Research

JAMA | Original Investigation

Association Between Alendronate Use and Hip Fracture Risk

in Older Patients Using Oral Prednisolone
Kristian F. Axelsson, MD, MSc; Anna G. Nilsson, MD, PhD; Hans Wedel, PhD; Dan Lundh, PhD;
Mattias Lorentzon, MD, PhD

Supplemental content
IMPORTANCE Oral glucocorticoid treatment increases fracture risk, and evidence is lacking
regarding the efficacy of alendronate to protect against hip fracture in older patients
using glucocorticoids.

OBJECTIVE To investigate whether alendronate treatment in older patients using oral

prednisolone is associated with decreased hip fracture risk and adverse effects.

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study using a national database
(N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at
Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3
months of oral prednisolone treatment (5 mg/d) were identified. Propensity score
matching was used to select 1802 patients without alendronate use from 6076 patients
taking prednisolone with the same dose and treatment time criteria. Follow-up occurred
between January 2008 and December 2014.

EXPOSURES Alendronate vs no alendronate use; no patients had previously taken

alendronate at the time of prednisolone initiation.

MAIN OUTCOMES AND MEASURES The primary outcome was incident hip fracture.

RESULTS Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524
(70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34
years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate
group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2)
fractures per 1000 person-years, with an absolute rate difference of 17.6 (95% CI, 24.8 to
10.4). The use of alendronate was associated with a lower risk of hip fracture in a
multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate
treatment was not associated with increased risk of mild upper gastrointestinal tract
symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0]
per 1000 person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5] vs 11.4 [95% CI,
8.0-16.2] per 1000 person-years; P = .86). There were no cases of incident drug-induced
osteonecrosis and only 1 case of femoral shaft fracture in each group.

CONCLUSIONS AND RELEVANCE Among older patients using medium to high doses of
prednisolone, alendronate treatment was associated with a significantly lower risk
of hip fracture over a median of 1.32 years. Although the findings are limited by the
observational study design and the small number of events, these results support
the use of alendronate in this patient group.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Mattias
Lorentzon, MD, PhD,
Geriatric Medicine, Institute of
Medicine, Sahlgrenska Academy,
Bldg K, Sixth Floor, Sahlgrenska
University Hospital, Mlndal,
431 80 Mlndal, Sweden
JAMA. 2017;318(2):146-155. doi:10.1001/jama.2017.8040 (mattias.lorentzon@medic.gu.se).

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 Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone
G
lucocorticoid therapy is widely used to treat inflam-
matory conditions and is the most common cause of
secondary osteoporosis.1 Treatment with glucocorti-
coids is especially common (2%-3%) in patients older than 65
years.2 Glucocorticoid treatment leads to rapid bone loss, re-
flected by reduced bone mineral density (BMD). The effect of
glucocorticoid treatment is most prominent on trabecular bone
and is therefore likely to be larger on vertebral bone than on
hip bone.3 Glucocorticoids are associated with an increased rate
of fracture, and higher doses and longer use of glucocorti-
coids are associated with higher risks of fracture.4 Compared
with patients not taking glucocorticoids, the risk of hip and ver-
tebral fracture among patients taking glucocorticoids is in-
creased by 60% and 160%, respectively.4 Among 80-year-old
patients, the hip fracture risk is increased by a magnitude of
2.1 and is independent of BMD.5 Most studies indicate that frac-
ture risk is increased following at least 3 months of treatment
with daily doses of 5 mg of prednisolone or more in older men
and women.4
High-quality evidence supports the use of alendronate for
prevention of vertebral fractures among glucocorticoid-
treated patients, but the quality of evidence is low for preven-
tion of nonvertebral fractures; evidence is lacking for preven-
tion of hip fracture because trials were small and were not
designed to study rare events such as hip fractures.6,7 De-
spite this evidence gap, pharmacotherapy for prevention and
treatment of osteoporosis among glucocorticoid-treated pa-
tients is recommended in US and European Union guidelines.8,9
Hip fracture is the most severe type of fracture and is strongly
associated with declining physical function and increased mor-
bidity and mortality.10 After hip fracture, 40% to 60% of pa-
tients are not likely to regain their prefracture level of mobility,11
and the absolute 1-year mortality rate ranges from 6% to 50%.12
Alendronate reduces the risk of hip fracture by 40% in post-
menopausal women13 who are not treated with glucocorti-
coids. Prednisolone is the primary glucocorticoid used for long-
term treatment of inflammatory diseases.1 The aim of this
retrospective cohort study was to investigate whether alen-
dronate prescribed to patients treated with prednisolone was
associated with reduced risk of hip fracture in a large cohort
of older men and women.
Methods
This study was approved by the regional ethical review board
of Gothenburg, Sweden, which issued a waiver regarding the
need for patient informed consent.
Setting and Study Population
All men and women aged 65 years or older who underwent a
health evaluation and were registered in the Senior Alert
database (baseline) between 2008 and 2014 were eligible
for this study. The Senior Alert database was designed to fol-
low and support improvements in preventive care for older
adults. Seniors were enrolled in connection to a health care
visit. The database included more than 90% of all munici-
palities and counties in Sweden.14 In 2014, Senior Alert cov-
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Original Investigation Research
Key Points
Question Is alendronate associated with lower risk of hip fracture
among older patients taking medium to high doses of oral
glucocorticoids?
Findings In this retrospective cohort study of 3604 patients using
medium or high doses of prednisolone, the additional use of
alendronate was associated with a significantly lower risk of hip
fracture over a median 1.32 years of follow-up (9.5 vs 27.2 fractures
per 1000 person-years).
Meaning Among older patients using medium to high doses of
prednisolone, alendronate use was associated with a lower risk
of hip fracture.
ered approximately 22% of the Swedish population aged 65
years or older. Patients with extreme entries regarding
height, weight, or body mass index (top and bottom 0.1%)
were excluded from the Senior Alert register data because of
probable register entry errors. Several Swedish national reg-
isters were linked to the Senior Alert database to create the
Fractures and Fall Injuries in the Elderly Cohort15 to study
associations regarding fractures, fall injuries, morbidity,
mortality, and medications. Patients with metastatic cancer
were excluded to avoid analysis of terminally ill patients.
Also, patients with severe kidney failure, who were not eli-
gible for alendronate treatment, were excluded. Patients
who stopped prednisolone treatment, had a short treatment
duration (<3 months of prednisolone or alendronate), started
alendronate before prednisolone, used glucocorticoids other
than prednisolone, or used osteoporosis medication other
than alendronate were also excluded.
Ascertainment of Treatment
Medication data were collected from the Swedish Prescribed
Drug Register for the years 2005-2014, but only predniso-
lone treatment before inclusion in the Senior Alert register
(baseline) was included. Treatment time was defined as the
time between the first and last dates of dispensation before
baseline. Average daily dose was calculated as the cumula-
tive dispensed dose divided by the treatment time.
Only patients who had not previously taken alendronate
and started alendronate treatment after prednisolone treat-
ment were included. Patients with other medication for os-
teoporosis (risedronate, zoledronic acid, denosumab, testos-
terone, systemic estrogens, strontium ranelate, parathyroid
hormone analogs, or selective estrogen receptor modulators)
were excluded. Treatment time was measured from the date
of the first prescription of alendronate to the date when the
last dispensed prescription was expected to be consumed. Only
treatment time before baseline (inclusion in the Senior Alert
register) was included. Medication possession ratio was de-
fined as the percentage (0%-100%) of days with treatment dur-
ing the treatment time.16
Ascertainment of Fracture and Other Outcomes
All nonmalignant fracture diagnoses in the International Sta-
tistical Classification of Diseases and Related Health Problems,
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 Research Original Investigation
Tenth Revision (ICD-10) regardless of type of trauma were in-
cluded, apart from fractures involving the head (eTable 1 in the
Supplement), using the Swedish National Patient Register.17
If a fracture diagnosis on the same skeletal site (defined as hav-
ing the same first 2 digits in the ICD-10 code) was repeated
within 5 months, the later diagnosis was not included be-
cause it was considered to reflect a revisit rather than a new
fracture.
The main outcome, hip fracture, was defined as a frac-
tured femoral head, neck, trochanter, or subtrochanteric part
of the femur if the code for surgical procedure was used
(eTable 2 in the Supplement). Identification of hip fracture in
registers using this combination has high accuracy.18 Ascer-
tainment of hip fracture was blinded with regard to alendro-
nate and prednisolone status. Time to hip fracture was calcu-
lated from baseline to the time of the hip fracture and censored
for emigration (from Statistics Sweden), death (from the
Swedish Cause of Death Register), or end of study period (De-
cember 31, 2014).
Other outcomes included major osteoporotic fractures, any
fracture, nonvertebral fracture, fall injury without fracture
(eTables 1-2), and death. Dyspepsia, acid reflux, and esopha-
gitis were collected from the Swedish National Patient Regis-
ter and combined to define mild upper gastrointestinal tract
symptoms. In addition, incidence of peptic ulcer, drug-
induced osteonecrosis, and femoral shaft fractures was ana-
lyzed (eTable 3 in the Supplement).
Ascertainment of Morbidity and Covariates
Data regarding prevalent (prebaseline) diseases were col-
lected from the National Patient Register (2001-2014 for out-
patient visits, including all patient visits to hospitals, and 1987-
2014 for admitted patients), but information from primary care
clinics was not included. The Charlson comorbidity index was
calculated to summarize and quantify comorbidity.19 The defi-
nitions of the covariates and secondary osteoporosis are pre-
sented in eTables 4 through 8 in the Supplement. General con-
dition, food intake, and liquid intake were characterized using
the validated Risk Assessment Pressure Sore or Norton scales,20
which were assessed at baseline along with measurements of
weight and height, all available in the Senior Alert register.
Prevalent calcium and vitamin D treatment according to the
Swedish Prescribed Drug Register was defined as any treat-
ment length exceeding 3 months during the last 2 years be-
fore baseline.
Statistical Analyses
Patients using both alendronate and prednisolone were
matched, using 1:1 propensity score matching, to patients using
only prednisolone.21,22 Matching variables are presented in
Table 1 for patients with 5-mg/d or higher dosages of pred-
nisolone treatment. To assess prematch imbalance and post-
match balance, standardized differences were estimated for
all baseline covariates before and after matching.23 For a given
covariate, a standardized difference of less than 10% indi-
cates a relatively small imbalance.23 To investigate differ-
ences between the treated and untreated groups, the Fisher
exact test was used for categorical variables and the t test for
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Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone
continuous variables if normally distributed; if not, the Mann-
Whitney test was used. Event rates per 1000 person-years were
calculated as number of events divided by total follow-up time
until the event, death, or censoring per 1000 years, with 95%
confidence intervals estimated by assuming Poisson distribu-
tion. The difference between 2 event rates was tested by as-
suming approximately normal distribution of the estimates
with the Z test statistic.
To investigate the association between fracture risk and
treatment with prednisolone, alendronate, or both (evalu-
ated up to baseline), a Cox proportional hazards model start-
ing at baseline was used. The multivariable Cox model was
adjusted for age, sex, weight, height, known fracture-free
time, any previous fracture, number of previous fractures,
previous hip fracture, previous vertebral fracture, previous
fall injury, osteoporosis (ICD-10 codes M80-M81), secondary
osteoporosis, Charlson comorbidity index, previous calcium
and vitamin D treatment, rheumatoid arthritis, and alcohol-
related diseases (multivariable adjustment). The Cox regres-
sion model used the length of each individuals follow-up
period (time at risk). Cox analyses were performed for hip
fracture, major osteoporotic fracture, any fracture, nonverte-
bral fracture, death, and adverse effects. The alendronate
analysis was repeated for all investigated treatment variables:
binary alendronate treatment variable (yes/no), treatment
length, and medication possession ratio.
The association between alendronate use and hip frac-
ture was also investigated using an unadjusted Cox model
according to tertiles of cumulative dose of prednisolone.
Using time-dependent Cox models with a linear interaction
term between time and alendronate and by visually review-
ing the log(log[survival]) vs log(time) curves for each out-
come, the Cox models satisfied the proportionality assump-
tion. To address the issue of potential persistence bias and
the possible healthy adherer effect,24 the persistence of the
common drug acetylsalicylic acid was analyzed and alendro-
nate users were compared with those not using alendronate.
Statistical analyses were performed using SPSS software,
version 22 (IBM), and the propensity score matching was per-
formed using R, version 3.3.2, with the MatchIt package.
Significance testing was 2-sided and P<.05 was considered
statistically significant.
Results
Compared with patients without prednisolone, the risk of hip
fracture was increased only among patients with 5-mg/d or
higher dosages of prednisolone treatment (eAppendix, eTables
9-10, and eFigure 1 in the Supplement). Therefore, all further
analyses were restricted to these patients. The investigated co-
hort consisted of 1802 patients with oral prednisolone and alen-
dronate treatment and 1802 matched controls, selected from
6076 patients with oral prednisolone but without alendro-
nate treatment (Figure 1 and Figure 2). The total and median
follow-up time for all 3604 patients were 5620 person-years
and 1.32 years (interquartile range, 0.57-2.34 years), respec-
tively. The primary inclusion sites were hospital wards (68%)
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 Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone Original Investigation Research

Table 1. Baseline Characteristics of Older Patients Receiving 5 mg/d or More of Prednisolone

With and Without Alendronate Treatment

No Alendronate
Alendronate Unmatched Standardized Matched 1:1a Standardized
Characteristics (n=1802) (n=6076) Difference, % (n=1802) Difference, %
Prednisolone dosage, 8.5 (6.4-11.8) 7.6 (5.8-10.9) 4.5 7.6 (6.0-10.8) 6.8
median (IQR), mg/d
Prednisolone 4.5 (2.2-6.4) 3.2 (1.2-5.8) 32.2 4.7 (2.1-6.5) 0.8
treatment time,
median (IQR), y
Prednisolone 12.8 (8.0-18.0) 9.0 (4.5-14) 34.4 12.0 (7.0-16.9) 5.9
accumulated dose,
median (IQR), g
Alendronate medication 88 (61-99)
possession ratio
since prednisolone
treatment start,
median (IQR), %b
Time from prednisolone 3.9 (0.5-20.0)
to alendronate initiation,
median (IQR), mo
Alendronate 2.9 (1.4-5.0)
treatment time,
median (IQR), y
Female, No. (%) 1276 (70.8) 3155 (51.9) 39.5 1248 (69.3) 3.4
Age, mean (SD), y 79.9 (7.1) 81.6 (7.7) 22.1 80.0 (7.8) 0.8
Weight, mean (SD), kg 70.6 (15.7) 72.7 (16.3) 13.0 71.2 (16.2) 3.9
Height, mean (SD), cm 164.8 (9.2) 167.2 (9.9) 25.3 165.2 (9.6) 4.6
Known fracture-free 24.8 (4.7-26.2) 24.8 (5.8-26.2) 5.7 24.9 (5.2-26.3) 3.0
time, median (IQR), y
Any previous 641 (35.6) 1948 (32.1) 7.4 618 (34.3) 2.7
fracture, No. (%)
No. of previous
fractures, No. (%)
0 1161 (64.4) 4128 (67.9) 7.4 1184 (65.7) 2.7
1 425 (23.6) 1386 (22.8) 1.8 427 (23.7) 0.3
2 136 (7.5) 373 (6.1) 5.6 108 (6.0) 6.2
3 80 (4.4) 189 (3.1) 7.0 83 (4.6) 0.8
Previous hip 104 (5.8) 518 (8.5) 10.7 104 (5.8) 0
fracture, No. (%)
Previous vertebral 186 (10.3) 417 (6.9) 12.4 173 (9.6) 2.4
fracture, No. (%)
Previous fall 605 (33.6) 2035 (33.5) 0.2 583 (32.4) 2.6
injury, No. (%)
Osteoporosis, 314 (17.4) 329 (5.4) 38.5 234 (13.0) 12.4
No. (%)
Secondary 130 (7.2) 431 (7.1) 0.5 114 (6.3) 3.5
osteoporosis,
No. (%)
Insulin-dependent 95 (5.3) 348 (5.7) 2.0 93 (5.2) 0.5
diabetes
Hyperthyroidism 28 (1.6) 81 (1.3) 1.8 22 (1.2) 2.8
Hypogonadism 2 (0.1) 3 (0.0) 2.2 1 (0.1) 1.9
Malnutrition 6 (0.3) 21 (0.3) 0.2 6 (0.3) 0
Osteogenesis 0 0 0
imperfecta
Chronic liver 34 (1.9) 101 (1.7) 1.7 32 (1.8) 0.8
disease
Charlson comorbidity 649 (36.0) 2170 (35.7) 0.6 654 (36.3) 0.6
index 0, No. (%)
Charlson comorbidity 555 (30.8) 1790 (29.5) 2.9 593 (32.9) 4.5
index 1-2, No. (%)
Charlson comorbidity 598 (33.2) 2116 (34.8) 3.5 555 (30.8) 5.1
index 3, No. (%)

(continued)

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 Research Original Investigation Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone

Table 1. Baseline Characteristics of Older Patients Receiving 5 mg/d or More of Prednisolone

With and Without Alendronate Treatment (continued)

No Alendronate
Alendronate Unmatched Standardized Matched 1:1a Standardized
Characteristics (n=1802) (n=6076) Difference, % (n=1802) Difference, %
Charlson comorbidity
index components, No. (%)
Ischemic heart diseases 421 (23.4) 1600 (26.3) 6.9 438 (24.3) 2.2
Congestive heart failure 344 (19.1) 1324 (21.8) 6.7 336 (18.6) 1.1
Cerebrovascular 248 (13.8) 966 (15.9) 6.0 246 (13.7) 0.3
diseases
Diseases of arterioles 234 (13.0) 664 (10.9) 6.3 235 (13.0) 0.2
and capillaries
Diabetes 331 (18.4) 1102 (18.1) 0.6 332 (18.4) 0.1
Dementia 108 (6.0) 557 (9.2) 12.0 117 (6.5) 2.1
Chronic liver disease 34 (1.9) 101 (1.7) 1.7 32 (1.8) 0.8
Chronic pulmonary 243 (13.5) 736 (12.1) 4.1 236 (13.1) 1.1
disease
Renal failure, mild 113 (6.3) 520 (8.6) 8.7 128 (7.1) 3.3
Renal failure, 20 (1.1) 66 (1.1) 0.2 23 (1.3) 1.5
moderate
Peptic ulcer 91 (5.0) 343 (5.6) 2.6 84 (4.7) 1.8
disease
Hemiplegia 15 (0.8) 118 (1.9) 9.5 11 (0.6) 2.6
Tumor without 366 (20.3) 1220 (20.1) 0.6 356 (19.8) 1.4 Abbreviation: IQR, interquartile
metastasis (<5 y) range.
a
Lymphoma or leukemia 50 (2.8) 245 (4.0) 6.9 43 (2.4) 2.4 Matched according to all variables
listed in the table (except for
Inflammatory-related
variables with data available only in
diseases, No. (%)
the alendronate group).
Polymyalgia 577 (32.0) 1309 (21.5) 23.8 567 (31.5) 1.2 b
rheumatica Medication possession ratio was
calculated as the sum of the defined
Other systemic 186 (10.3) 319 (5.3) 19.0 175 (9.7) 2.0
connective tissue daily doses during the treatment
disorders time divided by the time since
prednisolone start.
Noninfective 92 (5.1) 288 (4.7) 1.7 90 (5.0) 0.5
c
enteritis and colitis Data regarding prevalent calcium
Rheumatoid arthritis 342 (19.0) 986 (16.2) 7.2 346 (19.2) 0.6 and vitamin D treatment was
retrieved from the Swedish
Calcium and vitamin D 1572 (87.2) 2839 (46.7) 95.4 1581 (87.7) 1.5 Prescribed Drug Register and
treatment, No. (%)c
defined as any treatment length
Alcohol-related 4 (0.2) 59 (1.0) 9.7 4 (0.2) 0 exceeding 3 months during the last
diseases, No. (%) 2 years before baseline.

and nursing homes (18%), and the remaining patients came
from residential home care (6.7%), health centers (4.3%), and
rehabilitation units (2.6%). Patients immigrating to Sweden in
2004 or earlier accounted for 7.4% of the patients.
The standardized differences between the groups were be-
low 10% for all investigated baseline characteristics except for
osteoporosis, which was 12.4% (Table 1). The median alendro-
nate treatment time prior to baseline was 2.9 (interquartile
range, 1.4-5.0) years. The median alendronate medication pos-
session ratio since prednisolone treatment start was 88% and
the median time delay from start of prednisolone to alendro-
nate initiation was 3.9 (interquartile range, 0.5-20.0) months.
There were no significant differences between the alendronate-
treated and alendronate-untreated patients in terms of gen-
eral condition, liquid intake, or food portions (eTable 11 in the
Supplement).
There were 27 hip fractures in the alendronate group
and 73 in the alendronate-untreated group, corresponding to
incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI,
21.6-34.2) fractures per 1000 person-years, with an absolute rate
difference of 17.6 (95% CI, 24.8 to 10.4) (Table 2). In an un-
adjusted Cox model, alendronate treatment was associated with
lower of risk of hip fracture (hazard ratio [HR], 0.35; 95% CI, 0.23-
0.55), and the risk estimate did not substantially change in mul-
tivariable-adjusted Cox models (Table 2 and Figure 3). The
30-month absolute risk reduction, based on the multivariable
Cox model, was estimated to be 4.1% (95% CI, 2.8%-5.4%). These
associations were maintained for women but lacked statistical
power among men (eTable 12 in the Supplement). The associa-
tion between alendronate use and hip fracture risk was main-
tained in patients taking both medium- and high-dose pred-
nisolone (eTable 13 in the Supplement).
The association between alendronate use and hip frac-
ture risk was also investigated according to tertile of cumula-
tive prednisolone dose (eFigure 2 in the Supplement). The in-
cidence was lower in patients with than without alendronate
treatment, irrespective of cumulative prednisolone tertile
(lowest tertile: 9 vs 22 hip fractures or 9.4 [95% CI, 4.9-18.1]

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 Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone Original Investigation Research

vs 22.2 [95% CI, 14.6-33.7] per 1000 person-years, with a dif-

Figure 1. Study Population
ference of 12.8 [95% CI, 23.9 to 1.6]; middle tertile: 9 vs 29
hip fractures or 8.8 [95% CI, 4.6-16.8] vs 28.5 [95% CI, 19.8-
433 195 Patients aged 65 y with a health
41.1] per 1000 person-years, with a difference of 19.8 [95% assessment in 2008-2014
CI, 31.6 to 7.9]; highest tertile: 9 vs 22 hip fractures or 10.6
[95% CI, 5.5-20.4] vs 32.5 [95% CI, 21.4-49.3] per 1000 person- 3882 Excludeda
years, with a difference of 21.9 [95% CI, 37.1 to 6.6]). Using 260 Faulty mortality data
1369 Unreliable registration of weight,
an unadjusted Cox model, alendronate treatment was associ- height, or BMIb
ated with hip fracture risk in all tertiles of cumulative pred- 368 Not residing in Sweden at study
inclusion
nisolone dose (lowest tertile: HR, 0.43 [95% CI, 0.20-0.93]; 2240 Immigrated after 2004, thereby
not available during the entire
middle tertile: HR, 0.31 [95% CI, 0.15-0.65]; highest tertile: HR, drug evaluation period
0.33 [95% CI, 0.15-0.72]). Inclusion of cumulative predniso-
lone dose as a covariate in the multivariable Cox model (Table 2)
429 313 Patients enrolled in the Fractures and
did not affect the risk estimate for the association between alen- Fall Injuries in the Elderly Cohort
dronate use and risk of hip fracture (alendronate use HR, 0.35;
95% CI, 0.22-0.54). 350 742 Excludeda
For patients using prednisolone, the risk of major osteo- 344 105 No prednisolone treatment
19 601 Had metastatic cancer
porotic fracture, any fracture, and nonvertebral fracture was 5555 Had severe kidney failure
significantly lower in patients treated with alendronate than
in those not treated with it, both in percentage and per 1000 78 571 Had prednisolone treatment
person-years (Table 2). In unadjusted and multivariable Cox (17 574 Had alendronate treatment)

models, alendronate treatment was associated with risk of

major osteoporotic fracture (unadjusted HR, 0.53 [95% CI, 70 693 Excludeda
66 334 Prednisolone exclusion criteriaa
0.39-0.74]; multivariable-adjusted HR, 0.53 [95% CI, 0.38- 23 649 Average dosage <5 mg/d
0.73]), any fracture (unadjusted HR, 0.60 [95% CI, 0.48- 50 403 More than 3 mo since last
dispensation
0.76]; multivariable-adjusted HR, 0.58 [95% CI, 0.46-0.73]), 29 242 Treatment time <3 mo
and nonvertebral fracture (unadjusted HR, 0.57 [95% CI, 17 091 Other glucocorticoid
treatment
0.45-0.73]; multivariable-adjusted HR, 0.55 [95% CI, 0.43- 20 149 Alendronate exclusion criteriaa
0.71]) (Table 2). The 30-month absolute risk reduction of 10 463 Previously treated but
not treated at baseline
alendronate treatment, based on multivariable Cox models,
4464 Treatment started before
was estimated to be 3.9% (95% CI, 2.2%-5.4%) for major prednisolone
2747 Treatment time <3 mo
osteoporotic fracture, 5.7% (95% CI, 3.9%-8.0%) for any frac-
10 060 Received other medication
ture, and 5.5% (95% CI, 3.6%-7.5%) for nonvertebral fracture. for osteoporosis
These associations were maintained for women but lacked
statistical power for analysis in men (eTable 12 in the Supple- 7878 Eligible patients
ment). Alendronate was associated with risk of hip fracture
irrespective of prednisolone dose group (eTable 13 in the
Supplement). 6076 Treated with 1802 Treated with
When the multivariable Cox model was analyzed using prednisolone only prednisolone
+ alendronate
alendronate treatment length as an independent variable in-
stead of dichotomous alendronate use (yes or no), treatment
1802 1:1 Propensity 1802 Patients included
length in years was associated with risk of hip fracture (HR, scorematched in primary analysis
control patients
0.83; 95% CI, 0.74-0.92) (Table 2). Using the same Cox model included in
with medication possession ratio of alendronate instead of primary analysis

treatment length, a 10% increase in medication possession ra-

tio of alendronate was associated with lower risk of hip frac-
ture (HR, 0.89; 95% CI, 0.85-0.93) (Table 2).
Overall, there were 642 deaths (35.6%) among patients
using alendronate and 698 deaths (38.7%) among those not
using alendronate. Using a Cox model adjusted for age, sex,
height, weight, and Charlson comorbidity index, alendronate
treatment, in patients using prednisolone, was associated with
a lower risk of death (HR, 0.88; 95% CI, 0.79-0.98) (eTable 14
in the Supplement). Deaths for which hip fractures were listed
as a possible cause did not differ significantly between pa-
tients with and without alendronate use (8 [0.4%] vs 17 [0.9%];
P = .11, respectively; HR, 0.47; 95% CI, 0.20-1.08; P = .08 in a
Cox model adjusted for age, sex, height, weight, and Charlson
a
Each patient may be included in more than 1 exclusion group.
b
Accepted values after exclusion of top and bottom 0.1% of weight, height,
and body mass index (BMI): weight, 30-176 kg; height, 114-197 cm;
BMI, 12.23-73.05.
comorbidity index). Incident fall injuries did not differ signifi-
cantly between alendronate-treated and untreated patients
(eTable 14).
The incidence of mild upper gastrointestinal tract symp-
toms (15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000
person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5]
vs 11.4 [95% CI, 8.0-16.2] per 1000 person-years; P = .86) was
not higher among patients using alendronate (eTable 14). There

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 Research Original Investigation
Figure 2. Schematic Description of Study Design
Drug evaluation period
2005 to baseline
Prednisolone exposure prior to baseline (n=3604)
median (range), 55.0 (3.0-113.4), mo
Alendronate exposure prior to baseline (n=1802)
median (range), 34.5 (3.0-113.1), mo
The drug evaluation period was between 2005, when the Swedish Prescribed
Drug Register started, and baseline. All patients (n = 3604) had daily average
prednisolone doses of 5 mg or more, ongoing treatment at baseline, longer
treatment than 3 months (dashed vertical line), and no record of another
glucocorticoid than prednisolone. Patients with alendronate use (n = 1802)
started treatment after prednisolone, alendronate treatment was ongoing at
baseline for longer than 3 months (dashed vertical line), and there was no
record of another osteoporosis medication than alendronate. Median time from
prednisolone initiation to alendronate initiation in the alendronate group was
were no cases of incident drug-induced osteonecrosis and there
was only 1 case of femoral shaft fracture in each group.
The association between alendronate use and hip frac-
ture risk was also investigated using all unmatched predniso-
lone-treated patients (n = 6076) as controls (eTable 15 in the
Supplement). In unmatched prednisolone-treated patients, 251
hip fractures (28.8 [95% CI, 25.5-32.6] per 1000 person-
years) occurred over a median follow-up of 1.19 (interquartile
range, 0.45-2.26) years. In a multivariable Cox model, alen-
dronate treatment was associated with lower risk of hip frac-
ture (HR, 0.38; 95% CI, 0.25-0.57). Among the 3604 patients
using prednisolone, there was no difference in medication pos-
session ratio of acetylsalicylic acid (analysis of healthy ad-
herer effect) (eFigure 3 in the Supplement; P = .91) between pa-
tients with or without alendronate treatment.
Discussion
In this retrospective cohort study of older men and women using
prednisolone, alendronate treatment for a median duration of
2.9 years was associated with lower risk of hip fracture than no
alendronate treatment. Sensitivity analyses revealed that greater
duration of alendronate treatment and higher medication pos-
session ratio, a proxy for alendronate treatment adherence, were
also associated with a lower risk of hip fracture. The age-
specific hip fracture incidence in the investigated population
was higher than previously reported,25,26 which could be re-
lated to prednisolone use and the high proportion of patients
with multiple comorbidities.
In a meta-analysis of pooled randomized trials with bis-
phosphonate treatment in patients receiving glucocorticoids
equivalent to a daily dose of prednisolone of 5 mg or more, the
use of bisphosphonates was associated with a nonsignificant
152 JAMA July 11, 2017 Volume 318, Number 2 (Reprinted)
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Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone
Evaluation of outcome
Baseline to end of study
(December 31, 2014, or emigration or death)
Outcomes
Hip fracture Nonvertebral fracture
Major osteoporotic fracture Death
Any fracture Adverse effects
Time at risk (n=3604)
median (range), 15.9 (0-74.4), mo
0 20 40 60 80
Baseline Time, mo
2008-2014
3.9 months (interquartile range, 0.5-20.0 months). The evaluation period for
medical history data (prebaseline diseases, prevalent fall injuries, and fractures)
was 1987 to baseline. Weight and height were retrieved at baseline from the
Senior Alert Register. Evaluation of outcomes during the time at risk was
performed from baseline to end of study (December 31, 2014; emigration; or
death). The Cox model accounted for different time of follow-up, but the initial
setup of covariates and alendronate use (yes/no) remained the same during
follow-up. Solid vertical lines on the treatment exposure bars indicate median
length of treatment exposure.
21% risk reduction in nonvertebral fractures, but the number
of fractures was low and the risk of bias was high because these
were self-reported fractures.6 Data on alendronate treatment
and hip fracture specifically have previously not been re-
ported for patients using glucocorticoids. The observed 65%
relative risk reduction for hip fracture in this study exceeds the
40% risk reduction observed in women with postmeno-
pausal osteoporosis in randomized trials with alendronate,13
a difference that could be anticipated because the greatest rela-
tive risk reductions are usually seen in patients with several
strong risk factors and therefore particularly high fracture risk,
such as those treated with glucocorticoids.27
To minimize the possibility of selection bias, propensity
score matching was used to obtain well-balanced groups and
adjustment was done for anthropometric variables, clinical risk
factors, and comorbidity. There were no differences between
groups in regard to risk of fall injury, indicating a lack of dif-
ference in frailty. Also, alendronate treatment was associated
with reduced mortality, which is consistent with a meta-
analysis of randomized clinical trials demonstrating a rela-
tive risk of mortality of 0.90 with antiresorptive treatment.28
Furthermore, the observation that acetylsalicylic acid persis-
tence did not differ between patients treated with alendro-
nate or not suggests the absence of a healthy adherer effect.
Strengths of this study include the size of the initial cohort
(N = 433 195), enabling selection to achieve a well-balanced
control group through propensity score matching and the study
design that investigated associations between alendronate, pre-
scribed after prednisolone initiation, and subsequent out-
comes. To address possible sources of bias, extensive sensitiv-
ity analyses were performed with several alendronate treatment
variables. Associations of alendronate with incidence of fall in-
jury were also analyzed. Associations of alendronate with hip
fracture were also tested according to presence of fall injury and
jama.com
 Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone Original Investigation Research

Table 2. Fracture Risk in Older Patients Receiving Prednisolone With and Without Alendronate Treatmenta

No Alendronate (n=1802) Alendronate (n=1802) P Value

Time at risk, median (IQR), d 468 (187-855) 498 (228-851) .11
Hip Fractures
No. (%) 73 (4.1) 27 (1.5) <.001
Per 1000 person-years (95% CI) 27.2 (21.6-34.2) 9.5 (6.5-13.9) <.001
Difference per 1000 person-years (95% CI) Reference 17.6 (24.8 to 10.4) <.001
Alendronate treatment (yes/no)
Unadjusted HR (95% CI) 1 [Reference] 0.35 (0.23-0.55) <.001
HR adjusted for age, sex, weight, and height (95% CI) 1 [Reference] 0.35 (0.23-0.55) <.001
Multivariable-adjusted HR (95% CI)b 1 [Reference] 0.35 (0.22-0.54) <.001
30-mo multivariable-adjusted ARR, %b Reference 4.1 (2.8-5.4) <.001
30-mo multivariable-adjusted No. needed to treatb Reference 24 (19-36) <.001
Multivariable-adjusted HR per year for alendronate 1 [Reference] 0.83 (0.74-0.92) <.001
treatment length (95% CI)b
Multivariable-adjusted HR per 10% alendronate 1 [Reference] 0.89 (0.85-0.93) <.001
medication possession ratio (95% CI)b
Major Osteoporotic Fractures
No. (%) 106 (5.9) 59 (3.3) .001
Per 1000 person-years (95% CI) 40.1 (33.1-48.5) 21.2 (16.4-27.4) <.001
Difference per 1000 person-years (95% CI) Reference 18.9 (28.3 to 9.5) <.001
Alendronate treatment (yes/no)
Unadjusted HR (95% CI) 1 [Reference] 0.53 (0.39-0.74) <.001
HR adjusted for age, sex, weight, and height (95% CI) 1 [Reference] 0.53 (0.39-0.73) <.001
Multivariable-adjusted HR (95% CI)b 1 [Reference] 0.53 (0.38-0.73) <.001
30-mo multivariable-adjusted ARR, %b Reference 3.9 (2.2-5.4) <.001
30-mo multivariable-adjusted No. needed to treatb Reference 26 (18-45) <.001
Multivariable-adjusted HR per year for alendronate 1 [Reference] 0.91 (0.84-0.98) .02
treatment length (95% CI)b
Multivariable-adjusted HR per 10% alendronate 1 [Reference] 0.93 (0.90-0.96) <.001
medication possession ratio (95% CI)b
Any Fracture
No. (%) 186 (10.3) 118 (6.5) <.001
Per 1000 person-years (95% CI) 73.3 (63.5-84.7) 43.4 (36.3-52.0) <.001
Difference per 1000 person-years (95% CI) Reference 29.9 (43.0 to 16.8) <.001
Alendronate treatment (yes/no)
Unadjusted HR (95% CI) 1 [Reference] 0.60 (0.48-0.76) <.001
HR adjusted for age, sex, weight, and height (95% CI) 1 [Reference] 0.59 (0.47-0.75) <.001
Multivariable-adjusted HR (95% CI)b 1 [Reference] 0.58 (0.46-0.73) <.001
30-mo multivariable-adjusted ARR, %b Reference 5.7 (3.9-8.0) <.001
Multivariable-adjusted HR per year for alendronate 1 [Reference] 0.94 (0.89-0.99) .02
treatment length (95% CI)b
Multivariable-adjusted HR per 10% alendronate 1 [Reference] 0.94 (0.92-0.96) <.001
medication possession ratio (95% CI)b
Nonvertebral Fracture
No. (%) 169 (9.4) 102 (5.7) <.001
Per 1000 person-years (95% CI) 66.0 (56.8-76.8) 37.2 (30.6-45.1) <.001
Difference per 1000 person-years (95% CI) Reference 28.9 (41.2 to 16.6) <.001
Alendronate treatment (yes/no)
Unadjusted HR (95% CI) 1 [Reference] 0.57 (0.45-0.73) <.001
HR adjusted for age, sex, weight, and height (95% CI) 1 [Reference] 0.56 (0.44-0.72) <.001
Multivariable-adjusted HR (95% CI)b 1 [Reference] 0.55 (0.43-0.71) <.001
30-mo multivariable-adjusted ARR, %b Reference 5.5 (3.6-7.5) <.001
Multivariable-adjusted HR per year for alendronate 1 [Reference] 0.93 (0.88-0.99) .02
treatment length (95% CI)b
Multivariable-adjusted HR per 10% alendronate 1 [Reference] 0.93 (0.91-0.96) <.001
medication possession ratio (95% CI)b
b
Abbreviations: ARR, absolute risk reduction; HR, hazard ratio; Multivariable adjustment for age, sex, weight, height, known fracture-free
IQR, interquartile range. time, previous fracture, number of previous fractures, previous hip fracture,
a
Event rates per 1000 person-years were calculated as number of events previous vertebral fracture, previous fall injury, osteoporosis, secondary
divided by the total follow-up time until the event, death, or censoring per osteoporosis, Charlson comorbidity index, rheumatoid arthritis, previous
1000 years, with 95% CIs estimated by assuming Poisson distribution. calcium and vitamin D treatment, and alcohol-related diseases.

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 Research Original Investigation Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone

Figure 3. Hip Fracture Risk With and Without Alendronate in Patients With Prednisolone Treatment

1.0 0.10
Hazard ratio, 0.35 (95% CI, 0.22-0.54);
0.9 Log-rank P <.001 No alendronate use
0.08
0.8
Cumulative Hip Fracture Incidence

0.06
0.7

0.6 Cox regression model adjusted for

0.04
Alendronate use age, sex, weight, height, known
0.5 fracture-free time, previous fracture,
0.02 number of previous fractures,
0.4 previous hip fracture, previous
0 vertebral fracture, previous fall injury,
0.3
0 1 2 3 4 osteoporosis, secondary
Time to Hip Fracture, y osteoporosis, Charlson comorbidity
0.2
index, rheumatoid arthritis, previous
0.1 No alendronate use calcium and vitamin D treatment, and
Alendronate use alcohol-related diseases. The inset
0
0 1 2 3 4 shows the same data on an enlarged
Time to Hip Fracture, y y-axis. Median follow-up for
No. at risk alendronate use was 498
No alendronate use 1802 1044 556 226 42 (interquartile range, 228-851) days;
Alendronate use 1802 1110 588 230 64 for no alendronate use, 468
(interquartile range, 187-855) days.

a measure of persistent alendronate use. Furthermore, the use
of extensive comorbidity data allowed for adequate consider-
ation of confounding factors.
This study has several limitations. First, the observa-
tional design prevented assessment of causality. Second, the
number of hip fracture events was small. Third, densitom-
etry data were not available. Fourth, specific information re-
garding trauma type was not included, although evidence
shows that trauma type does not discriminate osteoporotic
from nonosteoporotic fractures29 and that 95% of hip frac-
tures in older patients are related to a fall.30 Fifth, it is pos-
sible that some of the patients in the control group had re-
ceived other medications for osteoporosis; zoledronic acid,
given intravenously, has become more common in Sweden31
but is seldom registered in the Prescribed Drug Register be-
cause it is mainly provided directly by osteoporosis clinics.
Sixth, the reporting of nonhip fractures is most likely less ac-
curate than for hip fractures in the National Patient Register,
which could have led to underestimation of nonhip fracture
events. Seventh, it is possible that not all adverse effects were
identified because primary care diagnoses are not included in
the National Patient Register. Eighth, the participants in this
study population were mainly white, so it is uncertain whether
the obtained results would be generalizable to other popula-
tion groups. Ninth, although patients stopping or starting alen-
dronate treatment after the baseline assessment could affect
the fracture risk in the present study, time-dependent Cox
models were not deemed appropriate considering knowl-
edge obtained from randomized trials with alendronate. Spe-
cifically, the risk of nonspine fracture risk is not affected within
5 years following alendronate withdrawal after long-term
treatment.32 In addition, the hip fracture risk reduction after
starting alendronate is delayed and cannot be detected until
18 months of treatment.33
Conclusions
Among older patients using medium to high doses of pred-
nisolone, alendronate treatment was associated with a signifi-
cantly lower risk of hip fracture over a median of 1.32 years.
Although the findings are limited by the observational study
design and the small number of events, these results support
the use of alendronate in this patient group.

ARTICLE INFORMATION
Accepted for Publication: June 13, 2017.
Author Affiliations: Department of Orthopaedic
Surgery, Skaraborg Hospital, Skvde, Sweden
(Axelsson); Geriatric Medicine, Department of
Internal Medicine and Clinical Nutrition, Institute of
Medicine, University of Gothenburg, Gothenburg,
Sweden (Axelsson, Nilsson, Lorentzon);
Department of Endocrinology, Internal Medicine,
Sahlgrenska University Hospital, Gothenburg,
Sweden (Nilsson); Health Metrics, Sahlgrenska
Academy, University of Gothenburg, Gothenburg,
Sweden (Wedel); School of Bioscience, University
of Skvde, Skvde, Sweden (Lundh); Geriatric
Medicine, Sahlgrenska University Hospital, Mlndal,
Sweden (Lorentzon).
Author Contributions: Drs Axelsson and Lorentzon
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Axelsson, Nilsson,
Lorentzon.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Axelsson, Nilsson,
Lorentzon.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: All authors.
Obtained funding: Axelsson, Lorentzon.
Administrative, technical, or material support:
Axelsson, Lorentzon.
Study supervision: Lorentzon.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Dr Axelsson has received lecture fees from Lilly and
Meda. Dr Nilsson has received lecture fees from
Shire and Pfizer. Dr Lorentzon has received lecture
fees from Amgen, Lilly, Meda, Renapharma, and
UCB and consulting fees from Radius Health
and Consilient Health. No other disclosures
were reported.

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 Alendronate and Hip Fracture in Older Patients Using Oral Prednisolone
Funding/Support: This study was funded by the
Research Fund at Skaraborg Hospital Skvde, the
Skaraborg Institute, the Swedish Research Council,
the ALF/LUA grant from the Sahlgrenska University
Hospital, and King Gustaf Vs and Queen Victorias
Freemason Foundation.
Role of the Funders/Sponsors: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; or decision to submit
the manuscript for publication.
Additional Contributions: Aldina Pivodic, MSc
(Statistiska Konsultgruppen, Gothenburg, Sweden)
contributed specific analyses regarding verification
of the Cox model proportionality assumption and
confidence intervals for incidence rates per 1000
person-years, for which she was financially
compensated.
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