Health and economic impact of a new drug intervention for osteoporosis
Submitting InstitutionUniversity of Sheffield
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences
Summary of the impact
Research at the University of Sheffield has demonstrated that zoledronic
acid is an effective and safe treatment for osteoporosis. It resulted in a
new drug intervention (Aclasta/Reclast) which has been licensed in more
than 100 countries and shows increased positive outcomes for patients.
As a result of the licensing of the drug, clinical guidelines have changed
globally. For patients, the drug provides a preferred method of treatment,
evidenced in surveys which show the majority of patients preferred an
annual infusion of zoledronic acid to the alternative, which is the
standard treatment of weekly oral alendronate.
Industry has invested in research and development of the drug. Novartis
has funded studies into the efficacy and safety profile (up to 2012); in
2011, sales of Aclasta/Reclast were US$0.6 billion.
Osteoporosis is a major public health problem; there are more than
230,000 osteoporosis-related fractures annually in the UK, 70,000 of which
are hip fractures, and these figures are set to rise with the increase in
the elderly population (www.nos.org.uk).
Treatments are available that reduce the risk of fracture; the most
commonly-used treatments are bisphosphonates. Zoledronic acid is a
bisphosphonate that can be given parenterally once a year and was licensed
for use in men and women with osteoporosis in 2008.
Research at the University of Sheffield played a pioneering role in the
development of the bisphosphonate drugs. Professor Graham Russell
(Department of Human Metabolism, 1975 to 2000) made a major contribution
to their early clinical development as well as the understanding of the
mechanism of action of bisphosphonates at the cellular and molecular level
which laid the scientific foundation for their current use. In a range of
research projects, he studied amoebae (Dictyostelium discoideum) and
immortalised macrophages (J774 cells) and showed that nitrogen-containing
bisphosphonates induced apoptosis by inhibiting the mevalonate pathway and
hence post-translational prenylation of GTP-binding proteins (inhibiting
the enzyme farnesyl diphosphate synthase) and published this in 1998 (R1).
Professor Richard Eastell (Department of Human Metabolism, University of
Sheffield, since 1995) developed assays for bone turnover markers,
evaluated physical measurements of bone and developed methods for defining
vertebral fractures. Sheffield was funded for this work by peer-review
organisations. For example, the work on quantitative computed tomography
was funded by the Medical Research Council (Biomarkers grant) and by
Arthritis Research UK (project grant). The work on vertebral fracture
definition was funded by the Medical Research Council (Fellowship) and
Arthritis Research UK (Project grant).
Thus, Eastell was able to help design the HORIZON study in 2001 to assess
the efficacy and safety of zoledronic acid in osteoporosis. This was a
phase III clinical trial of zoledronic acid sponsored by Novartis and
Sheffield was a study site. The drug was unique in that it was
administered as a once a year infusion; the standard approach to giving
bisphosphonates had been as daily or weekly tablets. The knowledge gained
from experiments in Sheffield between 1993 and 2001 allowed Eastell, along
with his fellow members of the trial steering committee (chairman Dr D
Black), to ensure the following state of the art methods were included in
the HORIZON trial: bone turnover marker response (R2), bone mineral
density response (R3), quantitative computed tomography of hip and spine
response (R4) and the effect of the drug on fracture risk (R5).
Findings of the HORIZON study showed that the drug reduced vertebral
fractures by 70%, hip fractures by 41% and non-vertebral fractures by 25%.
Statistical analysis by Richard Jacques (School of Health and Related
Research, University of Sheffield, since 2008) allowed a better
understanding of the link between change in bone mineral density, bone
turnover markers and fracture risk (R6), and this work provides a target
for response to zoledronic acid in the individual patient.
References to the research
University of Sheffield researchers in bold
R1. Luckman, S. P., Coxon, F. P., Ebetino, F. H., Russell, R. G.,
and Rogers, M. J. (1998) Heterocycle-containing bisphosphonates cause
apoptosis and inhibit bone resorption by preventing protein prenylation:
evidence from structure-activity relationships in J774 macrophages. J.Bone
Miner.Res. 13, 1668-1678 doi: 10.1359/jbmr.19188.8.131.528
R2. Delmas, P. D., Munoz, F., Black, D. M., Cosman, F., Boonen, S.,
Watts, N. B., Kendler, D., Eriksen, E. F., Mesenbrink, P. G., and Eastell,
R. (2009) Effects of yearly zoledronic acid 5 mg on bone turnover
markers and relation of PINP with fracture reduction in postmenopausal
women with osteoporosis. J.Bone Miner.Res. 24, 1544-1551
R3. Eastell, R., Black, D. M., Boonen, S., Adami, S., Felsenberg,
D., Lippuner, K., Cummings, S. R., Delmas, P. D., Palermo, L., Mesenbrink,
P., and Cauley, J. A. (2009) Effect of once-yearly zoledronic acid five
milligrams on fracture risk and change in femoral neck bone mineral
density. J.Clin.Endocrinol.Metab 94, 3215-3225 doi: 10.1210/jc.2008-2765
R4. Eastell, R., Lang, T., Boonen, S., Cummings, S., Delmas, P.
D., Cauley, J. A., Horowitz, Z., Kerzberg, E., Bianchi, G., Kendler, D.,
Leung, P., Man, Z., Mesenbrink, P., Eriksen, E. F., and Black, D. M.
(2010) Effect of once-yearly zoledronic acid on the spine and hip as
measured by quantitative computed tomography: results of the HORIZON
Pivotal Fracture Trial. Osteoporos.Int. 21, 1277-1285 doi:
R5. Black, D. M., Delmas, P. D., Eastell, R., Reid, I. R.,
Boonen, S., Cauley, J. A., Cosman, F., Lakatos, P., Leung, P. C., Man, Z.,
Mautalen, C., Mesenbrink, P., Hu, H., Caminis, J., Tong, K.,
Rosario-Jansen, T., Krasnow, J., Hue, T. F., Sellmeyer, D., Eriksen, E.
F., and Cummings, S. R. (2007) Once-yearly zoledronic acid for treatment
of postmenopausal osteoporosis. N.Engl.J.Med. 356,
1809-1822 doi: 10.1056/NEJMoa067312
R6. Jacques, R. M., Boonen, S., Cosman, F., Reid, I. R., Bauer, D. C.,
Black, D. M., and Eastell, R. (2012) Relationship of changes in
total hip bone mineral density to vertebral and nonvertebral fracture risk
in women with postmenopausal osteoporosis treated with once-yearly
zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). J.Bone
Miner.Res. 27, 1627-1634 doi: 10.1002/jbmr.1644
Details of the impact
This research has led to a new drug intervention for osteoporosis.
Through our research, we demonstrated that Zoledronic acid is effective
and it was subsequently licensed by the European Medicines Agency in 2007
The drug was approved based on the phase III clinical trial studies such
as the HORIZON trial. It was approved in women [S2, S3], men, people with
hip fractures [S4], and with glucocorticoid-induced osteoporosis. As a
result of this research, the drug has been licensed in over 100 countries
and more than 2 million doses of the drugs have been administered since
The main beneficiaries of this research are patients with osteoporosis;
they receive a well-tolerated and simple to administer treatment that they
prefer to the alternative (oral alendronate) and have a large reduction in
their risk of fracture (by 70% for vertebral fracture).
The development of zoledronic acid as a treatment for osteoporosis is
original as it is the first (and only) treatment that can be administered
as infrequently as once a year. This contribution allowed for the
successful development of this drug by conducting a well-designed trial,
and allows a clear understanding of the mechanism of action of the drug at
the molecular and whole body level. The Global Program Head at Novartis
has recognised the part played by the University of Sheffield in both
developing the use of zoledronic acid for treatment of osteoporosis, as
well as sales worth $0.6bn (S3) in 2011 [S5].
Clinical guidelines have changed as a result of the drug being
licenced. The Scottish Medicines Consortium has recommended that this
treatment should be used in patients who are unsuitable for or unable to
tolerate oral treatment options for osteoporosis [S6]. The treatment has
not yet been considered by NICE, although treatments for Osteoporosis are
currently under review by NICE.
The treatment has been included in international guidelines. Expertise
gained through our research has been called upon to inform international
practice which recommends zoledronic acid as best practice.
Eastell was an advisor on the Endocrine Society panel during 2009-2012
[S7] in the formation of new international guidelines for male
osteoporosis, which include the recommendation to use zoledronic acid
(S5). The treatment has also been included in the International
Osteoporosis Foundation (IOF) guidelines for glucocorticoid-induced
osteoporosis and three Sheffield professors were on that panel during
2009-2012 (John Kanis, Eugene McCloskey and Eastell).
The use of bone mineral density to identify response in the individual
patient was the basis for a guideline from the IOF, and Eastell and Kanis
were two of the members of the panel [S8]. Monitoring of zoledronic acid
with bone turnover markers and bone mineral density was described in
guidelines from the IOF on which Kanis and Eastell were members.
The user experience has improved. According to research into patient
experience conducted in the USA, 66-79% of patients preferred an annual
infusion of ZA to weekly oral alendronate [S9], the standard treatment of
osteoporosis currently recommended by NICE.
The costs of treatment have changed as a result of research-led
changes in practice. The treatment is the most cost-effective for
postmenopausal osteoporosis (Scottish Medicines Consortium). Research
conducted in France found that, for example, treatment with zoledronic
acid cost €1,216 per hip fracture avoided compared to €1,323 for standard
Industry has invested in research and development. Novartis has
funded studies into the efficacy and safety profile through establishing
clinical trials of more than 11,000 patients for up to 9 years.
Sources to corroborate the impact
S1. European Medicines Agency European public assessment report variation
WC500020936 for Aclasta (zoledronic acid) (http://tinyurl.com/o6qbwkd)
S2. FDA Label change for Reclast (zoledronic acid) approving it fo use in
treatment of osteoporosis in postmenopausal women and treatment of Paget's
disease of bone in men and women (http://tinyurl.com/psgsqw9).
S3. Press release gives details of approval of drug for use in men (http://tinyurl.com/lxskhth).
S4. Gives details of approval for drug to be used with hip fractures (http://tinyurl.com/kqrs7yn).
S5. E-mail from Global Program Head, Novartis, available on file.
S6. The Scottish Medicines Consortium recommendation for use of Aclasta (http://tinyurl.com/q5klw5n).
S7. Page 5, recommendation 3.2 corroborates inclusion of zoledronic acid
as a recommended treatment (http://tinyurl.com/m5fkuog).
S8. Vasikaran, S., Eastell, R., Bruyere, O., Foldes, A. J., Garnero, P.,
Griesmacher, A., McClung, M., Morris, H. A., Silverman, S., Trenti, T.,
Wahl, D. A., Cooper, C., and Kanis, J. A. (2011) Markers of bone turnover
for the prediction of fracture risk and monitoring of osteoporosis
treatment: a need for international reference standards. Osteoporos.Int.
22, 391-420 doi: 10.1007/s00198-010-1501-1
S9. McClung, M., Recker, R., Miller, P., Fiske, D., Minkoff, J.,
Kriegman, A., Zhou, W., Adera, M., and Davis, J. (2007) Intravenous
zoledronic acid 5 mg in the treatment of postmenopausal women with low
bone density previously treated with alendronate. Bone 41, 122-128 doi: 10.1016/j.bone.2007.03.011
S10. Fardellone, P., Cortet, B., Legrand, E., Bresse, X., Bisot-Locard,
S., Vigneron, A. M., and Beresniak, A. (2010) Cost-effectiveness model of
using zoledronic acid once a year versus current treatment strategies in
postmenopausal osteoporosis. Joint Bone Spine 77, 53-57 doi: 10.1016/j.jbspin.2009.04.009