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Intervenciones farmacológicas para la prevención de las fracturas por insuficiencia y necrosis avascular asociada con la radioterapia pelviana en adultos

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Fractures, Bone] explode all trees
#2 fracture*.mp.
#3 bone* near/5 (break or broke*)
#4 MeSH descriptor: [Femur Head Necrosis] this term only
#5 femur head necrosis
#6 avascular necrosis
#7 (bone* near/5 (fragility or fragile))
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7
#9 MeSH descriptor: [Radiotherapy] explode all trees
#10 radiotherap* or brachytherap* or IMRT
#11 radiat* or irradiat*
#12 Any MeSH descriptor with qualifier(s): [Radiotherapy ‐ RT]
#13 #9 or #10 or #11 or #12
#14 Any MeSH descriptor with qualifier(s): [Drug therapy ‐ DT]
#15 MeSH descriptor: [Calcium, Dietary] explode all trees
#16 MeSH descriptor: [Vitamin D] explode all trees
#17 MeSH descriptor: [Diphosphonates] explode all trees
#18 MeSH descriptor: [Selective Estrogen Receptor Modulators] explode all trees
#19 MeSH descriptor: [Hormone Replacement Therapy] explode all trees
#20 MeSH descriptor: [Contraceptives, Oral] explode all trees
#21 MeSH descriptor: [Testosterone] explode all trees
#22 (calcium or vitamin D or bisphosphonate* or alendronate or alendronic acid or etidronate or ibandronate or risedronate or zoledronate or pamidronate or (selective adj (oestrogen or estrogen) adj receptor modulator*) or raloxifene or hormone replacement or ((oestrogen or estrogen) adj replacement therapy) or oral contraceptive pill or testosterone or sustanon or strontium ranelate or teriparatide or denosumab or calcitonin)
#23 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22
#24 #8 and #13 and #23

Appendix 2. MEDLINE search strategy

1   exp Fractures, Bone/
2   fracture*.mp.
3   (bone* adj5 (break or broke*)).mp.
4   Femur Head Necrosis/
5   femur head necrosis.mp.
6   avascular necrosis.mp.
7   (bone* adj5 (fragility or fragile)).mp.
8   1 or 2 or 3 or 4 or 5 or 6 or 7
9   exp Radiotherapy/
10 (radiotherap* or brachytherapy or IMRT).mp.
11 (radiat* or irradiat*).mp.
12 radiotherapy.fs.
13 9 or 10 or 11 or 12
14 drug therapy.fs.
15 Calcium, Dietary/
16 exp Vitamin D/
17 exp Diphosphonates/
18 exp Selective Estrogen Receptor Modulators/
19 exp Hormone Replacement Therapy/
20 exp Contraceptives, Oral/
21 exp Testosterone/
22 (calcium or vitamin D or bisphosphonate* or alendronate or alendronic acid or etidronate or ibandronate or risedronate or zoledronate or pamidronate or (selective adj (oestrogen or estrogen) adj receptor modulator*) or raloxifene or hormone replacement or ((oestrogen or estrogen) adj replacement therapy) or oral contraceptive pill or testosterone or sustanon or strontium ranelate or teriparatide or denosumab or calcitonin).mp.
23 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22
24 8 and 13 and 23

key:
mp = Title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier

 

Appendix 3. Embase Ovid search strategy

1 exp fracture/
2 fracture*.mp.
3 (bone* adj5 (break or broke*)).mp.
4 femur head necrosis/
5 femur head necrosis.mp.
6 avascular necrosis.mp.
7 (bone* adj5 (fragility or fragile)).mp.
8 1 or 2 or 3 or 4 or 5 or 6 or 7
9 exp radiotherapy/
10 (radiotherap* or brachytherapy or IMRT).mp.
11 (radiat* or irradiat*).mp.
12 rt.fs.
13 9 or 10 or 11 or 12
14 dt.fs.
15 calcium intake/
16 exp vitamin D/
17 exp bisphosphonic acid derivative/
18 selective estrogen receptor modulator/
19 exp hormone substitution/
20 exp oral contraceptive agent/
21 androgen therapy/
22 (calcium or vitamin D or bisphosphonate* or alendronate or alendronic acid or etidronate or ibandronate or risedronate or zoledronate or pamidronate or (selective adj (oestrogen or estrogen) adj receptor modulator*) or raloxifene or hormone replacement or ((oestrogen or estrogen) adj replacement therapy) or oral contraceptive pill or testosterone or sustanon or strontium ranelate or teriparatide or denosumab or calcitonin).mp.
23 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22
24 8 and 13 and 23
25 (exp animal/ or nonhuman/ or exp animal experiment/) not human/
26 24 not 25

key:

mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword

fs=floating subheading

Appendix 4. Risk of bias

Random sequence generation

  • Low risk of bias (e.g. participants assigned to treatments on basis of a computer‐generated random sequence or a table of random numbers).

  • High risk of bias (e.g. participants assigned to treatments on basis of date of birth or clinic ID number or surname, or no attempt made to randomly assign participants).

  • Unclear risk of bias (e.g. not reported, information not available).

Allocation concealment

  • Low risk of bias (e.g. allocation sequence could not be foretold).

  • High risk of bias (e.g. allocation sequence could be foretold by participants, investigators or treatment providers).

  • Unclear risk of bias (e.g. not reported).

Blinding of participants and personnel

  • Low risk of bias if participants and personnel were adequately blinded.

  • High risk of bias if participants were not blinded to the intervention that they received.

  • Unclear risk of bias if this was not reported or was unclear.

Blinding of outcomes assessors

  • Low risk of bias if outcomes assessors were adequately blinded.

  • High risk of bias if outcomes assessors were not blinded to the interventions that participants received.

  • Unclear risk of bias if this was not reported or was unclear.

Incomplete outcome data

We recorded the proportion of participants whose outcomes were not reported at the end of the study. We coded a satisfactory level of loss to follow‐up for each outcome as:

  • low risk of bias if less than 20% of participants were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment groups;

  • high risk of bias if more than 20% of participants were lost to follow‐up or reasons for loss to follow‐up differed between treatment groups; and

  • unclear risk of bias if loss to follow‐up was not reported.

Selective reporting of outcomes

  • Low risk of bias (e.g. review reported all outcomes specified in the protocol).

  • High risk of bias (e.g. suspected that outcomes were selectively reported).

  • Unclear risk of bias (e.g. unclear whether outcomes were selectively reported).

Other bias

  • Low risk of bias: no suspicion of any other source of bias and trial appeared to be methodologically sound.

  • High risk of bias: suspected that the trial was prone to an additional bias.

  • Unclear risk of bias: uncertain whether an additional bias may have been present.

Non‐randomised studies

We assessed the risk of bias in non‐randomised controlled trials in accordance with four additional criteria concerning cohort selection and comparability of treatment groups.

Relevant details of criteria for assignment of participants to treatments

  • Low risk of bias (e.g. yes).

  • High risk of bias (e.g. no).

  • Unclear risk of bias.

Representative group of participants who received the experimental intervention

  • Low risk of bias if representative of adults undergoing pelvic radiotherapy.

  • High risk of bias if groups of participants were selected.

  • Unclear risk of bias if selection of group was not described.

Representative group of participants who received the comparison intervention

  • Low risk of bias if drawn from the same population as the experimental cohort.

  • High risk of bias if drawn from a different source.

  • Unclear risk of bias if selection of group was not described.

No differences between the two groups or differences controlled for, in particular with reference to age, gender, type/dose of radiotherapy, use of chemotherapy and performance status

  • Low risk of bias if at least two of these characteristics were reported.

  • High risk of bias if the 2 groups differed and differences were not controlled for.

  • Unclear risk of bias if fewer than two of these characteristics were reported even if no other differences were noted between the groups and other characteristics were controlled for.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Summary of findings for the main comparison. Pharmacological intervention compared with no intervention for prevention of radiation‐related insufficiency fractures and avascular necrosis

Pharmacological intervention compared with no intervention for prevention of radiation‐related insufficiency fractures and avascular necrosis

Patient or population: Adults undergoing pelvic radiotherapy

Settings: Intervention prior or during radiotherapy; hospital

Intervention: Zoledronic acid

Comparison: No intervention

Outcomes

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

The 2 included studies did not fully describe the radiotherapy techniques used.

The dose, delivery of treatment (conformal, intensity modulated, brachytherapy) and, therefore, volume of pelvis irradiated could influence the pattern of bone fractures, changes in BMD and risk of avascular necrosis.

Studies were heterogeneous in other aspects so meta‐analyses were not performed and results were reported as a narrative.

Insufficiency fractures and avascular necrosis

Kachnic 2013 (96 eligible participants)

Out of the 91 men (95% of eligible participants) who consented to QoL data collection, participant compliance for completing the FACT‐G was 96% at baseline, 82% at 12 months, 71% at 24 months and 58% at 36 months.

Denham 2014 (905 participants had thoracolumbar x‐rays available for assessment out of a possible 1167)

(222 participants for BMD sub study).

⊕⊝⊝⊝
Very low1,2

  • Kachnic 2013 reported 1 fracture occurring in each intervention group.

  • Denham 2014 reported 72 non‐spinal fractures (38 in intervention group). Only 3 fractures were near the radiation field and 1 case of avascular necrosis but details of the intervention group for these was not provided.

  • Data were sparse, and the imaging and investigations used did not meet the review criteria.

BMD and fracture risk

⊕⊝⊝⊝
Very low1,2

  • Improvements in BMD in both studies.

  • 1 RCT reported significant percentage increases in BMD at 36 months in the lumbar spine (6% with zoledronic acid versus ‐5% with control; P < 0.0001), left hip (1% with zoledronic acid versus ‐8% with control; P = 0.0002) and left femoral neck (3 with zoledronic acid versus ‐8% with control; P = 0.0002) (Kachnic 2013).

  • In comparison, the other RCT had a sub study assessing the change in mean total hip BMD at 24 and 48 months (Denham 2014). For the 6‐month androgen deprivation group, there was no change in BMD at 24 months (0.6%; P = 0.18) but a significant increase at 48 months (1.8%; P = 0.003). In the 12‐month androgen deprivation group, there was no significant change in BMD at 24 months (0.5%; P = 0.41) and a tendency towards significance at 48 months (1.2%; P = 0.09).

  • As different time points and sites were used to measure changes in BMD, a further analysis was difficult to perform.

  • Only 1 RCT reported fracture risk, but the risk was assessed using a non‐validated method, so further analysis was not conducted (Denham 2014).

Bone turnover markers

⊕⊝⊝⊝
Very low1,2

  • The 2 included RCTs did not report changes in bone turnover markers between control and intervention groups, preventing further reporting on these outcomes.

QoL

⊕⊝⊝⊝
Very low1,2,3

  • Only 1 RCT reported QoL and suggested there were no differences in QoL between groups (Kachnic 2013). However, this study only accrued small patient numbers and only 58% QoL data were obtained at 36 months so there was likely to be a lack of statistical power to detect any true differences.

  • Neither trial reported bone symptoms or unplanned hospital stays.

Mortality

⊕⊝⊝⊝
Very low1,2,4

  • Neither trial reported cancer‐specific mortality of overall mortality.

Adverse events

⊕⊝⊝⊝
Very low1,2

  • Both included RCTs did not fully describe the radiotherapy techniques used. The dose, delivery of treatment (conformal, intensity modulated, brachytherapy) and, therefore, volume of pelvis irradiated could influence the pattern of bone fractures, changes in BMD and risk of avascular necrosis.

  • 1 RCT had an imbalance in the sub study groups reporting on changes in BMD, where 1 group may have had higher risk factors for osteoporosis that could bias the results (Denham 2014).

  • The results reported by Kachnic 2013 need to be interpreted with caution as the study had inadequate accrual, therefore, lacked statistical power to detect differences.

  • Adverse events and compliance to the intervention reported descriptively.

BMD: bone mineral density; FACT‐G: Functional Assessment of Cancer Therapy ‐ General; QoL: quality of life; RCT: randomised controlled trial.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

1Downgraded as both studies had a low reported number of fractures but the details of the fracture (location, nature) were not described and hence there was uncertainty regarding these being insufficiency fractures from radiotherapy.

2Quality of evidence downgraded due to heterogeneity, poor reporting of results and limitations in study methodology (risk of bias).

3Downgraded as QoL not reported in the large trial (Denham 2014).

4Downgraded as neither trial reported other potentially important outcomes such as survival, bone symptoms and unplanned hospital stay.

Figures and Tables -
Summary of findings for the main comparison. Pharmacological intervention compared with no intervention for prevention of radiation‐related insufficiency fractures and avascular necrosis