485829 TAB5410.1177/1759720X13485829Therapeutic Advances in Musculoskeletal DiseaseI Ruza, S Mirfakhraee
`
`2013
`
`Review
`Therapeutic Advances in Musculoskeletal Disease
`~ - - - - - - - - - - - - - - - -
`
`Ther Adv Musculoskel Dis
`
`(2013) 5(4) 182 –198
`
`DOI: 10.1177/
`1759720X13485829
`
`© The Author(s), 2013.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Clinical experience with intravenous
`zoledronic acid in the treatment of male
`osteoporosis: evidence and opinions
`
`Ieva Ruza, Sasan Mirfakhraee, Eric Orwoll and Ugis Gruntmanis
`
`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.
`
`Keywords: bisphosphonates, bone mineral density, fracture, men, osteoporosis, zoledronic acid
`
`Correspondence to:
`Ugis Gruntmanis, MD
`Department of Internal
`Medicine, Division of
`Endocrinology, University
`of Texas Southwestern
`Medical Center and Dallas
`Veterans Affairs
`Medical Center, 5323
`Harry Hines Boulevard,
`Y5 332, Dallas, TX
`75390-8857, USA
`ugis.gruntmanis@
`utsouthwestern.edu
`Ieva Ruza, MD
`Department of Internal
`Medicine, Division of
`Endocrinology, Riga
`East Clinical University
`Hospital, Riga, Latvia
`Sasan Mirfakhraee, MD
`Department of Internal
`Medicine, Division of
`Endocrinology, University
`of Texas Southwestern
`Medical Center, Dallas,
`TX, USA
`Eric Orwoll, MD
`Bone and Mineral Unit
`Oregon Health and Science
`University, Portland, OR,
`USA
`
`Introduction
`Osteoporosis is a systemic skeletal disorder char-
`acterized by low bone mass and microarchitec-
`tural deterioration of bone
`tissue, with a
`consequent increase in bone fragility and suscep-
`tibility 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 osteopo-
`rosis or low bone mass in 2002; that figure is pro-
`jected 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 dispropor-
`tionate increase in the older male population
`[Werner, 2011]. The costs associated with osteo-
`porosis are expected to rise as the population
`ages. In fact, the economic burden from osteopo-
`rosis-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 per-
`formed 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
`
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` I Ruza, S Mirfakhraee et al.
`
`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 treat-
`ment 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, sig-
`nificantly 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 pub-
`lished trials and men recruited in them is much
`smaller than in women. Despite less clinical
`experience with the use of BPs in men, the ben-
`efits 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 absorptiom-
`etry (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 pre-
`dictive 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 inde-
`pendent 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 frac-
`tures and falls, history of hypogonadism, stroke
`and diabetes had statistically significant associa-
`tions 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 epide-
`miological studies of various population cohorts,
`the World Health Organization (WHO) devel-
`oped 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 guide-
`lines should be used. Osteoporosis treatment is
`also recommended in men who are receiving
`long-term glucocorticoid therapy in pharmaco-
`logical 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 reduc-
`tion in fracture risk and associated morbidity and
`mortality. Owing to the asymptomatic nature of
`osteoporosis, patients do not request and physi-
`cians 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 exer-
`cise, 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 signifi-
`cantly reduced risk of hip fracture and any non-
`vertebral fracture risk in people 65 and older
`[Bischoff-Ferrari et  al. 2012]. Drugs for the
`treatment of osteoporosis can be classified into
`
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`Therapeutic Advances in Musculoskeletal Disease 5 (4)
`
`antiresorptive, anabolic, or dual-action agents.
`Antiresorptive agents, or drugs that inhibit osteo-
`clast 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 main-
`stay of osteoporosis treatment in both men and
`women. They are synthetic analogs of the endog-
`enous bone mineralization regulator pyrophos-
`phate. 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 cal-
`cium 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 seal-
`ing 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 apopto-
`sis [Hughes et al. 1995; Green, 2004]. Depending
`on the pattern of amino groups in the side chain,
`each nitrogen-containing BP has different antire-
`sorptive potency. When the ability of BPs to
`inhibit FPPS in vitro is compared, zoledronic acid
`is 3, 17, and 67 times more potent than risedro-
`nate, 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 for-
`mulation. 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 compli-
`ance with BP therapy and will be discussed later in
`the article. In certain clinical situations, intrave-
`nous (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 infu-
`sion every 3 months, or once a year, has been
`studied in men with nonmetastatic prostate can-
`cer 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 sec-
`onds 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
`
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`

` I Ruza, S Mirfakhraee et al.
`
`reduction; Vert, vertebral; NonV, nonvertebral; TotH, total hip; FemN, femoral neck; LumbS, lumbar spine; BMD, bone mineral density
`FU, follow up; PU, prospective, unrandomized trial; RCT, prospective, randomized controlled trial; ZA, zoledronic acid; N, number; mo, months; Avg, average; RRR, relative risk
`
`BMD change from baseline (%)
`
`Fracture RRR
`
`Avg age
`
`Men
`
`FU (mo)
`
`Total N
`
`Study design
`
`Table 1. Studies with zoledronic acid for the treatment of osteoporosis in men (modified from Piper and Gruntmanis [2009]).
`
`(NTx); it indirectly decreases serum bone alka-
`line phosphatase. Various aspects of the detection
`of bone turnover markers in men are discussed in
`a recent review [Szulc, 2011]. Annual IV zole-
`dronic 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 signifi-
`cantly more than the alendronate group. The
`decrease of bone resorption and formation mark-
`ers 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 zole-
`dronic 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 post-
`menopausal 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 recommen-
`dations 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 strate-
`gies 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 pop-
`ulation was mixed, we extracted data relating to
`men only.
`
`Placebo-controlled trials with zoledronic acid
`The clinical efficacy of zoledronic acid in men
`in the secondary prevention of osteoporotic frac-
`tures was evaluated in the HORIZON-RFT trial
`[Lyles et al. 2007]; 24% (508) of the 2126 sub-
`jects were men aged 50 and over. Participants
`
`
`
`Reference
`
`7.7%
`
`
`
`3.5%
`4.8%
`6.3%
`
`
`
`
`
`3.4%
`3.8%
`
`NS
`4.3%
`
`LumbS
`
`FemN
`
`2.3%
`
`3.4%
`4.3%
`4.6%
`5.5%
`6.4%
`
`TotH
`
`67%
`
`27%
`
`NonV
`
`46%
`
`Vert
`
`35%
`
`Any
`
`65.8
`
`42
`49.1
`69.8
`74.5
`
`100%
`100%
`100%
`100%
`100%
` 78%
` 24%
`
`24
`24
`48
`36
`24
`12
`36
`
`1199
`505
`35
`66
`43
`27
`2126
`
`RCT
`RCT
`RCT-Ext
`PU
`RCT
`RCT
`RCT
`
`Boonen et al. [2012]
`Boonen et al. [2011]
`Bolland et al. [2012]
`Brown et al. [2007]
`Bolland et al. [2007]
`Poole et al. [2007]
`HORIZON-RFT – Lyles et al. [2007]
`
`http://tab.sagepub.com
`
`185
`
`

`

`Therapeutic Advances in Musculoskeletal Disease 5 (4)
`
`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 signifi-
`cant increase in BMD from baseline at total hip
`and femoral neck and a decrease in any new frac-
`ture 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 ana-
`lyzed 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 percent-
`age change from baseline in femoral neck BMD at
`24 months was significantly higher with zoledronic
`acid (3.8%) than with placebo. New clinical frac-
`tures 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 oste-
`oporosis due to hypogonadism; 32.1% of the par-
`ticipants 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] con-
`cluded 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 phar-
`macological 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 sur-
`gical 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 dos-
`ing [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 tri-
`als 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 syn-
`ergic 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 hor-
`mone-releasing hormone agonists (LHRHAs).
`However, 1 year after the last infusion of zole-
`dronic 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 zole-
`dronic acid and other BPs used for the preven-
`tion 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 inter-
`vals between zoledronic acid infusions compar-
`ison between studies are difficult.
`
`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 zole-
`dronic 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.
`
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`

`

` I Ruza, S Mirfakhraee et al.
`
`AL, alendronate; Co, comparator; GIO, glucocorticoid-induced osteoporosis; HG, hypogonadism; Pr, primary; Prev, prevention; RI, risedronate; Th, therapy; ZA, zoledronic acid
`
` 3.3%
`−0.2%
`
`
`
`
`
` 6.2%
`
` 0.2%4.7%
`−0.4%2.5%
`4.1%
`..
`2.6%
`..
`6.1%
`
`1.8%
`1.1%
`..
`..
`
`Co
`
`ZA
`
`Co
`
`ZA
`
`Lumbar spine
`
`Total hip
`
`56.4
`56.4
`
`100%
`100%
`31.8%
`31.8%
`100%
`
`12
`12
`12
`12
`24
`
`177
` 88
`545 (272)
`288 (144)
`302 (154)
`
`RCT
`RCT
`RCT
`RCT
`RCT
`
`GIO (Th)
`GIO (Prev)
`GIO (Th)
`GIO (Prev)
`Pr/HG
`
`RI
`RI
`RI
`RI
`AL
`
`Sambrook et al. [2012]
`Sambrook et al. [2012]
`HORIZON – Reid et al. [2009]
`HORIZON – Reid et al. [2009]
`Orwoll et al. [2010]
`
`
`
`
`
`Avg ageBMD change from baseline (%)
`
`FU (mo)Men
`
`Total N (ZA incl)
`
`Type of OPStudy design
`
`ZA versus
`
`Reference
`
`Gruntmanis [2009]).
`Table 3. Studies with zoledronic acid for the treatment of osteoporosis in men: comparison of zoledronic acid with other bisphosphonates (modified from Piper and
`
`LumbS, lumbar spine; BMD, bone mineral density
`ADT, androgen deprivation therapy; FU, follow up; RCT, prospective, randomized controlled trial; ZA, zoledronic acid; N, number; mo, months; Avg, average; FemN, femoral neck;
`
`7.93%
`2.2% / 5.4%
`4.17%
`5.95% / 6.08%
`
`
`
`6.7%
`7.1%
`7.1%
`6.7%
`7.8%
`
`LumbS
`
`5.53%
`2.8% / 3.8%
`3.23% / 3.35%
`
`2.27%
`1.8% / 3.9%
`3.55% / 2.36%
`
`5.1%
`
`4.2%
`2.1%
`3.6%
`3.3%
`
`FemN
`
`1.1%
`3.7%
`
`2.6%
`3.8%
`3.9%
`
`Hip
`
`74.7
`77
`73
`
`70.5
`
`65
`65.5
`72
`70.7
`
`4
`
`4 (2nd year)
`
`4
`
`4
`
`1
`
`4
`
`4
`
`1
`
`4
`
`4
`
`12
`36
`12
`12
`12
`12
`12
`12
`12
`12
`
` 42
` 58
` 28
` 93
` 40
`215
` 42
` 40
`120
`106
`
`RCT
`RCT
`RCT
`RCT
`RCT
`RCT
`RCT
`RCT
`RCT
`RCT
`
`BMD change from baseline (%)
`
`Avg age
`
`N of ZA infusions
`
`FU (mo)
`
`N
`
`Study design
`
`Kapoor et al. [2011]
`Wadhwa et al. [2010]
`Campbell et al. [2010]
`Bhoopalam et al. [2009]
`Satoh et al. [2009]
`Israeli et al. [2007]
`Ryan et al. [2007]
`Michaelson et al. [2007]
`Ryan et al. [2006]
`Smith et al. [2003]
`
`
`
`Reference
`
`Table 2. Trials in prostate cancer with ADT (modified from Piper and Gruntmanis [2009]).
`
`http://tab.sagepub.com
`
`187
`
`

`

`Therapeutic Advances in Musculoskeletal Disease 5 (4)
`
`The efficacy and safety of once-yearly IV infu-
`sions 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 zole-
`dronic acid groups (6.2% versus 6.1%, respec-
`tively). 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 risedro-
`nate 5 mg in the prevention and treatment of glu-
`cocorticoid-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 partici-
`pants 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, tro-
`chanter, 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 treat-
`ment 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 com-
`pared with daily risedronate 5 mg, there was a sig-
`nificantly greater increase in BMD from baseline
`at the lumbar spine (4.7% versus 3.3% in treat-
`ment group and 2.5% versus −0.2% in prevention
`group) and total hip (1.8% versus 0.2% in treat-
`ment 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 risedro-
`nate in increasing lumbar spine BMD in the pre-
`vention 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 ther-
`apy. Yearly IV infusions of zoledronic acid
`could serve as a good and safe alternative and
`improve the noncompliance and nonpersis-
`tence 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 prac-
`tice. However, trial participants often are better
`motivated and educated, have less comorbidities,
`are followed more closely, and adherence is regu-
`larly 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 ther-
`apy 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 effective-
`ness of restarting BPs after such extended gaps in
`treatment.
`
`188
`
`http://tab.sagepub.com
`
`

`

` I Ruza, S Mirfakhraee et al.
`
`The costs of BP noncompliance are high. Patients
`who are less than 66% compliant with osteoporo-
`sis medications have significantly less of an
`increase in BMD [Yood et al. 2003]. In an analy-
`sis of insurance claims databases involving 35,537
`women on BPs, only 43% of women filled at least
`80% of their prescriptions. The medication-com-
`pliant women had 37% fewer hip fractures at 24
`months [Siris et  al. 2006]. Modeling, based on
`actual clinical practice of 44,531 patients, includ-
`ing 8367 (18.8%) men, demonstrated that at least
`an additional 68.4 hip fractures per 10,000
`patients would be prevented with yearly BP treat-
`ments (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 reduc-
`tion, overall rate of fractures was reduced by 22%,
`hip fracture rate by 23%, and vertebral fracture
`rate by 26% in individuals who were more com-
`pliant. 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-exist-
`ing 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 swallow-
`ing problems due to different causes (Parkinson’s
`disease, stroke etc.), other reasons for reduced
`compliance could be memory difficulties, cogni-
`tive impairment, patient’s inability to detect
`symptom improvement in an asymptomatic dis-
`ease, and lack of motivation [Cramer et al. 2007].
`
`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 o