treated and decreased 3.5% in the untreated group. On the unaffected side, metacarpal BMD increased 3.3% in the treated and decreased 2.0% in the unaffected side. Differences between groups were highly significant (p < 0.001). During the study period, 87 men fell a total of 547 times. The risedronate group experienced fewer hip fractures (ARR 5.7%) and overall fractures (ARR 8.6%) though asymptomatic vertebral fractures were not assessed, and no vertebral fractures were reported (See Table 2 ). The NNT to prevent hip fracture was 16.
Hypogonadism affects approximately 50% men with leprosy due to gonadal atrophy from testicular Mycobacterium leprae infection. 54 As a result, osteoporosis is very common in men with leprosy. Among 197 men with leprosy residing at a national leprosarium, Ishikawa and colleagues 55 found the prevalence of osteoporosis to be 33% in men 50–59 aged years and 75% in men aged at least 80 years. Kanaji and colleagues 56 followed 23 elderly men with leprosy randomized to 2.5 mg daily oral risedronate or placebo and found a significant reduction in urinary N-telopeptides and a significant increase in lumbar spine BMD at six and 12 months (See Table 2 ). Though there was a low incidence of vertebral fractures observed, the treatment group experienced fewer (ARR 1.06%).
Risedronate is approved in the US for the treatment of osteoporosis in men.
Limitations of oral therapy
Because of their relative ease of use and low cost of generic alendronate, oral bisphosphonates have become mainstays of osteoporosis pharamacotherapy. Yet oral dosing is poorly absorbed, may worsen gastrointestinal toxicities, and side effects can decrease patient compliance. Esophageal injury may occur in patients on oral bisphosphonates, though randomized trials have failed to show significant association. Even in patients who strictly adhere to recommended use directions, case reports have shown oral alendronate has the potential to cause erosive esophagitis, esophageal or gastric ulcers and esophageal strictures. 57 Recent reports of oral bisphosphonate-associated esophageal carcinoma have emerged. 58 A meta-analysis of 76 randomized controlled trials of osteoporosis drug trials found that esophageal ulcerations and complications such as perforation and hemorrhage were reported in trials of all bisphosphonates except zoledronic acid. 59 Other gastrointestinal symptoms related to oral bisphosphonates include pyrosis, dyspepsia, abdominal pain, nausea, and vomiting.
Long-term compliance with oral bisphosphonate therapy is low, and patients most commonly cite adverse drug effects as the reason for stopping therapy. 60 , 61 One systematic review of seven observational studies of bisphosphonate compliance as measured by patient surveys indicates that the discontinuation rate at one year of daily dosing ranged 19%–29%. In the study that included men, the rate was 22%. However, when compliance is measured by administrative data, the discontinuation rate was 68% for daily dosing and 56% for weekly dosing. Moreover, 76% patients had at least some interruption in bisphosphonate therapy during the first year of therapy. 61 The costs of bisphosphonate noncompliance are high. Patients who are less than 66% compliant with osteoporosis medications have significantly lower increases in BMD. 62 In an analysis of insurance claims databases involving 35,537 women prescribed bisphosphonates, only 43% women filled at least 80% of their prescriptions. However, the medication-compliant women had 37% fewer hip fractures at 24 months. 63
Oral bisphosphonates are poorly absorbed, and dietary calcium, calcium supplements, and antacids further impede absorption. In order to optimize bioavailability, the patient should take the medication apart from food and all other medications for at least two hours before and 30 minutes after the dose. In order to minimize gastrointestinal side effects, the patient should take the medication with 6–8 ounces of water and remain upright for 30 minutes thereafter. In a review of three observational trials of adherence to dosing instructions, up to 52% patients did not comply with at least one instruction. 61 In one of the studies, 26% patients were not taking risedronate correctly and among these patients 28% experienced adverse effects. 64
Factors associated with poorer bisphosphonate compliance include older age, male gender, nonwhite race, and greater number of comorbid conditions and nonosteoporosis medications. Compliance is improved with weekly vs daily dosing, and residence in a nursing home. 61 , 65 Though not reported in these trials, compliance with the complex administration instructions is very likely also limited by cognitive dysfunction and physical debility.
Ibandronate
In an uncontrolled open label pilot, Lamy and colleagues 66 enrolled 14 men with primary osteoporosis and either a prior osteoporotic fracture or a BMD at least 1.5 standard deviations below the age-matched mean. Subjects received 2 mg IV ibandronate every three months. At two years, the authors noted significant reductions in osteocalcin and β-crosslaps assay for degradation products of type I collagen. During the two years of treatment, they showed significant increases in BMD at the lumbar spine, femoral neck, and total hip (See Table 2 ).
Another as yet unpublished trial of 168 men randomized to monthly oral ibandronate 150 mg or placebo has the primary outcome of change in lumbar spine BMD. One year follow-up has been completed, and data will soon be presented (personal communication).
Ringe and colleagues 67 studied 115 subjects with established glucocorticoid induced osteoporosis. The subjects required chronic prednisone use of at least 7.5 mg/day for other systemic illnesses, most commonly COPD, rheumatoid arthritis, or polymyalgia rheumatica. Subjects were randomized to 2 mg intravenous (IV) ibandronate every three months vs. daily oral alfacalcidol. Ibandronate-treated subjects experienced significantly greater increases in BMD at the spine and femoral neck, and improvements were progressive throughout the 36-month study period. The ibandronate group had less lower back pain and less height loss. Though not powered to detect fracture difference, the study did show significantly fewer vertebral fractures in the ibandronate group (relative risk reduction [RRR] 62%) and a nonsignificant trend toward fewer nonvertebral fractures (See Table 2 ).
Ibandronate is not approved in the US for the treatment of osteoporosis in men.
Zoledronic acid
Currently available IV nitrogen-containing bisphosphonates include pamidronate, ibandronate, and zoledronic acid. Zoledronic acid is the only IV bisphosphonate FDA-approved for the treatment of osteoporosis in men. It has the highest binding affinity to hydroxyapatite and the highest skeletal uptake 68 and is the most potent osteoclast inhibitor. Zoledronic acid is the only bisphosphonate with an indication for annual use.
Evidence of benefit
The HORIZON investigators studied zoledronic acid in secondary prevention of osteoporotic fractures. 69 They randomized 2127 subjects (24% men) within 90 days of surgical repair of a hip fracture to receive 5 mg annual IV zoledronic acid or placebo with first dose given within 90days of hip fracture repair. At 36 months, the treated group had significantly increased bone density at the total hip and femoral neck compared to the placebo group. Over 1.9 years median follow-up, they observed significant decreases in any new fracture (139 vs 92, ARR 5.3%), clinical vertebral fracture (39 vs 21, ARR 2.1%), nonvertebral fracture (107vs 79, ARR 3.1%), and recurrent hip fracture (33 vs 23, ARR 1.5%; see Table 2 ). Further, in this population at high risk for deadly recurrent fractures, the zoledronic acid-treated group experienced a survival advantage (RRR 28%, ARR 3.7%). 69 Men enjoyed a greater survival benefit than women (overall mortality ARR 6.4%) and a marked reduction in cardiac-related deaths (RRR 62%, RRR 4.8%). 70
Zoledronic acid has been approved in the US for treatment of osteoporosis in men on the basis of an as yet unpublished trial. 71 The study randomized 302 hypogonadal men to annual 5 mg IV zoledronic acid or weekly 70 mg oral alendronate. At two years, the zoledronic acid group had 6.1% increase in lumbar spine BMD compared to 6.2% increase in alendronate group. The all-cause mortality and serious adverse events were similar between treatment groups.
Poole and colleagues 72 randomized 27 hemiplegic subjects within seven weeks after stroke zoledronic acid 4mg or placebo. The authors showed that treatment prevented significant bone loss at the hip. Without treatment, at one year the mean BMD of the total hip decreased 5.5% on the affected (hemiplegic) side and by 2.7% in the unaffected hip. With treatment, the mean BMD remained stable on the hemiplegic side and increased by 1% at the unaffected hip (see Table 2 ). 72% subjects fell, but there were no fractures during the study period.
Human immunodeficiency virus (HIV) infection and antiretroviral therapy are associated with low bone density and osteoporosis. Brown and colleagues 73 found that HIV-infected patients were 3.7 times as likely to have osteoporosis as uninfected individuals. Triant and colleagues 74 reported that HIV-infected men and women have a significantly higher prevalence of hip, vertebral, and wrist fractures. Bolland and colleagues 75 studied zoledronic acid in 43 HIV+ men with decreased bone mineral density receiving antiretroviral therapy. The men were randomized to 4 mg IV annual zoledronic acid or placebo. Urinary N-telopeptide decreased by 61%, and serum total alkaline phosphatase decreased by 21% from baseline by three months in the zoledronic acid-treated group. These values were significantly less than the untreated group, and the levels did not further decrease over the remaining two years in the study. In the zoledronic acid group, BMD increased significantly at the lumbar spine and total hip over the control group (see Table 2 ).
Studies confirm both clinical efficacy 69 , 72 , 75 of annual zoledronic acid dosing and noninferiority compared to more frequent dosing, 76 but it is not yet known how long a single dose of zoledronic acid can suppress bone turnover. Borba and colleagues 77 showed persistent suppression of C-telopeptide and bone-specific alkaline phosphatase and persistent increase in bone mineral density at the lumbar spine and total hip at 18 months after a single dose of zoledronic acid. In an extension of a previous trial, Bolland and colleagues 78 showed persistence of drug effect in men at two years after a second annual dose of zoledronic acid in suppressing markers of bone turnover and increasing bone mineral density. Brown and colleagues 79 studied 66 subjects with osteopenia after curative cancer treatment. All subjects received a single dose 4 mg zoledronic acid and were followed for 36 months. Data were reported for men and women separately, and both showed durable decreases in urinary NTx/Cr and increases in BMD at the spine and hip after at 36 months after a single zoledronic acid dose. Less frequent dosing regimens offer potential advantages such as reduced toxicity, greater convenience, improved compliance, and reduced cost. Though markers of bone turnover remain suppressed for more than one year, it is not known whether dosing zoledronic acid less than annually is as effective in terms of reduction in fracture risk.
Comparing therapies for osteoporosis
Few studies have made direct comparison of osteoporosis therapies in men. In theory, drugs such as teriparatide that stimulate bone formation may complement bisphosphonates (which inhibit osteoclast action) and provide even greater increases in BMD. Finkelstein and colleagues 34 , 80 randomized 83 men with low bone mass to receive alendronate, teriparatide, or both daily. Subjects receiving alendronate started treatment at the beginning of the study, and subjects receiving teriparatide started at month 6. Sixty-three men completed the study. At 30 months, the authors found that teriparatide increased BMD at the lumbar spine and femoral neck significantly more than combination therapy, and combination therapy increased BMD at the lumbar spine and femoral neck significantly more than alendronate alone. 34 The authors went on to show that marker of bone turnover such as serum N-telopeptide (NTX), osteocalcin, and amino-terminal propeptide of type 1 procollagen increased markedly upon starting teriparatide monotherapy and then declined toward baseline. With alendronate monotherapy, the markers of bone turnover decreased and remained stable. Combination therapy led to an initial decline in bone markers on alendronate alone followed by a rebound with teriparatide so that levels returned to baseline or above. Alendronate pre-treatment blunted the treatment effect of teriparatide, 80 and the authors conclude that alendronate impairs the ability of teriparatide to increase bone turnover or increase the BMD at the lumbar spine and the femoral neck in men.
Welch and colleagues 81 retrospectively studied 149 men treated with testosterone, alendronate, or both for at least one year. Men in the testosterone group were referred for treatment of hypogonadism, and men in the alendronate group were referred for treatment of osteoporosis. Yet at baseline, the groups were similar in terms of age, weight, body mass index, and BMD at the lumbar spine and total hip. Compared with the baseline values, lumbar spine BMD increased significantly by 2.1% in the testosterone group, 2.6% in the alendronate group, and 2.5% in the group receiving combination therapy. There were no significant differences in BMD at the lumbar spine or total hip between groups, suggesting that the combination of testosterone and alendronate does not appear to be superior to either drug used alone.
A recently conducted, unpublished trial at our institution directly compares alendronate and zoledronic acid in the treatment of male osteoporosis. The investigators retrospectively reviewed the charts of 64 men: 26 received annual IV zoledronic acid 4 mg and 38 received weekly oral alendronate 70 mg. At one year, they found no differences in BMD at the lumbar spine or femoral neck between groups (personal communication).
Bisphosphonate use in bone loss due to androgen deprivation
Prostate cancer becomes increasingly common as men age, and androgen deprivation therapy (ADT) for prostate cancer places men at uniquely high risk for osteoporosis and fracture. ADT, which may include orchiectomy or GnRH agonist therapy, markedly reduces circulating testosterone to prepubertal levels. In one prospective cohort study of 152 men with nonmetastatic prostate cancer including 30 on acute ADT <6 months and 50 on chronic ADT >6 months, Greenspan and colleagues 82 found that men starting ADT experienced significant reductions in bone mineral density (2.5% total hip, 4.0% spine) by 12 months follow-up. When compared to healthy age-matched controls and to patients with prostate cancer but not on ADT, the acute ADT had five- to tenfold increased bone density loss at multiple skeletal sites. When compared to men on chronic ADT, it appeared that the greatest bone loss occurred in the first 12 months of ADT. Shananian and colleagues 83 measured fracture rates on 50,613 men with the diagnosis of prostate cancer. Among the men that survived five years after diagnosis, they found that 19.4% men on ADT experienced a fracture, as compared to 12.6% those not receiving ADT (p < 0.001). Furthermore, fractures at every site, fractures requiring hospitalization, and diagnosis of osteoporosis were all significantly increased in patients receiving ADT.
Smith and colleagues 84 studied 47 men with advanced or recurrent nonmetastatic prostate cancer. The authors randomized the subjects to receive pamidronate 60 mg IV every 12 weeks plus leuprolide or leuprolide alone. All measured biomarkers of bone turnover; osteocalcin, bone-specific alkaline phosphatase, urinary deoxypyridinoline, and urinary N-telopeptide were significantly reduced in the pamidronate group. Treatment with pamidronate prevented the significant reductions in BMD experienced by the leuprolide-only group. They reported an absolute difference between groups in BMD at the lumbar spine and total hip, but there was no change in either group at the femoral neck (see Table 3 ).
Greenspan and colleagues 85 studied 112 men with non-metastatic prostate cancer receiving ADT in a partial-crossover design. Subjects were randomly assigned to receive alendronate 70 mg weekly or placebo at enrollment. At 12 months, all subjects in the placebo group crossed over to the alendronate group, and subjects in the alendronate group were re-randomized to continue alendronate or placebo. At two years, the subjects randomized to alendronate treatment both times had the greatest decrease in N-telopeptide, C-telopeptide, type 1 procollagen, and bone-specific alkaline phosphatase. The alendronate-alendronate group also had the highest BMD at the lumbar spine, total hip, femoral neck, and distal 1/3 radius. Fractures were not studied. The investigators found that a second year of alendronate resulted in continued improvements in bone density and decreases in bone markers.
Delay in alendronate initiation (as in the placebo–alendronate group) resulted in lower bone density and decreased suppression of bone markers compared to early treatment. 85 Discontinuation of alendronate (in the alendronate–placebo group) resulted in increases in markers of bone turnover and significantly decreased BMD at all skeletal sites compared to the alendronate–alendronate arm. The authors also performed post-hoc analysis of changes in BMD depending on length of ADT prior to alendronate treatment. They found that men who received ADT for less than 36 months experienced significantly greater increases in BMD on alendronate than men who received ADT for 36 months or more.
Ryan and colleagues 86 studied 120 men with nonmetastatic prostate cancer on ADT for 12 months or less prior to enrollment. Subjects were randomized to zoledronic acid 4 mg IV every three months or placebo and stratified by duration of ADT (less than six months or 6–12 months). Treated subjects had significant reductions in urinary N-telopeptide and serum bone-specific alkaline phosphatase compared to the placebo group and significant improvements in BMD at one year at the femoral neck, total hip, and lumbar spine (see Table 3 ). The results were not differentiated based on duration of ADT. Taken together, these studies 85 , 86 support initiation of bisphosphonates within one year of ADT and continued treatment for greater than one year in men on ADT.
Smith and colleagues 87 studied zoledronic acid in 106men with nonmetastatic prostate cancer beginning ADT. Subjects were randomized to zoledronic acid 4 mg IV every three months or placebo. At one year, the placebo group lost 2%–3% BMD at the lumbar spine, femoral neck, and total hip. By comparison, treated group had gains in BMD and showed significantly greater BMD at each skeletal site (see Table 3 ).
Michaelson and colleagues 88 randomized 40 men with nonmetastatic prostate cancer on ADT and osteoporosis (T < −2.5), to receive a single dose 4 mg IV zoledronic acid or placebo. Subjects who received zoledronic acid had significant reductions in N-telopeptide and bone-specific alkaline phosphatase at 12 months as well as significantly greater BMD at the lumbar spine, total hip and femoral neck (see Table 3 ).
Ryan and colleagues 89 studied 42 men with hormone-sensitive prostate cancer with and without metastasis on ADT less than one year. The subjects were randomized to zoledronic acid 4 mg IV every three months or placebo. Skeletal sites with metastasis were excluded from DEXA measurement of BMD. At 12 months, subjects treated with zoledronic acid had significantly greater decreases in N-telopeptide and bone-specific alkaline phosphatase. Men with bone metastases had significantly higher baseline N-telopeptide and bone-specific alkaline phosphatase, but the improvements in suppression of these markers of bone turnover was independent of the presence of metastases. Treated subjects also had significantly greater BMD at the lumbar spine and femoral neck (see Table 3 ).
Raloxifene in ADT
Estrogen deficiency plays a significant role in bone loss in men. Doran and colleagues 90 randomized 50 elderly men without osteoporosis to receive the selective estrogen receptor modulator (SERM) raloxifene 60 mg per day or placebo. At six months, the treated group overall showed no effect in decreasing urinary N-telopeptide (NTx) excretion. However, in the subset of men with baseline low estradiol levels (mean 22 pg/mL), raloxifene treatment decreased urinary NTx. Smith and colleagues 91 found a similar treatment effect in 48 men with nonmetastatic prostate cancer on GnRH agonist therapy treated with raloxifene 60 mg daily. The average estradiol level was 5 pg/mL. At 12 months, the raloxifene-treated group had significantly decreased serum amino-terminal propeptide of type I collagen and significantly increased BMD in the total hip (+1.1% vs −2.6%, p <0.001) and a nonsignificant trend to increased density in the lumbar spine (+1.0% vs −1.0%, p = 0.07).
Raloxifene is not approved in the US for the treatment of osteoporosis in men.
Indications
Zoledronic acid (Reclast) is approved in the US as an annual IV infusion of 5 mg to treat osteoporosis in men or women and to treat Paget’s disease. Zoledronic acid is also marketed as a 4 mg dose (Zometa ® ) IV infusion every 3–4 weeks to treat hypercalcemia of malignancy, multiple myeloma, and bone metastases from all solid tumors including lung and prostate cancer.
Zoledronic acid is the only IV bisphosphonate approved in the US for the treatment of osteoporosis in men.
Adverse drug effects
Eight trials of zoledronic acid including men for nonmetastatic bone loss have been published, 69 , 72 , 75 , 79 , 86 – 89 and all eight reported basic safety data such as number of subjects who died or withdrew because of adverse events. Six of these studies 69 , 72 , 75 , 86 , 87 , 89 reported more extensive safety analyses. In the largest of these trials, 69 there was no association between zoledronic acid and early study withdrawal due to adverse event.
Prior studies 92 have identified five typical infusion-related symptoms that occur in more than 30% subjects receiving a first dose zoledronic acid within three days of drug administration. These symptoms include myalgias, influenza-like symptoms, fever, arthralgias, and headache. The reported rates of these symptoms in the eight trials described are generally lower than in prior studies, though myalgias and fever were significantly more common in the zoledronic acid-treated subjects. 69 These symptoms are typically mild, resolve within 3–4 days, and occur less frequently with successive infusions of the drug. Patients should be pretreated with acetominophen.
Many symptoms were variably described among the studies. The frequency of a composite of reports of bone or back pain, myalgias, and arthralgias was 9% among zoledronic acid-treated subjects vs 5% among those receiving placebo. Currently the US FDA is investigating reports of “severe and sometimes incapacitating bone, joint, and/or muscle pains” in chronic use of bisphosphonates as a class. 93
Infusing zoledronic acid over at least 15 minutes reduces the risk of renal toxicity. In each of the studies cited, zoledronic acid was given over 15 minutes, and there was no significant difference in rates of rise of serum creatinine >0.5mg/dL. 69 , 72 Zoledronic acid 5 mg dose (Reclast ® ) is not recommended for patients with creatinine clearance <35 mL/min due to lack of experience in this patient population. Zoledronic acid 4 mg (Zometa ® ) is recommended at full dose for patients with estimated creatinine clearance >60 mL/min with dose reductions for creatinine clearances between 30–60 mL/min. Because of the lack of clinical data to date, it is not recommended for use in patients with creatinine clearance <30 mL/min. Asymptomatic and generally transient hypocalcemia and hypophosphatemia have been reported independent of baseline 25-OH vitamin D levels. 72
Osteonecrosis of the jaw (ONJ) is a serious complication of bisphosphonate use defined as an area of exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a health care provider. 94 It appears that potency of the bisphosphonate and duration of exposure to the drug increase the risk of ONJ. Patient factors which increase the risk of ONJ include cancer diagnosis, chemotherapy, glucocorticoid use, tobacco use, and pre-existing dental and periodontal disease. Although the true incidence of ONJ is unknown, recent expert consensus 94 estimates 1/10,000 to less than 1/100,000 patient-years in patients receiving oral bisphosphonate treatment for osteoporosis.
In the above eight zoledronic acid trials including 2563 subjects studied over 6960 patient-years, not a single case of ONJ was reported. However, these numbers must be interpreted with caution in that cumulative exposure and duration of follow-up (average 1–2 years) may not be enough to detect ONJ. The incidence of ONJ in patients receiving IV zoledronic acid for treatment of malignancy is much higher, as high as 1%–10%. 94 Boonyapakorn and colleagues 95 prospectively studied 80 patients receiving monthly IV zoledronic acid or pamidronate for cancer diagnosis, most commonly multiple myeloma and breast cancer. Using dental radiographs and intraoral examinations, they found that 22 (28%) patients developed ONJ after bisphosphonate exposure. The mean time from exposure to ONJ in the zoledronic acid-treated patients was 26 months. Initiation of bisphosphonate therapy need not be delayed for routine dental work, but patients should be counseled on the importance of dental hygiene and recommended to have regular dental visits for routine care.
Black and colleagues 92 reported an increased incidence of serious atrial fibrillation in women treated with zoledronic acid infusion, and Heckbert and colleagues 96 found greater likelihood of prior alendronate use among 719 women with confirmed new onset atrial fibrillation. In contrast, Lyles and colleagues 69 found no association between zoledronic acid and atrial fibrillation, stroke, myocardial infarction, or death from cardiovascular causes. Sørensen and colleagues 97 retrospectively studied 13,586 Danish women with atrial fibrillation and atrial flutter and found that alendronate and etidronate use was not more common among affected patients than population controls (adjusted relative risk among women with current bisphosphonate use 0.95). US FDA review of 19,687 bisphosphonate-treated patients found no association with atrial fibrillation. 98 Whether bisphosphonate use predisposes a patient to atrial fibrillation remains an open question. However, this small potential risk must be considered in relation to potentially large benefits in terms of fracture reduction and survival.
Summary
Osteoporosis and low bone mass are under-recognized and undertreated in men. As the population ages, the rates of osteoporosis and osteoporotic fractures are expected to rise. Men with prior fragility fractures, older men, and men with lower BMD are at highest risk of fracture. Men with glucocorticoid use, hypogonadism, tobacco or heavy alcohol intake, vitamin D deficiency, or androgen deprivation therapy for prostate cancer are also at increased risk for osteoporosis. Laboratory evaluation for secondary causes of osteoporosis and radiographic screening for occult vertebral fractures in men with height loss are essential parts of the workup of men with osteoporosis. All men should receive adequate dietary calcium and vitamin D. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, and decrease fracture risk in patients at high risk of fracture. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology.
Disclosure
The authors report no conflicts of interest in this work.
References
1 NIH Consensus Development Panel on Osteoporosis Prevention, Detection, and Therapy Osteoporosis prevention, diagnosis, and therapy JAMA 2001 285 785 795 11176917 10.1001/jama.285.6.785
2 National Osteoporosis Foundation Advocacy News and Updates The state of osteoporosis and low bone mass in the US. 2009 Cited 2009 Feb 18. Available from: http://www.nof.org/advocacy/prevalence/index.htm
3 Jones G Nguyen T Sambrook PN Kelly PJ Gilbert C Eisman JA Symptomatic fracture incidence in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES) Osteoporosis Int 1994 4 277 282 10.1007/BF01623352 7812076
4 Winner SJ Morgan CA Evans JG Perimenopausal risk of falling and incidence of distal forearm fracture BMJ 1989 298 6686 1486 1488 2503081 10.1136/bmj.298.6686.1486 PMC1836686
5 Office of the Surgeon General The burden of bone disease Bone health and osteoporosis: A report of the Surgeon General 2004 Cited 2009 Jan 31. Available from: http://www.surgeongeneral.gov/library/bonehealth/chapter_5.html 20945569
6 Leibson CL Tosteson AN Gabriel SE Ransom JE Melton LJ Mortality, disability, and nursing home use for persons with and without hip fracture: a population-based study J Am Geriatr Soc 2002 50 10 1644 1650 12366617 10.1046/j.1532-5415.2002.50455.x
7 Center JR Nguyen TV Schneider D Mortality after all major types of osteoporotic fractures in men and women: an observational study Lancet 1999 76 235 242 10.1016/S0140-6736(98)09075-8 10093980
8 Magaziner J Fredman L Hawkes W Changes in functional status attributable to hip fracture: a comparison of hip fracture patients to community-dwelling aged Am J Epidemiol 2003 157 11 1023 1031 12777366 10.1093/aje/kwg081
9 Chrischilles EA Butler CD Davis CS Wallace RB A model of lifetime osteoporosis impact Arch Intern Med 1991 151 10 2026 2032 1929691
10 Tosteson AN Orwoll ES Economic impact of fractures Osteoporosis in men: The effects of gender on skeletal health San Diego Academic Press 1999 15 27
11 Hasserius R Karlsson MK Jonsson B Long-term morbidity and mortality after a clinically diagnosed vertebral fracture in the elderly: a 12- and 22-year follow-up of 257 patients Calcif Tissue Int 2005 76 235 242 15812579 10.1007/s00223-004-2222-2
12 Lewis CE Ewing SK Taylor BC for the Osteoporotic Fractures in Men (MrOS) Study Research Group Predictors of non-spine fracture in elderly men: the MrOS study J Bone Miner Res 2007 22 2 211 219 17059373 10.1359/jbmr.061017
13 Nguyen TV Eisman JA Kelly PA Risk factors for osteoporotic fractures in elderly men Am J Epidemiol 1996 144 255 263 8686694 10.1093/oxfordjournals.aje.a008920
14 Gruntmanis U Male osteoporosis: deadly, but ignored Am J Med Sci 2007 333 2 85 92 17301586 10.1097/00000441-200702000-00004
15 Kelepouris N Harper KD Gannon F Kaplan FS Haddad JG Severe osteoporosis in men Ann Intern Med 1995 123 6 452 460 7639446 10.7326/0003-4819-123-6-199509150-00010
16 Orwoll ES Klein RF Osteoporosis in men Endocr Rev 1995 16 1 87 116 7758434 10.1210/edrv-16-1-87
17 World Health Organization Collaborating Centre for Metabolic Bone Diseases FRAX ® WHO Fracture Risk Assessment Tool Sheffield, UK World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK 2009 Cited 2009 Feb 13. Available from: http://www.shef.ac.uk/FRAX/index.htm
18 Khosla S Amin S Orwoll E Osteoporosis in men Endocr Rev 2008 29 4 441 464 18451258 10.1210/er.2008-0002 PMC2528848
19 Ebeling PR Osteoporosis in men N Engl J Med 2008 358 1474 1482 18385499 10.1056/NEJMcp0707217
20 Sherrington C Whitney JC Lord SR Herbert RD Cumming RG Close JC Effective exercise for the prevention of falls: a systematic review and meta-analysis J Am Geriatr Soc 2008 56 12 2234 2243 19093923 10.1111/j.1532-5415.2008.02014.x
21 Martyn-St James M Carroll S High-intensity resistance training and postmenopausal bone loss: a meta-analysis Osteoporos Int 2006 17 8 1225 1240 16823548 10.1007/s00198-006-0083-4
22 Larsen ER Mosekilde L Foldspang A Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study J Bone Miner Res 2004 19 3 370 378 15040824 10.1359/JBMR.0301240
23 Trivedi DP Doll R Khaw KT Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial BMJ 2003 326 7387 469 12609940 10.1136/bmj.326.7387.469 PMC150177
24 Dawson-Hughes B Harris SS Krall EA Dallal GE Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older N Engl J Med 1997 337 10 670 676 9278463 10.1056/NEJM199709043371003
25 Grant AM Avenell A Campbell MK for RECORD Trial Group Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial Lancet 2005 365 9471 1621 1628 15885294 10.1016/S0140-6736(05)63013-9
26 National Osteoporosis Foundation Clinician’s guide to prevention and treatment of osteoporosis 2009 Cited 2009 Feb 18. Available from: http://www.nof.org/professionals/cliniciansguide_form.asp
27 Trovas GP Lyritis GP Galanos A Raptou P Constantelou E A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers J Bone Miner Res 2002 17 3 521 527 11874243 10.1359/jbmr.2002.17.3.521
28 Toth E Csupor E Meszaros S The effect of intranasal salmon calcitonin therapy on bone mineral density in idiopathic male osteoporosis without vertebral fractures – an open label study Bone 2005 36 1 47 51 15664001 10.1016/j.bone.2004.09.003
29 Wang C Cunningham G Dobs A Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men J Clin Endocrinol Metab 2004 89 5 2085 2098 15126525 10.1210/jc.2003-032006
30 Snyder PJ Peachey H Berlin JA Effects of testosterone replacement in hypogonadal men J Clin Endocrinol Metab 2000 85 8 2670 2677 10946864 10.1210/jcem.85.8.6731
31 Snyder PJ Peachey H Berlin JA Effect of testosterone treatment on bone mineral density in men over 65 years of age J Clin Endocrinol Metab 1999 84 6 1966 1972 10372695 10.1210/jcem.84.6.5741
32 Katznelson L Finkelstein JS Schoenfeld DA Rosenthal DI Anderson EJ Klibanski A Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism J Clin Endocrinol Metab 1996 81 12 4358 4365 8954042 10.1210/jcem.81.12.8954042
33 Anderson FH Francis RM Peaston RT Wastell HJ Androgen supplementation in eugonadal men with osteoporosis: effects of six months’ treatment on markers of bone formation and resorption J Bone Miner Res 1997 12 3 472 478 9076591 10.1359/jbmr.1997.12.3.472
34 Finkelstein JS Hayes A Hunzelman JL Wyland JJ Lee H Neer RM The effects of parathyroid hormone, alendronate, or both in men with osteoporosis N Engl J Med 2003 349 1216 1226 14500805 10.1056/NEJMoa035725
35 Saag KG Shane E Boonen S Teriparatide or alendronate in glucocorticoid-induced osteoporosis N Engl J Med 2007 357 2028 2039 18003959 10.1056/NEJMoa071408
36 Russell RG Bisphosphonates: from bench to bedside Ann NY Acad Sci 2006 1068 367 401 16831938 10.1196/annals.1346.041
37 Dunford JE Thompson K Coxon FP Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates J Pharmacol Exp Ther 2001 296 2 235 242 11160603
38 Smith MR Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer Drugs Aging 2003 20 3 175 183 12578398 10.2165/00002512-200320030-00002
39 Drake MT Clarke BL Khosla S Bisphosphonates: mechanism of action and role in clinical practice Mayo Clin Proc 2008 83 9 1032 1045 18775204 10.4065/83.9.1032 PMC2667901
40 Reid IR Bisphosphonates: new indications and methods of administration Curr Opin Rheumatol 2003 15 4 458 463 12819475 10.1097/00002281-200307000-00014
41 Hall A Rho GTPases and the actin cytoskeleton Science 1998 279 5350 509 514 9438836 10.1126/science.279.5350.509
42 Weinstein RS Roberson PK Manolagas SC Giant osteoclast formation and long-term oral bisphosphonate therapy N Engl J Med 2009 360 53 62 19118304 10.1056/NEJMoa0802633 PMC2866022
43 Ryan PJ Blake GM Davie M Haddaway M Gibson T Fogelman I Intermittent oral disodium pamidronate in established osteoporosis: a 2 year double-masked placebo-controlled study of efficacy and safety Osteoporos Int 2000 11 2 171 176 10793877 10.1007/PL00004179
44 Brumsen C Papapoulos SE Lips P Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension J Bone Miner Res 2002 17 6 1057 1064 12054161 10.1359/jbmr.2002.17.6.1057
45 Boutsen Y Jamart J Esselinckx W Devogelaer JP Primary prevention of glucocorticoid-induced osteoporosis with intravenous pamidronate and calcium: a prospective controlled 1-year study comparing a single infusion, an infusion given once every 3 months, and calcium alone J Bone Miner Res 2001 16 1 104 112 11149473 10.1359/jbmr.2001.16.1.104
46 Ho YV Frauman AG Thomson W Seeman E Effects of alendronate on bone density in men with primary and secondary osteoporosis Osteoporos Int 2000 11 2 98 101 10793867 10.1007/PL00004182
47 Orwoll E Ettinger M Weiss S Alendronate for the treatment of osteoporosis in men N Engl J Med 2000 343 604 610 10979796 10.1056/NEJM200008313430902
48 Ringe JD Dorst A Faber H Ibach K Alendronate treatment of established primary osteoporosis in men: 2-year results of a prospective, comparative, two-arm study Rheumatol Int 2004 24 110 113 13680141 10.1007/s00296-003-0388-y
49 Sawka AM Papaioannou A Adachi JD Gafni A Hanley DA Thabane L Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women BMC Musculoskelet Disord 2005 6 39 16008835 10.1186/1471-2474-6-39 PMC1182376
50 Ringe JD Faber H Farahmand P Dorst A Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study Rheumatol Int 2006 26 427 431 16001181 10.1007/s00296-005-0004-4
51 Boonen S Orwoll ES Wenderoth D Stoner KJ Eusebio R Delmas PD Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study J Bone Miner Res 2009 24 719 725 19049326 10.1359/jbmr.081214
52 Reid DM Adami S Devogelaer J-P Chines AA Risedronate increases done density and reduces vertebral fracture risk within one year in men on corticosteroid therapy Calcif Tissue Int 2001 69 242 247 11730260 10.1007/s00223-001-1060-8
53 Sato Y Iwamoto J Kanoko T Satoh K Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke Arch Intern Med 2005 165 1743 1748 16087822 10.1001/archinte.165.15.1743
54 Leal AM Foss NT Endocrine dysfunction in leprosy Eur J Clin Microbiol Infect Dis 2009 28 1 7 18629555 10.1007/s10096-008-0576-5
55 Ishikawa S Ishikawa A Yoh K Tanaka H Fujiwara M Osteoporosis in male and female leprosy patients Calcif Tissue Int 1999 64 144 147 9914322 10.1007/s002239900593
56 Kanaji A Higashi M Namisato M Nishio M Ando K Yamada H Effects of risedronate on lumbar bone mineral density, bone resorption, and incidence of vertebral fracture in elderly male patients with leprosy Lepr Rev 2006 77 147 153 16895071
57 Parfitt JR Driman DK Pathological effects of drugs on the gastrointestinal tract: a review Hum Pathol 2007 38 527 536 17367604 10.1016/j.humpath.2007.01.014
58 Wysowski DK Reports of esophageal cancer with oral bisphosphonate use N Engl J Med 2009 360 1 89 90 19118315 10.1056/NEJMc0808738
59 MacLean C Newberry S Maglione M Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis Ann Intern Med 2008 148 197 213 18087050 10.7326/0003-4819-148-3-200802050-00198
60 Tosteson AN Grove MR Hammond CS Early discontinuation of treatment for osteoporosis Am J Med 2003 115 3 209 216 12947959 10.1016/s0002-9343(03)00362-0
61 Papaioannou A Kennedy CC Dolovich L Lau E Adachi JD Patient adherence to osteoporosis medications: problems, consequences and management strategies Drugs Aging 2007 24 1 37 55 17233546 10.2165/00002512-200724010-00003
62 Yood RA Emani S Reed JI Lewis BE Charpentier M Lydick E Compliance with pharmacologic therapy for osteoporosis Osteoporos Int 2003 14 965 968 14504697 10.1007/s00198-003-1502-4
63 Siris ES Harris ST Rosen CJ Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases Mayo Clin Proc 2006 81 8 1013 1022 16901023 10.4065/81.8.1013
64 Hamilton B McCoy K Taggart H Tolerability and compliance with risedronate in clinical practice Osteoporos Int 2003 14 259 262 12730745 10.1007/s00198-002-1370-3
65 Solomon DH Avorn J Katz JN Compliance with osteoporosis medications Arch Intern Med 2005 165 2414 2419 16287772 10.1001/archinte.165.20.2414
66 Lamy O Sandini L Pache I Fatio S Burnand J Burckhardt P Intravenous ibandronate in men with osteoporosis: an open pilot study over 2 years J Endocrinol Invest 2003 26 8 728 732 14669826 10.1007/BF03347354
67 Ringe JD Dorst A Faber H Ibach K Sorenson F Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative study Osteoporos Int 2003 14 801 807 14610641 10.1007/s00198-003-1425-0
68 Nancollas GH Tang R Phipps RJ Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxy-apatite Bone 2006 38 617 627 16046206 10.1016/j.bone.2005.05.003
69 Lyles KW Colón-Emeric CS Magaziner JS for the HORI -ZON Recurrent Fracture Trial Zoledronic acid and clinical fractures and mortality after hip fracture N Engl J Med 2007 357 1799 1809 17878149 10.1056/NEJMoa074941 PMC2324066
70 Colón-Emeric C Mesenbrink P Lyles K Potential mediators of the reduction in mortality with zoledronic acid after hip fracture [abstract] Presented at the American Society for Bone Mineral Research meeting Sept 13, 2008 10.1359/jbmr.090704 PMC5770987 19580467
71 Novartis Pharmaceuticals Reclast prescribing information 3 2009 Cited 2009 May 18. Available from: http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8476
72 Poole KE Loveridge N Rose CM Warburton EA Reeve J A single infusion of zoledronate prevents bone loss after stroke Stroke 2007 38 1519 1525 17395868 10.1161/STROKEAHA.106.474262
73 Brown TT Qaqish RB Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review AIDS 2006 20 17 2165 2174 17086056 10.1097/QAD.0b013e32801022eb
74 Triant VA Brown TT Lee H Grinspoon SK Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system J Clin Endocrinol Metab 2008 93 9 3499 3504 18593764 10.1210/jc.2008-0828 PMC2567857
75 Bolland MJ Grey AB Horne AM Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial J Clin Endocrinol Metab 2007 92 1283 1288 17227801 10.1210/jc.2006-2216
76 Reid IR Brown JP Burckhardt P Intravenous zoledronic acid in postmenopausal women with low bone mineral density N Engl J Med 2002 346 653 661 11870242 10.1056/NEJMoa011807
77 Borba VZ Paz-Filho G Kulak CA Seibel MJ Bilezikian JP Bone turnover 18 months after a single intravenous dose of zoledronic acid Int J Clin Pract 2007 61 6 1058 1062 17504370 10.1111/j.1742-1241.2007.01392.x
78 Bolland MJ Grey AB Horne AM Effects of intravenous zoledronate on bone turnover and BMD persist for at least 24 months J Bone Miner Res 2008 23 1304 1308 18627266 10.1359/jbmr.080312
79 Brown JE Ellis SP Lester JE Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid Clin Cancer Res 2007 13 18 5406 5410 17875770 10.1158/1078-0432.CCR-07-0247
80 Finkelstein JS Leder BZ Burnett SM Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men J Clin Endocrinol Metab 2006 91 8 2882 2887 16684825 10.1210/jc.2006-0190
81 Welch BJ Denke MA Kermani A Adams-Huet B Gazmen NM Gruntmanis U Comparison of testosterone, alendronate, and a combination of both therapies in men with low bone mineral density J Invest Med 2007 55 4 168 173 10.2310/6650.2007.06047 17651670
82 Greenspan SL Coates P Sereika SM Nelson JB Trump DL Resnick NM Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer J Clin Endocrinol Metab 2005 90 6410 6417 16189261 10.1210/jc.2005-0183
83 Shahinian VB Kuo Y-F Freeman JL Goodwin JS Risk of fracture after androgen-deprivation for prostate cancer N Engl J Med 2005 352 154 164 15647578 10.1056/NEJMoa041943
84 Smith MR McGovern FJ Zietman AL Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer N Engl J Med 2001 345 948 955 11575286 10.1056/NEJMoa010845
85 Greenspan SL Nelson JB Trump DL Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy J Clin Oncol 2008 26 4426 4434 18802155 10.1200/JCO.2007.15.1233 PMC2653114
86 Ryan CW Huo D Demers LM Beer TM Lacerna LV for the Zometa US05 Investigators Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer J Urol 2006 176 972 978 16890673 10.1016/j.juro.2006.04.078
87 Smith MR Eastham J Gleason DM Shasha D Tchekmedyian S Zinner N Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer J Urol 2003 169 2008 2012 12771706 10.1097/01.ju.0000063820.94994.95
88 Michaelson MD Kaufman DS Lee H Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist–induced bone loss in men with prostate cancer J Clin Oncol 2007 25 1038 1042 17369566 10.1200/JCO.2006.07.3361 PMC3047397
89 Ryan CW Huo D Bylow K Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid BJU Int 2007 100 70 75 17552955 10.1111/j.1464-410X.2007.06853.x
90 Doran PM Riggs BL Atkinson EJ Khosla S Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men J Bone Miner Res 2001 16 11 2118 2125 11697809 10.1359/jbmr.2001.16.11.2118
91 Smith MR Fallon MA Lee H Finkelstein JS Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial J Clin Endocrinol Metab 2004 89 3841 3846 15292315 10.1210/jc.2003-032058
92 Black DM Delmas PD Eastell R for the HORIZON Pivotal Fracture Trial Fracture trial once-yearly zoledronic acid for treatment of postmenopausal osteoporosis N Engl J Med 2007 356 1809 1822 17476007 10.1056/NEJMoa067312
93 FDA Medwatch Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa) Washington DC US Food and Drug Administration Updated 2008 Jan 7. Cited 2008 Dec 12. Available from: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Bisphosphonates
94 Khosla S Burr D Cauley J Bisphosphonate-associated osteone-crosis of the jaw: report of a task force of the american society for bone and mineral research J Bone Miner Res 2007 22 1479 1491 17663640 10.1359/jbmr.0707onj
95 Boonyapakorn T Schirmer I Reichart PA Sturm I Massenkeil G Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies Oral Oncol 2008 44 9 857 869 18282788 10.1016/j.oraloncology.2007.11.012
96 Heckbert SR Li G Cummings SR Smith NL Psaty BM Use of alen-dronate and risk of incident atrial fibrillation in women Arch Intern Med 2008 168 8 826 831 18443257 10.1001/archinte.168.8.826
97 S⊘rensen HT Christensen S Mehnert F Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study BMJ 2008 336 813 816 18334527 10.1136/bmj.39507.551644.BE PMC2292333
98 US Food and Drug Administration Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates Washington DC: US Food and Drug Administration Updated 2008 Nov 12. Cited 2009 Apr 22. Available from: http://www.fda.gov/CDER/drug/early_comm/bisphosphonates_update_200811.htm