J of Bone Mineral Res - 2019 - Ferrari - Relationship Between Bone Mineral Density T Score and Nonvertebral Fracture Risk
J of Bone Mineral Res - 2019 - Ferrari - Relationship Between Bone Mineral Density T Score and Nonvertebral Fracture Risk
J of Bone Mineral Res - 2019 - Ferrari - Relationship Between Bone Mineral Density T Score and Nonvertebral Fracture Risk
See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ORIGINAL ARTICLE
Abstract
Although treat‐to‐target strategies are being discussed in osteoporosis, there is little evidence of what the target should be to
reduce fracture risk maximally. We investigated the relationship between total hip BMD T‐score and the incidence of nonvertebral
fracture in women who received up to 10 years of continued denosumab therapy in the FREEDOM (3 years) study and its long‐
term Extension (up to 7 years) study. We report the percentages of women who achieved a range of T‐scores at the total hip or
femoral neck over 10 years of denosumab treatment (1343 women completed 10 years of treatment). The incidence of
nonvertebral fractures was lower with higher total hip T‐score. This relationship plateaued at a T‐score between ‐2.0 and ‐1.5 and
was independent of age and prevalent vertebral fractures, similar to observations in treatment‐naïve subjects. Reaching a specific
T‐score during denosumab treatment was dependent on the baseline T‐score, with higher T‐scores at baseline more likely to result
in higher T‐scores at each time point during the study. Our findings highlight the importance of follow‐up BMD measurements in
patients receiving denosumab therapy because BMD remains a robust indicator of fracture risk. These data support the notion of a
specific T‐score threshold as a practical target for therapy in osteoporosis. © 2019 The Authors Journal of Bone and Mineral
Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
KEY WORDS: ANTIRESORPTIVES; DXA; FRACTURE RISK ASSESSMENT; OSTEOPOROSIS; TREAT TO TARGET
INTRODUCTION risks associated with the disease. As examples, there are clear
goals for blood pressure thresholds in patients with hyperten-
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
Received in original form January 2, 2018; revised form February 15, 2019; accepted February 22, 2019. Accepted manuscript online May 29, 2019.
Correspondence to: Serge Ferrari, MD, Geneva University Hospital, 1211 Geneva, Switzerland. Email: [email protected]
Presented at: This study was first presented as an abstract and poster at ASBMR 2014 and as an abstract and oral presentation at ASBMR 2015.
Public clinical trial registration: http://clinicaltrials.gov/show/NCT00089791, A Study to Evaluate Denosumab in the Treatment of Postmenopausal Osteop-
orosis. Extension: http://clinicaltrials.gov/show/NCT00523341, Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment
of Osteoporosis. Additional Supporting Information may be found in the online version of this article.
Journal of Bone and Mineral Research, Vol. 34, No. 6, 2019, p. 1033–1040
DOI: 10.1002/jbmr.3722
© 2019 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research
(ASBMR)
1033 ◼
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complications of diabetes.(1,2) These goals have proven value in Term Safety and Efficacy of Denosumab in the Treatment
guiding treatment strategies to improve clinical outcomes. of Osteoporosis) provide a unique opportunity to perform
Such goals have not been defined for the treatment of this analysis: Subjects with a wide range of total hip baseline
osteoporosis, which is considered successful when there is no T‐scores were enrolled, and BMD increased in serial measure-
significant loss of BMD and no new fracture events. This ments obtained over time with continued denosumab treatment,
approach may be partly because of the limited capacity of most allowing us to study the relationship between different T‐scores
existing therapies to realize large improvements in BMD, a achieved in response to treatment and subsequent 1‐year
surrogate known to reflect bone strength. Attributing success incidence of nonvertebral fractures. Our findings underscore the
to the lack of a negative clinical outcome, however, does not importance of total hip T‐score as a predictor of nonvertebral
provide adequate guidance regarding the most appropriate fracture risk during treatment for osteoporosis and provide
therapeutic strategy to minimize fracture risk over time. additional insights into the use of BMD as a clinically relevant
For treatment‐naïve patients, specific (BMD) T‐score thresh- target for osteoporosis treatment.
olds are used to diagnose osteopenia and osteoporosis, and
BMD is a robust predictor of fracture risk. Conversely, only a few
studies have examined the extent to which the risk of fracture MATERIALS AND METHODS
depends on the BMD achieved during treatment. After 3 years
of annual intravenous zoledronic acid treatment in the Study design
HORIZON extension study, the subsequent fracture risk (both
nonvertebral and vertebral) over 3 additional years was a The study designs of the FREEDOM trial (NCT00089791) and its
function of BMD achieved after treatment.(3) In patients who Extension (NCT00523341) have been published previously(9,12,14–16);
achieved nonosteoporotic hip T‐scores, future fracture risk was key methods are described in this report. In brief, the 3‐year
reduced the most. Similarly, after 5 years of oral alendronate FREEDOM trial was a phase 3, multicenter, randomized, double‐
treatment in the FLEX extension study, future fracture risk over blind, placebo‐controlled study conducted at 214 centers world-
the ensuing 5 years was a function of hip BMD.(4) In addition, T‐ wide. Enrolled subjects were postmenopausal women between the
scores achieved after 3 years of denosumab treatment in ages of 60 to 90 years with a lumbar spine or total hip T‐score < ‐
FREEDOM (A Study to Evaluate Denosumab in the Treatment of 2.5 at either site but ≥ ‐4.0 at both sites. Subjects were randomized
Postmenopausal Osteoporosis) determined the relative efficacy to receive 60 mg of denosumab or placebo subcutaneously (s.c.)
of continued treatment in year 4 and beyond.(5) These findings every 6 months for 3 years and took daily vitamin D (≥ 400 IU) and
support the use of the T‐score as an easily obtainable clinical calcium (≥ 1 g) supplements.
variable to evaluate therapeutic success and the opportunity to Subjects who completed the 3‐year FREEDOM trial, did not
stop or continue treatment. discontinue the investigational product, and did not miss > 1
Investigational and recently approved therapies, either dose were eligible to enroll in the Extension. During the
alone or in combination, have led to large and continued Extension, all subjects were scheduled to receive open‐label
gains in BMD, (6–9) thus a BMD target for osteoporosis 60 mg denosumab s.c. every 6 months for 7 years with daily
treatment is relevant and of increasing interest. In this vitamin D and calcium supplements. Investigators and subjects
context, it has been proposed that potential targets for were blinded to the BMD results throughout the 10‐year study.
osteoporosis treatment could include achieving a T‐score The data reported here represent up to 10 years of denosumab
associated with acceptable fracture risk, with the caveat exposure for women who received 3 years of denosumab in the
that such a T‐score could vary depending on other risk FREEDOM trial and continued for up to 7 years in the Extension
factors, such as age, prior fracture history, and a propensity (long‐term group) study.
for falls. No consensus has been reached regarding what Study subjects provided written consent. The study protocols
that T‐score should be or which site—spine or hip—should were approved by the ethics committee or institutional review
be the basis for that potential target.(10,11) board at each site.
Denosumab is a fully human monoclonal antibody that
specifically binds RANKL to inhibit osteoclast formation,
Study procedures and assessments
function, and survival. In the pivotal, 3‐year FREEDOM trial in
postmenopausal women with osteoporosis, denosumab sig- In the FREEDOM trial, subjects were evaluated every 6 months,
nificantly reduced bone turnover markers, increased lumbar and DXA measurements of the proximal femur were obtained
spine and total hip BMD, and reduced new vertebral fractures, every year for the 3‐year duration. Subjects and investigators
nonvertebral fractures, and hip fractures compared with were blinded to the BMD results throughout the study. During
placebo.(12) Importantly, the gains in total hip BMD explained the Extension study, study visits continued every 6 months for
a large proportion of the observed reduction in fracture risk.(13) an additional 7 years. Over the 10‐year total duration of
Over 10 years of continued denosumab administration, long‐ observation (3 years in the FREEDOM and 7 years in the
term progressive increases in BMD resulted in an improvement Extension trials), proximal femur DXA scans were evaluated for
of 21.7% at the lumbar spine, 9.2% at the total hip, and 9.0% at all subjects once per year from baseline to year 6, and
the femoral neck (all P < 0.05).(9,14–16) thereafter at years 8 and 10. Subjects were asked about the
The main objective of the current analysis was to determine the occurrence of clinical fractures, including nonvertebral frac-
relationship between the incidence of nonvertebral fractures and tures,(12) at every scheduled visit, and they could also report
total hip T‐scores at the time of the fracture (while receiving clinical fractures at unscheduled visits. All fractures were
denosumab treatment). In addition, we evaluated the proportion adjudicated by a central imaging vendor (Synarc Inc., San
of patients who reached a given T‐score at different time points. Francisco, CA, USA) based on diagnostic imaging or a
Ten years of continued denosumab therapy in the FREEDOM radiologist’s report, as described previously.(12) Subjects’
trial and its Extension (Extension Study to Evaluate the Long propensity to fall was not evaluated.
Table 1. Participant characteristics at FREEDOM baseline and FREEDOM extension baseline: denosumab treatment
Journal of Bone and Mineral Research T-SCORES AND NONVERTEBRAL FRACTURES WITH 10 YEARS OF DENOSUMAB 1035 ◼
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A B
Denosumab (N = 3,612) Age ≥ 75 (N = 1,118)
6.0 6.0
4.0 4.0
3.0 3.0
2.0 2.0
1.0 1.0
–3.0 –2.5 –2.0 –1.5 –1.0 –0.5 –3.0 –2.5 –2.0 –1.5 –1.0 –0.5
Total Hip T-score Total Hip T-score
C
Prior Nonvertebral Fracture (N = 1,416)
Expected 1-Year Nonvertebral
6.0 95% CI
Fracture Incidence (%)
4.0
3.0
2.0
1.0
–3.0 –2.5 –2.0 –1.5 –1.0 –0.5
Total Hip T-score
Fig. 1. Relationship between total hip T‐score and incidence of nonvertebral fracture with up to 10 years of denosumab treatment (A) overall,
(B) considering age, and (C) considering prior nonvertebral fracture. N = number of subjects randomized to denosumab in the FREEDOM study who
had an observed total hip T‐score at FREEDOM baseline and ≥ 1 observed total hip T‐score during the FREEDOM or the Extension study. The 95% CIs
are represented by dotted lines
(4.3%) had wrist fractures (Supplemental Table S1). The Table 2. Effect of initial total hip T‐score on reduction in
incidence of nonvertebral fractures and hip fractures was nonvertebral fracture risk.
significantly lower among subjects who had at least one
postbaseline total hip T‐score of > ‐1.5 versus those who did Initial Total Total Hip T Nonvertebral Fracture
not (9% versus 12% for nonvertebral fractures, and 0.5% versus Hip T‐scorea ‐score + 1a Risk Reduction P‐value
2% for hip fractures; P < 0.0001 for both).
–2.5 –1.5 –1.01% 0.011
There was an inverse relationship between the incidence of
–2.4 –1.4 –0.91% 0.016
nonvertebral fractures and total hip T‐scores attained during
–2.3 –1.3 –0.83% 0.023
denosumab treatment (Fig. 1A). The 1‐year nonvertebral
–2.2 –1.2 –0.75% 0.034
fracture incidence was about 3.0% (95% CI, 2.3 to 3.7) in
–2.1 –1.1 –0.67% 0.049
women with a total hip T‐score of ‐2.5. In contrast, the 1‐year
–2.0 –1.0 –0.60% 0.071
nonvertebral fracture incidence was about 2.0% (95% CI, 1.5 to
–1.9 –0.9 –0.54% 0.101
2.4%) in women with a total hip T‐score of ‐1.5. The relationship
–1.8 –0.8 –0.48% 0.140
between attained total hip T‐score and nonvertebral fracture
–1.7 –0.7 –0.42% 0.190
risk reduction begins to plateau at a T‐score between ‐2.0 and ‐
–1.6 –0.6 –0.37% 0.251
1.5, above which fracture risk reductions are less robust with
–1.5 –0.5 –0.32% 0.322
further increases in T‐score. This relationship is further
a
illustrated in Table 2, which shows the absolute nonvertebral Pairs of total hip T‐scores differ by increments of 1.0.
fracture risk reductions after a 1.0 T‐score unit increase for
initial total hip T‐scores between ‐2.5 and ‐1.5. For initial T‐
scores between ‐2.5 and ‐2.1, a 1.0 T‐score unit increase was nonvertebral fracture risk was of lesser magnitude (0.3% to
associated with a significant reduction in nonvertebral fracture 0.6% risk reduction) and was no longer significant.
risk (risk reductions ranged from 0.7% to 1.0%). In contrast, for Like the 10‐year data, there was an inverse relationship
initial T‐scores between ‐2.0 and ‐1.5, the reduction in between the incidence of nonvertebral fractures and total hip
T‐scores attained during treatment with denosumab and with plateau seen in the relationship between higher T‐score levels
placebo (Supplemental Fig. S2). and fracture risk reduction was also maintained independently
Absolute fracture risk was higher in older women and of baseline age and fracture history.
women with previous fractures for any T‐score level; however, Analyses of the relationship between nonvertebral fractures
the inverse relationship between T‐score attained and fracture and femoral neck T‐scores and between vertebral fractures and
risk reduction was maintained regardless of age (Fig. 1B) or total hip T‐scores also showed a similar inverse relationship
prior nonvertebral fracture history (Fig. 1C). Additionally, the (Supplemental Figs. 3 and 4).
Journal of Bone and Mineral Research T-SCORES AND NONVERTEBRAL FRACTURES WITH 10 YEARS OF DENOSUMAB 1037 ◼
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1.0
0.5
0.0
–0.5
T-score
–1.0
–1.5
–2.0
–2.5
–3.0
–3.5
–4.0
n 584 584 589 577 554 558 566 552 334 397 407 396 247 327 328 327
Fig. 4. Total hip BMD by quartile over time T‐score over time by baseline total hip T‐score quartile. Each box represents the respective baseline
T‐score quartile. The bottom and top of each box represent Q1 and Q3 T‐scores within the respective baseline T‐score quartile; the line within each
box represents the median T‐score; the dot represents the mean T‐score
When subjects were grouped by their baseline total hip T‐ This is the largest long‐term study of therapeutic intervention in
score quartile, each group had improvement in T‐scores the osteoporosis treatment setting to date and provides important
throughout 10 years of denosumab treatment, with higher insights into the relationship between absolute BMD and fracture
T‐scores at baseline more likely to result in higher T‐scores at risk among subjects receiving ongoing treatment with denosumab.
each time point (Fig. 4). It remains to be determined if similar conclusions can be made for
other therapeutic agents that reduce fracture risk in patients with
osteoporosis. However, for all approved therapies, preclinical data
show that the relationship between BMD achieved on treatment
DISCUSSION and bone strength remains intact, thus it would be logical to infer
that a similar relationship would be observed from clinical data. The
In this study, we have shown that a high proportion of subjects Foundation for the National Institutes of Health Biomarkers
with osteoporosis achieved T‐scores above the osteoporosis Consortium Bone Quality Project is currently evaluating this
threshold (ie, T‐score ≥ ‐2.5) with up to 10 years of continued relationship in pooled data from multiple clinical trials of
denosumab treatment. The incidence of nonvertebral fractures osteoporosis agents.(20)
decreased significantly as a function of the T‐score achieved There is abundant evidence demonstrating a relationship
during therapy; this relationship was consistent across im- between low BMD/T‐score and increased risk of fracture in
portant demographic variables, such as age and prior fracture untreated postmenopausal women.(21–23) However, there is
history, indicating that the absolute BMD attained on treatment uncertainty regarding the strength of this relationship among
is a key indicator of fracture risk. Within the relationship patients receiving osteoporosis treatments. This may partly be
between total hip T‐score and observed nonvertebral fracture explained by the relatively modest changes in T‐score observed
risk, nonvertebral fractures began to plateau upon reaching a to date with most existing therapies (particularly in the hip); the
total hip T‐score above ‐2.0 (associated with a 1‐year small number of subjects from completed, long‐term studies;
nonvertebral fracture incidence of approximately 2%). A 1.0 and previous attempts to link fracture reductions with
T‐score unit increase was associated with a significant percentage change in BMD rather than the absolute BMD
reduction in fracture risk for T‐scores up to, but not > ‐2.0, achieved while receiving different therapeutic agents.
suggesting that a T‐score threshold ≥ ‐2.0 would be an A previous analysis of data from the FREEDOM trial demon-
appropriate target for therapy to maximize treatment benefits. strated that change (gain) in BMD is a predictor of fracture risk
Further improvements in BMD were not associated with major reduction in patients treated with denosumab(13); however, as
additional changes in 1‐year nonvertebral fracture incidence. demonstrated in the current study, absolute BMD achieved and
The implication of this finding is that nonvertebral fracture risk corresponding T‐score appear to be better predictors of fracture
may be maximally reduced if BMD T‐scores above ‐2.0 are risk reduction. For example, for initial T‐scores of between ‐2.5 and
achieved and maintained, assuming an annual background rate ‐2.1, a 1.0 T‐score unit increase led to a significant reduction in
of osteoporosis‐related fracture of 1% to 1.5%.(19) nonvertebral fracture risk, whereas for initial T‐scores of between
Journal of Bone and Mineral Research T-SCORES AND NONVERTEBRAL FRACTURES WITH 10 YEARS OF DENOSUMAB 1039 ◼
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Mylan, CNIEL, Dairy Research Council. EML: Grant from Amgen; 11. Krege JH, Wan X, Lentle BC, et al. Fracture risk prediction:
Consultancy for Amgen, Radius Health; Board membership of importance of age, BMD and spine fracture status. Bonekey Rep.
2013;2:404.
National Osteoporosis Foundation, International Society for Clinical
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Densitometry, Osteoporosis Foundation of New Mexico. prevention of fractures in postmenopausal women with osteo-
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13. Austin M, Yang YC, Vittinghoff E, et al. Relationship between bone
ACKNOWLEDGMENTS mineral density changes with denosumab treatment and risk
reduction for vertebral and nonvertebral fractures. J Bone Miner
This study was funded by Amgen Inc. Medical writing Res. 2012;27:687–93.
assistance was provided by Michelle N. Bradley, PhD, of Amgen 14. Papapoulos S, Chapurlat R, Libanati C, et al. Five years of
denosumab exposure in women with postmenopausal osteo-
Inc.; Jennifer Villa, PhD, of Oxford PharmaGenesis, Inc., funded
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by Amgen Inc.; and Kathryn Boorer, PhD, of KB Scientific J Bone Miner Res. 2012;27:694–701.
Communications, LLC, funded by Amgen Inc. Formatting 15. Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six
support was provided by Cactus, on behalf of Amgen Inc. years of denosumab exposure in women with postmenopausal
In memory of Silvano Adami. osteoporosis: results from the FREEDOM extension. J Clin
Authors’ roles: Study design: SF, CL. Data collection: JB, EC, Endocrinol Metab. 2013;98:4483–92.
LHG, JYR, EML. Data analysis: SF, CL, JB, FC, EC, LHG, JM, JYR, 16. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of
ATW, RBW, EML. Drafting manuscript: SF, CL, CJFL, JB, FC, EC, denosumab treatment in postmenopausal women with osteo-
porosis: results from the FREEDOM Extension study. Osteoporos Int.
LHG, JM, JYR, ATW, RBW, EML. Approving final version of 2015;26(12): 2773–83.
manuscript: SF, CL, CJFL, JB, FC, EC, LHG, JM, JYR, ATW, RBW,
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