Gateway to Clinical Prescription about Zoledronic AcidHeung Yeol Kim

Gateway to Clinical Prescription about Zoledronic Acid

Heung Yeol Kim

Department of Obstetrics & Gynecology, College of Medicine, Kosin University, Busan, Korea

Zoledronic Acid 임상 적용

고신대학교 의과대학 산부인과학교실 김 흥 열

골다공증은 예방이 가능한 질환이지만 적절한 치료를 하지 않을 경우 골밀도 감소, 골격계 기능 저하, 골절에 대한 저항력 감소, 골절의 위험도증가 등으로 인하여 질병의 이환 및 사망이 급격하게 증가한다. 특히 골절은 폐경 후 여 성에서의 신체적 장애를 유발하는 주요한 원인 중의 하나로 보건 의료의 비용을 현저히 증가시킨다.

비스포스포네이트 제제는 골다공증 치료에 가장 흔히 사용되는 약물로써 파골세포의 골 재흡수를 억제하며 골다공 증성 골절의 위험을 감소시키는 것으로 잘 알려져 있다.

일년 일회 졸레드론산 5 mg을 정맥 주사하였을 때 폐경 후 여성에서 모든 부위의 골다공증성 골절의 위험 감소와 골다공증 성 고관절 골절이 있는 환자에서 재골절의 위험 감소, 골밀도와 골형성 표지자의 개선을 보였으며 내약성 또한 우수하였다. 장기적 사용 후 안전성에 대하여 현재의 임상자료와 더불어 기존의 약제들과 차별화할 수 있는 추 가적인 임상 연구가 더 필요하다.

결론적으로 연 1회 졸레드론산 5 mg 정맥 투여는 내약 순응도가 낮은 기존의 경구 약제에 비하여 보다 순응도를 높 인 편리하고 효과적인 치료법이라고 생각된다.

중심단어: 골다공증, 졸레드론산, 치료법

2)

INTRODUCTION

Osteoporosis is a preventable disease associated with substantial morbidity and mortality characterized by loss of bone mineral density, progression to diminished skeletal integrity, extensive bone fragility, and an increased risk of fracture. Fractures are an important cause of disability among postmenopausal women, and the public health costs are substantial.

Received: August 1, 2009, Revised: August 17, 2009 Accepted: August 19, 2009

Corresponding Author : Heung Yeol Kim, Obstetrics & Gynecology, College of Medicine, Kosin University

Tel: +51-990-6226, Fax: +51-990-3300 E-mail: [email protected]

Bisphosphonates, the most commonly used treatment for established osteoporosis, inhibit osteoclast-mediated bone resorption and reduce the risk of vertebral fracture.

Bisphosphonates, alendronate, risedronate, and iban-

dronate are the current first line therapy, have been

shown to reduce nonvertebral and hip fractures in

women with osteoporosis

. However, adherence to

treatment is suboptimal, largely because the treatment

regimen is difficult to follow. Nearly 50% of all

patients receiving weekly alendronate or risedronate

remain on treatment for less than 1 year. Rates of

compliance and persistence also are suboptimal with the

use of once-monthly ibandronate. Poor adherence has

been shown to compromise the effectiveness of treatment against fracture and to increase the costs of medical care

.

Zoledronic acid is a potent bisphosphonate that can be administered intravenously once yearly for the treatment of postmenopausal osteoporosis, assuring compliance and persistence over the 12 months dosing interval.

PHARMACOLOGICAL FEATURES

The high binding affinity and potency of zoledronic acid for bone mineral and unique pharmacological property of bisphosphonate may be responsible for its prolonged duration of action.

The stored drug is not on the bone surface and is not available to inhibit osteoclast activity. However, release of the drugs by continued remodeling would allow

“recycling” of the drug and persistent metabolic effects.

Additionally an important pharmacologic property of bisphosphonate which can make the once yearly dosing possible is that the total dose administered is a major determinant of their effects

.

In two in vivo studies using intravenous bisphos- phonate, the same inhibition of bone resorption has been documented regardless of whether the bisphos- phonate was given in small frequent (e.g., daily) doses compared with larger doses given less frequently. This was the basis for the development of intermittent- dosing regimens in humans

.

Zoledronic acid is a member of the nitrogen containing class of bisphosphonate, and is a potent inhibitor of bone resorption. Like other bisphos- phonates, zoledronic acid binds with high affinity to the calcium phosphate bone mineral hydroxyl apatite, predominantly localizing at regions of high bone turnover. The affinity of zoledronic acid for hydroxy- apatite was higher than that of other bisphosphonates in an in vitro study

(binding affinity constant of 3.47×10

mol/L compared with 2.94, 2.36, 2.19, 1.19 and 0.72×

10

mol/L for alendronic acid, ibandronic acid, rise- dronic acid, etidronic acid and clodronic acid, respec- tively).

Zoledronic acid inhibits farnesyl diphosphate synthase 3-, 7-, 17- and 67-fold more effectively than risedronic acid, ibandronic acid, alendronic acid and pamidronic acid, respectively, according to data from an in vitro study; the respective mean concentrations required to inhibit enzymatic activity by 50% were 0.003, 0.01, 0.02, 0.05 and 0.20μmol/ L. Generally consistent with this finding, the drug inhibits bone resorption in rats with a potency similar to that of ibandronic acid, and 3-, 10- and 300-fold greater than that of risedronic acid, alendronic acid and pamidronic acid, respectively

. Zoledronic acid does not undergo metabolism and is excreted via the kidney unchanged. Elimination of ≈ 39% of an intravenous zoledronic acid dose occurred via the urine within the first 24 hours post-dose in patients with bone metastases, with the rest of the dose (i.e. 61%) presumed to be bound to bone; very little zoledronic acid was detected in the urine after 48 hours. Zoledronic acid that is bound to bone is released back into the circulation very slowly, which may explain why the plasma concentration of the drug is low for a prolonged period ≥24 hours after admini- stration.

Elimination of zoledronic acid occurs via a triphasic process. The first two phases are rapid with elimination half-lives of 0.24 and 1.87 hours, and are followed by a long terminal elimination phase with a terminal elimination half-life of 146 hours.

The renal clearance of zoledronic acid was 3.7 L/

hour during the first 24 hours post-dose, and the total body clearance was ≈5 L/hour, independent of dose, age, gender, bodyweight or race.

The clearance of zoledronic acid is dependent on

creatinine clearance (CLCR). However, no significant

changes in exposure to zoledronic acid were seen in

patients with cancer who had mild (CLCR 50～80

mL/min [3.0～4.8 L/h]) to moderate (CLCR 10～50

mL/min [0.6～3.0 L/h]) renal impairment relative to patients with normal renal function. Thus, dosage adjust- ment is not required in patients with mildly or mode- rately impaired renal function; however, the drug is not recommended for use in patients with severe renal impairment (CLCR <35 mL/min [<2.1 L/h]) because of limited clinical experience in such patients (section 6).

No pharmacokinetic data are available in patients with hepatic impairment, and dosage adjustments are not required for this patient population in the EU. Zole- dronic acid did not inhibit the in vitro activity of cytochrome P450 enzymes. Although in vivo drug interaction data for zoledronic acid are not available, caution is recommended when zoledronic acid is administered concomitantly with drugs that may signifi- cantly affect renal function, such as diuretics, amino- glycosides or nephrotoxic agents

.

CLINICAL EFFICACY

Black et al. investigated the efficacy of once yearly intravenous infusions of zoledronic acid, 5 mg, in postmenopausal osteoporosis. This double-blind, placebo- controlled trial

(Health Outcomes and Reduced Inci- dence with Zoledronic Acid Once Yearly Pivotal Fracture Trial: HORIZON PFT) enrolled 7765 women who were followed for 3 years.

A treatment window of 90 days was used for the administration of repeat infusions. Compared with placebo, zoledronic acid treatment significantly reduced the relative risk of morphometric vertebral fracture by 70% (3.3% vs. 10.9%, absolute risk reduction [ARR]=

7.6%; P<0.001) and hip fracture by 41% (1.4% vs.

2.5%, ARR=1.1%; P=0.002). Zoledronic acid also significantly reduced the incidence of clinical vertebral fractures by 77% (0.5% vs. 2.6%, ARR=2.1%), non- vertebral fractures by 25% (8.0% vs. 10.7%, ARR=

2.7%), and all clinical fractures by 33% (8.4% vs.

12.8%, ARR=4.4%; P<0.001 for all comparisons;

clinical nonvertebral fractures were comprised of hip,

wrist, arm, rib, and “other” fractures, with the latter category excluding clinical vertebral, hip, wrist, arm, rib, finger, toe, and facial bone fractures).

The mean serum levels of the bone resorption marker β-C-telopeptide of type I collagen (β-CTX) and the bone formation markers N-terminal propeptide of type I collagen (P1NP) and alkaline phosphatase (ALP) were 59%, 58% and 30% lower than in placebo recipients 12 months after initial study drug administration However, mean levels of the markers did not progressively decline with repeated administration of zoledronic acid during the 3-year study, but were generally similar 6 and 12 months after each yearly infusion of the drug, remaining within the premenopausal reference range.

In addition, BMD was increased significantly at the total hip (6.02%), lumbar spine (6.71%), and femoral neck (5.06%) in the zoledronic acid versus the placebo group (P<0.001 for all comparisons). With respect to persistence with the administration regimen, 7714 patients received at least one infusion, and 81% of this group (6260/7714) received the maximum of three infusions. Retention rates were comparable for the two arms of the trial, with 2.1% of patients (80/3875) in the zoledronic acid group discontinuing treatment due to adverse events, compared with 1.8% (70/3861) of the placebo group.

Zoledronic acid has also been studied in osteoporosis patients with a history of hip fractures

. Men and women aged older than 50 years who had suffered an osteoporotic hip fracture within the previous 90 days were randomized into the HORIZON-Recurrent Fracture Trial (HORIZON-RFT). Patients received once-yearly intravenous infusions of zoledronic acid, 5 mg, (n=

1065) or placebo (n=1062) and were followed until at least 211 new clinical fractures were confirmed (the primary efficacy endpoint); the median follow-up time was 1.9 years. Compared with placebo, the zoledronic acid group had a significantly reduced relative risk of clinical fractures (35%; 8.6% vs. 13.9%, ARR=5.3%; P

=0.001), clinical vertebral fractures (46%; 1.7% vs. 3.8%,

ARR=2.1%; P=0.02), and nonvertebral fractures (27%;

7.6% vs. 10.7%, ARR=3.1%; P=0.03; fracture defini- tions were consistent with those for HORIZON-PFT).

BMD at the total hip increased in the zoledronic acid group by 2.6%, 4.7%, and 5.5% at 12, 24, and 36 months, respectively, over 3 years, compared with decreases in the placebo group of 1.0%, 0.7%, and 0.9% at the corresponding time points. Femoral neck BMD increased in the zoledronic acid group by 0.8%, 2.2%, and 3.6% at 12, 24, and 36 months, respectively, compared with declines of 1.7%, 2.1%, and 0.7% in the placebo group at corresponding time points. All increases in total hip and femoral neck BMD were statistically significantly compared with placebo (P<

0.001). Patients receiving zoledronic acid also had a 28% lower risk of death than did those receiving placebo infusions, the first time such a mortality benefit has been reported for an antiresorptive drug.

In another study, McClung et al. reported that postmenopausal women with low BMD who were previously treated with alendronate may be directly switched to zoledronic acid with maintenance of therapeutic effect

. In this 1year, double-blind, multi- center trial, women with low BMD who had been receiving alendronate for at least 1 year were randomized to a single infusion of zoledronic acid followed by 52 weeks of oral placebo (n=113) or a placebo infusion and 52 weeks of oral alendronate (n=

112). Mean levels of markers of bone resorption (urine N-telopeptide of type I collagen, serum C-telopeptide of type I collagen) and bone formation (serum amino terminal propeptide of type I collagen, serum bone- specific alkaline phosphatase) remained constant in alendronate patients. In the zoledronic acid group, the biomarkers fell during the first 3 months, returned to baseline at month 6, and then increased to levels that were significantly above baseline but within the pre- menopausal reference range from month 6 to month 12.

The switch from weekly alendronate to zoledronic acid infusion was generally well tolerated. An in-study

patient preference survey also found that 78.7% of patients favored an annual infusion over weekly oral therapy.

SAFETY AND TOLERABILITY

Overall, once-yearly zoledronic acid, 5 mg, had a favorable safety profile and was generally well tolerated in multiple randomized clinical trials, consistent with other agents in its class.

1. Post dose symptoms

The incidence of post-dose symptoms occurring within the first three days after administration of zoledronic acid (Aclasta

) can be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta administration.

Bisphosphonates have been associated with side effects caused by accumulation of mevalonate pathway metabolites leading to increased liberation of pro- inflammatory cytokines from gamma-delta T-lympho- cytes

. These adverse drug reactions include a wide variety of symptoms: fever, myalgia, headache, and arthralgia commonly covered by the term “post-dose-”

or “flu-like-” symptoms. The incidence of these symp- toms decreases markedly after the first infusion, and they are not associated with organ damage. Most of these symptoms occurred within the first 3 days after infusion and resolved within 3 days of onset, but resolution could take up to 7 to 14 days. The incidence of these symptoms decreased with subsequent annual infusions.

Such post-dose symptoms are well known with intravenous bisphosphonate therapy and are easily managed with acetaminophen or ibuprofen

.

2. Osteonecrosis of the jaw

ONJ has been reported predominantly in patients

with cancer receiving treatment regimens including

bisphosphonates

. Many of these patients were also

receiving chemotherapy and corticosteroids. For other patient populations, there is currently not enough evidence to establish a causal relationship.

In HORIZON- PFT Study, there was no increase in the risk of osteonecrosis of the jaw (ONJ) and there were no spontaneous reports of ONJ. One patient in the zoledronic acid 5 mg group met the predefined criteria for ONJ, and one patient in the placebo group had a possible case of ONJ (incidence of 0.3% in both groups). In both cases, delayed healing of many months duration following surgical manipulation in either the mandible or maxilla was clearly documented

.

An independent adjudication committee that was blinded to study treatment then reviewed all identified events. Possible ONJ cases were defined as exposed bone in the maxillofacial area with delayed healing for greater than 6 weeks despite appropriate care. Two potential cases of ONJ were identified, one in the placebo arm and one in the zoledronic acid group; each of these resolved with antibiotic treatment and debridement. These findings are consistent with previous research and clinical experience, which confirm that the incidence of ONJ in osteoporosis patients is low (an estimated prevalence of <1 in 100,000 patients) and that the benefits of bisphosphonate therapy in preventing fracture outweigh the risk of ONJ

.

In general, a routine oral examination should be performed by the prescribing physician before initiation of bisphosphonate treatment. In addition, a dental examination with appropriate preventive dentistry should be considered before treatment in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids, poor oral hygiene).

3. Renal effects

Bisphosphonates are excreted by the kidney and are known to have the potential to affect renal function, especially when given intravenously and administered as a bolus.

However, no long-term effects of zoledronic acid on

renal function had been observed among patients in HORIZON-PFT or HORIZON-RFT

.

In HORIZON-PFT, there was a transient increase in serum creatinine of more than 0.5 mg/dL in 1.2% of zoledronic acid–treated patients, compared with 0.4% of placebo patients (P<0.001) ; within 30 days, the levels in more than 85% of patients had returned to within 0.5 mg/dL of preinfusion values, and the remainder had returned to this level by the next annual follow-up

. After reviewing of the data from HORIZON PFT study, experts said the effects of zoledronic acid on renal function are marginal and transient

Comparable results were reported in HORIZON-RFT;

the incidence of serum creatinine elevations greater than 0.5 mg/dL did not differ between the zoledronic acid and placebo groups (6.2% and 5.6%, respectively;

P=not significant)

.

Patients should be appropriately hydrated before administration of zoledronic acid, and the drug should be used with caution with nephrotoxic agents. Transient increases in serum creatinine may be greater in patients with impaired renal function; thus, zoledronic acid is not recommended for use in patients with creatinine clearance less than 35 mL/min. In addition, the drug should not be infused over a period less than 15 minutes

.

4. Others

In HORIZON-PFT, adjudicated serious adverse events

of atrial fibrillation (AF) occurred in 1.3% of patients in

the zoledronic acid treatment group (50 of 3862),

compared with 0.5% (20 of 3852) in the placebo group

.

The overall incidence of all AF adverse events was

2.4% of patients (94 of 3862) in the zoledronic acid

group, compared with 1.9% of patients (73 of 3852) in

the placebo group. In an electrocardiogram substudy,

there was no difference in the incidence of AF between

treatment groups, suggesting these events were not

related to the acute infusions. Similarly, the HORIZON-

RFT trial did not find an imbalance in the incidence of

AF events: the overall rate of AF was nearly identical for the two treatment groups (29 [2.8%] and 27 [2.6%]

cases for zoledronic acid and placebo patients, respectively)

. Although the imbalance in atrial fibri- llation SAEs between the zoledronic acid and placebo groups was observed in HORIZON PFT study, the overall incidence of atrial fibrillation AEs is com- parable between the two treatment groups and also there was lack of temporal relationship of atrial fibrillation with zoledronic acid 5 mg infusion as the vast majority of these events occurred more than 30 days after study drug infusion when zoledronic acid is expected to be cleared from systemic circulation

.

CONCLUSION

Compared with other bisphosphonates, zoledronic acid has the highest affinity for bone mineral and appears to be the most potent inhibitor of farnesyl diphosphate synthase. This may explain the marked inhibition of bone resorption it produces and its prolonged duration of action in patients with post- menopausal osteoporosis

.

Intravenous zoledronic acid 5 mg once yearly was effective over a 3-year treatment period in patients with postmenopausal osteoporosis, according to data from the HORIZON-PFT study; zoledronic acid reduced the risk of a new morphometric vertebral fracture relative to placebo in patients who were not receiving concomi- tant osteoporosis medication.

Moreover, the risk of hip fracture was reduced with zoledronic acid compared with placebo in the overall population of patients who were or were not receiving concomitant treatment for osteoporosis.

The drug was also effective in reducing the risk of other categories of fracture, including clinical vertebral fractures and nonvertebral fractures in the overall patient population, as well as multiple morphometric vertebral fractures in patients receiving no other osteoporosis medications. Zoledronic acid also produced

significant improvements in total hip, lumbar spine and femoral neck BMD compared with placebo.

Notably, <15% of patients in the HORIZON-PFT study had been previously treated with bisphosphonates, with a washout period included prior to the study for such patients.

Adherence to osteoporosis treatment regimens is generally poor

. The fact that zoledronic acid is administered in a once-yearly 15-minute infusion in a clinical setting may confer an advantage in terms of patient adherence to therapy compared with other available agents that require more frequent and/or self administration. Indeed, limited data from the large1- year trial in patients with postmenopausal osteoporosis or low BMD suggest that a once-yearly.

Furthermore, intermittent intravenous regimens such as once-yearly infusion circumvent the complex and inconvenient administration procedures that impede adherence to treatment with oral bisphosphonates, particularly once-daily regimens, which require admini- stration in a fasted state with water at least 30 minutes before a meal whilst staying in an upright position to maximize drug absorption and minimize potential gastrointestinal adverse events

. Adverse events associated with some osteoporosis medications also impact on patient adherence to therapy, such as those of gastrointestinal nature that can occur with oral bisphosphonates. However, there are currently no randomized studies comparing zoledronic acid with other intravenous or oral bisphosphonates with regard to patient therapy adherence, although such studies would certainly be of interest.

There is some concern that the long-term accumu-

lation of bisphosphonates in the skeleton may over

suppress bone turnover, resulting in brittle, weak bone

with unrepaired microdamage

. However, bone remo-

deling was still evident in the majority of bone biopsies

taken from patients with postmenopausal osteoporosis

after 3 years of treatment with zoledronic acid in the

HORIZON-PFT study, and no bone abnormalities were

observed

. These data are generally supported by the findings of the 1-year study in postmenopausal patients with low BMD or osteoporosis. In addition, preliminary quantitative CT data from the HORIZON-PFT suggest zoledronic acid may improve the compression strength of bone. Moreover, zoledronic acid did not appear to affect fracture healing in patients with a recent low trauma hip fracture in the HORIZON -RFT study.

However, longer-term data would be beneficial to evaluate this concern.

In conclusion, intravenous zoledronic acid 5 mg once yearly is effective in reducing the risk of several types of fracture in patients with postmenopausal osteoporosis or recent low-trauma hip fracture. Moreover, improve- ments in BMD and reductions in markers of bone turnover are also generally observed. Zoledronic acid is generally well tolerated. Additional comparative data are required to definitively position zoledronic acid with respect to other agents. In the meantime, intra- venous zoledronic acid 5 mg once yearly is a convenient and effective treatment option that may have an advantage over some other agents, for which adherence to treatment regimens is a recognized problem.

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￭ ABSTRACT ￭

Osteoporosis is a preventable disease associated with substantial morbidity and mortality characterized by loss of bone mineral density, progression to diminished skeletal integrity, extensive bone fragility, and an increased risk of fracture. Fractures are an important cause of disability among postmenopausal women, and the public health costs are substantial.

Bisphosphonates, the most commonly used treatment for established osteoporosis, inhibit osteoclast-mediated bone resorption and reduce the risk of vertebral fracture.

Intravenous zoledronic acid 5 mg once yearly is effective in reducing the risk of several types of fracture in patients with postmenopausal osteoporosis or recent low-trauma hip fracture. Moreover, improvements in BMD and reductions in markers of bone turnover are also generally observed. Zoledronic acid is generally well tolerated. Additional comparative data are required to definitively position zoledronic acid with respect to other agents. In the meantime, intravenous zoledronic acid 5 mg once yearly is a convenient and effective treatment option that may have an advantage over some other agents, for which adherence to treatment regimens is a recognized problem.

Key Words: Osteoporosis, Zoledronic acid, Treatment