Interventions for treating simple bone cysts in the long bones of children

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects (benefits and harms) of interventions for treating simple bone cysts in the long bones of children, including adolescents.

Our main comparisons will be between:

  • invasive (e.g. injections, curettage, surgical fixation) versus non-invasive interventions (e.g. observation, plaster cast, restricted activity)

  • different categories of invasive interventions (i.e. injections, curettage, drilling holes and decompression, surgical fixation and continued decompression)

  • different variations of each category of invasive intervention (e.g. different injection substances: autologous bone marrow versus steroid)

Background

Description of the condition

Simple bone cysts, also known as a unicameral bone cysts or solitary bone cysts, were first reported by Virchow (Virchow 1876). They are benign, fluid-filled lesions, mainly located in the metaphyses of the long bones (parts of the bone where growth takes place that are situated between the middle shaft section and each of the two bone ends) in children and adolescents. The most common site for a simple bone cyst is the proximal humerus (top end of the upper arm bone) followed by the proximal femur (top end of the thigh bone). The peak age of occurrence is around 10 years (Capanna 1982). Simple bone cysts amount to around 3% of bone lesions and occur around twice as often in boys than in girls (Boseker 1968). Attempts have been made to classify simple bone cysts into active and inactive types (Norman 1977). Active cysts have been defined as those that are in direct contact with the adjacent growth plate in skeletally-immature children, while inactive ones are those that are separate from the growth plate.

The causes of simple bone cysts are unclear. The finding by Chigira 1983 of higher osseous pressures (relating to blood circulation within the bone) within the cysts compared with the normal pressure of the bone marrow lends support to the popular theory that obstruction of venous drainage in the bone is the likely cause of these cysts.

On an X-ray, a cyst appears as a well-localised and distinct lesion without signs of formation of new bone (periosteal reaction) in the medullary canal. Although most cysts become static or resolve (disappear) near skeletal maturity (Capanna 1982), cysts weaken the bone and may lead to pathological fracture of the bone through the thin cortex. Most children with simple bone cysts present with pain because of a fracture. In some cases, however, the fracture may be more disabling and serious, such as a displaced fracture of the proximal femur. These pathological fractures may result in symptomatic malunion of the bone, particularly in the proximal femur (Chuo 2003). Furthermore, simple bone cysts may result in growth disturbance (Stanton 1998). Although growth arrest is a relatively rare complication, it may occur through many mechanisms. The causes of growth arrest include the disruptive assault of active cyst fluid on the physis (growth plate), direct extension of the cyst through the physis, pathological fracture through the cyst that damages the physis, or as a result of treatment for cysts adjacent to the growth plate (Haims 1997; Stanton 1998). Ultimately, growth retardation in the involved limb may result in angular deformity or discrepancy in limb length, or both (Haims 1997). Parents or surgeons are fearful of possible fractures in children with bone cysts, and this can lead to restrictions to activity and exercise that may harm a child's physical and mental development further.

Description of the intervention

The main goals of treatment are to decrease the risk of pathological fracture, enhance cyst healing and resolve pain. The main interventions used are listed below.

  • Non-invasive interventions

    • Observation: waiting only, with no other active intervention (Neer 1966; Chuo 2003);

    • Activity restriction and other non-invasive interventions; these include cast immobilisation for children with a pathological fracture (Garceau 1954)

  • Invasive (surgical) interventions

    • Mechanical disruption of cyst wall or lining with or without grafts. Curettage: a small skin incision is made at the level of the thinnest cyst wall. After a curette (tool designed for scraping or removing tissue) is inserted into the cyst by puncturing the thinned cortical bone, systematic curettage of the inner wall of the cavity is performed repeatedly using straight and angled curettes in order to remove the membrane lining of the cyst. The fluid in the cyst cavity is then suctioned away. No substance is injected or placed back into the cyst. Curettage, as described above, is a less invasive procedure than open curettage with grafts. The latter technique consists of the incision of skin and overlying tissue of the bone, opening up the medullary canal, removing the cyst membrane, filling in the void with bone-graft materials, and, finally, the closure of the incision. Subtotal-resection involves a more extensive removal and then replacement of overlying bone after removal of the cyst.

      • Curettage only (Canavese 2011)

      • Curettage (opening up the medullary canal) with grafts (Neer 1966)

      • Subtotal-resection with or without bone graft or muscle graft (Fahey 1973)

    • Injection treatment of steroid or autologous (the patient's own) bone marrow: after localisation of the lesion, a sharp needle is introduced percutaneously into the cyst, through the thinnest area of the cyst wall, to inject one of the following materials.

    • Drilling holes and decompression: the technique consists of drainage of cyst fluid, washing the cyst cavity with saline and drilling holes through the cortical and the medullary bone of the cyst wall. If a cannulated screw is used, it is inserted through a small hole to provide continuous decompression (drainage).

      • Drilling holes and continued decompression with a cannulated screw (Saraph 2004)

      • Drilling holes and decompression without a cannulated screw (Komiya 1993)

    • Use of several bone substitutes: after drilling a hole, one of the following materials is injected or filled.

    • Internal fixation and continued decompression: insertion of one of the following internal devices into the cyst through a percutaneous or mini-open approach. These devices aim to stabilise the affected region, as well as enabling drainage.

    • Combinations of the above methods

How the intervention might work

A simple bone cyst is considered to be a benign, self-limiting condition that usually heals spontaneously after skeletal maturity (Wilkins 2000). Thus observation is included as a treatment option on the basis of some evidence of cysts healing without treatment, particularly for children with an asymptomatic and inactive cyst (Neer 1966; Wilkins 2000). Curettage can eradicate the source of bone-destroying enzymes through removal of the cyst membrane. As mentioned above, percutaneous curettage is a minimally invasive technique. Compared with curettage only, the technique of resection or open curettage is relatively straightforward as the cyst cavity is exposed widely and the cyst membrane can be removed under direct vision. Then either autologous (from the person's own body) or allogenic (from an external source) bone-graft materials can be used to fill in the area of the bone defect. While the mechanism underlying the effects of steroid injection is still unclear, Scaglietti 1979 conjectured, on the basis of experimental work, that microcrystals caused destruction of the connective tissue coat of the cyst wall, thus allowing secondary bone repair to occur. The anti-inflammatory action of the steroid may also play an important role (Scaglietti 1982). Lokiec 1996 suggested that injection of bone marrow might work due to both the perforation of the cyst wall and the injection of bone marrow; the latter would, by itself, engender the formation of normal bone. Injected methods may have a high recurrence rate, but injection procedures can be carried out repeatedly. Additionally, calcium sulphate, demineralised bone matrix and calcium phosphate bone cement could stimulate new bone formation (Rougraff 2002). Several in situ implants, such as Kirschner wires, intramedullary nails and cannulated screws, have been used to treat simple bone cysts. These implants can achieve drainage and continuous decompression of the intraosseous pressure to promote cyst healing and reduce the rate of recurrence. In addition, flexible intramedullary nailing provides stability, which allows early mobilisation and an early return to normal activity. The continued stability provided by flexible intramedullary nailing should also decrease the risk of pathological fracture (De Sanctis 2006).

Why it is important to do this review

Simple bone cysts are the most common benign bone lesion in growing children. Cysts make the bone cortex thin and may lead to repeated pathological fracture. Furthermore, fractures may result in unequal limb lengths and angular deformity. Perceived risk for fracture prevents many children from participation in physical activities until the cyst is resolved. This can disrupt normal childhood for extended periods and limit activities (Lokiec 1998). Therefore, it is important to strike an optimal balance between potential for healing and invasiveness, and risk of complications, when contemplating treatment methods.

Despite the numerous treatment methods that have been used for simple bone cysts, there is no consensus on what is the best procedure. It is necessary to review the available evidence for the different methods of treating simple bone cysts in the long bones of children systematically in order to inform treatment choice.

Objectives

To assess the effects (benefits and harms) of interventions for treating simple bone cysts in the long bones of children, including adolescents.

Our main comparisons will be between:

  • invasive (e.g. injections, curettage, surgical fixation) versus non-invasive interventions (e.g. observation, plaster cast, restricted activity)

  • different categories of invasive interventions (i.e. injections, curettage, drilling holes and decompression, surgical fixation and continued decompression)

  • different variations of each category of invasive intervention (e.g. different injection substances: autologous bone marrow versus steroid)

Methods

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised (method of allocating participants to a treatment that is not strictly random, e.g. by date of birth, hospital record number, alternation) controlled trials evaluating methods for treating simple bone cysts in children will be included.

Types of participants

Children, including adolescents, with simple bone cysts in long bones. Trials including a few participants with cysts in other bones will be included. There will be no restrictions regarding either the activity of the cyst or a history of previous pathological fracture.

Types of interventions

We will include all trials comparing different interventions used for treating simple bone cysts in children and adolescents. We will choose the less invasive or non-invasive interventions as our control group. The detailed comparisons will be:

  • invasive (e.g. curettage, injections, surgical fixation) versus non-invasive interventions (e.g. observation, plaster cast, restricted activity)

  • different methods of invasive interventions (e.g. curettage with bone graft versus steroid injection, drilling holes and decompression versus autologous bone marrow, curettage with bone graft versus internal fixation and continued decompression)

  • different methods of mechanical disruption of cyst wall or lining (e.g. open curettage with bone graft versus curettage only)

  • different injected substances (autologous bone marrow versus steroid)

  • different methods of drilling holes and decompression (drilling holes and decompression with versus without a cannulated screw)

  • different materials as a filling treatment (e.g. calcium sulphate or calcium phosphate (or both), demineralised bone matrix)

  • different internal fixation devices (elastic stable intramedullary nail versus Kirschner wire)

  • different combinations of multiple interventions

  • Combinations of multiple interventions versus a single method

Types of outcome measures

Primary outcomes
  • Success rate. Most surgical procedures are carried out only once, and the outcomes will be used to assess success rate. However, injection procedures, such as injection of steroid and bone marrow, may be repeated. If injection therapy was planned as a series, the outcomes after the last injection will be used to assess success rate. The Neer/Cole rating system will be used to evaluate success rate (Neer 1966; Hashemi-Nejad 1997). In this system, the radiographic results are graded as follows: grade 1, cyst clearly visible; grade 2, cyst visible but multilocular and opaque; grade 3, sclerosis around or within a partially visible cyst; grade 4, complete obliteration of the cyst. Grade 1 and grade 2 results are considered to indicate failure and grades 3 and 4 are considered to indicate success (Hashemi-Nejad 1997; Wright 2008).

  • Functional outcome measures, such as the Activity Scale for Kids (Young 2000) and Pediatric Orthopaedics Society of North America (POSNA) instruments (Daltroy 1998)

  • Recurrence of bone cyst (reappearance after it has 'healed')

Secondary outcomes
  • Adverse events (e.g. pathological fracture, infection, growth arrest of growth plate)

  • Unacceptable malunion (angular, rotational and shortening), leg-length discrepancy, limping

  • Return to normal activities

  • Patient and parent satisfaction

  • Pain scores

Cost and resource use data will be collected where available.

Timing of outcome measurement

For the primary outcomes of success rate and recurrence, we will give preference to data from follow-ups of over two years.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, current issue), MEDLINE (Ovid Online) (1946 to present), EMBASE (Ovid Online) (1974 to present) and the China National Knowledge Infrastructure Platform. We will also search the World Health Organization International Clinical Trials Registry Platform, and Current Controlled Trials for ongoing and recently completed studies. No restrictions will be applied based on language or publication status.

In MEDLINE, the subject-specific strategy will be combined with the sensitivity-maximising version of the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2011) (see Appendix 1). The Cochrane Central Register of Controlled Trials search strategy is also shown in Appendix 1.

Searching other resources

We will search reference lists from all relevant articles obtained. To identify unpublished studies, we will contact institutions and experts in the field. We plan to search the The Bone and Joint Journal Orthopaedic Proceedings for relevant trials.

Data collection and analysis

Selection of studies

Two review authors (JS and JW), independently, will scan the titles, abstracts and keywords of every record retrieved, and make inclusion decisions according to the pre-stated eligibility criteria. Full texts of trials that fulfil our inclusion criteria and those that are unclear from perusal of the abstracts will be obtained. Differences in opinion between authors will be resolved by discussion and a third author (JGZ) will be consulted. Where necessary, we will attempt to contact trial authors for clarification of study methods and characteristics.

Data extraction and management

Independently, two review authors (JS and JW) will extract trial details and data for the included trials using a data collection form. Disagreement will be resolved by consensus or a third author (JGZ). When necessary, trial authors will be contacted directly to complete data forms or clarify methodology.

Assessment of risk of bias in included studies

Two review authors (JS and JW) will independently assess the risk of bias for each study using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The following items will be assessed:

  • randomisation: assessment for selection bias

  • allocation concealment: assessment of selection bias

  • blinding of participants and personnel: assessment for performance bias

  • blinding of outcome assessment: assessment of detection bias

  • incomplete outcome data: assessment for attrition bias at short-term and long-term follow-up from drop-out/loss to follow-up

  • selective outcome reporting: assessment for reporting bias

  • other bias: as identified on risk of bias assessment

We will assess the risk of bias associated with patient-rated outcomes and clinician-rated outcomes for blinding of outcome assessment and incomplete outcome data separately.

We will classify items into low risk of bias, high risk of bias and unclear risk of bias (indicating either lack of information or uncertainty over the potential for bias).

Any unresolved disagreement will be resolved by discussion with the third author (JGZ). Titles of journals, names of authors or supporting institutions will not be masked at any stage.

Measures of treatment effect

We will calculate risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and mean differences (MD) and 95% CIs for continuous outcomes. Where we pool continuous data from outcomes measured using different scales, we will calculate standardised mean differences (SMD) and 95% CI.

Unit of analysis issues

The unit of randomisation in these trials is usually the individual patient. Exceptionally, as in the case of trials including people with more than one simple bone cyst in different limbs, data for trials may be presented for simple bone cysts rather than individual participants. Where such unit of analysis issues arise and appropriate corrections have not been made, we will consider presenting the data for such trials only where the disparity between the units of analysis and randomisation is small. When we pool data, we will perform a sensitivity analysis to examine the effects of pooling these incorrectly-analysed trials with the other correctly-analysed trials. We will be alert to other potential unit of analysis issues such as those resulting from multiple applications of an intervention, multiple assessment points and recurrence.

Dealing with missing data

When necessary, we will seek missing data, particularly denominators and standard deviations, from the authors of the primary studies. We will perform intention-to-treat analyses wherever possible. Unless we can calculate missing standard deviations from standard errors, exact P values or 95% CIs, we will not impute these.

Assessment of heterogeneity

Besides the visual inspection of forest plot analyses, we intend to examine heterogeneity using the Chi² statistic with significance set at P < 0.1 (Higgins 2003). Our interpretation of the I² results will follow that suggested in Higgins 2011: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100% may represent considerable heterogeneity.

Assessment of reporting biases

In the unlikely event that sufficient data are available, we will attempt to assess publication bias by preparing a funnel plot; this would require at least 10 trials included in a meta-analysis for primary outcomes.

Our pursuit of trials listed in clinical trial registers should help to avoid publication bias. If found, abstracts and unpublished papers will be included.

Data synthesis

When we consider it appropriate, we will pool results of comparable groups of trials using both fixed-effect and random-effects models. The choice of the model used to report will be guided by a careful consideration of the extent of heterogeneity and whether it can be explained, in addition to other factors such as the number and size of studies that are included. We will use 95% CIs throughout. We will consider not pooling data where there is considerable heterogeneity (I² > 75%) that cannot be explained by the diversity of methodological or clinical features among the trials. Where it is not appropriate to pool data, we will still present trial data in the analyses or tables for illustrative purposes and report these in the text.

Subgroup analysis and investigation of heterogeneity

We intend to explore the following potential sources of heterogeneity using subgroup analyses.

  • Upper versus lower limb

  • Active versus inactive (latent) cysts

  • Children under the age of 10 years versus children aged 10 years or over

We will investigate whether the results of subgroups are significantly different by inspecting the overlap of confidence intervals and performing the test for subgroup differences available in Review Manager software (RevMan 2011).

Sensitivity analysis

Where possible, we plan to perform sensitivity analyses to examine various aspects of trial and review methodology. These will include the effects of missing data; inclusion of trials at high or unclear risk of bias (such as from lack of allocation concealment); trials only reported in abstracts; and the selection of statistical model (fixed-effect versus random-effects) for meta-analysis.

Assessing the quality of the evidence

We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Schünemann 2011) to assess the quality of the body of evidence for each primary outcome and, if possible, the first four secondary outcomes listed in Types of outcome measures. The quality rating 'high' is reserved for a body of evidence based on randomised controlled trials. We may ‘downgrade’ the quality rating to 'moderate', 'low' or 'very low' depending on the presence and extent of five factors: study limitations, inconsistency of effect, imprecision, indirectness or publication bias.

'Summary of findings' tables

Where data are sufficient, we will present the results and the quality assessments for the main comparisons in 'Summary of findings' tables (Schünemann 2011).

Acknowledgements

We acknowledge with gratitude the constructive comments and guidance provided by Helen Handoll, James Wright, Lindsey Elstub, Joanne Elliott, and Diane Horsley. We acknowledge Joanne Elliott and Catherine Deering for developing the search strategies, and Laura MacDonald for support during the writing of the protocol.

Appendices

Appendix 1. Search strategies

The Cochrane Library (Wiley Online Library)

#1 MeSH descriptor Bone Cysts explode all trees
#2 (bone near cyst*):ti,ab,kw
#3 (#1 OR #2)
#4 MeSH descriptor Child explode all trees
#5 (child* or pediat* or paediat* or adolesc* or infan* or toddler* or baby or babies or young* or newborn or boy or boys or girl or girls or minor or minors or pubescen* or teen*):ti,ab,kw
#6 (#4 OR #5)
#7 (#3 AND #6)

MEDLINE (Ovid Online)

1   exp Bone Cysts/
2   (bone* adj cyst*).tw.
3   1 or 2
4   exp Jaw/ or exp Jaw Cysts/ or exp Jaw Neoplasms/
5   3 not 4
6   exp Child/
7   (child* or paediat* or pediat* or adolesc* or infan* or toddler* or bab* or young* or preschool* or "pre-school*" or newborn* or "new-born*" or juvenile* or neonat* or neo-nat* or boy*1 or girl*1 or kid*1 or school* or minor*1 or pubescen* or teen* or under*age*).tw.
8   6 or 7
9   5 and 8 (1845)
10 Randomized controlled trial.pt.
11 Controlled clinical trial.pt.
12 randomized.ab.
13 placebo.ab.
14 Drug Therapy.fs.
15 randomly.ab.
16 trial.ab.
17 groups.ab.
18 or/10-17
19 exp Animals/ not Humans/
20 18 not 19
21 9 and 20

Contributions of authors

Jia-Guo Zhao: conceived the review, prepared and designed the protocol and co-ordinated the protocol process.
Jia Wang, Jian Shang, and Peng Zhang: prepared the protocol.

Declarations of interest

Jia-Guo Zhao: none known
Jia Wang: none known
Jian Shang: none known
Peng Zhang: none known

Sources of support

Internal sources

  • Tianjin Hospital, China.

External sources

  • No sources of support supplied

Ancillary