Clinical experience with intravenous zoledronic acid in the treatment of male osteoporosis: evidence and opinions

Abstract

Osteoporosis frequently remains underrecognized and undertreated in men. Most osteoporosis-related fractures could be prevented if men at risk would be diagnosed, treated, and remained compliant with therapy. Bisphosphonates, the mainstay of osteoporosis treatment, are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and likely improve survival in men with osteoporosis. The focus of the article is on intravenous zoledronic acid, which may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, polypharmacy, significant gastrointestinal pathology or suspected medication noncompliance. Zoledronic acid is approved in the United States (US) and European Union (EU) as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy. This article reviews the evidence for zoledronic acid, currently the most potent bisphosphonate available for clinical use, and its therapeutic effects in the treatment of men with osteoporosis.

Introduction

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 [World Health Organization, 2003]. While the age-related mechanisms of bone loss have been increasingly characterized in recent years, osteoporosis remains underrecognized in men [Gruntmanis, 2007]. It is estimated that over 14 million men in the United States had osteoporosis or low bone mass in 2002; that figure is projected to increase to over 20 million by 2020 [National Osteoporosis Foundation, 2002]. More than one third of all osteoporotic fractures occur in men [Johnell and Kanis, 2006]. Following a hip fracture, disability is substantial [Craik, 1994] and nearly 33% of men die within 1 year [Brauer et al. 2009].

Per the 2010 Census, individuals over 60 years of age represent the fastest growing cohort in the United States, and there has been a disproportionate increase in the older male population [Werner, 2011]. The costs associated with osteoporosis are expected to rise as the population ages. In fact, the economic burden from osteoporosis-related fractures is projected to increase from US$19 billion in 2002 to US$25.3 billion in 2025 [Burge et al. 2007].

Despite the personal and societal costs of male osteoporosis, the bone health of men is frequently overlooked by clinicians [Panneman et al. 2004]. Feldstein and colleagues found that in men over 65 years of age who had experienced a fracture, only 1.5% had bone density measurement performed and only 2.8% received pharmacological treatment for their fracture [Feldstein et al. 2003]. In a separate study, only 4.5% of men who sustained a low-energy hip fracture received medical treatment of any kind upon discharge [Kiebzak et al. 2002]. Less than 10% of men with an osteoporotic fracture or at high risk of fracture received adequate treatment for osteoporosis [Szulc et al. 2012]. Recognizing this problem, the American College of Physicians in 2008 and the Endocrine Society in 2012 published practice guidelines for the screening, diagnosis and treatment of osteoporosis in men [Qaseem et al. 2008; Watts et al. 2012].

Bisphosphonates (BPs) are first-line therapy for the treatment of osteoporosis and have been shown to reduce markers of bone turnover, significantly increase bone density, and decrease the risk of hip, vertebral, and other fractures [Favus, 2010]. While all medically-approved BPs have been studied in men, the number of published trials and men recruited in them is much smaller than in women. Despite less clinical experience with the use of BPs in men, the benefits are unequivocal. In this article we review the evidence for zoledronic acid, currently the most potent BPs available for clinical use, and its therapeutic effects in the treatment of men with osteoporosis.

Diagnosis

In clinical practice, osteoporosis is defined based on the presence of a fragility fracture or bone mineral density (BMD) assessment, as BMD is strongly correlated with future fracture risk in men [Melton et al. 1998; Schuit et al. 2004]. The most validated means of assessing BMD is through the use of dual-energy X-ray absorptiometry (DXA). One of the limitations of DXA is the lack of specificity in identifying individuals at high risk of fracture [Briot et al. 2009]. Therefore, it is essential to identify other risk factors that are predictive for future fractures and osteoporosis.

Numerous risk factors for osteoporosis-related fractures have been identified. The Osteoporotic Fractures in Men Study (MrOS) [Orwoll et al. 2005] followed 5995 US men age 65 or older and found that low hip BMD was a powerful independent indicator of fracture risk [Lewis et al. 2007; Schwartz et al. 2011]. Secondary causes of osteoporosis may account for up to 40% of the cases of osteoporosis in men [Khosla et al. 2008]. A recent meta-analysis of 55 studies [Drake et al. 2012] established that age, low body mass index (BMI), current smoking, excessive alcohol use, chronic corticosteroid use, history of prior fractures and falls, history of hypogonadism, stroke and diabetes had statistically significant associations with low bone density and fractures.

Aside from DXA, other factors that increase osteoporotic fracture risk include bone quality indicators, such as microarchitecture, porosity, cortical thickness, turnover, rate and quality of mineralization; however, these are difficult to incorporate into clinical practice. Based on epidemiological studies of various population cohorts, the World Health Organization (WHO) developed the fracture risk assessment tool (FRAX™), which combines bone density measurement and several clinical risk factors in order to estimate 10-year fracture risk and help to determine when pharmacologic therapy is indicated [Kanis et al. 2008, 2011]. Other risk calculators have been developed but are less used in daily practice.

The Endocrine Society 2012 guidelines [Watts et al. 2012] recommend treatment of osteoporosis in men who have had a hip or vertebral fracture without major trauma, BMD of the spine, femoral neck, and/or total hip −2.5 SD or below based on T-score, or with T-score between −1.0 and −2.5 in the spine, femoral neck and in whom a 10-year risk of major osteoporotic fractures is ≥20% or a 10-year risk of hip fracture ≥3% using FRAX™. For men outside the US, region-specific guidelines should be used. Osteoporosis treatment is also recommended in men who are receiving long-term glucocorticoid therapy in pharmacological doses (e.g. prednisone or equivalent >7.5 mg/day), as per 2010 guidelines from the American College of Rheumatology [Grossman et al. 2010].

Treatment strategies

The main goal of osteoporosis treatment is reduction in fracture risk and associated morbidity and mortality. Owing to the asymptomatic nature of osteoporosis, patients do not request and physicians frequently do not offer treatment for those with osteoporosis and/or prior fragility fractures [McGlynn et al. 2003; Neubecker et al. 2011]. Nonpharmacologic treatment for osteoporosis includes balanced diet with adequate calcium and vitamin D intake [Rejnmark et al. 2012; Bischoff-Ferrari et al. 2012], regular weight-bearing exercise, and avoiding smoking and high intake of alcohol [National Osteoporosis Foundation, 2010]. A recent study on high-dose vitamin D supplementation (>800 IU daily) showed significantly reduced risk of hip fracture and any nonvertebral fracture risk in people 65 and older [Bischoff-Ferrari et al. 2012]. Drugs for the treatment of osteoporosis can be classified into antiresorptive, anabolic, or dual-action agents. Antiresorptive agents, or drugs that inhibit osteoclast action, include most of the commonly-used therapies in men, such as BPs. Only zoledronic acid will be discussed in this article.

Bisphosphonates

BPs have been studied extensively and are a mainstay of osteoporosis treatment in both men and women. They are synthetic analogs of the endogenous bone mineralization regulator pyrophosphate. Their central structure contains two phosphate groups with high affinity to bind to hydroxyapatites, and each of the two side chains (R1 and R2) has different effects: R1 binds calcium in the bone matrix and R2 is responsible for the potency and properties of each BP. BPs are classified based on the absence or presence of nitrogenous groups in their structure (R2 chain), which influences their action. Metabolites of non-nitrogen-containing BPs compete with adenosine triphosphate (ATP) in cellular energy metabolism within osteoclasts, resulting in their apoptosis.

Addition of amino-group helps to increase the BP activity markedly. All nitrogen-containing BPs accumulate in bones where they bind to hydroxyapatite crystals with preference to active remodeling sites with high bone turnover. BP are incorporated into the bone matrix and released later following the acidification by osteoclasts during bone resorption [Lin, 1996]. Nitrogen-containing BPs act in the HMG-CoA reductase (mevalonate) pathway by inhibiting farnesyl pyrophosphate synthase (FPPS), preventing the prenylation of small GTP-binding proteins in osteoclasts and disrupting their cytoskeleton [Dunford et al. 2001; van Beek et al. 2003; Kavanagh et al. 2006]. The released BP impairs the ability of osteoclasts to form the ruffled sealing zone, preventing their attachment to the bone surface. Owing to reduced osteoclast progenitor development, differentiation of osteoclasts is decreased as well. This leads to an inhibition of osteoclast-mediated bone resorption and apoptosis [Hughes et al. 1995; Green, 2004]. Depending on the pattern of amino groups in the side chain, each nitrogen-containing BP has different antiresorptive potency. When the ability of BPs to inhibit FPPS in vitro is compared, zoledronic acid is 3, 17, and 67 times more potent than risedronate, alendronate, and pamidronate, respectively [Dunford et al. 2001]. This effect might be related to the increased ability of zoledronic acid to inhibit bone resorption in vivo, although clinical trial data demonstrate a smaller difference when compared with alendronate or risedronate [Russell et al. 2008].

BPs are prescribed most frequently in an oral formulation. However, oral BPs have very limited bioavailability [Lin, 1996]. Owing to their poor lipophilicity, less than 1% of orally taken BPs are absorbed in the gut; half of this amount is excreted by the kidneys and another half binds to hydroxyapatite crystals on the bone surface and becomes incorporated into osteoclasts. To increase absorption and avoid esophageal irritation, patients must take most oral BPs on an empty stomach and remain in an upright position for at least 30 minutes. Various factors influence compliance with BP therapy and will be discussed later in the article. In certain clinical situations, intravenous (IV) BP administration would be beneficial.

Treatment with zoledronic acid

Zoledronic acid is a potent nitrogen-containing BP with high affinity for hydroxyapatite and a strong ability to inhibit osteoclast action. It is used for the treatment of Paget’s disease, skeletal metastases of some malignancies, tumor-induced hypercalcemia, and osteoporosis. An annual IV infusion of zoledronic acid 5 mg is approved in the US and EU to treat osteoporosis in men and has been demonstrated to positively affect BMD and fracture risk. Zoledronic acid 4 mg IV infusion every 3 months, or once a year, has been studied in men with nonmetastatic prostate cancer on androgen deprivation therapy (ADT).

Pharmacokinetics

The bioavailability of systematically administered BPs is 100%; thus, maximal plasma concentrations of zoledronic acid can be reached by the end of each IV infusion. The infusion time of zoledronic acid is recommended to be 15 minutes, compared with 1–4 hours for pamidronate and 15–30 seconds for ibandronate. Around 40% of the drug is excreted renally, but the remaining 60% of the dose is retained in the skeleton [Weiss et al. 2008].

Bone turnover

Zoledronic acid treatment decreases serum levels of C-terminal cross-linking telopeptides of type I collagen (CTx) and urinary levels of N-terminal cross-linking telopeptides of type I collagen (NTx); it indirectly decreases serum bone alkaline phosphatase. Various aspects of the detection of bone turnover markers in men are discussed in a recent review [Szulc, 2011]. Annual IV zoledronic acid infusions have been shown to decrease bone resorption in men with osteoporosis [Bolland et al. 2007; Brown et al. 2007; Orwoll et al. 2010; Boonen et al. 2012] or those with prostate cancer who are receiving ADT [Ryan et al. 2006]. A comparison trial of zoledronic acid with alendronate in men [Orwoll et al. 2010] demonstrated that zoledronic acid reduced levels of bone resorption and formation markers significantly more than the alendronate group. The decrease of bone resorption and formation markers with BPs in eugonadal and hypogonadal men is similar to what has been described in women [MacLean et al. 2008]. Due to the potent effect of zoledronic acid on bone turnover, annual zoledronic acid infusions seem to be noninferior to more frequent dosing [Reid et al. 2002]. Yet, the exact duration of bone turnover suppression after a single zoledronic acid injection is unknown.

Zoledronic acid seems to suppress bone turnover for at least 5 years in HIV-infected men [Bolland et al. 2012]. In the HORIZON-PFT extension trial, annual zoledronic acid over 6 years maintained BMD and reduced vertebral fracture risk in postmenopausal women. The investigators concluded that many patients can discontinue treatment after 3 years, but those at high risk of fracture may benefit from continuing annual infusions [Black et al. 2012]. It is unknown whether the same recommendations would be applicable to men, but data from a recent meta-analysis of 116 osteoporosis trials [Murad et al. 2012], which included 139,647 patients (24% men), suggest that treatment strategies should work similarly in both genders.

Evidence of efficacy

The efficacy data from the published trials on osteoporosis treatment with zoledronic acid in men are summarized in Table 1. If the study population was mixed, we extracted data relating to men only.

Table 1.

Studies with zoledronic acid for the treatment of osteoporosis in men (modified from Piper and Gruntmanis [2009]).

Reference	Study design	Total N	FU (mo)	Men	Avg age	Fracture RRR			BMD change from baseline (%)
						Any	Vert	NonV	TotH	FemN	LumbS
HORIZON-RFT – Lyles et al. [2007]	RCT	2126	36	24%	74.5	35%	46%	27%	6.4%	4.3%
Poole et al. [2007]	RCT	27	12	78%	69.8				5.5%	NS
Bolland et al. [2007]	RCT	43	24	100%	49.1				4.6%		6.3%
Brown et al. [2007]	PU	66	36	100%	42				4.3%		4.8%
Bolland et al. [2012]	RCT-Ext	35	48	100%					3.4%		3.5%
Boonen et al. [2011]	RCT	505	24	100%						3.8%
Boonen et al. [2012]	RCT	1199	24	100%	65.8		67%		2.3%	3.4%	7.7%

FU, follow up; PU, prospective, unrandomized trial; RCT, prospective, randomized controlled trial; ZA, zoledronic acid; N, number; mo, months; Avg, average; RRR, relative risk reduction; Vert, vertebral; NonV, nonvertebral; TotH, total hip; FemN, femoral neck; LumbS, lumbar spine; BMD, bone mineral density

Placebo-controlled trials with zoledronic acid

The clinical efficacy of zoledronic acid in men in the secondary prevention of osteoporotic fractures was evaluated in the HORIZON-RFT trial [Lyles et al. 2007]; 24% (508) of the 2126 subjects were men aged 50 and over. Participants received 5 mg of IV zoledronic acid or placebo within 90 days of surgical repair of a low-trauma hip fracture. After 36 months, there was a significant increase in BMD from baseline at total hip and femoral neck and a decrease in any new fracture as compared with the placebo group. The study was not powered to show a reduction in clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with zoledronic acid versus 8.7% for placebo.

The same HORIZON-RFT population of men aged 50 and over with recent hip fracture was analyzed by other investigators [Boonen et al. 2011]. They found a larger increase in total hip BMD from baseline to 12 and 24 months with zoledronic acid than with placebo (between-group differences were 2.0%, and 3.8%, respectively). The percentage change from baseline in femoral neck BMD at 24 months was significantly higher with zoledronic acid (3.8%) than with placebo. New clinical fractures occurred in 36 (7.1%) participants, but the difference between groups was not significant.

The first osteoporosis trial in men with a fracture endpoint was recently published [Boonen et al. 2012]. Investigators enrolled 1199 men (mean age 65.8 years) with primary osteoporosis or osteoporosis due to hypogonadism; 32.1% of the participants had a history of one or more vertebral fractures at baseline. To evaluate the antifracture efficacy and safety of annual IV zoledronic acid 5 mg infusions, groups were randomized into a zoledronic acid arm (5 mg IV yearly; n = 588) or a placebo arm (n = 611). After 24 months, the relative risk reduction of new vertebral fracture was significantly higher in the zoledronic acid group when compared with the placebo group (1.6% versus 4.9%). Secondary endpoints included less loss of height in the zoledronic acid group (−2.34 mm versus −4.49 mm, p = 0.0020). Zoledronic acid increased BMD and reduced fractures to the same degree in hypogonadal or eugonadal men. The results of this trial supports antifracture efficacy of annual 5 mg zoledronic infusion in men with decreased BMD.

A recent meta-analysis [Murad et al. 2012] concluded that effects on BMD, biochemical markers of bone remodeling and fracture reduction seen in studies with osteoporosis in men closely mirror those seen in larger trials with postmenopausal women. This supports the use of available pharmacological therapies in men with osteoporosis and increased fracture risk [Watts et al. 2012].

Men with prostate cancer and ADT

Patients with prostate cancer may undergo surgical or medical castration with ADT. The annual incidence of prostate cancer in the US is about 200,000, and about 40% of men receive ADT [Meng et al. 2002; Shahinian et al. 2005]. In these patients, older age and more advanced cancer stages were associated with ADT and increased fracture risk [Shahinian et al. 2005]. Zoledronic acid IV infusions 4 mg every 3 months and annual dosing [Michaelson et al. 2007; Satoh et al. 2009] have been studied as treatment options for the prevention of bone loss associated with ADT. Data from available randomized controlled trials are summarized in Table 2, and demonstrate significant increases in BMD in the lumbar spine and hip after 12 months. Only one trial [Wadhwa et al. 2010] was performed for a longer observational period (36 months). It included four subgroups and the possible synergic effect of nonsteroidal antiandrogens (bicalutamide) was evaluated. In this study, treatment with zoledronic acid every 3 months increased BMD more in the bicalutamide group than in those receiving luteinizing hormone-releasing hormone agonists (LHRHAs). However, 1 year after the last infusion of zoledronic acid, BMD significantly decreased in both groups, but to a smaller extent in the bicalutamide group, suggesting that perhaps annual administration of zoledronic acid for these patients could be insufficient. The same article [Wadhwa et al. 2010] has included detailed data (BMD values, duration of ADT before zoledronic acid treatment, etc.) from available randomized controlled trials of zoledronic acid and other BPs used for the prevention of bone loss in prostate cancer patients with ADT and osteopenia or osteoporosis. Owing to different medications used for ADT, inconsistent length of studies and varied intervals between zoledronic acid infusions comparison between studies are difficult.

Table 2.

Trials in prostate cancer with ADT (modified from Piper and Gruntmanis [2009]).

Reference	Study design	N	FU (mo)	N of ZA infusions	Avg age	BMD change from baseline (%)
						Hip	FemN	LumbS
Smith et al. [2003]	RCT	106	12	4	70.7	3.9%	3.3%	7.8%
Ryan et al. [2006]	RCT	120	12	4	72	3.8%	3.6%	6.7%
Michaelson et al. [2007]	RCT	40	12	1	65.5	2.6%	2.1%	7.1%
Ryan et al. [2007]	RCT	42	12	4	65		4.2%	7.1%
Israeli et al. [2007]	RCT	215	12	4		3.7%		6.7%
Satoh et al. [2009]	RCT	40	12	1	70.5	1.1%	5.1%
Bhoopalam et al. [2009]	RCT	93	12	4				5.95% / 6.08%
Campbell et al. [2010]	RCT	28	12	4	73	3.55% / 2.36%	3.23% / 3.35%	4.17%
Wadhwa et al. [2010]	RCT	58	36	4 (2nd year)	77	1.8% / 3.9%	2.8% / 3.8%	2.2% / 5.4%
Kapoor et al. [2011]	RCT	42	12	4	74.7	2.27%	5.53%	7.93%

ADT, androgen deprivation therapy; FU, follow up; RCT, prospective, randomized controlled trial; ZA, zoledronic acid; N, number; mo, months; Avg, average; FemN, femoral neck; LumbS, lumbar spine; BMD, bone mineral density

Comparison trials with zoledronic acid

A total of three trials have been reported with head-to-head comparisons of a yearly IV infusion of 5 mg zoledronic acid versus oral BPs in the treatment of osteoporosis in men. Two of these trials examined the efficacy and safety of zoledronic acid in the prevention and treatment of glucocorticoid-induced osteoporosis. The data from comparison trials with zoledronic acid in men are summarized in Table 3.

Table 3.

Studies with zoledronic acid for the treatment of osteoporosis in men: comparison of zoledronic acid with other bisphosphonates (modified from Piper and Gruntmanis [2009]).

Reference	ZA versus	Type of OP	Study design	Total N (ZA incl)	FU (mo)	Men	Avg age	BMD change from baseline (%)
								Total hip		Lumbar spine
								ZA	Co	ZA	Co
Orwoll et al. [2010]	AL	Pr/HG	RCT	302 (154)	24	100%				6.1%	6.2%
HORIZON – Reid et al. [2009]	RI	GIO (Prev)	RCT	288 (144)	12	31.8%		..	..	2.6%
HORIZON – Reid et al. [2009]	RI	GIO (Th)	RCT	545 (272)	12	31.8%		..	..	4.1%
Sambrook et al. [2012]	RI	GIO (Prev)	RCT	88	12	100%	56.4	1.1%	−0.4%	2.5%	−0.2%
Sambrook et al. [2012]	RI	GIO (Th)	RCT	177	12	100%	56.4	1.8%	0.2%	4.7%	3.3%

AL, alendronate; Co, comparator; GIO, glucocorticoid-induced osteoporosis; HG, hypogonadism; Pr, primary; Prev, prevention; RI, risedronate; Th, therapy; ZA, zoledronic acid

The efficacy and safety of once-yearly IV infusions of 5 mg zoledronic acid was compared with a weekly-administered dose of oral alendronate 70 mg in a 24-month randomized, multicenter, double-blind, active-controlled study of 302 men [Orwoll et al. 2010]. Changes in lumbar spine BMD from baseline were not statistically different between the alendronate and zoledronic acid groups (6.2% versus 6.1%, respectively). However, the latter group had greater reductions in the levels of bone resorption and formation markers compared with the former group, especially at months 3, 6, 15, and 18. The difference in the levels of bone turnover markers between both groups after 3 or 6 months can be due to the more rapid effect of zoledronic acid, but values after 15 and 18 months reflect the pharmacological strength.

The efficacy of a yearly infusion of zoledronic acid 5 mg was compared with daily oral risedronate 5 mg in the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) in a 1-year randomized, double-blind trial: the HORIZON study [Reid et al. 2009]. In total, 416 and 417 patients received zoledronic acid and risedronate, respectively; 31.8% of the participants were men and 94% were White. Investigators found that zoledronic acid was significantly more effective than risedronate in increasing BMD from baseline at the lumbar spine (4.1% versus 2.7% in the treatment group and 2.6% versus 0.6% in the prevention group), femoral neck, trochanter, and total hip in both subpopulations at 12 months, thus confirming noninferiority and superiority of a single infusion of zoledronic acid 5 mg over daily oral risedronate 5 mg in the treatment and prevention of GIO.

Another HORIZON trial analysis included data from 265 men [Sambrook et al. 2012]. When a yearly IV zoledronic acid 5 mg dose was compared with daily risedronate 5 mg, there was a significantly greater increase in BMD from baseline at the lumbar spine (4.7% versus 3.3% in treatment group and 2.5% versus −0.2% in prevention group) and total hip (1.8% versus 0.2% in treatment group and 1.1% versus −0.4% in prevention group) in the zoledronic acid group after 12 months. The post hoc analysis of the HORIZON trial [Roux et al. 2012] confirmed that zoledronic acid was significantly more effective than risedronate in increasing lumbar spine BMD in the prevention and treatment of GIO across a wide range of patients.

Compliance and persistence

Most commonly, BPs are prescribed to be taken orally, and this can contribute to decreased compliance and persistence to therapy. Yearly IV infusions of zoledronic acid could serve as a good and safe alternative and improve the noncompliance and nonpersistence seen with oral BPs.

Owing to the finding of a marked reduction in fracture risk in randomized clinical trials, there is a common assumption that the high compliance with oral BP therapy could be seen in daily practice. However, trial participants often are better motivated and educated, have less comorbidities, are followed more closely, and adherence is regularly encouraged [MacLean et al. 2008]. The real-world data have shown [Cramer et al. 2007; Kothawala et al. 2007] that long-term compliance with oral BP therapy is low and at least one-third of patients do not take their BPs as directed [Cramer et al. 2007; Kothawala et al. 2007; Patrick et al. 2010].

One systematic review of seven observational studies of BP compliance as measured by patient surveys indicates that the discontinuation rate at 1 year of daily dosing was in the range 19–29%. In a study that included men, the rate was 22%. When compliance is measured by administrative data, the discontinuation rate was 68% for daily dosing and 56% for weekly dosing. Moreover, 76% of patients had at least some interruption in oral BP therapy during the first year of therapy [Papaioannou et al. 2007]. Analysis of the pooled database-derived data from 24 studies showed a drop in persistence rate to 42% for osteoporosis treatment lasting 13–24 months, which increased to 52% if drugs were used for more than 2 years. Also, refill compliance was only 68% for long-term treatment [Kothawala et al. 2007]. Another study with 26,636 new drug users aged 65 years or greater [Brookhart et al. 2007] estimated the restart rate of oral osteoporosis medications, looking specifically at refill compliance. If therapy was stopped for more than 2 months, 30% restarted the medication within 6 months, and 50% restarted it within 2 years. More eager to return to medication use were younger patients, women, and those with a history of a fracture. Recent hip fractures, discharges from nursing homes, and BMD testing also predicted a return to therapy. Yet, there are no data on the effectiveness of restarting BPs after such extended gaps in treatment.

The costs of BP noncompliance are high. Patients who are less than 66% compliant with osteoporosis medications have significantly less of an increase in BMD [Yood et al. 2003]. In an analysis of insurance claims databases involving 35,537 women on BPs, only 43% of women filled at least 80% of their prescriptions. The medication-compliant women had 37% fewer hip fractures at 24 months [Siris et al. 2006]. Modeling, based on actual clinical practice of 44,531 patients, including 8367 (18.8%) men, demonstrated that at least an additional 68.4 hip fractures per 10,000 patients would be prevented with yearly BP treatments (compared with weekly BPs) if long-term persistence remained unchanged. Improved long-term persistence by 20% would prevent the occurrence of an additional 88.6 hip fractures per 10,000 patients [Rietbrock et al. 2009]. In a cohort study with 19,987 patients (3% men) [Patrick et al. 2010] there was a relationship between high BP adherence and fracture reduction, overall rate of fractures was reduced by 22%, hip fracture rate by 23%, and vertebral fracture rate by 26% in individuals who were more compliant. Yet there are not sufficient data regarding long-term clinical outcomes with IV zoledronic acid attributed to improved compliance.

Patients most commonly point to adverse drug effects as the reason for stopping therapy [MacLean et al. 2008]. Based on the analyses of different studies, authors of one review [Cryer and Bauer, 2002] suggested that the reason for more frequent upper gastrointestinal (GI) tract symptoms may be a higher incidence of pre-existing upper GI tract complaints, and it may not have causal relationship to therapy. Pooled meta-analysis of various randomized BP trials [MacLean et al. 2008] reported several types of GI events after oral BP use: nausea, vomiting, acid reflux, heartburn, esophageal irritation, ulcerations, perforations, or bleeding episodes. Apart from upper GI tract irritation or swallowing problems due to different causes (Parkinson’s disease, stroke etc.), other reasons for reduced compliance could be memory difficulties, cognitive impairment, patient’s inability to detect symptom improvement in an asymptomatic disease, and lack of motivation [Cramer et al. 2007].

Compliance improvement

A recent review [Silverman et al. 2011b] analyzed the problem of noncompliance with oral osteoporosis medications. They found that patient preferences played a more important role than forgetfulness. A questionnaire to determine the preferred therapy by patients was used at the end of a 24-month long trial which compared efficacy and safety of annual IV infusions of zoledronic acid with weekly oral alendronate [Orwoll et al. 2010]. Among the 275 participants who responded to the questionnaire, 204 participants (74.2%) preferred once-yearly IV infusion of zoledronic acid 5 mg, 42 participants (15.3%) preferred weekly oral alendronate 70 mg, and 29 participants (10.5%) had no preference.

In a review on adherence interventions [Gleeson et al. 2009] only seven randomized trials could be identified; none of them were double blind and only one included fracture outcomes. In a recent, blinded randomized controlled trial, investigators followed 879 persons (6.6% men) as part of a motivational interviewing study [Solomon et al. 2012]. After 1 year of intervention, no statistically significant improvement in adherence to an osteoporosis medication regimen was found. To achieve good compliance and persistence, it is critical to understand not only patients’ medical needs but also what factors influence their decisions (e.g. concerns about dosing or costs) [Cramer et al. 2007]. Various strategies can help to improve compliance and persistence with treatment [Papaioannou et al. 2007]. Reducing drug administration frequency (from daily to weekly or monthly) or mode of delivery (from oral to IV) is one possibility. Owing to its once-yearly administration as an IV infusion, zoledronic acid improves BP therapy compliance and long-term persistence [Rietbrock et al. 2009].

Side effects and safety issues

Adverse drug effects

A total of 12 trials that include study safety data have been published on men receiving zoledronic acid either for osteoporosis or because of high risk for developing bone loss (e.g. ADT for nonmetastatic prostate cancer). The adverse drug effects (ADEs) from these trials are listed in Table 4 and a detailed description follows. Important aspects of BP treatment and safety issues are summarized in recent reviews [Khosla et al. 2012; McClung et al. 2013].

Table 4.

Incidence of adverse drug events in trials of male subjects receiving zoledronic acid (listed in reverse chronological order) [modified from Piper and Gruntmanis, 2009]

	Boonen (2012)		Sambrook (2012)		Boonen (2011)		Orwoll (2010)		Wadhwa (2010)	Bhoopalam (2009)		Reid (2009)		Ryan (2007)		Lyles (2007)		Brown (2007)	Ryan (2006)		Smith (2003)
	ZA	P	ZA	RI	ZA	P	ZA	AL	ZA	ZA	P	ZA	RI	ZA	P	ZA	P	ZA	ZA	P	ZA	P
	n=588	n=611	n=131	n=134	n=244	n=261	n=153	n=148	n=58	n=48	n=45	n=416	n=417	n=22	n=20	n=1054	n=1057	n=66	n=61	n=59	n=55	n=51
Any ADE	91%	76%	80%	66%	83%	81%	88%	91%				77%	67%			82%	81%
Any serious ADE	25%	25%	20%	21%	43%	46%	18%	21%				18%	18%	0%	5%	38%	41%	0%	21%	31%	24%	39%
Death	3%	3%	2%	1%	13%	20%	1%	1%		0%	2%	1%	1%	14%	0%	10%	13%	0%			2%	0%
D/C due to ADE	2%	2%	3%	1%	3%	2%	4%	8%		4%	0%	2%	1%			2%	2%	0%	2%	2%	4%	6%
AKI	2%	3%			7%	8%	5%	1%	0%	0%	9%	2%	1%			6%	6%	0%	0%	0%	0%	0%
Myalgias	22%	4%	6%	4%	3%	0%	17%	3%				9%	3%			3%	1%		5%	7%
Flu-like illnessa			8%	1%	1%	0%	9%	2%	9%	6%	2%	6%	1%			1%	0%	63%
Headache	14%	4%			1%	1%	10%	2%				6%	2%			2%	1%	<5%
Arthralgia	21%	11%	8%	10%	4%	2%	11%	1%		12%	9%	10%	7%	53%	38%	3%	2%	<5%	13%	10%	22%	14%
Pyrexia	24%	4%	12%	5%	9%	1%	16%	1%				13%	4%	11%	13%	7%	1%		12%	3%
Atrial fibrillation	1%	1%			3%	2%	3%	2%				1%	0%			3%	3%
Stroke					6%	7%	1%	1%								4%	4%
Ocular ADEb							3%	2%				1%	1%			0%	0%
Jaw osteonecrosis	0%	0%					0%	0%	3%	0%	0%		0%	0%		0%	0%	0%	0%	0%
Hypocalcemia							1%	0%		2%	0%	0%	0%			0%	0%

Abbreviations: AL, alendronate; ADE, adverse drug effect; AKI, acute kidney injury; D/C, discontinuation; n, number of subjects; P, placebo; RI, risedronate; ZA, zoledronic acid

^aThe interval in which flu-like illness develops after zoledronic acid infusion is only rarely given in these studies. When specified, an interval ≤3 days was used.

^bOcular ADE include iritis, uveitis, episcleritis, and/or conjunctivitis

Acute-phase reaction

Some of the more common ADEs after infusion of zoledronic acid include the development of fever, musculoskeletal pain, GI symptoms, eye inflammation, and other symptoms (including fatigue and influenza-like symptoms) [Reid et al. 2010]. The symptoms generally occur within 3 days of drug infusion and their incidence varies widely across studies (see Table 4). This acute-phase reaction is thought to be mediated by BP-induced release of inflammatory cytokines; to date, tumor necrosis factor alpha and interleukin 6 have been implicated [Dicuonzo et al. 2003]. The reaction is much less likely to occur on successive administrations of zoledronic acid [Black et al. 2007] and the use of acetaminophen four times daily for 3 days following zoledronic acid infusion has been shown to significantly reduce its incidence and severity [Silverman et al. 2011a].

Renal toxicity

Patients with pre-existing renal compromise, advanced age, concurrent diuretic therapy or on other nephrotoxic medications, and with severe dehydration are at higher risk of nephrotoxicity from zoledronic acid [Novartis, 2011]. In human studies, the toxicity associated with zoledronic acid use appears to be associated mostly with tubular injury, resulting in a toxic form of acute tubular necrosis [Perazella and Markowitz, 2008]. The nephrotoxicity from zoledronic acid is greatest shortly after infusion. In a group of 31 patients who developed deteriorating renal function from annual zoledronic acid infusion, an increase of serum creatinine >0.5 mg/100 ml occurred predominantly 9–11 days after treatment [Boonen et al. 2008]. This highlights the need for early reassessment of renal function in those patients thought to be at higher risk of nephropathy. However, all of the patients in the Boonen and colleagues study experienced recovery of their pre-infusion serum creatinine level within 12 months [Boonen et al. 2008]. Of note, renal injury is more likely when an infusion is given quickly; it is recommended that zoledronic acid be infused over a 15-minute period to reduce the risk of renal injury [Berenson and Hirschberg, 2004]. A longer infusion rate (i.e. 30 minutes) has been used for patients with more compromised renal function based on clinic experience [Miller, 2011].

When administered appropriately, the risk of nephrotoxicity after infusion of zoledronic acid is low, ranging from 0–9% across studies (see Table 4). In the largest study to date of male patients receiving zoledronic acid, there was no difference in the percentage of patients experiencing renal injury after receiving zoledronic acid versus placebo [Lyles et al. 2007]. Nevertheless, an evaluation of renal function (i.e. serum creatinine assessment) should be performed before a zoledronic acid infusion. According to the package insert for zoledronic acid, the drug is contraindicated in patients with creatinine clearance (CrCl) <35 ml/min (in 5 mg dosage), CrCl <30 ml/min (in 4 mg dosage), and/or with evidence of acute renal impairment. Dose adjustment for patients with reduced renal function (CrCl <60 ml/min) is possible.

Osteonecrosis of the jaw

BP use has been associated with an increased incidence of osteonecrosis of the jaw (ONJ). BP-induced ONJ is defined as an area of exposed bone in the maxillofacial region that does not heal within 8 weeks of identification by a healthcare provider, in a patient who currently receives or has been exposed to a BP and has not had radiation therapy to the craniofacial region [Khosla et al. 2007]. Other factors that increase the risk for ONJ include cancer and anticancer therapy, dental extraction or intraoral trauma, glucocorticoid use, alcohol and/or tobacco use, and pre-existing dental or periodontal disease [Khosla et al. 2007]. A proposed mechanism for the development of ONJ is as follows. BPs reduce bone remodeling and turnover through an osteoclast-inhibiting effect; if the mineral matrix is not reabsorbed by osteoclasts, the osteon becomes acellular and necrotic, the bony capillaries involute, and the bone becomes avascular [Marx et al. 2005]. The jaw may be at greater risk for osteonecrosis because it has a greater blood supply than other bones and a faster turnover rate because of daily activity, so BPs are concentrated in the jaw; after minor injury or surgery, the exposed bone then fails to heal [Marx et al. 2005].

The risk of ONJ is related to both the potency and duration of BP therapy. Since patients with solid tumors are dosed with zoledronic acid more frequently than patients with osteoporosis, the incidence of ONJ in the former group is as high as 1–10% [Khosla et al. 2007]. ONJ is extremely rare in male patients with osteoporosis. In the 12 studies reported in Table 4, only 2 men developed ONJ: both had received zoledronic acid 4 mg IV every 3 months for concurrent nonmetastatic prostate cancer. In a clinically diverse group of nearly 6000 patients with osteopenia or osteoporosis who received zoledronic acid 5 mg yearly (comprising 5 clinical trials), the incidence of ONJ was less than 1 in 14,200 patient treatment years [Grbic et al. 2010]. It is important to note that the incidence of ONJ may be underreported in clinical trials due to the short follow-up period. Owing to the long half-life of BPs, ONJ can occur months to years following drug administration [Woo et al. 2006]. For this reason, it is important that patients receiving zoledronic acid for osteoporosis be encouraged to maintain good oral hygiene and regular dental visits.

Atrial fibrillation

In the HORIZON-PFT, patients receiving annual zoledronic acid were found to have a significant increase in the incidence of serious atrial fibrillation (AF) versus those receiving placebo (1.3% and 0.5%, respectively) [Black et al. 2007]. The vast majority of patients who experienced AF developed symptoms more than 30 days after infusion of zoledronic acid, when zoledronic acid is no longer detectable in the circulation; changes in serum calcium levels following zoledronic acid administration that might have contributed to AF did not explain the association. A few mechanisms have been proposed as to how BPs might increase the risk of atrial arrhythmias, including changes in intracellular ion concentrations and well as proinflammatory, profibrotic, and antiangiogenic effects [Pazianas et al. 2010].

However, subsequent studies looking at a correlation between BP therapy and AF have given conflicting results. A higher risk of incident AF was found in a group of women taking alendronate versus those not taking alendronate after adjusting for matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease [Heckbert et al. 2008]. However, a recent review showed no significant difference in the development of AF in users of zoledronic acid, risedronate, or alendronate [John Camm, 2010]. Also, a large meta-analysis of 7 studies with 266,761 subjects showed that BP exposure was not associated with an increased risk of AF [Kim et al. 2010]. Specifically pertaining to zoledronic acid, other trials randomizing male subjects to zoledronic acid or placebo showed no significant difference in the incidence of AF between groups [Boonen et al. 2011; Lyles et al. 2007]. In November 2008, the US Food and Drug Administration (FDA) stated that no clear association between overall BP exposure and the rate of serious or non-serious atrial fibrillation was observed and that healthcare professionals should not alter their prescribing patterns for BPs [FDA, 2007].

Atypical fractures

In recent years, a distinctive type of femoral fracture has been described in association with BP use, including zoledronic acid. These so-called atypical femoral fractures share five distinctive features: location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution [Shane et al. 2010]. Prodromal symptoms such as groin or thigh pain are common, and the radiographic appearance prior to fracture often includes a periosteal reaction, indicative of a stress fracture [Shane et al. 2010]. A proposed mechanism is that BPs impair the repair process of bone, allowing fatigue cracks to propagate until the moment of fracture [Neer, 1995].

The occurrence of atypical femoral fracture in patients receiving zoledronic acid is limited to a small number of case reports [Abrahamsen, 2012]. A secondary analysis of three large BP trials (including HORIZON-PFT) showed a low rate of atypical femoral fractures (2.3 per 10,000 patient-years), although the study was underpowered for definitive conclusions [Black et al. 2010]. The incidence of atypical femoral fracture has been reported as 1.78 per 100,000 patient-years for BP exposure of less than 2 years but 113.1 per 100,000 patient-years for BP exposure from 8 to 9 years [Dell et al. 2012]. In a large population-based study of woman aged 68 years or older treated with a BPs for 5 years, only 0.22% developed an atypical fracture with two additional years of therapy [Park-Wyllie, 2011].

After discontinuation of BP therapy, the risk of atypical femoral fracture has been shown to decline by 70% yearly [Schilcher et al. 2011]. While atypical femoral fractures have shown an association with BP use, the relationship is not definitively causal. Furthermore, the small possible risk of atypical fracture should be taken in the context of the substantial reduction in osteoporotic fracture incidence in patients receiving BPs.

Seizures

Analysis of short clinical case series [Tsourdi et al. 2011] concluded that zoledronic acid was not a primary cause of seizures itself, but its use might be associated with several predisposing factors for seizures. Hypocalcemia lowers the seizure threshold; therefore, sufficient calcium supplementation must be provided before treatment. A febrile episode after zoledronic acid infusion could conceptually increase seizure risk.

Identifying the people to treat with zoledronic acid

We concur with Endocrine Society 2012 guidelines [Watts et al. 2012] on the most appropriate use of zoledronic acid. For most men who are candidates for pharmacological therapy due to increased fracture risk, we would suggest using generic alendronate as there have been extensive experience with its use, there is no evidence that other agents are more effective or better tolerated, and it is available at low cost. There are four subgroups however, in which we would suggest using yearly zoledronic acid infusion as first-line therapy.

First, zoledronic acid is the only medication shown to be effective for secondary prophylaxis of hip fractures, and we recommend using it during the first 90 days after hip fracture, provided that men are calcium and vitamin D replete and there is no other contraindication for treatment with this drug. Second, we recommend zoledronic acid use in men with peptic ulcer disease, gastroesophageal reflux, malabsorption syndromes, cognitive dysfunction of different etiologies, and in men who are simply on too many medications to be able to remember to take oral BPs correctly. Third, the majority of clinical trials in men with nonmetastatic prostate cancer on ADT and its associated bone loss have been done with zoledronic acid. Its use has been associated with increased BMD and fracture reduction in this group of patients. Fourth, many HIV-infected patients are shown to be more noncompliant with oral BP use, and yearly zoledronic acid infusions may be a better osteoporosis treatment alternative. Specific issues on osteoporosis treatment in HIV-infected individuals are discussed in recent guidelines [McComsey et al. 2010].

Summary

Although both the prevalence and costs associated with osteoporosis and osteoporotic fractures are projected to increase, the condition remains underdiagnosed and undertreated in men. Improved treatment of men at increased risk for future fractures could reduce the individual and societal costs of osteoporosis. The screening for osteoporosis and treatment in accordance with recent Endocrine Society guidelines is pivotal for preventing future fractures.

Zoledronic acid is a potent nitrogen-containing BP administered intravenously on a yearly basis for the treatment of male osteoporosis. It is safe and effective for reducing fracture risk. Zoledronic acid is particularly advantageous in patients who do not tolerate or adhere to oral BPs (e.g., those with cognitive dysfunction, polypharmacy, inability to remain upright or gastrointestinal pathology). In addition, zoledronic acid therapy is indicated in men who have experienced a hip fracture and men with increased fracture risk in the setting of ADT.