The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT)

Black, Dennis M.; Reid, Ian R.; Cauley, Jane A.; Cosman, Felicia; Leung, Ping Chung; Lakatos, Péter L.; Lippuner, Kurt; Cummings, Steven R.; Hue, Trisha F.; Mukhopadhyay, Amitava; Tan, Monique; Aftring, R. Paul; Eastell, Richard

doi:10.1002/jbmr.2442

Cited by 231 publications

(166 citation statements)

References 21 publications

(62 reference statements)

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“…However, there is a wide range of values of C-telopeptide, indicating that >50 % of patients have bone resorption rates well within the postmenopausal normal range at the time they are due for re-dosing. This appears to contrast with similar data from alendronate and zoledronate, which seem to produce more consistent suppression of resorption [3,10]. Also contrasting with bisphosphonates is the continued increase in bone density with long-term use, albeit not at the same rate observed in the first 1-2 years of treatment.…”

contrasting

confidence: 72%

“…This equates to an incidence of ∼4/10,000 patient-years. By comparison, there was one case of ONJ in both the zoledronate and placebo groups in Black et al [13], 1 during 1914 patients-years of observation in the study extensions [10,14], and no cases in the other phase 3 zoledronate study [15]. These data do not suggest a difference in incidences of this problem with these two medications.…”

mentioning

confidence: 85%

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Denosumab after 8 years

Reid

2015

Osteoporos Int

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It is now more than 20 years since the alendronate phase 3 program produced the first trials demonstrating global antifracture efficacy for an osteoporosis medication [1,2]. This brought the osteoporosis field into the era of evidence-based medicine. The euphoria that followed from knowing that the interventions we were prescribing really were preventing fractures soon passed as durations of therapy reached 3 years, the endpoint of most fracture prevention clinical trials. A series of unanswered questions then arose. How long should treatment be continued? Are there long-term side-effects? Do these drugs continue to prevent fractures and, if so, is their continued use necessary for sustained fracture prevention? For alendronate, some of these questions were answered by the FLEX trial, which suggested that dose reduction with long-term use did not reduce efficacy, and that for patients whose femoral neck bone density was no longer in the osteoporotic range, drug discontinuation did not negatively impact on fracture rate [3,4]. Similar data have now been published from the zoledronate extension studies [5].In the last decade, osteonecrosis of the jaw (ONJ) and transverse stress fractures of the femoral shaft, referred to as an atypical femoral fractures (AFFs), have emerged as significant new safety concerns associated with the long-term use of anti-resorptive drugs. Most information on these problems is from case series or from analyses of medical claims databases.Some such studies have even suggested that the incidence of atypical femoral fractures attributable to bisphosphonate use might exceed the number of hip fractures prevented by these drugs [6], though other analyses do not support this conclusion [7]. In this context, longer-term data from clinical trials become critically important in assessing the ongoing safety and efficacy of medications for osteoporosis. Longer clinical trials are desirable, though maintaining patients at high risk of fracture on placebo raises ethical and practical issues. The next-best option is to continue long-term follow-up of the cohorts of patients involved in the pivotal clinical trials. While not as robust as a longterm randomized controlled trial because a control group is not continued on placebo, this strategy does provide longitudinal data on a well-characterized cohort, allowing fracture rates and adverse events to be related to duration of therapy. It also allows documentation of chronic effects on bone turnover markers and bone density. The loss of a control group for these measures is not such a problem, since current technology usually generates stable measurements, and the evolution of these parameters in placebo-treated women with osteoporosis is already well documented.The recent report by Papapoulos et al. in Osteoporosis International provides important new information regarding the efficacy and safety of the anti-RANKL monoclonal antibody, denosumab [8]. This drug is a potent antiresorptive which reduces median bone formation rate to zero after 2-3 years use ...

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confidence: 72%

mentioning

confidence: 85%

Denosumab after 8 years

Reid

2015

Osteoporos Int

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“…It results in a reduction in CTX by 2 weeks and when it is given for 6 years as in the Horizon Study, the suppression of CTX and PINP is maintained (26). PINP was found to be even better than CTX and BMD in the horizon study at identifying clinical (fracture) efficacy and responders (27).…”

Section: Bisphosphonatementioning

confidence: 97%

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Eastell

Pigott

Gossiel

et al. 2018

European Journal of Endocrinology

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113

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Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.

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“…The benefits however, might outweigh the risks [13]. Reports on the complications of odd fractures appear conflicting.…”

Section: How Serious Are the Complications Related To Bisphosphonate mentioning

confidence: 99%

Osteoporosis and the Orthopedist

Leung¹

2014

Orthopedic Muscul Sys

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Orthopaedic surgeons are serving more and more elderly people suffering from bone fractures and spinal fractures, many of which are suffering from osteoporosis. They are aware of the special precautions to be taken while dealing with the soft bones, they need to be fully informed about the pathology of osteoporosis, the treatment, the complications and the safe practice.As more reports about jaw necrosis and odd fractures are appearing in relation to long term treatment using bisphosphonates, orthopaedists should objectively evaluate the individual cases to give comprehensive recommendations.

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The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT)

Cited by 231 publications

References 21 publications

Denosumab after 8 years

Denosumab after 8 years

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Osteoporosis and the Orthopedist

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