Is There Enough Evidence to Use Bisphosphonates
in HIV-Infected Patients? A Systematic Review
and Meta-analysis
Marilia Rita Pinzone1, Santiago Moreno2, Bruno Cacopardo1 and Giuseppe Nunnari1
1Department of Clinical and Molecular Biomedicine, Division of Infectious Diseases, University of Catania, Catania, Italy; 2Department of
Infectious Diseases, Institute for Health Research (IRICYS), University Hospital Ramón y Cajal, Madrid, Spain
Abstract
An increased prevalence of osteopenia and osteoporosis has been observed in HIV-infected cohorts.
We investigated the effect of bisphosphonates on bone mineral density in adults with HIV infection.
Outcomes of interest were bone mineral density changes measured by dual-energy X-ray absorptiometry
at the lumbar spine, femoral neck, and total hip, and adverse events. Data were pooled using the
fixed-effects model.
We identified eight randomized controlled trials meeting our inclusion criteria, involving 328 participants.
Five trials compared alendronate with placebo or no intervention; in three trials the intervention arm
received zoledronate. A significant increase in bone mineral density at the lumbar spine was observed
in the bisphosphonate group at 48 weeks (MD: 2.84%; 95% CI: 2.11-3.57) and 96 weeks (MD: 6.76%;
95% CI: 4.98-8.54); analogously, bisphosphonates were associated with an increase in total hip bone
mineral density at 48 weeks (MD: 2.12%; 95% CI: 1.43-2.81) and 96 weeks (MD: 3.2%; 95% CI: 1.52-4.88).
Bisphosphonates were generally well tolerated; no drug-related withdrawals were reported in the five
randomized controlled trials assessing alendronate, whereas two patients out of 104 receiving zoledronate experienced acute-phase reactions.
In conclusion, administration of oral and intravenous bisphosphonates was associated with increased
bone mineral density at the lumbar spine and total hip over two years in HIV-positive patients. However,
none of the included trials were long enough to detect the impact of bisphosphonates on a clinically
important outcome such as fracture risk. Larger studies with extended follow-up are warranted.
(AIDS Rev. 2014;16:213-22)
Corresponding author: Giuseppe Nunnari, [email protected]
Key words
Alendronate. Bisphosphonate. HAART. HIV. Osteoporosis. Zoledronate.
Introduction
The natural history of HIV infection has been dramatically changed by the introduction of HAART. Most
patients taking HAART experience durable control of
Giuseppe Nunnari
Department of Clinical and Molecular Biomedicine
Division of Infectious Diseases
ARNAS Garibaldi Nesima, University of Catania
Via Palermo 636, 95125
Catania, Italy
E-mail: [email protected]
HIV replication, so that the incidence of AIDS-related
events has significantly declined1. However, a concomitant increase in the morbidity and mortality attributable
to noninfectious complications, such as malignancies,
cardiovascular, renal, and bone disease, has been
observed2-5.
Osteoporosis is a skeletal disorder characterized by
micro-architectural abnormalities and reduced bone mineral density (BMD), which results in increased fracture
risk6. Osteopenia refers to a milder degree of bone demineralization. The BMD is usually measured using dualenergy X-ray absorptiometry (DXA) and expressed as
standard deviations from the population mean, either
as a z-score (compared to age- and sex-matched data)
© Permanyer Publications 2014
Marilia Rita Pinzone, et al.: Bisphosphonates for Increasing BMD in HIV
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
AIDS Rev. 2014;16:213-22
213
214
Search strategy, assessment of risk
of bias, and statistical methods
We did a systematic review and meta-analysis in
accordance with the PRISMA (Preferred Reporting Items
for Systematic reviews and Meta-analyses) guidelines37.
All RCTs comparing bisphosphonates to controls for
the treatment of low BMD in HIV-infected adults were
included. Outcomes of interest were BMD changes
measured by DXA at the lumbar spine, femoral neck,
and total hip, and adverse events.
Relevant RCTs were identified by electronic searching of the Cochrane Central Register of Controlled Trials
(CENTRAL) in The Cochrane Library, MEDLINE, EMBASE,
LILACS, the conference databases Aegis and NLM, the
prospective trials registers ClinicalTrials.gov and Current
Controlled Trials (www.controlled-trials.com/). Searches
were conducted in September 2013. An update was
made in July 2014, with the inclusion of the study presented at CROI 2014 by Negredo, et al.36.
Two authors (Pinzone and Nunnari) independently
reviewed all studies identified by the search strategy
and assessed the risk of bias by means of the Cochrane
Collaboration’s tool for assessing risk of bias in randomized trials38.
Data were analyzed using Review Manager 5.2.7.
For dichotomous outcomes (i.e. number of participants
with adverse events), we calculated risk ratios (RR) and
95% confidence intervals (CI). For quantitative outcomes
(i.e. BMD) we estimated the difference in mean percentage change from baseline in the bisphosphonate and
control group. When BMD values were not presented
in the manuscript text, an electronic caliper was used to
extract the data from figures39. For continuous outcomes,
the effect estimates were combined using the fixedeffects model (also known as the weighted-average
method). We examined statistical heterogeneity by the
I² statistic and the Chi² test40.
Additional data on the search strategy and statistical
methods are shown as Supplementary data.
Main characteristics of included studies
The literature searches retrieved a total of 387 citations (Fig. 1). From these, 13 articles were selected for
further scrutiny and nine were included in the systematic
review29-35,41,42. Two of these articles41,42 were extensions
of a previously published trial33 and were considered as
a single study in the systematic review. Our search for
ongoing trials retrieved two studies that potentially met
our inclusion criteria: one trial (ClinicalTrials.gov Identifier
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
or a t-score (compared to the mean BMD for a healthy,
young (25-35 years old), sex- and ethnicity-matched
reference population). The World Health Organization
classifies osteopenia as a t-score between –1 and –2.5
and osteoporosis as a t-score of –2.5 or less6.
Decreased BMD has been observed in several HIVinfected cohorts7-11. A recent meta-analysis reported
the prevalence of osteoporosis and osteopenia in HIVpositive patients as 15 and 67%, respectively12. Osteoporosis was three times more prevalent in HIV-infected
individuals compared with HIV-uninfected controls.
The causes of altered bone mass acquisition and bone
loss are not completely understood. Traditional risk
factors, such as smoking, alcohol use, vitamin D deficiency, hypogonadism, physical inactivity, and low
body weight, may contribute to the increased risk of
osteopenia/osteoporosis7,13,14. The HIV virus itself can
directly or indirectly alter osteoblastogenesis and osteoclastogenesis. In fact, HIV viral proteins vpr and
gp120 have been shown to stimulate osteoclast activity15,16, whereas p55-gag was found to suppress osteoblast activity and induce osteoblast apoptosis17. Furthermore, increased production of proinflammatory
cytokines, such as interleukin-6 and tumor necrosis
factor-α, may promote bone resorption18,19. Though
several studies have suggested an association between BMD loss and certain antiretroviral drugs, such
as tenofovir (TDF)14,20,21 and protease inhibitors (PI)7,22,
other studies have reported a 2-6% decrease in BMD
after initiation of HAART regardless of the initial regimen
choice23. The reasons for the early loss of BMD following HAART initiation are unclear. Moreover, longitudinal
studies have found that after the initial bone loss, BMD
seems to stabilize over time despite prolonged HAART
administration24,25.
Bisphosphonates are pyrophosphate analogues that
inhibit bone resorption by binding to hydroxyapatite
crystals26. Bisphosphonates are the most widely used
drugs in the treatment of postmenopausal osteoporosis27. In HIV-infected patients, both alendronate and
zoledronate have been used to increase BMD5. However, in a systematic review of Lin and Rieder28, the
authors concluded that no recommendation could be
made concerning the use of bisphosphonates in HIVpositive patients with low BMD as only three short-term
small studies were available when their systematic review was published29-31. Other randomized controlled
trials (RCTs) have been subsequently performed32-36. In
light of recently published studies, we aimed at reviewing the current evidence on the use of bisphosphonates to increase BMD in patients with HIV infection.
© Permanyer Publications 2014
AIDS Reviews. 2014;16
Additional records identified
through other sources
(n = 0)
Records after duplicates removed
(n = 154)
Records screened
(n = 154)
Records excluded
(n = 143)
Articles assessed for eligibility
(n = 13)
Articles excluded (n = 3)
n = 1 secondary analysis of a randomized
controlled trial included in this systematic review
n = 1 not a randomized controlled trial
n = 1 ongoing trial
Studies included in qualitative
synthesis (n = 8) corresponding
to 10 publications
Studies included in quantitative
synthesis (meta-analysis) (n = 8)
Figure 1. Flow diagram of studies considered for inclusion (adapted from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6:e1000097. For more
information, visit www.prisma-statement.org).
NCT00795483) evaluated the efficacy and safety of
annual and biennial zoledronic acid for the treatment
of osteoporosis in HIV-positive patients. At the time of our
first search, no results had been published; however,
an abstract was presented at CROI 201436 and these
results were used to update our meta-analysis in July
2014, for a total of eight studies meeting our inclusion
criteria. The other trial (ClinicalTrials.gov Identifier
NCT00662077) aimed at evaluating the efficacy and
safety of ibandronate for the treatment of osteoporosis
in HIV-infected adults. However, it has currently been
suspended due to financial difficulties.
The characteristics of the studies included in the systematic review are described in table 1. We identified
and included eight RCTs29-36, which assessed the effect
of bisphosphonates on BMD in a total of 328 adult participants with HIV infection. The trials were conducted
in the USA30,32,34, France35, Italy29, New Zealand33, and
Spain31,36. The majority of participants were male and
taking HAART at baseline. Most of them had consistent
suppression of viral replication at the time of enrollment.
Median baseline CD4+ T-cell counts ranged from 422 to
561 cells/μl. Four studies32-35 provided details on the
number of patients receiving TDF, which ranged from
0 to 53%. Four trials30,32,33,35 reported the number of
participants treated with regimens that included a PI
(range 37-66%). Three studies31,35,36 recruited only participants who had BMD t-score ≤ –2.5, two studies29,30
recruited participants with BMD t-score < –1, two studies32,34 included participants with BMD t-score ≤ –1.5,
and one trial33 enrolled subjects with BMD t-score
≤ –0.5. Five trials29-32,35 assessed alendronate versus
placebo or no intervention in 224 participants. In all five
studies, oral alendronate was given in a dose of 70 mg
weekly. Three trials33,34,36 assessed zoledronate versus
placebo or no drug in 104 participants. Intravenous zoledronate was given in a single dose of 5 mg in the Huang
trial34; in the Bolland trial33,41,42, patients received two
annual 4 mg doses of zoledronate. In the Negredo
2014 trial36, patients in the intervention arm received
an annual or biennial 5 mg dose of zoledronate; moreover, all participants received lifestyle modifications. In
© Permanyer Publications 2014
Records identified
through database searching
(n = 387)
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
Included
Eligibility
Screening
Identification
Marilia Rita Pinzone, et al.: Bisphosphonates for Increasing BMD in HIV
215
216
Italy
USA
Spain
USA
New
Zealand
USA
France
Spain
Guaraldi, et al.
200429
Mondy, et al.
200530
Negredo, et al.
200531
McComsey, et al.
200732
Bolland, et al.
200733, 200841,
201242
Huang, et al.
200934
Rozenberg, et al.
201235
Negredo, et al.
201436
96
96
52
96††
48
96
48
52
19
–
100
≤ –2.5 at the LS 100
and/or hip
≤ –1.5 at the LS 27
or hip
< –0.5 at the LS 7
or total hip
≤ –1.5 at the LS 21
Calcium carbonate
1 g/day and vitamin
D 400 IU/day
Two annual 5 mg doses Lifestyle
of intravenous
modifications
zoledronate vs. one
biennial 5 mg dose of
intravenous zoledronate
vs. no drug
Calcium carbonate
500 mg/day and
vitamin D 400 IU/day
Single 5 mg infusion of Calcium 1 g/day
zoledronate vs. placebo and vitamin D 400
IU/day
Alendronate 70 mg/
week vs. placebo
44
44
–
45‡
49
49
48‡
–
95
90
100
71
96
87
71
Age
Male
(years)† participants
(%)
Dietary counseling 49§/40¶
to ensure a calcium
dietary intake
of 1.2 g/day
Calcium carbonate
1 g/day and vitamin
D 400 IU/day
Calcium carbonate
1 g/day and vitamin
D 500 IU/day
Co-interventions
Two annual 4 mg doses Calcium 400 mg/
of intravenous
day and vitamin D
zoledronate vs. placebo 50,000 IU/month
Alendronate 70 mg/
week vs. placebo
Alendronate 70 mg/
week vs. no drug
Alendronate 70 mg/
week vs. no drug
Alendronate 70 mg/
week vs. no drug
Participants Intervention
with
osteoporosis
(%)*
≤ –2.5 at the LS, 100
hip or trochanter
< –1 at the LS
< –1 at the LS
or FN
31 (21/10)§§ < –2.5 at the
LS, hip and/
ortrochanter
44 (20/24)
30 (15/15)
43 (21/22)
82 (42/40)
26 (12/14)
31 (15/16)
41 (18/23)
Trial Sample size BMD t-score
duration (treatment/ for inclusion
(weeks)
control
group) (n)
–
422‡
523
540
469‡
346§/367¶
561‡
533
CD4+
T-cell
count
(cells/μl)†
–
84
–‡‡
81**
91
88**
–
–
–
100
97
100
99
100
100
100
–
32
53
0
38
–
–
–
–
57
–
37
66
–
61
–
Participants
Participants Participants Participants
with HIV viral on HAART (%) on TDF (%) on PI (%)
load < 400
copies/ml (%)
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
© Permanyer Publications 2014
*BMD t-score ≤ –2.5. †Mean unless otherwise indicated. ‡Median. §Median value in the intervention group. ¶Median value in the control group. **Participants with HIV viral load < 50 copies/ml. ††The initial trial duration was 96 weeks33, however patients
were followed up for an additional four years after completion of the trial in an unblinded, open-ended extension study and results were published41,42. ‡‡The majority of participants had HIV viral load < 400 copies/ml, but the exact proportion was not
stated. §§Patients were initially randomized in a 2:1 fashion to receive zoledronate (n = 21) plus lifestyle modifications or lifestyle modifications only (n = 10). At week 48, subjects from the zoledronate group were reallocated to the annual group (n = 12,
zoledronate 5 mg/year for two years) or biennial group (n = 9, one 5 mg dose in two years).
BMD: bone mineral density; FN: femoral neck; LS: lumbar spine; PI: protease inhibitors; TDF: tenofovir; –: not reported.
Country
Study authors,
year [reference]
Table 1. Characteristics of included studies
AIDS Reviews. 2014;16
Effect of bisphosphonates
on bone mineral density percentage
change after 48 weeks of treatment
Lumbar spine
Four trials29,30,32,35 involving 198 patients compared
the effect of alendronate versus placebo or no treatment. A significant increase in BMD at the lumbar
spine was observed at 48 weeks in the treatment group
(MD: 2.45%; 95% CI: 1.64-3.26). However, there was
evidence for substantial statistical heterogeneity between
trials (I2 = 71%, Chi2 p = 0.02).
Three trials33,34,36 involving 104 patients compared the
effect of zoledronate versus placebo or no drug. Zoledronate improved lumbar BMD by 4.6% (95% CI: 2.89-6.32)
after 48 weeks. There was no evidence for statistical
heterogeneity between trials (I2 = 33%; Chi2 p = 0.22).
Pooling 48-week results for trials assessing oral and
intravenous bisphosphonates, the positive effects of
bisphosphonates on BMD at the lumbar spine were
confirmed (MD: 2.84%; 95% CI: 2.11-3.57). However,
there was evidence for statistical heterogeneity between
trials (I2 = 67%, Chi2 p = 0.005) (Fig. 2).
Femoral neck
Three trials involving 154 patients evaluated the effect
of alendronate on femoral neck BMD at 48 weeks29,30,32.
Alendronate significantly improved BMD at the femoral
neck (MD: 1.27%; 95% CI: 0.39-2.16). There was no statistically significant heterogeneity between trials (I2 = 34%,
Chi2 p = 0.22).
In two trials comparing zoledronate to placebo33,34,
BMD at the femoral neck did not significantly differ between the two groups (MD: 0.6%; 95% CI: –1.56-2.76).
There was substantial statistical heterogeneity between
trials (I2 = 75%, Chi2 p = 0.05).
Pooling 48-week results for trials assessing oral and
intravenous bisphosphonates, a positive effect of bisphosphonates on BMD at the femoral neck was observed
(MD: 1.18%; 95% CI: 0.35-2). There was evidence
for moderate statistical heterogeneity between trials
(I2 = 46%, Chi2 p = 0.12) (Fig. 3).
Total hip
In three trials comparing alendronate versus placebo
or no treatment30,32,35, alendronate increased total hip
BMD by 2.26% (95% CI: 1.45-3.07) after 48 weeks.
There was no evidence for statistical heterogeneity
between trials (I2 = 36%, Chi2 p = 0.21).
In three trials involving 104 patients33,34,36, zoledronate
was found to increase BMD at the total hip (MD: 1.74%;
95% CI: 0.43-3.06).
Pooling 48-week results for trials assessing oral and
intravenous bisphosphonates, a positive effect of
bisphosphonates on total hip BMD was observed (MD:
2.12%; 95% CI: 1.43-2.81). There was no statistically
significant heterogeneity between trials (I2 = 28%, Chi2
p = 0.22) (Fig. 4).
Effect of bisphosphonates on bone
mineral density percentage change
after 96 weeks of treatment
Lumbar spine
Only three studies evaluated BMD at the lumbar
spine after 96 weeks. In the zoledronate trials33,36, a
significant increase in lumbar spine BMD was observed in the treatment group when compared to the
control arm (MD: 7.12%; 95% CI: 4.74-9.51). Analogously, in the Rozenberg trial35 alendronate had a
positive impact on lumbar spine BMD (MD: 6.3%;
95% CI: 3.61-8.99).
Pooling 96-week results, the positive effects of
bisphosphonates on BMD at the lumbar spine were
confirmed (MD: 6.76%; 95% CI: 4.98-8.54).
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
the majority of studies, vitamin D and calcium supplements were given to all participants. In the Negredo
2005 trial31, participants received dietary counseling to
ensure adequate daily calcium intake. In two trials, the
duration of administration of bisphosphonates was
48 weeks30,32, in two trials it was 52 weeks29,34, in four
trials it was 96 weeks31,33,35,36. However, Bolland, et al.
followed up patients for an additional four years after
completion of the trial in an unblinded, open-ended
extension study without administration of additional
antiresorptive medication41,42. Those studies were included in the qualitative analysis, but not in the quantitative one. In the Negredo 2014 trial36, patients assigned
to the zoledronate group were reallocated at week 48 to
the annual group (5 mg per year, two doses in two
years) or biennial group (one dose in two years). As a
consequence, at week 96 only data from subjects belonging to the annual group could be included in the
quantitative analysis.
The review authors’ judgments regarding risk of bias
in the included studies are shown as Supplementary data.
© Permanyer Publications 2014
Marilia Rita Pinzone, et al.: Bisphosphonates for Increasing BMD in HIV
217
Favors control
Total
Weight
Mean difference
IV, fixed, 95% CI
23
40
16
24
103
12.9%
51.1%
9.5%
8.3%
81.8%
0.30 (–1. 73, 2.33)
2.28 (1.26, 3.30)
3.90 (1.53, 6.27)
5.20 (2.66, 7.74)
2.45 (1.64, 3.26)
22
15
10
47
4.6%
7.9%
5.7%
18.2%
5.00 (1.59, 8.41)
3.00 (0.40, 5.60)
6.50 (3.44, 9.56)
4.60 (2.89, 6.32)
Total (95% CI)
152
150 100.0%
Heterogeneity: Chi2 = 18.32, df= 6 (p = 0.005); I2 = 67%
Test for overall effect: Z = 7.63 (p < 0.00001)
Test for subgroup differences: Chi2 = 4.96; df = 1 (p = 0.03); I2 = 79.8%
2.84 (2.11, 3.57)
Study or subgroup Mean SD
Total
Mean SD
Alendronate versus placebo or no drug
Guaraldi 2004
4 3.36 18
3.7 3.2
McComsey 2007
3.38 2.76 42
1.1 1.9
Mondy 2005
5.2 2.63 15
1.3
4
Rozenberg 2012
5.5 4.7 20
0.3 3.7
Subtotal (95% CI)
95
Heterogeneity: Chi2 = 10.37; df = 3 (p = 0.02); I2 = 71%
Test for overall effect: Z = 5.95 (p < 0.00001)
Zoledronate versus placebo or no drug
Bolland 2007
8.4 5.4 21
3.4
6
Huang 2009
3.7 4.1 15
0.7 3.1
Negredo 2014
5.9
3
21
–0.6 4.48
Subtotal (95% CI)
57
Heterogeneity: Chi2 = 2.99; df = 2 (p = 0.22); I2 = 33%
Test for overall effect: Z = 5.27 (p < 0.00001)
–4
–2
Favors
control
0
2
4
Favors
bisphosphonate
Figure 2. Forest plot of the effect of bisphosphonates on lumbar spine bone mineral density after 48 weeks of treatment.
Femoral neck
Only Bolland, et al.33 reported on femoral neck BMD
at 96 weeks; BMD did not significantly differ in the two
groups (MD: 2.3%; 95% CI: –0.69-5.29).
Total hip
Three RCTs evaluated the impact of bisphosphonates
on total hip BMD at 96 weeks. Zoledronate significantly
increased BMD at the total hip (MD: 3.67%; 95% CI:
1.66-5.69)33,36. In the Rozenberg trial35, the difference
between the alendronate and control group was not
statistically significant (MD: 2.1%; 95% CI: –0.95-5.15).
Pooled 96-week data showed BMD significantly increased in the bisphosphonate group (MD: 3.2%; 95%
CI: 1.52-4.88). There was no evidence for statistical
heterogeneity between trials (I2 = 0%, Chi2 p = 0.54).
In the Negredo 2014 trial, no significant differences in BMD at the lumbar spine and total hip were
218
observed over 96 weeks between patients receiving
annual and biennial zoledronate36. Analogously, Bolland, et al. reported that the effects of two annual 4 mg
doses of zoledronate on BMD persisted for at least
five years after the second dose41,42. In fact, the
authors have shown patients receiving zoledronate
had significantly higher BMD at the lumbar spine
(+3.7%; 95% CI: 0.3-7%) and total hip (+2.3%; 95%
CI: 0.3-4.3%) between one and five years after the
second dose.
The Negredo 2005 trial31 could not be included in
the meta-analysis of quantitative outcomes because the
authors did not report on BMD percentage change
over time (only t-scores were provided) and did not
provide standard deviations. For the Guaraldi trial29, we
imputed standard deviation from the average standard
deviation of the other RCTs assessing alendronate,
which were included in the meta-analysis. Sensitivity
analysis with exclusion of this trial did not significantly
change the results (data not shown).
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
Favors
bisphosphonate
© Permanyer Publications 2014
AIDS Reviews. 2014;16
Study or subgroup Mean SD
Total
Favors control
Mean SD
Total
Weight
Mean difference
IV, fixed, 95% CI
23
40
16
79
14.0%
65.3%
6.2%
85.6%
3.00 (0.81, 5.19)
1.00 (–0.02, 2.02)
0.24 (–3.05, 3.53)
1.27 (0.39, 2.16)
22
15
37
11.6%
2.9%
14.4%
–0.50 (–2.91, 1.91)
5.00 (0.16, 9.84)
0.60 (–1.56, 2.76)
Alendronate versus placebo or no drug
Guaraldi 2004
–0.5 3.93 18
–3.5 3
McComsey 2007
2.2 2.56 42
1.2 2.12
Mondy 2005
2.33 5.3 15
2.09 3.88
Subtotal (95% CI)
75
Heterogeneity: Chi2 = 3.04; df = 2 (p = 0.22); I2 = 34%
Test for overall effect: Z = 2.81 (p = 0.005)
Zoledronate versus placebo or no drug
Bolland 2007
2.5 4.7 21
3
3.2
Huang 2009
3.2 2.2 15
–1.8 9.3
Subtotal (95% CI)
36
Heterogeneity: Chi2 = 3.98; df = 1 (p = 0.05); I2 = 75%
Test for overall effect: Z = 0.54 (p = 0.59)
Total (95% CI)
111
116 100.0%
Heterogeneity: Chi2 = 7.34, df= 4 (p = 0.12); I2 = 46%
Test for overall effect: Z = 2.81 (p = 0.005)
Test for subgroup differences: Chi2 = 0.32; df = 1 (p = 0.57); I2 = 0%
1.18 (0.35, 2.00)
–4
–2
Favors
control
0
2
4
Favors
bisphosphonate
Figure 3. Forest plot of the effect of bisphosphonates on femoral neck bone mineral density after 48 weeks of treatment.
Tolerability profile of bisphosphonates
Alendronate
All included studies29-32,35 reported on adverse events;
however, we were able to combine data in a metaanalysis only for gastrointestinal side effects. For other
adverse events we presented the data in narrative form.
In two trials30,31, the authors did not report any adverse events in either the treatment or control group.
In one study29, no serious drug-related adverse events
occurred. The incidence of gastrointestinal side effects,
a concern with bisphosphonates, was reported to be
10% in both groups. The Rozenberg trial35 reported
only on serious adverse events: 19 serious adverse
events occurred in 13 patients, comprising four patients
in the alendronate arm (acute prostatitis and lithotripsy;
adrenal insufficiency and left otitis externa; iron deficiency anemia; and death after diagnosis of epidermoid
carcinoma) and nine patients in the placebo arm (three
episodes of benzodiazepine withdrawal syndrome,
Helicobacter pylori gastritis, and a depressive syndrome;
inferior myocardial infarction; pneumopathy; viral gastroenteritis; vitrectomy; Mycoplasma pneumoniae pneumonia; lung superinfection; pneumonia; and an allergic
reaction). However, none of these adverse events
appeared clearly associated with alendronate use. The
incidence of gastrointestinal adverse events was not
reported. In the McComsey trial32, the incidence of
serious adverse events was 19% in the alendronate
group and 35% in the placebo group. Two out of 42 participants in the alendronate group compared with four
out of 40 participants in the placebo group suffered from
gastrointestinal manifestations.
No drug-related withdrawals were reported in the five
RCTs assessing alendronate versus placebo or no intervention29-32,35. Four trials29-32 involving 180 patients reported on gastrointestinal adverse events. There was no statistically significant difference in the risk of gastrointestinal
side effects in the alendronate group versus the control
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Favors
bisphosphonate
© Permanyer Publications 2014
Marilia Rita Pinzone, et al.: Bisphosphonates for Increasing BMD in HIV
219
Favors control
Total
Weight
Mean difference
IV, fixed, 95% CI
40
16
24
80
56.5%
7.8%
8.3%
72.6%
2.64 (1. 72, 3.56)
0.55 (–1.93, 3.03)
1.30 (–1.09, 3.69)
2.26 (1.45, 3.07)
22
15
10
47
11.2%
2.0%
14.2%
27.4%
0.50 (–1.56, 2.56)
5.00 (0.16, 9.84)
2.25 (0.42, 4.08–)
1.74 (0.43, 3.06–)
Total (95% CI)
134
127 100.0%
Heterogeneity: Chi2 = 6.98, df= 5 (p = 0.22); I2 = 28%
Test for overall effect: Z = 6.02 (p < 0.00001)
Test for subgroup differences: Chi2 = 0.44; df = 1 (p = 0.51); I2 = 0%
2.12 (1.43, 2.81)
Study or subgroup Mean SD
Total
Mean SD
Alendronate versus placebo or no drug
McComsey 2007
3.95 2.21 42
1.31 2.03
Mondy 2005
2.79 3.88 15
2.24 3.08
Rozenberg 2012
2.7 4.6 20
1.4 3.2
Subtotal (95% CI)
77
Heterogeneity: Chi2 = 3.11; df = 2 (p = 0.21); I2 = 36%
Test for overall effect: Z = 5.48 (p < 0.00001)
Zoledronate versus placebo or no drug
Bolland 2007
2.5 3.2 21
2
3.7
Huang 2009
3.2 2.2 15
–1.8 9.3
Negredo 2014
3.5 2.07 21
1.25 2.58
Subtotal (95% CI)
57
Heterogeneity: Chi2 = 3.43; df = 2 (p = 0.18); I2 = 42%
Test for overall effect: Z = 2.59 (p = 0.010)
–4
–2
Favors
control
0
2
4
Favors
bisphosphonate
Figure 4. Forest plot of the effect of bisphosphonates on total hip bone mineral density after 48 weeks of treatment.
group (RR: 0.72; 95% CI: 0.22-2.37). There was no
evidence for heterogeneity between trials (I2 = 0%, Chi2
p = 0.43).
Zoledronate
Adverse events occurring in RCTs assessing zoledronate versus placebo could not be pooled together
in a meta-analysis, so we presented a narrative synthesis.
In the Huang trial34, one patient developed uveitis
within 72 hours of the drug infusion. In addition, the
authors reported that serum calcium levels dropped
slightly over the study period in zoledronate recipients
as compared to placebo. Premedication with 1 g
acetaminophen was offered to all participants prior to
the infusion. In the Bolland trial33, no premedication
was given. Two patients in the zoledronate group
experienced acute-phase reactions that led them to
discontinue study treatment after the first infusion. No
220
other treatment-related adverse events were reported.
During the extension studies41,42, none of the participants
had any potential adverse events from zoledronate. In
the Negredo 2014 trial36, two patients in the zoledronate
group had asthenia and two had fever within 48 hours
after the infusion; these symptoms were treated with
acetaminophen or ibuprofen. No discontinuations were
due to drug-related adverse events.
Discussion
In our systematic review, we evaluated the effect of
oral and intravenous bisphosphonates on BMD in HIVinfected adults. We found that bisphosphonates significantly increased BMD at the lumbar spine and total
hip after 48 and 96 weeks of treatment. The BMD also
increased at the femoral neck after 48 weeks, though
the estimated effect was driven by alendronate RCTs,
with zoledronate showing no significant impact on
femoral neck BMD at 48 and 96 weeks.
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Favors
bisphosphonate
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AIDS Reviews. 2014;16
week is also recommended to prevent bone loss as well
as smoking cessation and limitation of alcohol intake5.
Our meta-analysis has several limitations: first, it was
based on a limited number of trials with a small sample size and a short length of follow-up. None of the
trials were adequately powered to detect the impact
of bisphosphonates on a clinically important outcome
such as fracture risk. Secondly, for quantitative outcomes
there was considerable statistical heterogeneity among
trials. Several factors, including different study design
and enrollment criteria, may have contributed to heterogeneity. However, heterogeneity describes variation in
the magnitude not the direction of the effect, with all effect
measures consistent with an increase in BMD at the
lumbar spine and total hip over the short-term for both
oral and intravenous bisphosphonates. Thirdly, considering the small number of included studies, we were not
able to conduct a sensitivity analysis with exclusion of
trials at high risk of bias. Finally, we could not assess
whether differences in HAART regimens across studies
might have contributed to the observed changes in BMD.
In conclusion, our meta-analysis showed that administration of oral and intravenous bisphosphonates was
associated with increased BMD at the lumbar spine and
total hip over two years in patients with HIV infection.
However, the majority of participants were relatively
young men with well-controlled HIV and a low risk of
fragility fractures in the immediate future. Further studies
in high-risk populations, such as older persons and postmenopausal women, are warranted. Larger studies with
extended follow-up are needed to better define the longterm safety and efficacy profile of bisphosphonates for
the treatment of low BMD in the setting of HIV infection.
Acknowledgements
We thank the following trial authors who responded to our requests for
further information: Mark Bolland, Eugenia Negredo, and Giovanni Guaraldi.
We also thank Katharine Ker for her valuable comments and suggestions.
Conflict of interest
None of the authors have any conflict of interest to declare.
Funding sources
None to declare.
Supplementary Data
Supplementary data is available at AIDS Reviews journal online (http://www.
aidsreviews.com).
This data is provided by the author and published online to benefit the
reader.
The contents of all supplementary data are the sole responsibility of the
authors.
No part of this publication may be reproduced or photocopying without the prior written permission of the publisher.
The ultimate goal of long-term osteoporosis treatment
is the prevention of fractures. However, since fractures
may occur at a variable length of time after the onset
of osteoporosis, short-term trials are not able to find
significant differences between patients receiving
bisphosphonates and patients who do not. In addition,
it is unclear if patients receiving bisphosphonates may
discontinue treatment after a few years without increasing their fracture risk. Extension studies in postmenopausal women taking bisphosphonates suggest that
patients with a t-score < –2.5 at the femoral neck after
3-5 years of treatment are still at increased risk of
vertebral fractures and may benefit from continued
therapy43. In patients with HIV infection, the only extension study evaluating the long-term effect of zoledronate
was published in 2012 by Bolland, et al.42. The authors
showed that the effects of two annual doses of 4 mg
zoledronate on BMD in HIV-positive men persisted for
five years after the second dose. However, the study
was relatively small and was not powered to detect
significant differences in fracture risk. In addition, the
authors enrolled relatively young men with a baseline
t-score < –0.5 and well-controlled HIV; as a consequence,
their results may not be generalizable to populations
with lower BMD or uncontrolled HIV infection.
Bisphosphonates were generally well-tolerated. No
drug-related withdrawals were reported in the five
RCTs assessing alendronate versus placebo or no intervention. The incidence of gastrointestinal adverse events
was similar in the treatment and control group. As for
zoledronate, one patient in the Huang trial34 developed
uveitis and two patients in the Bolland trial33 discontinued
treatment after the first dose because of acute-phase
reactions. Major concerns associated with prolonged
use of bisphosphonates are osteonecrosis of the jaw44
and atypical femoral fractures due to over-suppression
of bone turnover45. These complications were not reported in any trial included in our systematic review.
This is not unexpected considering the rarity of these
adverse effects as well as the small number of participants involved and the short duration of RCTs.
Adequate calcium and vitamin D intake is important
to prevent BMD loss and reduce the risk of fractures5.
Vitamin D deficiency has been shown to be highly
prevalent in HIV-positive subjects46. As a consequence,
current European guidelines suggest screening patients
at risk for vitamin D hypovitaminosis and consider calcium/vitamin D supplementation when dietary intake is
insufficient to maintain good bone health47. Lifelong
participation in 30 minutes of weight-bearing and
muscle-strengthening exercise at least three days a
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Marilia Rita Pinzone, et al.: Bisphosphonates for Increasing BMD in HIV
221
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AIDS Reviews. 2014;16