Tcrm_3768_chapurlat.indd

Treatment of osteoporosis with annual iv zoledronic acid: effects on hip fracture Background: Several treatments for postmenopausal osteoporosis have been available in the
past decade, but adherence to these treatments has been judged inadequate. The prevention of hip fracture by these medications is still modest.
Methods: A literature search was performed for treatment with zoledronic acid for the preven-
tion of hip fracture.
Results: In the The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly
(HORIZON) Pivotal Fracture Trial, involving 7765 postmenopausal women with low bone min-
eral density or with prevalent vertebral fracture, women taking zoledronic acid had a 41% relative risk reduction for hip fracture, at 3 years, compared to placebo. In the HORIZON Recurrent Fracture Trial, 2127 patients (76% were women) were randomized to receive either zoledronic acid or placebo after sustaining a fi rst hip fracture. A reduction of 30% in the second hip fracture risk was observed, but it did not reach statistical signifi cance. Zoledronic acid was generally safe in these trials, although a slightly increased rate of severe atrial fi brillations was observed in the HORIZON Prevention Fracture Trial, but not in the HORIZON Recurrent Fracture Trial.
Conclusion: Yearly zoledronic acid reduces the risk of hip fracture, both in postmenopausal
osteoporotic women with and without prevalent vertebral fracture and in men and women with
a recent fi rst hip fracture.
Keywords: osteoporosis, bisphosphonates, hip fracture, zoledronic acid
Introduction
Hip fracture is the most devastating complication due to bone fragility. Mortality is
increased in women with hip fracture, 10% to 20% higher than expected for their age within the fi rst year1,2 and this excess mortality persists for several years after hip fracture.3,4 Loss of independence and entry in nursing homes are also common consequences of hip fractures.5 Prevention of hip fracture, however, is challenging because one needs to target both the bone – with anti-osteoporosis agents – and the triggering event that is generally a fall from standing height. In addition, hip fracture occurs mostly in individual over 75 years of age,6 and the mean age at hip fracture is currently increasing.7,8 The second hip fracture is not a rare event, with an estimated incidence of around 2% per year.9,10 Elderly patients with hip fracture often present with several comorbidities hampering pharmacologic treat- ment because of drug interaction, and a negative infl uence on drug persistence. Cognitive impairment may also have a negative impact on drug persistence.
Preventing falls has proven to be diffi cult, although some studies suggest that vitamin D supplements,11 certain types of exercise, including tai chi,12 and cataract surgery13 might reduce the risk of fall. Limiting the consequences of the fall may Professor of Rheumatology, INSERM U831, Université de Lyon, Division be possible with hip protectors, but their effectiveness has never been convincingly established, mainly due to poor compliance.14 Hospices Civils de Lyon, 69437, Lyon cedex 03, France A reduction in the incidence of hip fracture has been observed in some trials test- ing the effi cacy of oral alendronate and risedronate,15–17 but the magnitude of fracture Therapeutics and Clinical Risk Management 2009:5 169–175 2009 Chapurlat, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
risk reduction was about half of that observed for vertebral androgen-def iciency-induced bone loss in prostate cancer fracture effi cacy. For the other drugs the evidence is less patients, prostate cancer bone metastases, and osteolytic compelling. In the BONE trial, examining the effect of iban- bone metastases. This BP has also been marketed more dronate on fracture risk, no effi cacy on hip fracture events recently for the treatment of postmenopausal osteoporosis, could be obtained in the primary intent to treat analysis.18 and should be available soon for the treatment of male With teriparatide, a 50% reduction in non-vertebral fracture osteoporosis and of glucocorticoid-induced bone loss.
risk was shown, but the hip fracture risk reduction was not In rat models, zoledronic acid – administered with sub- signifi cant. This latter result may stem from the study design, cutaneous injections for 10 days – produces dose-dependent as women were too young to have a sizeable hip fracture increases in cancellous bone volume and connectivity, incidence.19 With intact parathyroid hormone, no effi cacy 100-times more effectively than pamidronate, and decreases on non-vertebral fracture, and hip fracture specifi cally, was observed either.20 Although treatment with strontium In another animal model of postmenopausal bone loss – the ranelate has been able to diminish the rate of non-vertebral ovariectomized adult rhesus monkey – animals were randomly fracture by 16%, it is only in a post-hoc analysis that a 33% assigned to one control group and four ovariectomy groups. reduction of hip fracture risk could be found in a sub-group The control and one ovariectomized group received saline, of women at higher risk of hip fracture.21 No reduction in and the three other ovariectomized groups were given 0.5, 2.5 hip fracture risk and all non-vertebral fracture risk has been or 12.5 μg/kg by a single weekly subcutaneous injection, for shown with the fi rst selective estrogen receptor modulator 69 weeks.25 Spine, total body and radius bone mineral den- (SERM) to be marketed for the treatment of postmenopausal sity (BMD) were either preserved or increased by zoledronic osteoporosis, raloxifene.22 With a new, more potent com- acid, dose-dependently, up to week 39, and stabilized there- pound, lazofoxifene, it has been shown that a reduction of after. Simultaneously, biochemical markers of bone turnover 24% in the incidence of non-vertebral fracture risk could be decreased signifi cantly in monkeys receiving zoledronic acid, obtained, but the 23% reduced risk in hip fracture risk did proportionally to the dosage, and remained reduced until the end of the study, compared with animals on placebo.
So, there is a clear need for new drugs to improve reduc- In a phase II, randomized, double-blind, placebo-controlled tion in hip fracture risk. These drugs should be adequately trial, zoledronic acid or placebo were given intravenously to tolerated in the elderly and their regime should be acceptable 351 postmenopausal women with low BMD (T score Յ 2), in those patients who often have many co-prescriptions. In this for 1 year. These patients received placebo or intravenous context, we will review the effectiveness of the treatment with zoledronic acid at doses of 0.25, 0.5 or 1.0 mg every 3 months, annual intravenous zoledronic acid to prevent hip fracture.
or 2.0 mg every 6 months, or a single annual 4.0 mg dose.26 All women received a 1 g per day calcium supplement. All zoledronic acid regimens produced similar increases in lum- Our literature search in PubMed used the following terms: bar spine and femoral neck BMD, spanning 4.3% to 5.1% at zoledronic acid and hip fracture (50 articles), bisphosphonates the spine, compared with stable BMD in the placebo group. and hip fracture (693 articles). Titles and/or abstracts were Biochemical markers of bone resorption (urinary N-terminal reviewed to determine the relevance for this review. We have telopeptide of type I collagen [NTX], serum C-terminal telo- selected articles relevant to the prevention of hip fracture with peptide of type I collagen [CTX]) were suppressed during the zoledronic acid, including all clinical trials and some relevant trial, while markers of bone formation were also diminished, papers on the pharmacology of the compound and some stud- albeit later after beginning treatment. Post-infusion myalgia ies related to the clinical use of bisphosphonates. We have and transient fever were the most common adverse events.
also used studies on zoledronic acid we were aware of, which Two consecutive, open-label extensions of this phase II had been released only in the form of abstracts at the time of study have been conducted over 5 years.27 In the fi rst exten- sion, most patients received 4 mg once a year. They entered the second extension thereafter and received either zoledronic Pharmacology of zoledronic acid
acid 4 mg per year or calcium alone. Patients were analyzed Zoledronic acid is a potent nitrogen-containing BP, according to the duration of their treatment with zoledronic which has been widely used in the treatment of Paget’s acid (2, 3 or 5 years). Substantial increases in BMD were disease of bone, hypercalcemia, multiple myeloma, observed in all groups, along with signifi cant reduction in Therapeutics and Clinical Risk Management 2009:5 biochemical markers of bone turnover. A third of patients, osteoporosis therapies. Patients with no bone medication at however, did not benefit from an optimal reduction in baseline were in stratum 1, whereas those in stratum 2 were bone-specifi c alkaline phosphatase, even after several zole- on an antiosteoporosis drug when they started the trial.
dronic acid infusions. This frequent suboptimal response Two primary endpoints were adopted in this trial: the was not observed when examining results of serum CTX-1 incidence of new vertebral fracture in stratum 1 and the measurements. Taken together, these results may suggest incidence of hip fracture in both strata 1 and 2. Secondary that a 4 mg yearly infusion may not have been adequate for effi cacy endpoints included any non-vertebral fracture, any clinical fracture, and clinical vertebral fracture. Other second- The one-year phase II trial26 has paved the way for ary endpoints were changes in BMD at the total hip, femoral conducting a large phase III trial program (the HORIZON neck, and lumbar spine, and changes in markers of bone trials) designed to demonstrate the ability of zoledronic acid resorption (serum C-telopeptide of type I collagen, CTX) 5 mg once a year given intravenously to reduce osteoporotic and formation (bone-specifi c alkaline phosphatase, BSAP, and N-terminal propeptide of type I collagen, PINP).
A total of 7765 women were randomized to receive Clinical results with zoledronic acid
either zoledronic acid (n = 3889) or placebo (n = 3876). in the prevention of hip fracture
Their mean age was 73 years, 63% had prevalent vertebral Results of two large phase III multicenter randomized fracture and 79% had no other osteoporosis medication at placebo-controlled trials have been published so far. The baseline (stratum 1). Eighty-four percent of patients were HORIZON Pivotal Fracture Trial has been conducted among postmenopausal osteoporotic women with and without preva- The relative risk reduction for hip fracture in women lent fracture.27 The HORIZON Recurrent Fracture Trial has taking zoledronic acid was 41% with zoledronic acid and the tested the ability of the compound to reduce fracture risk vertebral fracture relative risk reduction at 3 years was 70%. among men and women with a recent hip fracture.28 Fracture risk reduction after 1 and 2 years of treatment was comparable to that observed after 3 years. Non-vertebral frac- tures were reduced by 25%, all clinical fractures by 33% and The Health Outcomes and Reduced Incidence with Zole- clinical vertebral by 77%, in women on zoledronic acid.
dronic Acid Once Yearly (HORIZON) Pivotal Fracture BMD at the hip increased by 6% and at the spine by 6.7% Trial was an international, multicenter, randomized, double- after 3 years of follow-up, compared with the placebo. All blind, placebo-controlled trial in postmenopausal women three markers of bone turnover (serum CTX, BSAP and with osteoporosis, who were randomly assigned to receive PINP) decreased signifi cantly compared with the placebo either a 15-minute intravenous injection of zoledronic acid group, when they were measured 12 months after starting (5 mg) or placebo, at baseline (day 0), at 12 months, and at therapy. At 6 and 12 months after each infusion, there was 24 months. All women received oral daily calcium (1000 to no further decline in their concentrations.
1500 mg) and vitamin D (400 to 1200 IU) and were moni- The numbers of patients who died, had a serious adverse tored for 3 years, to estimate the incidence of new vertebral event, or discontinued follow-up because of an adverse event did not signifi cantly differ between the study groups. Postmenopausal women between the ages of 65 and Among patients on zoledronic acid, 31.6% had a brief fl u-like 89 years could be enrolled if they had a BMD T-score syndrome after the fi rst infusion, compared with 6.2% in the of −2.5 or less at the femoral neck, with or without preva- placebo group. A transient increase of more than 0.5 mg/dL lent vertebral fracture, or a T-score of −1.5 or less, with in serum creatinine levels was observed 9 to 11 days after radiological evidence of at least two mild vertebral frac- the infusion, among 1.3% of patients with zoledronic acid tures or one moderate vertebral fracture. Previous use of and 0.5% of patients in the placebo group. The number of oral bisphosphonates was permitted, the duration of the patients who had arrhythmia in the zoledronic acid group washout period depending on the duration of previous use. (266 patients, or 6.9%) was signifi cantly higher than that in Concomitant use of several other antiosteoporosis drugs was the placebo group (203 patients, or 5.3%; p = 0.003), as well allowed, such as raloxifene, calcitonin, tibolone, tamoxifen, as serious atrial fi brillation. In the zoledronic acid group, dehydroepiandrosterone, iprifl avone, and medroxyproges- 50 patients had serious atrial fi brillation (1.3%), compared terone. Patients were stratifi ed according to these baseline with 20 patients (0.5%) in the placebo group. Among these Therapeutics and Clinical Risk Management 2009:5 50 serious atrial fi brillation events, 47 occurred more than comparable in the groups. Similarly, there was no difference 30 days after the infusion. The occurrence of stroke, or death for the occurrence of serious renal adverse events, arrhythmia from stroke, did not differ between the two groups. Two cases and atrial fi brillation. No case of osteonecrosis of the jaw of potential osteonecrosis of the jaw were identifi ed (one in the placebo group and one in the zoledronic acid group).
In a substudy of the HORIZON fracture trial, 152 patients Discussion
underwent a bone biopsy. Zoledronic acid reduced bone Among postmenopausal women with osteoporosis, zole- turnover by a median 63% and preserved bone structure and dronic acid administered once a year at 5 mg was associated volume, with evidence of ongoing bone remodeling in 99% of with a 40% reduction in hip fracture risk. In men and women the biopsies.30 Bone formation was normal, with no evidence receiving the same regimen starting shortly after a fi rst hip of mineralization defect. The concomitant administration of fracture, a trend toward a one third reduction in second hip other antiosteoporosis drugs did not affect the tissue-level fracture incidence has been observed.
Although no direct comparison in head-to-head trials examining fracture effi cacy has been made in comparison with other antiresorptive drugs, prescribed orally, the mag- The Health Outcomes and Reduced Incidence with Zole- nitude of the effect looks somewhat larger with zoledronic dronic Acid Once Yearly (HORIZON) Recurrent Fracture acid. It is also possible to make an indirect comparison Trial was an international, multicenter, randomized, placebo- between placebo-controlled trials, as outlined by Bucher controlled trial involving men and women with recent hip and al.31 In indirect comparisons examining risedronate vs fracture.29 Patients were randomized to receive a yearly zoledronic acid and alendronate vs zoledronic acid, there infusion of either 5 mg of zoledronic acid or an infusion of was no signifi cant difference between these drugs for hip placebo. The treatment was administered within 90 days of fracture effi cacy.32 Several assumptions, however, need to be the surgical repair of the hip fracture, and once a year thereaf- made when those calculations are made. First, the samples ter. All patients were supplemented with calcium and a load- of patients in the different trials must be drawn from the ing dose of vitamin D was administered soon after the fi rst hip same kind of population. This is not necessarily the case in fracture. All these patients were unable or unwilling to take these studies, as inclusion/exclusion criteria differed mark- an oral bisphosphonate. A parallel therapy with calcitonin, a edly between these trials. Second, the relative risks have SERM, tibolone and hip protectors was authorized.
to be derived from the intent-to-treat analyses, which was The primary endpoint was a new clinical fracture. Sec- the case. Third, the dropouts must be accounted for in the ondary endpoints included a second hip fracture and death, as trials, which was possible. Rates of compliance, defi nition well as the change in BMD at the non-fractured hip, and new of outcomes and methodologic quality of the trials can also vertebral and non-vertebral fracture. Among 2127 patients, affect the inferences from these indirect comparisons. So, at 1065 received zoledronic acid and 1062 were on placebo, this stage, there is no absolute answer as to whether the hip fracture risk reduction observed with zoledronic acid is more After a median follow-up of 1.9 years, the observed important than with other bisphosphonates.
fracture rate of clinical fracture was 8.6% in the zoledronic The Pivotal Fracture Trial involved both women with acid group and 13.9% in the placebo group, representing an and without prevalent fracture. This the fi rst time that a absolute risk reduction of 5.3% and a relative risk reduction reduction in hip fracture risk has been demonstrated in a of 35%. There was also a non-signifi cant 30% second hip population treated with bisphosphonates including women fracture relative risk reduction associated with the use of with no prevalent vertebral fracture. So, this compound zoledronic acid. Death from all causes was reduced by 28% appears to be effi cacious at various stages of the severity of in the zoledronic acid group. BMD at the total hip increased in the zoledronic acid group by 2.6% at 12 months, 4.7% The Recurrent Fracture Trial is the fi rst trial with an anti- at 24 months, and 5.5% at 36 months and declined in the osteoporosis drug that showed a decrease in mortality. This placebo group by 1.0%, 0.7%, and 0.9%, respectively.
reduction was observed after about 16 months of follow-up. The incidence of pyrexia, myalgia and bone pain was Given the number of fractures that were avoided by the reduc- increased among patients who received zoledronic acid, tion of bone fragility, the reduction in fracture risk explained whereas the incidence of serious adverse events was 2% of the mortality reduction.33 In a post-hoc sub-group Therapeutics and Clinical Risk Management 2009:5 analysis, men experienced a greater mortality benefit, after 3 years in the FIT I trial testing alendronate,15 complete with fewer cardiac-related events. Death from pneumonia, follow-up data at 3 years were available for only 64% of the neoplasms, and cardiovascular disease in patients treated with women in the HIP trial examining risedronate,16 or 64% to zoledronic acid were reduced, whereas the incidence of these 68% (according to different treatment groups) completed diseases was similar to that in the placebo group, suggesting the study in the 3-year BONE trial testing the effi cacy of that the drug might infl uence physiologic reserves.
oral ibandronate.18 In the HORIZON Recurrent Fracture One of the limitations of the fi rst oral bisphosphonates Trial.29 which was an event-driven trial, 71% of the patients was their daily dosage. Weekly regimens have been devel- completed the trial, but only 3% were lost to follow-up. oped later to diminish the treatment annoyance. In a recent Results from the HORIZON program apply to a large range analysis, 46% of women on a weekly formulation were still of severity of postmenopausal osteoporosis, because women taking their drug at 1 year, whereas only 33% of those on could have osteoporosis with or without prevalent vertebral a daily dosage were still on medication.34 Another limita- fracture, the ages ranging from 65 to 89. They could have tion of oral bisphosphonates is the possibility of digestive already received certain osteoporosis medications, and there adverse events such as abdominal pain, dyspepsia and, were few exclusion criteria. Patients in the HORIZON Recur- rarely, oesophagitis. Persistence on antiosteoporosis drugs rent Fracture Trial had a recent hip fracture.
is poor, like with most chronic diseases.34 Thus, in a cohort Patients at risk of hip fracture are generally elderly, of older american women, drug persistence was only 45% over 75. So, the tolerability of drugs is essential in this frail 1 year after starting a treatment for osteoporosis.35 In another population. In the HORIZON Pivotal Fracture Trial, 2.3% analysis performed in California, only 25% of women were of women had hypocalcemia, defi ned as serum calcium still taking their medication at 1 year.36 In another study below 2.075 mmol/L, 9 to 11 days after the infusion. These conducted in North America, raloxifene and bisphosphonates episodes were transient and asymptomatic in all cases. In were frequently stopped and the main reason for treatment the HORIZON Recurrent Fracture Trial, although patients interruption was the occurrence of adverse events.37 Anti- were older and more frail, fewer episodes of hypocalcemia fracture benefi t, however, improves as much as compliance were observed (0.3%), possibly due to the loading dose of increases.38 The effi cacy of zoledronic acid on hip fracture vitamin D patients received before their fi rst infusion. So, may be related, at least in part, to its iv administration, hypocalcemia appears to be a rare and subclinical event in allowing for a better delivery of the drug at the bone level, women receiving zoledronic acid. In older patients, however, it is probably wise to measure serum dihydroxy-vitamin D This effect of yearly intravenous zoledronic acid on hip and to give an adequate vitamin D supplement, including a fracture may also be infl uenced by the quick onset of the loading dose if judged necessary, to avoid hypocalcemia as antiresorptive action. In a randomized, double blind, double- dummy trial comparing the onset of action of zoledronic acid In the HORIZON Pivotal Fracture Trial, but not in the 5 mg and alendronate 70 mg in postmenopausal women with HORIZON Recurrent Fracture Trial, serious atrial fi brillation low BMD,39 the reduction in markers of bone resorption was occurred more frequently in the zoledronic acid group (1.3%) signifi cantly greater at week one in women on zoledronic than in the placebo group (0.5%, p Ͻ 0.001). This fi nding has acid than in those on alendronate. The difference between the prompted several groups to report data on atrial fi brillation two drugs waned over time, but a slight difference in favor from other bisphosphonates trials. In the FIT trials, a trend was of zoledronic acid remained after 12 weeks.
observed for the occurrence of serious atrial fi brillation, with The quality of trials, ie, their validity, is critical for a relative hazard of 1.51 (0.97, 2.40).40 In the phase III trials clinical practice and for health care systems who reimburse of risedronate for osteoporosis, there was no difference in the the drugs. The drop-out rate must be low so the intention to incidence of atrial fi brillation, stroke, or death related to car- treat analysis remains reliable, along with sound randomiza- diovascular disease between the placebo and treated groups.41 tion and statistical analysis. A wide spectrum of the disease In a population-based case control study in Denmark based must be enrolled to allow for good generalizability of trial on medical databases, involving 13,694 patient with atrial results. In the HORIZON Pivotal Fracture trial,28 84% of fi brillation/fl utter and 68,470 controls, there was no associa- patients remained in active follow-up and 81% received all tion between use of oral bisphosphonate and the risk of atrial three infusions. For comparison with other major phase III fi brillation/fl utter.42 In this context of confl icting data on the osteoporosis trials, 88% of patients were still taking the drug infl uence of bisphosphonates on the risk of atrial fi brillation, Therapeutics and Clinical Risk Management 2009:5 it remains possible that the observation of increased risk in the osteonecrosis of the jaw that might be observed in patients HORIZON Pivotal Fracture Trial is a chance fi nding induced receiving zoledronic acid is comparable to that encountered by multiple comparisons. The possibility that this arrhythmia with previous oral bisphosphonates used for osteoporosis. might be related to subclinical hypocalcemia and the result- The occurrence of this adverse event is certainly related to the ing secondary hyperparathyroidism,43 however, points to the dose and not to the mode of administration. So, at this stage, need for monitoring this potential cardiovascular event when it has been recommended by the American Society for Bone and Mineral Research Task Force45 that patients be informed One of the concerns with new antiresorptive agents about the risk of osteonecrosis of the jaw, maintain good oral is their bone safety, regarding the risk of mineralization hygiene and have regular dental visits. There is no contra- defects and the risk of over-suppression of bone turnover. indication to dental implant placement. Current evidence In the ancillary bone biopsy study of the HORIZON trial, supports the same recommendations for annual zoledronic there was no mineralization defect.30 All 152 but 1 biopsies acid as for older oral bisphosphonate therapies.
showed evidence of tetracycline label, indicating preserved remodeling capacity. One year after treatment, before the next Conclusion
infusion, an increase in serum markers of bone resorption was Yearly intravenous zoledronic acid 5 mg is an effective visible, consistent with this preservation of bone remodel- treatment to reduce the incidence of hip fracture among ing capacity. It is likely that zoledronic acid may be started postmenopausal osteoporotic women. A trend toward a among patients who have already received other bisphos- second hip fracture risk reduction has also been observed phonates. In a randomized double blind double dummy trial, in patients with a fi rst hip fracture. This treatment has been conducted in postmenopausal women with low BMD who had been previously treated with alendronate for an average 4 years, patients received either yearly zoledronic acid 5 mg Disclosures
or oral weekly alendronate 70 mg over 1 year.44 BMD was The author discloses no confl icts of interest.
maintained in both groups, with no signifi cant difference in BMD change between the two groups. In addition, zoledronic References
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