21 April, 2015

The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis was examined by Black and colleagues in a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT) [1]. The first extension study (EXT1) with zoledronic acid 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), a decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers compared with discontinuation after 3 years, but left the optimal duration of treatment uncertain.

To investigate the longer-term efficacy and safety of zoledronic acid, a second extension (EXT2) was conducted to 9 years, in which 190 women, out of 451 women on zoledronic acid for 6 years in EXT1, were randomized to either zoledronic acid (Z9) (n = 95) or placebo (Z6P3) (n = 95) for three additional years. The primary endpoint was the change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Secondary endpoints included fractures, bone turnover markers, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% CI -0.37% to 1.93%; p = 0.183). Bone turnover markers showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits.

Comment

Oral regimens for the treatment of osteoporosis, mostly oral bisphosphonates, expose only low efficacy due to their relatively high rate of side-effects and adverse events, with very low persistence rates [2] of about 30% and 9% after 1 and 5 years, respectively [3]. The introduction of intravenous bisphosphonates improved persistence and rendered possible for the first time reliable study outcomes on the efficacy and safety of these drugs, particularly of zoledronic acid, as described in the paper by Black and colleagues [1]. Nevertheless, according to a former study, approximately one-third of patients treated with zoledronic acid suffer from post-infusion symptoms such as pyrexia, influenza-like symptoms, myalgia, headache and arthralgia after the first infusion, and the number of patients with arrhythmia or serious atrial fibrillation is significantly higher in the zoledronic acid group than in the placebo group [4]. Such side-effects and adverse events might be one reason for the small participation rate (only 190 patients started the EXT2 out of the 451 patients who had completed EXT1) and the additional high discontinuation rate of 27% in the HORIZON-PFT [1]. Persistence with zoledronic acid in the real-world setting of an outpatient clinic has also shown to be suboptimal: only 94 out of 259 patients (36.3%) agreed to a second infusion and 83% stated that the post-infusion syndrome was responsible for refusing the second administration [5]. When the authors of the HORIZON-PFT state that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits, this has to be put into the perspective of a considerable number of non-persistent patients.

Persistence with another potent anti-resorptive regimen, denosumab 60 mg s.c. every 6 months, is obviously higher according to both the first results of an ongoing, prospective, observational study in routine clinical practice conducted in Germany, Austria, Greece and Belgium, with 91.5% of patients being persistent at year 1 [6], and to our prospective observational data with persistence of 92% at month 6, 88% at month 12, 83% at month 24, 81% at month 36 and 81% at month 48 [7]. These high rates of persistence with denosumab in comparison to reported rates of other bone-specific regimens may be attributed to a low frequency of side-effects and adverse events, with a concurrently high efficacy and the very comfortable method of subcutaneous administration every 6 months.

Regarding the efficacy measurements of BMD and bone turnover markers in the randomized, clinical trials, there is only a small additional benefit with zoledronic acid over placebo in years 7–9 (EXT2) of the HORIZON-PFT [1] in contrast to denosumab, which revealed continued increases in BMD and a persistent reduction of bone turnover markers compared to placebo in years 4–8 of the FREEDOM Extension Study [8]. While the HORIZON-PFT was underpowered to detect differences in fracture rates, new fracture incidences (vertebral, non-vertebral and hip) in the FREEDOM Extension Study remained constantly low. These data suggest that treatment with denosumab can be prolonged for 8 years or more – the recent presentation of the 9-year data at the WCO-IOF-ESCEO Congress supports the benefits of an extended duration of use [9] – without increasing disruptive side-effects and adverse events.

The question of how long osteoporosis treatment should continue cannot be answered without differentiated considerations of the characteristics of the respective regimens. The most potent antiresorptive drugs, zoledronic acid and denosumab, display different mechanisms of action, with one key pharmacological distinction being the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This may explain their differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions [10].

Ewald Boschitsch

KLIMAX Menopause and Osteoporosis Clinic, Vienna, Austria

References

1. Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2014 Dec 26. Epub ahead of print http://www.ncbi.nlm.nih.gov/pubmed/25545380

2. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008;11:44-7 http://www.ncbi.nlm.nih.gov/pubmed/18237359

3. Li L, Roddam A, Gitlin M, et al. Persistence with osteoporosis medications among postmenopausal women in the UK General Practice Research Database. Menopause 2012;19:33-40 http://www.ncbi.nlm.nih.gov/pubmed/21926926

4. Black DM, Delmas PD, Eastell R, et al. HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-22< http://www.ncbi.nlm.nih.gov/pubmed/17476007

5. Lee YK, Nho JH, Ha YC, Koo KH. Persistence with intravenous zoledronate in elderly patients with osteoporosis. Osteoporos Int 2012;23:2329-33 http://www.ncbi.nlm.nih.gov/pubmed/22179417

6. Hadji P, Papaioannou NA, Gielen E, et al. 12-Month persistence with denosumab in women with postmenopausal osteoporosis: interim results of a 24-month prospective observational study in Germany, Austria, Greece and Belgium. Poster Nr. P150, WCO-IOF-ESCEO, Seville, Spain; April 2–5, 2014

7. Boschitsch E, Trinker N, Durchschlag E. Persistence with denosumab in a menopause and osteoporosis clinic. Poster Nr. P357, ECTS-IBMS 2015 Congress, Rotterdam, The Netherlands; April 25–28, 2015

8. Papapoulos S, Lippuner K, Roux C, et al. Eight years of denosumab treatment in postmenopausal women with osteoporosis: results from the first five years of the FREEDOM Extension. Oral Poster Session, Presentation Number: LB-MO26, ASBMR, Baltimore, USA; October 4–7, 2013 9. Papapoulso S, Roux C, Bone HG, et al. Denosumab treatment in postmenopausal women with osteoporosis for up to 9 years: results through year 6 of the FREEEDOM extension. OC4, WCO-IOF-ESCEO, Milan, Italy; March 27, 2015

10. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011;48:677-92 http://www.ncbi.nlm.nih.gov/pubmed/21145999