Researchers from Australia and Spain conducted a randomised trial to compare:
(i) switching from TDF and (ii) the maintenance of patients on their TDF-based
ART, to which zoledronic acid was added.
Eligibility criteria were virological suppression < 50 copies/ml for
a minimum of three months; having been on a TDF-containing ART for at least 6
months, and; having a T-score of < 1 at the spine (L1-L4) or the left neck
of the femur (hip), obtained with a DEXA scan.
Between July 2012 and January 2015, 87 individuals were randomly
assigned to either pursue their treatment, and receive two 5mg doses of IV zoledronic
acid (at baseline and at month 12), or to switch from TDF to another
antiretroviral, but without ever taking any bisphosphonate.
Participants in this open-label study knew which of the two groups they
were assigned to and remained in the study for 24 months. All of them received
calcium supplementation and, in case of insufficiency or deficiency, vitamin D
Most of the participants were men (only 4% of women), white, and around 50
years of age. CD4 counts were generally high (median 618 cells/ml) and the
median duration of prior TDF exposure was 6.2 years. Of note, 23 participants
(27%) had osteoporosis, and 32 (38%) had a BMD too low for their age at the spine, total hip and femoral neck. No
difference was seen in the estimated risk of a major osteoporotic or hip
fracture between the study groups at baseline.
The study’s primary and secondary
outcome measures were the mean percentage change, from baseline, in the lumbar
spine BMD and in the hip BMD, respectively. The lumbar spine was preferred for
the primary outcome as it is known to respond more rapidly to interventions.
The BMD measures were done annually by DEXA. Data could be analysed for 85 of
the 87 participants (43 in the zoledronic acid group and 42 in the TDF-switching
The results show a significant
difference between the two approaches. In terms of the primary outcome, at
month 24, the mean percentage changes in BMD at the lumbar spine in the zoledronic
acid and the TDF-switching groups were 7.4% and 2.9% respectively. For both
strategies, the BMD increase was the greatest in the first 12 months, but slowed
in the second year in the zoledronic acid group, while plateauing in the second
year in the TDF-switching group.
Positive effects of zoledronic acid were also observed in terms of the secondary
outcome: at the total hip, mean percentage changes in BMD in the zoledronic
acid and TDF-switching groups were 4.6% and 2.9%, by the 24th month.
By month 12, the prevalence
of osteoporosis at the hip or spine had decreased from 30% to 12% in the
zoledronic acid group, and from 24% to 12% in the TDF-switching group. It did
not further decrease by month 24.
Eight fractures were
reported by five participants, of which only one was considered as relevant to
bone fragility. For fractures, no significant differences were seen between the
two strategy groups.
Likewise, there were
no significant difference in the number of serious adverse events between
groups during the study follow-up, and no adverse event was considered to be
related to the interventions received.
Like any other study,
this one has limitations. First, and incomprehensibly, too few women were
recruited to participate in the trial, and one can question the recruitment strategy.
Second, 24 month follow-up of patients to measure the potential impact of a
strategy on the rather lengthy bone reconstitution process and on fractures is
short. Finally, we must keep in mind that the study was initiated prior to the
availability of tenofovir alafenamide (TAF), which is associated with less bone
loss than with TDF.
limitations, Jennifer Hoy and colleagues conclude that, in a period of 24
months, their trial has demonstrated that annual zoledronic acid 5mg IV
dosing is superior to TDF-switching in HIV-positive adults on TDF, in terms of
improving low bone mineral density. Results of the follow-up to month 36 will
be necessary to confirm the durability of the benefit, as zoledronic acid was
administered only at baseline and month 12.