Reviewer's report
Title: The role of the combination of bone and fall related risk factors on
short-term subsequent fracture risk and mortality
Version: 1 Date: 13 September 2012
Reviewer: Dana Bliuc
Reviewer's report:
Major:
1) In my opinion, the classification into 4 groups is quite arbitrary, as there is no
evidence that each of the factors that grant inclusion in one group has similar risk
value (i.e. does having a prior fracture after the age of 50 have the same predictive
value as a family history of fracture?) The rationale for this classification should be
better explained in the methodology and acknowledged in the discussion.
We hypothesized that patients with the combination of risk factors had a higher
subsequent fracture risk compared to all others (BRF, FRF, no additional RF).
The rationale behind the pre-specified groups and comparisons was that in fracture
prevention only bone targeted therapy has shown to reduce fracture risk and not fall
targeted therapies. Unfortunately there were too few events to analyse all risk
factors independently. Therefore, pre-specified groups were made on bone-, fall and
the combination of risk factors.
We explained this rationale better in
Methods, page 5:
“The rationale behind these groups is that there is a known treatable risk factor in
group 1 and 2, but not in group 3 because in fracture prevention only bone targeted
therapy has shown to reduce fracture risk and not fall targeted therapies.
Discussion, page 9:
“However, we made 4 pre-specified groups because in fracture prevention only bone targeted
therapy has shown to reduce fracture risk and not fall targeted therapies.
2) The cohort is assessed by the Fracture Liaison Service, implemented to evaluate
bone and fall risk factors and to prescribe anti-osteoporosis treatment and fall
prevention programs, yet there is no information on the osteoporosis medication
and its up-take. The efficacy of osteoporosis medication in fracture and re-fracture
risk is well documented, and there is emerging evidence that it may also decrease
mortality risk. Thus, information on the osteoporosis medication, and fall
prevention for each of the groups should be made available in this paper.
All patients were advised and treated accordingly to the guideline on osteoporosis in
The Netherlands at time of the study. A letter to the general practitioners was send
give information about the treatment and asked to take over the treatment. No
information was known about adherence, so therefore we cannot adjust our
analyses for possible treatment effect. This is also mentioned in the discussion.
Discussion page 9 lines 11-13:
“A limitation of this study is that there are no data on adherence to the proposed osteoporosis
treatment and fall prevention. Persistence is indeed low, as has been shown in a recent publication
for oral anti-osteoporosis medications in the Netherlands [28].”
3) Authors state that subsequent fracture risk was highest at time 0. However, in
the methodology section it is written that time of subsequent fracture is calculated
from the current fracture to subsequent fracture; therefore time 0 must be the
time of current fracture. This is confusing, and should be clarified in the
methodology.
By time 0 the authors meant time of current fracture. We did not show the data of
the time dependent analyses because of the number of events were to low to draw
reliable conclusions and also as suggested by the reviewer and changed the methods
section.
4) The rate of subsequent fractures and mortality is lower in this study compared
to other studies. This may be the result of a short follow-up period, but also the
result of osteoporosis treatment. There should be a detailed discussion and head
to head comparison with other published papers.
The rate of subsequent fractures and mortality is lower compared to other studies.
However, the patients in the present study are only the patients seen and treated at
the Fracture Liaison Service and not those who were not willing or able to visit the
outpatient clinic. We did not do an intention to treat analysis due to the fact that the
authors wanted to observe the risk factors in these patients and therefore could only
include those patients with known risk factors inquired after at the Fracture Liasion
Service.
A possible explanation for the difference in subsequent fracture rate could be
difference in patient selection. Another reason could be the treatment effect as the
reviewer suggests. The authors added this to the discussion.
Discussion, page 8:
“ However, the event rate was lower in our research compared to other published articles. In a
study among patients aged 60 years and over a relative risk of subsequent fracture incidence of
1.95 in women and 3.45 in men was found[3]. A subsequent fracture risk of 10.8% was found within
2-years after a fracture, and of 17.6% in patients of 50+ years who sustained a NVF after a NVF[4,
5]. The two retrospective studies were performed according to intention-to-treat, and therefore, a
difference in subsequent fracture rate and mortality could be found. Mortality is known to be
increased after a fracture, especially after a hip fracture[24]. A recent study showed an increased
risk of mortality especially within 5-years after the fracture[11]. In the described studies, [3] [4, 5]
[24] [11] not all patients were treated at a Fracture Liaison Service. This might explain the lower
subsequent fracture (6.8%) and mortality rate (3.5%) in our study compared with the studies
mentioned above (due to a possible treatment effect). In addition, the minimum age of inclusion
was different, and only patients who did attend the Fracture Liaison Service were included.”
5) Authors state that their major finding is the higher risk of re-fracture in the
patients with combination of risk factors compared to patients with only bone
factors. However, I think that this analysis should be adjusted for treatment, as the
groups with bone factors may have a higher percentage of treated people and this
may be the cause of a lower re-fracture rate.
Unfortunately we cannot adjust for treatment, because we do not have these data.
The authors mentioned this as a significant limitation in the discussion section.
Discussion page 9 lines…
“ A limitation of this study is that there are no data on prescription and adherence of the proposed
osteoporosis treatment and fall prevention. Persistence might be low, as has been shown in a
recent publication for oral anti-osteoporosis medications in the Netherlands [28].”
6) It would be interesting to find out whether fall factors are associated with refracture risk independent of bone factors when the entire cohort is analyzed
together and adjusted for all risk factors independently. The authors can then
check whether there is any interaction between bone and fall factors.
Unfortunately there were too few events to analyse all risk factors independently.
Therefore, pre-specified groups were made on bone-, fall and the combination of
risk factors. However, the authors checked whether there was an interaction
between the groups (BRF and FRF). There was no significant interaction (p=0.064)
present.
7) As per point 5, mortality analysis should also be adjusted for treatment rates.
Unfortunately we cannot adjust for treatment, because we do not have these data.
The authors mentioned this as a significant limitation in the discussion section.
Discussion page 9:
“ A limitation of this study is that there are no data on prescription and adherence of the proposed
osteoporosis treatment and fall prevention. Persistence might be low, as has been shown in a
recent publication for oral anti-osteoporosis medications in the Netherlands [28].”
8) In order to conclude that there is no increase mortality in this cohort, a
comparison with an age-and sex adjusted general population mortality is needed.
The authors checked the mortality incidence in this period in the Netherlands,
according to sex and age. We compared these data to our studied patients. The
relative risk between the studied population and the general population in the
Netherlands was 0.03477/0.02700 = 1.29. This means that our studied population
had a higher mortality incidence compared to the general population of 29%, but our
mortality rate was still very low.
Minor
1. Figure 2 should include the fracture-free probability for all groups
The authors made the stratified Cox regression plot with all 4 groups and included
this in the manuscript as figure 4.
Multivariable Cox regression stratified by groups.
Subsequent fracture incidence by groups
10
Groups
Combination
No RFs
BRF
FRF
Subsequent fracture
8
6
4
2
0
0
3
6
9
12
15
18
21
24
Follow-up (months)
2. I just feel that the wording “More than 1 in 2 had at least one clinical risk
factor…” (used in first paragraph of results section) is not quite adequate in the
context.
The authors changed this and deleted these 2 sentences, because of a similar
sentence with exact similar results.
Page 6
“ 51.2% of patients had least one bone RF and 60.4% had at least one fall RF.”
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.