This study aims to assess the impact of smoking and calorie intake on bone fracture healing in osteoporotic patients. It will be a prospective cohort study of 500 osteoporotic patients comparing fracture healing rates of 250 smokers to 250 non-smokers matched for other factors. The study will also assess calorie intake in non-smokers and examine outcomes like time to union, quality of life, hospital stay, and infections. Findings may help emphasize the negative effects of smoking and importance of nutrition on fracture healing to clinicians and patients.
CAC Protocol Impact of smoking and calorie intake on bone fracture healing
1. PROTOCOL
The Impact of Smoking and
Calorie Intake on Bone Fracture
Healing in Osteoporotic Patients
4th
year project report, submitted to the University of
Manchester in partial fulfilment of the MPharm
degree
Richmond Arcillas
7990554
richmond.arcillas@student.manchester.ac.uk
7th
May 2015
School of Pharmacy and Pharmaceutical Sciences
Project Supervisor: Prof Leon Aarons
2. I
Executive summary
Introduction: Osteoporosis is one of the major causes of fractures in the
elderly population worldwide. Osteoporotic patients who are admitted into
hospital with fragility fractures – especially of the hip – are associated with
longer hospital stay, permanent disability, and other complications such as
infections. Bone fracture healing is a complex process and orthopaedic studies
have been conducted to assess the effects of environmental factors such as
smoking and nutrition on fracture healing. Evidence from human orthopaedic
studies suggest that smoking negatively impacts fracture healing, as shown by
longer healing times, higher rates of surgical non-union and post-operative
complications. Evidence from experimental animal model studies suggest that
dietary protein, calcium, phosphorous, and vitamin D have a positive influence
on fracture healing, however, there is limited evidence on their impact based
on human studies.
Aims: The aim of this study is to assess the impact of smoking and calorie
intake on the rate of bone fracture healing in a cohort of osteoporotic patients.
Methods: This study is a non-blinded prospective cohort study of 500
osteoporotic patients recruited from the inpatient and outpatient fracture clinics
in the Manchester Royal Infirmary. The rates of fracture healing of 250 smokers
will be compared with 250 non-smokers matched by age, sex, ethnicity, BMI,
and fracture classification. The calorie intakes of the non-smoking group will be
assessed. The primary outcome measurement is time to union fracture healing.
Secondary outcome measurements will be quality of life, duration of hospital
stay, and presence of infections. The effect of smoking and calorie intake at a
3. The impact of smoking and calorie intake on bone fracture healing
II
cellular level is outside the scope of this study. Data will be analysed using an
unpaired comparison test.
Implications to public health and pharmacy: This research will help to
emphasise the need for clinicians to make fracture patients become more
aware of the negative effects of smoking and the importance of nutritional intake
on the rate of fracture healing. Gaining a better understanding of the impact of
calorie intake can possibly lead to the implementation of recommended
nutritional intakes into guidelines on the management of fragility fractures.
Optimisation of fracture healing requires a holistic approach from the
multidisciplinary team and appropriate patient counselling on smoking and
nutritional intake during a fracture can also help patients to further improve the
rate of fracture healing so that they are able to return to their pre-fracture state
of independence in performing day-to-day tasks, as soon as possible.
4. The impact of smoking and calorie intake on bone fracture healing
III
Table of contents
Executive summary…………………………………………………………………..I
1 Introduction…………………………………………………………………….......1
1.1 Osteoporosis…………………………………………………………….1
1.2 Fragility Fractures……………………………………………………….1
1.3 Bone structure and function…………………………………………....2
1.4 Bone modelling and remodelling………………………………………4
2 Literature review …………………………...……………………………….…….6
2.1 Bone fracture healing………………………………………..…………6
2.2 Smoking and bone fracture healing…………………………………..8
2.3 Calorie intake and bone fracture healing………..……….…………10
2.4 Rationale for the study………..………………………………………11
3 Methods/Design………………………………………………………….………12
3.1 Study aims………………………….……………………………..……12
3.2 Study design…………...………………………………………….…...12
3.3 Study population......................................................................…...13
3.4 Research procedures………………………...…………….…………15
3.5 Ethics……………………………………………………………………18
3.6 Sample size calculation and data analysis…………………..……..19
3.7 Timeline of the study…………………………………………..………20
5. The impact of smoking and calorie intake on bone fracture healing
IV
4 Discussion………………………………………………………...…………...…22
4.1 Limitations of the study…………………………..…………………...22
4.2 Impact of research………………………..…………………………...24
5 Acknowledgements……………..……………………………………………….26
6 References……………………………………………………………………….27
7 Appendices……………………………………………………………………….33
7.1 Appendix 1 – Brief information sheet for eligible patients…….…….33
7.2 Appendix 2 – Full information leaflet for participants………..………35
7.3 Appendix 3 – Consent form………………………………….….…….41
7.4 Appendix 4 – Self-completion questionnaire at baseline……...……43
6. The impact of smoking and calorie intake on bone fracture healing
V
Declaration
“I understand the nature of plagiarism and that it is serious academic offence. I
confirm that no material in the project has been plagiarised.”
Signed: Richmond Arcillas Date: 06/05/2015
7. The impact of smoking and calorie intake on bone fracture healing
1
1. Introduction
1.1 Osteoporosis
Osteoporosis causes approximately nine million fractures annually worldwide1
and more than 300,000 patients in the UK are admitted to secondary care with
fragility fractures each year.2 Osteoporosis is a progressive systemic skeletal
disease caused by an imbalance in the bone remodelling process resulting in
weak, fragile bones. It is characterised by low bone mass, deterioration of bone
micro-structure, and increased skeletal fragility and fracture risk. Fragility
fractures can cause patients severe pain and disability thus affecting their
quality of life; and are associated with an increased risk of morbidity and
mortality.3 Direct medical costs of fragility fractures could potentially rise to £2.2
billion by 2025,4 mostly relating to hip fracture care, thus putting a huge strain
on the UK National Health Service.
The risk of osteoporosis increases with age but women are approximately four
times more likely than men to develop the disease,5 mainly due to an increased
rate of bone loss after menopause when the ovaries stop producing
oestrogen.3,5,6 The problems associated with an ageing population is that the
incidence of osteoporosis and fragility fractures will increase, especially for hip
fractures, which is predicted to rise from 91,500 fractures in 2015 to 101,000 in
2020.2
1.2 Fragility fractures
A ‘fracture’ is a medical term used to describe a broken or cracked bone.
Fragility fractures result from mechanical forces that would not normally result
in a fracture, known as low-level trauma.6 The World Health Organisation has
8. The impact of smoking and calorie intake on bone fracture healing
2
measured low-level trauma as forces equivalent to a fall from a standing height
or less.3
There are a number of factors that can predispose an individual to fragility
fractures. A major risk factor is reduced bone density, however, other risk
factors include: age, sex, oestrogen deficiency, previous fractures, family
history of osteoporosis, and the use of oral or systemic glucocorticoids.3 An
individual’s lifestyle can also influence their risk of developing osteoporosis,
such as lack of exercise, low calcium and vitamin D intake, smoking, and
excessive alcohol consumption.5,6
Fragility fractures occur most commonly in the vertebrae (spine), proximal
femur (hip), and distal radius (wrist), as well as in the humerus (arm), pelvis,
ribs, and in other bones.3 Hip fractures are the most common in the elderly
population and typically results from a fall.2 It is currently the biggest challenge
in the epidemic of osteoporotic fractures: patients with a fractured neck of femur
nearly always require hospitalisation, and are associated with a prolonged
hospital admission – 20% of cases are fatal, 50% are permanently disabled,
and only 30% of cases fully recover.2
1.3 Bone structure and function
An adult human skeleton comprises of 206 bones which have a variety of
functions. Firstly, the skeleton acts as a scaffold to provide structural support
and to protect vital internal organs including the heart, brain, and lungs from
damage. They also provide a site for muscles to attach in order to facilitate
movement, and serve as a storage for various growth factors, cytokines, and
minerals such as calcium and phosphate.7,8,9 The bones help maintain calcium
9. The impact of smoking and calorie intake on bone fracture healing
3
homeostasis and acid-base balance,9 and provide the right environment for the
production of red and white blood cells within the bone marrow spaces through
a process known as haematopoiesis.7,8,9
Bones are predominantly made up of calcium salts and other minerals, which
are bound together by strong collagen (protein) fibres.5 Bones can be divided
into two types: cortical and trabecular. Cortical bone, which comprises 80% of
the skeleton, is dense and forms the thick outer part of the bone surrounding
the marrow space, thus providing mechanical strength and protection.9,10 In
contrast, trabecular bone, which forms the other 20% of the skeletal mass, is
composed of a spongier, honeycomb-like structure comprising of trabecular
plates and rods distributed within the bone marrow compartment.9 Trabecular
bone has a higher turnover rate and is more metabolically active compared to
cortical bone, however, both can provide supplies of mineral at times of
deficiency.10 The ratio of cortical and trabecular bones vary in composition
between various locations, with osteoporotic fractures occurring more
frequently at sites with greater trabecular bone composition,7 such as the
vertebra, proximal femur, and distal radius.3
The skeleton is a complex, living, metabolically active organ that is continuously
adapting throughout life and undergoes constant regeneration (bone turnover),
through bone modelling (construction) and remodelling (reconstruction).7,11
These mechanisms help to repair any micro-damage to the bones and maintain
calcium homeostasis,7 enabling us to achieve peak bone density during growth
and to preserve it thereafter in adulthood.12
10. The impact of smoking and calorie intake on bone fracture healing
4
1.4 Bone modelling and remodelling
Bone modelling is the process by which bones adapt their overall shape and
structure in response to mechanical forces or physiological influences, resulting
in the gradual adjustment of the skeleton to the forces it encounters.9,11
Bone remodelling is the lifelong process by which bone is continuously renewed
in order to maintain bone strength and mineral homeostasis.9 This homeostatic
equilibrium involves the continuous resorption of old bone tissue by osteoclasts,
replacement with newly synthesised bone tissue matrix by osteoblasts, and
subsequent mineralisation of the matrix to form new bone.5,9 This process not
only helps to prevent the accumulation of old bone by repairing micro-damages
in the bone matrix,10 but also plays an important role in maintaining plasma-
calcium homeostasis.9,10
The remodelling cycle comprises of four phases: activation, resorption,
reversal, and formation. This cycle is composed of a tightly coupled group of
osteoclasts and osteoblasts,9 and is mediated by osteocytes which are highly
abundant throughout the skeleton.7 It is suggested by Seeman and Delmas12
that apoptosis of osteocytes produce the signals necessary to initiate
remodelling and thus targets a particular site that is in need of repair.
The activation phase involves the interaction between osteoclast and
osteoblast pre-cursor cells in order to accelerate osteoclastogenesis
(production of osteoclasts).13,14 The initial activation of osteoblast pre-cursor
cells (known as lining cells) result from various triggers including: micro-
fractures, and the presence of insulin growth factor-I, tumour necrosis factor-α,
parathyroid hormone, and interlukin-6 in the bone microenvironment.13 This
11. The impact of smoking and calorie intake on bone fracture healing
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leads to an increase in expression of Receptor Activator of Nuclear κB Ligand
(RANKL) on the surface of their own cells.13 RANKL then binds with its receptor,
Receptor Activator of Nuclear κB (RANK), which are expressed on osteoclast
precursor cells, in order to enhance the nuclear κB signalling pathway.10,13 This
RANKL/RANK interaction between coupled osteoblast and osteoclast pre-
cursor cells trigger the differentiation, migration, and fusion into large
multinucleated osteoclasts.10,14
Once differentiated, osteoclast cells adhere on to the mineralised bone surface
and initiate resorption by releasing lysosomal enzymes such as cathepins K,
and hydrogen ions, which dissolves bone at low pH.13,14
The reversal phase transitions bone resorption to bone formation. This phase
is not well understood but it is thought to involve the recruitment of mononuclear
cells onto the bone surface in order for new bone to be formed.9,13,14
Finally, during the formation phase, osteoblast cells are recruited to the
resorbed area and fill the cavity with new bone matrix that is subsequently
mineralised, in order to complete the bone remodelling cycle.13
In osteoporosis, coupling is lost which leads to a reduced osteoblast activity
and/or an increased osteoclast activity.13 This imbalance between bone
resorption and bone formation leads to a lower peak bone mass,7 which
progressively worsens with age, with the highest rate of bone loss occurring
after the age of 65 years.15
12. The impact of smoking and calorie intake on bone fracture healing
6
2. Literature review
2.1 Bone fracture healing
Bone fracture healing is a complex physiological process that involves various
cell types and proteins coordinated to regenerate and unite fractures. In order
to assess the impact of certain environmental factors such as smoking and
calorie intake on bone fracture healing, we need to have an understanding of
the physiological processes involved in fracture healing.
The stages of fracture healing was first classified by John Hunter in the 1700s
and is still used as the main framework for describing bone fracture healing. It
initially involved four distinct overlapping stages: inflammation, soft callus, hard
callus, and remodelling.16 Current understanding now divides fracture healing
into three stages: inflammation, repair, and remodelling;16,17,18,19-20 which
underpins the same biology as Hunter’s four-stage classification.
The inflammatory stage occurs alongside wound healing in response to
trauma.16 Firstly, a haematoma develops at the fracture site within the first few
hours and days following an injury.17 Osteocytes at the fracture ends die as a
result of nutrient deprivation and is noted to play a passive role in repair.16
Inflammatory cells such as macrophages, lymphocytes, and leucocytes are
then recruited into the fracture site and release pro-inflammatory cytokines
which induce extracellular bone matrix synthesis, stimulate the development of
new blood vessels (angiogenesis), and recruit endogenous fibroblasts and
mesenchymal cells.20 These recruited mesenchymal cells then differentiate into
specialised cells, i.e. fibroblasts, chrondoblasts, and osteoblasts, which help
build new connective tissue, cartilage, and bone tissue, respectively, on the
13. The impact of smoking and calorie intake on bone fracture healing
7
fracture gap.16,18 Osteoclasts also play a role in removing damaged material
through resorption of dead calcified bone.16
The reparative stage begins several days after the initial inflammatory
response.16 Fibroblasts begin to lay down connective tissue which helps to
support angiogenesis.17 As this progresses, a collagen matrix is laid down while
new bone matrix is formed and subsequently mineralised, leading to the
formation of a soft, new bone substance known as a soft callus, around the
fracture site.16,17 This soft callus is very weak during the first 4 to 6 weeks of the
healing process and therefore requires adequate protection.17 As the bone
weaves together over the next 6-12 weeks, the soft callus eventually solidify
and harden into a hard callus.18
The final remodelling stage completes fracture healing by restoring the bone to
its original shape, structure, and mechanical strength.17 In this stage,
osteoclasts slowly resorb the callus until the original shape of the cortex is
restored and osteoblast cells lay down new bone where it is needed, in order to
remodel the woven bone into stronger lamellar bone.22
A study in an osteoporotic rat model produced by ovariectomy and low calcium
diet found that osteoporosis influences the late period of fracture healing.23 Rats
were monitored over a 12 week period and at 12 weeks, newly generated bones
in the group with osteoporosis showed a decreased bone mineral density on
the fracture site compared to the control group. Furthermore, the authors
concluded that oestrogen deficiency and low calcium intake do not markedly
affect the early healing process but largely effect the later stage of fracture
healing.
14. The impact of smoking and calorie intake on bone fracture healing
8
In contrast, a more recent study has been conducted in a rat osteoporotic model
which demonstrated the influence of bone loss on the early phase of fracture
healing.24 The authors found that under osteoporotic conditions, fracture callus
healing was delayed alongside a reduction in callus strength. Although this
study provides evidence on the effect of excessive bone loss towards the early
fracture healing process in osteoporotic rats, its long-term effects have not been
evaluated. Differences in conclusions from these studies could be due to
differences in the length of monitoring and the outcomes measured, but both
studies suggest that osteoporosis could alter the bone fracture healing process.
2.2 Smoking and bone fracture healing
There have been a number of studies documenting the negative effect of
smoking on the healing process and fracture-related morbidities. Patel et al.25
conducted a systematic review of 17 orthopaedic studies, of which, 13
concluded that smoking has a negative influence on fracture healing. For
instance, five tibia studies found that smokers took significantly longer to heal
than non-smokers.26,27,28,29-30
A comparison study by Brown et al.31 investigating the relationship between
smoking and the rate of surgical non-union (i.e. permanent failure of healing
following a fracture) in 50 patients that undertook spinal fusion reported a higher
rate of surgical non-union in smokers than the non-smoking control group (40%
vs 8%). The findings were statistically significant and appeared to be
independent of age, sex, or race. The authors hypothesised that this higher rate
of non-union in smokers may be due to blood gas levels, as smokers showed
a significant deficiency in the mean p02 (78.5%; normal range: 95-97%) and O2
15. The impact of smoking and calorie intake on bone fracture healing
9
saturation levels (92.9%; normal range: >95%) because of an increased carbon
monoxide and smoking-induced arterial constriction.31,32
The effects of smoking on the healing time is also shown on a study focusing
on tibia shaft fractures by Schmitz et al.33 In this study, a higher rate of union
healing at follow-up was observed in non-smokers than smokers (84% vs 58%).
Also, 103 out of 146 patients had a complete follow-up to union but in this group
of patients, the average time of clinical healing was much longer in patients who
smoked compared to the patients who did not smoke (269 days vs 136 days).
Interestingly, statistical differences in the observed healing rates were observed
for those receiving intramedullary or external fixation, but not in patients treated
with cast immobilisation. Nonetheless, the tibias of smokers treated with cast
immobilisation took 62% longer to heal. The authors concluded that patients
who smoke and require treatment with intramedullary nailing or external fixation
require more time to heal than those who do not smoke.
Further studies have also observed a higher frequency of post-operative
complications such as delayed healing, infection, and non-union fracture
healing among smokers.34 Studies conducted by Folk, et al.36 and Abidi, et al.,37
which both investigated calcaneal (heel bone) fractures, have observed a
longer healing period post-surgery in patients that smoked. Furthermore, there
was a higher rate of post-operative local wound complications such as
sloughing or deep infection in patients who smoked. Therefore, the studies
concluded that smoking should be contraindicated in surgery.34
16. The impact of smoking and calorie intake on bone fracture healing
10
2.3 Calorie intake and bone fracture healing
A calorie is defined as a unit of energy supplied from food.38 Calories are
contained in all sources of food, including carbohydrates, fats, sugars, or
proteins. There have not been many studies, especially in humans,
investigating the association of calorie intake and fracture healing. However,
experimental animal studies39,40,41 in the 1980s have looked at the effect of
dietary protein and mineral on fracture healing. Einhorn, Bonnarens and
Burstein39 showed that dietary protein, calcium, phosphorous, and vitamin D
are important in fracture healing; and Hughes, et al.40 found that dietary
supplementation with protein positively influenced bone mineralisation, body
mass, and muscle mass in malnourished animals. The study by Pollak et al.41 in
the injured rat model found that the group which had a low protein diet resulted
in significantly weaker and stiff calluses despite adequate calorie intake;
however, they also did not find a significant improvement in fracture healing
with the high protein diet group.
In humans, a study consisting of 490 hip-fracture patients reported that an
albumin level of <3.5 gs/100ml was predictive for increased duration of hospital
stay and in-hospital mortality following a fracture.42 This study found that
patients with abnormal albumin and total lymphocyte count were 2.9 times more
likely to stay in hospital for more than two weeks and 3.9 times more likely to
die within one year post-surgery. However, these parameters were not
predictive for patients developing post-operative complications.
Malnourishment seem to negatively impact on the bone fracture healing
process, but more human studies are required in gain a better understanding
17. The impact of smoking and calorie intake on bone fracture healing
11
of the clinical implications that deficiencies in nutrition will have on the rate of
fracture healing in humans.
2.4 Rationale for the study
There is a lot of evidence from human studies which assess the impact of
smoking on bone fracture healing. The effects of smoking is thought to be due
to vasoconstriction and platelet activation by nicotine, hypoxia-inducing effect
of carbon monoxide, and the inhibition of oxidative metabolism by hydrogen
cyanide.43 In contrast, limited studies have been conducted with regards to the
impact of calorie intake, most of which were conducted in animal models.
Various studies implied that adequate nutrition is required, especially in
calcium, phosphorous, vitamin C and D, and protein levels, in order to aid the
bone fracture healing process.
Although it is unlikely that the majority of patients presenting with fractures will
be malnourished, there is a higher likelihood that the elderly population
presenting with fragility fractures will have some form of nutritional deficiency.
It is therefore important to assess the nutritional intake of these patients in order
to optimise the rate of fracture healing and to minimise complications. This
research study will help to strengthen our current knowledge of the impact of
smoking, as well as find new evidence of an association between calorie intake
and bone fracture healing, so that health practitioners can help to optimise the
management of fractures not only in osteoporotic patients, but also in the wider
population.
18. The impact of smoking and calorie intake on bone fracture healing
12
3 Methods/Design
3.1Study aims
To determine the impact of smoking and calorie intake on the rate of bone
fracture healing in a cohort of osteoporotic patients.
3.2 Study design
This study is a non-blinded prospective cohort study of 500 patients presenting
with a fragility fracture who have been admitted to the out-patient fracture clinics
or in-patient trauma and orthopaedic department in the Manchester Royal
Infirmary (MRI) hospital.
The primary outcome measurement is time to union fracture healing.
Participants must provide written consent to be observed for 24 months or until
they reach the primary outcome. This study will use the definitions used in a
study conducted by Schmitz et al.,33 where clinical fracture union is defined as
the ability to fully bear weight without pain at the fracture site, and radiographic
union is the evidence of bridging of 3-4 cortices on standard antero-posterior
lateral views. Delayed union is defined as a fracture taking >18 weeks to heal44
and non-union is defined as failure to achieve union within the final follow-up
period. The total length of follow-up is based on a systematic review of 17
orthopaedic studies conducted by Patel et al.25 which identified a mean length
of follow-up which ranged from 21.6 months to 41 months.
Secondary outcomes will also be measured, specifically the presence of soft-
tissue and deep post-surgical infections, duration of hospital stay, and quality
of life. This is in order to gain a wider scope of the impact of smoking and calorie
19. The impact of smoking and calorie intake on bone fracture healing
13
intake with regards to complications in the patient’s recovery, similar to other
studies conducted by Adams et al.,27 Folk, et al.,36 and Abidi, et al.37
3.3 Study population
The study will work closely with the Central Manchester University Hospitals
Trust (CMFT) and the recruitment of volunteers will take place in the MRI
hospital, Manchester. Orthopaedic surgeons and radiologists in the MRI
hospital will be recruited for this study and will act as the gatekeepers. Eligible
patients will be identified by the participating orthopaedic surgeons using an
inclusion and exclusion criteria (see Figure 1). They will then be contacted
initially in hospital and will be verbally informed of the study and receive a brief
information sheet (Appendix 1). Patients who are interested in volunteering in
the study will then be provided with full written information regarding the study,
including: the purpose of the study, their rights, the procedures of data
collection and how their data will be used, as well as reimbursement at follow-
up periods (Appendix 2). Patients are also required to complete a written
consent form (Appendix 3) and hand back to the research team in order to
participate in the study.
In order to be eligible, patients must have a diagnosed history of osteoporosis
and have a current fragility fracture of the femur, distal radius, or knee as these
will be the fractures of interest in the study. Controls will be appropriately
matched by age, sex, ethnicity, BMI, and fracture classification.
Patients will not be eligible for the research study if they refuse to provide written
informed consent. Patients with co-morbidities including diabetes mellitus,
anaemia, peripheral vascular disease, and hypothyroidism will also be
20. The impact of smoking and calorie intake on bone fracture healing
14
excluded as these have been found to further increase the risk of non-union in
patients.45 Similarly, patients on long-term corticosteroid therapy and regular
non-steroidal anti-inflammatory drug (NSAID) therapy will also be excluded as
these too can elongate the healing process.45
Figure 1. Flow diagram defining the population of the study.
Admission to out-patients
fracture clinic (MRI).
Admission to in-patients
trauma and orthopaedic
department (MRI).
Confirmation of fracture
cases by radiography.
Inclusion criteria:
Known diagnosis of
osteoporosis.
Current fracture of
the femur, knee, or
distal radius.
Smokers and non-
smokers.
Exclusion criteria:
Refusal to provide written
informed consent.
Other upper body
fractures including: pelvis,
humerus, and ribs.
Other lower leg fractures,
including foot and ankle.
Diabetes mellitus,
anaemia, peripheral
vascular disease,
hypothyroidism.
Regular use of oral or
systemic corticosteroid
and non-steroidal anti-
inflammatory drugs.
250 controls:
identification of
non-smoker patients
with osteoporosis
during the same
study; matched with
cases by age (2 year
bands), sex (M/F),
ethnicity, BMI, and
fracture
classification.
250 cases who are current
smokers.
Measurement
of calorie
intake (total
calories per
week).
Collect information on
confounders and effect modifiers,
surgical or non-surgical
interventions (e.g. cast
immobilisation or intramedullary
rod fixation), and co-morbidities,
using PMR records.
Measurement of smoking
status (cigarettes per day).
Provision of written
informed consent.
Primary outcome:
time to union fracture
healing.
Secondary outcomes:
quality of life, duration
of hospital stay, and
post-surgical
infections.
21. The impact of smoking and calorie intake on bone fracture healing
15
3.4 Research procedures
The study will comprise of an initial baseline measurement (during hospital
admission), T2 follow-up (two weeks after discharge) and every 3 months
thereafter for 24 months from the date of discharge (T3-T10) or until union
fracture healing is achieved (see Table 1). This is similar to a study conducted
by Adam et al.27 which had a mean follow-up of 21.6 months, however,
trimonthly assessments will help to reduce inconvenience for the participants
but still enable close monitoring of clinical outcomes. Participants will be
reminded about their follow-up a week in advance by telephone call. The
primary outcome of fracture union will be assessed using clinical and
radiographic data; and the length of hospital stay due to fracture and presence
of infections will also be measured. The participant’s study period will end at
T10 follow-up or once union fracture healing has been confirmed.
At baseline, the participants’ age, sex, BMI, co-morbidities, intervention
(surgical or non-surgical) and fracture classification will be recorded by
participating orthopaedic surgeons, using the patient’s most recent patient
medical (PMR) and radiographic records. Only the gatekeepers may have
access to these records. Furthermore, the participants will need to complete a
questionnaire to assess their smoking history (Appendix 4). The calorie intake
will not be recorded on baseline but will be recorded on the subsequent follow-
up periods (T2-T10). This is because the calorie intake during the fracture, not
before, is the point of interest in this study. For convenience, the questionnaire
will be done via an electronic tablet and participants will be provided with an
electronic diary to keep a record of their food intake and the amounts of
cigarettes smoked daily. Participants will be reimbursed with £35 for the T2
22. The impact of smoking and calorie intake on bone fracture healing
16
follow-up and trimonthly follow-ups (T3-T10) and any additional catering and
travelling expenses will be paid for, for their time and effort.
Table 1. Data collection and reimbursement at relative time points.
At two weeks follow-up after discharge (T2) and every trimonthly follow-up (T3-
T10), participants will be assessed by a participating fully-trained diagnostic
radiologist in the MRI hospital. They will also be required to complete the
questionnaire on the same day. In addition, the patient’s current medications
will be checked by the orthopaedic surgeons every 6 months using their PMR
to look for any changes in medications made in between the follow-up periods.
Baseline T2 T3 T4 T5
PMR
Questionnaire
(smoking
status)
Electronic diary
Radiography
Questionnaire
£35
Radiography
Questionnaire
£35
PMR
Radiography
Questionnaire
£35
Radiography
Questionnaire
£35
T6 T7 T8 T9 T10
PMR
Radiography
Questionnaire
£35
Radiography
Questionnaire
£35
PMR
Radiography
Questionnaire
£35
Radiography
Questionnaire
£35
Radiography
Questionnaire
£35
23. The impact of smoking and calorie intake on bone fracture healing
17
There will be 250 cases in each primary arm of the study, based on their
smoking status (see Figure 2). Non-smokers will form the comparison group
and will be defined as patients who stated that they had never smoked or had
stopped smoking over six months ago. Smokers will be further divided into
groups based on the average amount of cigarettes they smoke daily to allow
for comparison of the outcomes between groups with varying numbers of
cigarettes smoked. Participants will be asked to record the number of cigarettes
they smoke each day using the electronic diary provided.
The non-smoker arm will be further divided into groups based on their calorie
intake. The calorie intake of the non-smoking group will be considered in this
study as this will help to minimise any confounding effects of current smoking
and enable comparison between groups with varying calorie intakes.
Participants will be asked to record the type of food they consume each day
using the electronic diary, and if possible, the number of calories they contain.
The foods where calories have not been quantified will be searched up on a
standard easy-to-use food database46 to enable their calories to be measured.
The same database will be used throughout the whole study.
500 participants
250 smokers 250 non-smokers
Primary and secondary
outcomes
Number of
cigarettes
smoked daily
Amount of calories
(kcal) consumed daily
Primary and secondary
outcomes
Figure 2. Number of participants in each arm of the study.
24. The impact of smoking and calorie intake on bone fracture healing
18
3.5 Ethics
The study will be submitted to the Northwest Centre for Research Ethics
Committee’s for approval of conducting the research at the Manchester Royal
Infirmary.
Participants who agree to partake in this study must have the capacity to give
informed consent. All questionnaires, clinical and radiographic data, and patient
medical records (PMR) will be kept confidential throughout and after the study.
Only the participating orthopaedic surgeons and radiologists, who will act as
gatekeepers, will have access to the PMR records and relay the relevant data
back to the research team for the purpose of the study. Participant information
details will also be anonymised throughout and after data analysis. Instead,
each participant will be given a randomly generated identification number.
Participants and the participating orthopaedic surgeons and radiologists will
also be given contact details of the research team if they wish to ask any
questions at any point in time relating to the study.
Participants will remain on their usual medications throughout the study,
including any medications and supplementations indicated for osteoporosis as
per NICE guidelines. However, participants will be told not to purchase and
consume any over-the-counter NSAID such as ibuprofen, or aspirin for pain
relief; however, this cannot be fully controlled when patients have been
discharged. Furthermore, participants have the right to withdraw at any point of
the study; however, they will receive no further reimbursement and their data
may not be used.
25. The impact of smoking and calorie intake on bone fracture healing
19
3.6 Data analysis and sample size calculation
The sample size for this study was calculated using equation 1 (see below),47
in order to detect a predicted 50% reduction of clinical union in smokers
compared to non-smokers. Using a population size of 300,000 and a desired
confidence level of 95% with a 5% margin of error, a minimum of 384
participants will be required in order to produce a power of 80%. An additional
116 participants will be recruited in this study to account for any drop outs or
losses to follow-up during the study period, leading to a total of 500 participants.
Two statisticians will also be recruited to perform the data analysis. An unpaired
comparison test will be used to analyse the data in order to compare results
between the non-smoking comparison group and the various smoking groups;
and between the various calorie-intake groups within the non-smoking
comparison group.
Sample size =
𝒛 𝟐×𝒑(𝟏−𝒑)
𝒆 𝟐
𝟏 +(
𝒛 𝟐 ×𝒑(𝟏−𝒑)
𝒆 𝟐 𝑵
)
(Equation 1)
Z = z-score(1.96 at 95% confidence level)48
P = response distribution (50%; 0.5)
e = margin of error (5%; 0.05)
N = population size (300,000)
Desired
confidence
level
z-score
80% 1.28
85% 1.44
90% 1.65
95% 1.96
99% 2.58
26. The impact of smoking and calorie intake on bone fracture healing
20
3.7 Timeline
The study will last for 36 months in total. Recruitment of volunteers will begin
after the CPRD and University approval, and will last for 12 months after taking
into consideration the limited number of hospital beds. This is to ensure that
there is enough time to recruit 500 volunteers and to receive written informed
consent. A summary of the timescale of the study is shown in Table 2 below.
Table 2. Summary of the study timescale.
Data collection will begin approximately one month after the start of the
recruitment process, or as soon as the participant provides informed consent,
in order for baseline measurements to be taken during hospital admission. This
will continue for a maximum of 24 months after discharge or until the primary
Action
Month
2 4 6 8 10 12 14 16 18
CPRD and University protocol
and approval
Recuitment
Data collection
Data cleaning and
management
Data analysis
Report write-up and
additional analysis
Final publication
Action 20 22 24 26 28 30 32 34 36
CPRD and University protocol
and approval
Recuitment
Data collection
Data cleaning and
management
Data analysis
Report write-up and
additional analysis
Final publication
27. The impact of smoking and calorie intake on bone fracture healing
21
outcome of union fracture healing has been established. Data cleaning and
management will run alongside data collection to minimise compilation of bulks
of unorganised data at the end of data collection.
Considering the amount of data that is being collected, data analysis will
overlap the last four months of data collection so that analysis of data for the
participants who have finished can begin, and will continue for a further two
months after the end of the data collection process. Lastly, the report write-up
and final publication will require approximately four months to complete.
28. The impact of smoking and calorie intake on bone fracture healing
22
4 Discussion
4.1 Limitations of the study
Cohort studies require a large study population that need to be observed for a
long period of time. This study is therefore expensive and the 24 month follow-
up period requires long-term commitment from the participants and naturally
has a higher rate of dropouts and chance of losing participants to follow-up.
Furthermore, since the study population is observed prospectively, there will be
unknown outcomes which would be difficult to predict and control. For instance,
patients on long-term corticosteroids and regular NSAID treatment have been
excluded from the study; however, participants may have their medications
changed by their physicians throughout the study period, which could affect the
outcome of results. It is also difficult to account for patients on nicotine
replacement therapy (NRT) or have decided to switch to NRT as nicotine is
thought to affect fracture healing.43 The non-smoking group is also defined
based on the assumption that cessation for over 6 months after long-term
smoking do not have any long-lasting or long-term effects on the bone fracture
healing process, and therefore, this assumption has the possibility of affecting
the results.
The study population is not randomised and so it will be difficult to avoid
confounding. Additionally, the study is subject to selection bias and variation
between groups of participants cannot be controlled, especially for co-
morbidities, which can potentially lead to biased results. The participants are
not blinded in this study, which makes it difficult to control bias in the outcomes.
Participants having full knowledge of what the research is assessing may be
29. The impact of smoking and calorie intake on bone fracture healing
23
enough to change their normal behaviours, but it is also difficult to blind
participants with this particular study design. Furthermore, this study is limited
to osteoporotic patients and is therefore not representative of the general
population presenting with fractures.
With regards to data collection, data gathered from the questionnaire could be
subject to recall bias since retrospective data is used on the exposure of
smoking and calorie intake. Since information about dietary intake is completely
dependent on self-reports, it is difficult to assess the accuracy, as participants
may not be able to record their daily intake on a regular basis or may be
underreporting or underestimating the amount they consume. This means that
the data may be inconsistent and unreliable. To help with the monitoring
process, participants will be provided with an electronic diary. However, when
combined with the length of follow-up, this strategy can potentially backfire and
become tedious, thus discouraging participants from accurately monitoring their
calorie intakes and smoking status, and possibly even contribute to the dropout
rates or loss to follow-up. The margin of error from the secondary groups that
will have their calorie intake assessed will also be higher in comparison to the
primary groups of smoker vs non-smoker, since that particular group will be
smaller.
Lastly, patients attending the pre-operative clinic for elective surgery may be
advised to stop or reduce smoking which could misrepresent the exposure on
the study population and thus affect results. On the other hand, it is unethical
to tell participants to continue smoking or drinking, therefore it is difficult to fully
isolate the effect of the exposure on the outcome.
30. The impact of smoking and calorie intake on bone fracture healing
24
4.2 Impact of research
Various studies have found a negative correlation between smoking and bone
fracture healing in fracture patients. In contrast, there has not been a lot of
research on the clinical impact of calorie intake on bone fracture healing in
humans. Patients undergoing surgery for fractures are advised not to smoke on
the morning of general surgery,29 however, there is a lack of advice given with
regards to calorie or nutritional intake. Relating this to orthopaedics, it is
important that factors that can compromise the process of fracture healing are
minimised in order to optimise the management of fractures. This study will be
one of the largest studies to be conducted in a cohort of osteoporotic patients.
This can provide the foundation for the development of human studies to
assess the impact of these two exposures, especially of calorie intake and
nutrition, on the rate of bone fracture healing
Conducting this study will help to provide further evidence on the negative
impact of smoking to the rate of fracture healing in patients diagnosed with
osteoporosis. There is a lack of understanding on the clinical impact of calorie
intake on bone fracture healing; therefore, this study will help contribute new
evidence towards the impact of calorie consumption on bone fracture healing
in humans. Gaining a better understanding on the impact of these two
environmental factors can lead to the implementation of recommended
nutritional intakes into hospital or local guidelines on the management of
fragility fractures.
Optimisation of fracture healing requires a holistic approach from the
multidisciplinary team and appropriate patient counselling on the risks of
31. The impact of smoking and calorie intake on bone fracture healing
25
smoking and the benefits of nutritional intake during a fracture can also help to
improve the rate of fracture healing so that patients are able to quickly return to
their pre-fracture state of independence in performing day-to-day tasks.
32. The impact of smoking and calorie intake on bone fracture healing
26
5 Acknowledgements
I wish to thank Professor Leon Aarons from the University of Manchester for his
guidance with writing this research protocol.
33. The impact of smoking and calorie intake on bone fracture healing
27
6 References
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and disability associated with osteoporotic fractures. Osteoporosis
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3) National Institute for Health and Clinical Excellence. NICE [Internet].
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19) Einhorn TA. The Cell and Molecular Biology of Fracture Healing. Clin
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22) Marsh, DR and Li, G. The biology of fracture healing: Optimising
outcome. British Medical Bulletin. 1999; 55(4):856-869.
23) Kubo T, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, Kitajima
I, Semba I, Hirasawa Y. Osteoporosis influences the late period of
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diet. J Steroid Biochem Mol Biol. 1999 Mar; 68(5-6): 197-202.
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Swain M, Mason RS. Murrell GAC, Diwan AD, Diamond T. Osteoporosis
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25) Patel RA, Wilson RF, Patel PA, Palmer RM. The effect of smoking on
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28) Gaston MS, Simpson AHRW. Inhibition of fracture healing. J Bone Joint
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prospective study of 200 patients operated on by the hemicallotasis
technique. Acta Orthop Scand 2004;75:347–351.
30) W-Dahl A, Toksvig-Larsen S. No delayed bone healing in Swedish male
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31) Brown CW, Orme TJ, Richardson HD. The rate of pseudoarthrosis
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32) Haverstock BD, Mandracchia VJ. Cigarette smoking and bone healing:
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33) Schmitz MA, Finnegan M, Natarajan R, Champine J. Effect of smoking
on tibial shaft fracture healing. Clin Orthop Relat Res. 1999 Aug; (365):
184-200.
34) Abidi NA, Dhawan S, Gruen GS, Vogt MT, Conti SF: Wound-healing risk
factors after open reduction and internal fixation of calcaneal fractures.
Foot Ankle Int 1998;19:856–861.
35) Buckley RE, Tough S. Displaced intra-articular calcaneal fractures. J Am
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36) Abidi NA, Dhawan S, Gruen GS, Vogt MT, Conti SF: Wound-healing risk
factors after open reduction and internal fixation of calcaneal fractures.
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37) Folk JW, Starr AJ, Early JS: Early wound complications of operative
treatment of calcaneus fractures: Analysis of 190 fractures. J Orthop
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38) Centers for Disease Control and Prevention [Internet]. Atlanta; 2015
[updated 2014 Jan 15; cited 2015 May 01]. Available from:
http://www.cdc.gov/healthyweight/calories/
39) Einhorn TA, Bonnarens F, Burstein AH. The contributions of dietary
protein and mineral to the healing of experimental fractures. A
biomechanical study. J Bone Joint Surg Am. 1986 Dec; 68(9): 1389-95.
40) Hughes MS, Kazmier P, Burd TA, Anglen J, Stoker AM, Kuroki K, Carson
WL, Cook JL. Enhanced fracture and soft-tissue healing by means of
anabolic dietary supplementation. J Bone Joint Surg Am. 2006 Nov;
88(11): 2386-94.
41) Pollak D, Floman Y, Simkin A, Avinezer A, Freund HR. The Effect of
Protein Malnutrition and Nutritional Support on the Mechanical
Properties of Fracture Healing in the Injured Rat. J Parenter Enteral Nutr.
1986 Nov; 10(6): 564-67.
42) Koval KJ, Maurer SG, Su ET, Aharonoff GB, Zuckerman JD. The effects
of nutritional status on outcome after hip fracture. J Orthop Trauma
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43) Sloan A, Hussain I, Maqsood M, Eremin O, El-Sheemy M. The effects of
smoking on fracture healing. Surgeon. 2010 Apr; 8(2): 111-6.
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44) Ellis H. The Speed of healing after fracture of the tibial shaft. J Bone
Joint Surg Br. 1958 Feb; 40-B(1): 42-46.
45) Gaston MS, Simpson AHRW. Inhibition of fracture healing. J Bone Joint
Surg Br. 2007 Dec; 89-B(12): 1553-60.
46) CalorieKing [Internet]. CalorieKing Wellness Solutions, Inc. 2015 [cited
06/05/2015]. Available from: http://www.calorieking.com/foods/
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39. The impact of smoking and calorie intake on bone fracture healing
33
7 Appendix
7.1 Appendix 1 – Brief information sheet for
eligible patients
40. The impact of smoking and calorie intake on bone fracture healing
34
The impact of smoking and calorie intake on bone fracture healing
Hello, we are conducting a research study in the Manchester Royal Infirmary
Hospital to assess the impact of smoking and calorie intake on the rate of
bone fracture healing.
We are looking for 500 volunteers with osteoporosis who are presenting with
a current fracture of the hip, wrist, or knee. You have been given this brief
information sheet because you are eligible to participate in this study.
The study will comprise of periodic follow-ups at the Manchester Royal Infirmary
Hospital after discharge in order to observe the progress of your fracture
healing and to complete a questionnaire. We are also interested in your weekly
calorie intake and smoking status as we are assessing their impact on the rate
of bone fracture healing.
It is completely voluntary to participate in this study but we will first need to
receive a signed written consent form from you before the study can proceed.
If you are interested in this study, please mention this to your doctor or
orthopaedic surgeon so that they can provide you with a full information sheet.
Many Thanks,
Mr Richmond Arcillas
University of Manchester School of Pharmacy
Email: richmond.arcillas@student.manchester.ac.uk Tel: 0161 257 6861
41. The impact of smoking and calorie intake on bone fracture healing
35
7.2 Appendix 2 – Full information sheet for
participants
42. The impact of smoking and calorie intake on bone fracture healing
36
The impact of smoking and calorie intake on bone fracture healing
We appreciate you for taking interest in our research. Please take your time to
read this sheet for full the information regarding our study.
1. Introduction
You have been given this full information leaflet because you are eligible
and have shown interest towards partaking in this study. It is important for
us that you read this information leaflet thoroughly so that you understand
the purpose of this study, what information we need from you, and what we
will do with that information for the purpose of our research. Before you can
participate, we will need you to sign and submit a written information
consent form. Please do not hesitate to contact us using the details provided
at the bottom of this leaflet if you wish to ask any other questions regarding
the study before agreeing to take part. If you change your mind and decide
not to participate in this study, the standard of treatment and care you will
receive will not be affected.
2. Purpose of the study
The purpose of this study is to assess how smoking and the amount of
calories you consume will affect the time it takes for your fracture to heal.
You have been chosen because we want to look at these effects particularly
in the population with osteoporosis. From this, we hope to find ways in which
we can improve the rate of fracture healing so that we can minimise the
43. The impact of smoking and calorie intake on bone fracture healing
37
length of hospital stay and help to return patients with fractures to the level
of independence before the fracture, as soon as possible.
3. The research team
I will be leading the research team on behalf of the University of Manchester,
and will be working alongside participating orthopaedic surgeons and
radiologists in Manchester Royal Infirmary, where the study will be
conducted. You will be able to contact any member of the research team if
you want to ask any further questions regarding the study.
4. Your role in the research study
You will be required to complete a questionnaire at the start of the study
regarding your smoking status. You will also have follow-ups with the
radiologist in the Manchester Royal Infirmary so that we can X-ray your
fracture in order to keep track of the progress of healing. The follow-ups will
be at two weeks after your discharge from the hospital and every three
months after discharge until your fracture has healed, for a maximum of 24
months (2 years). If your fracture has healed before 24 months then your
participation in this study has completed and you will no longer be required
to go to your follow-ups.
Furthermore, you will be provided an electronic diary at the start of the study.
In this study, we would like you to record the amount of cigarettes you smoke
each day (if applicable). If you do not smoke or have stopped smoking over
6 months ago, then please keep track of the foods you consume each day,
and whenever possible, the amount of calories you are consuming for each
meal or snack.
44. The impact of smoking and calorie intake on bone fracture healing
38
At each follow-up period, you will be required to complete a questionnaire
regarding your smoking status, calorie intake, and quality of life. This may
take approximately 20 minutes. Please ensure that the information you
provide is as accurate as possible so that results gained from this study is
viable and is not misinterpreted.
For each follow-up period, you will be reimbursed with £35 for your time and
effort. All your travel expenses to and from Manchester Royal Infirmary will
also be paid for, as well as any catering expenses in the hospital.
5. Confidentiality and data protection
The data we receive from you will be used for comparison between other
participants, so that we can assess the impact of smoking and calorie intake
on the rate of bone fracture healing. The results will be written up in a report
that will be peer-reviewed and possible be published in scientific journals.
All questionnaires and your patient medical records will be kept confidential
throughout and after the study. Only the participating orthopaedic surgeons
and radiologists will have access to your medical records and will only
provide me with the necessary information required for the purpose of the
study. The information we require are: age, sex, BMI, other medical
conditions, smoking status, fracture classification, and the method for
treating the fracture. This is in order for us to group the participants
accordingly so that we can limit the variation in the results due to these
factors.
Your information details, including your name and address will be
anonymised for the purpose of data analysis. This means that your
45. The impact of smoking and calorie intake on bone fracture healing
39
information is used only for the purpose of the research and will not be able
to be traced back to you. All electronic records will be stored in a secure
password-encrypted system and any unused information will be destroyed
at the end of the study.
6. Your rights
Participation in this study is completely voluntary therefore you have the
right to withdraw at any point throughout this study. If you choose to, then
you will no longer receive further reimbursement and your data may not be
used. However, you may keep any reimbursement prior to withdrawing from
the study. You also have the right to request for the summary of our findings
if you wish to see how we are interpreting your results.
7. Risk and benefits
There are no significant risks apart from what you are normally exposed to
on a day-to-day basis, if you partake in this study. This study is merely
observational and we will only require you to report your calorie intake and
smoking status during the follow-up periods. The X-ray scans the radiologist
will be performing on you is safe and will not be detrimental to your health.
We cannot guarantee that you will benefit from this study, however, you will
be partaking in one of the largest studies of this kind and you will be
contributing to future scientific research that may benefit patients with
conditions similar to yours in the future.
46. The impact of smoking and calorie intake on bone fracture healing
40
8. Next step
If you have read the information above and have decided to volunteer to
take part in this study then please complete and sign the written consent
form enclosed in this envelope. Please return it to your doctor or your
orthopaedic surgeon so that we can provide you with a diary.
Thank you very much for your time and consideration
If you have any further questions regarding this study, then please contact:
Mr Richmond Arcillas
University of Manchester School of Pharmacy
Email: richmond.arcillas@student.manchester.ac.uk Tel: 0161 257 6861
47. The impact of smoking and calorie intake on bone fracture healing
41
7.3 Appendix 3 – Consent form
48. The impact of smoking and calorie intake on bone fracture healing
42
Participant Consent Form
Please complete this form and return to your orthopaedic surgeon.
1. I have read the information sheet thoroughly and I have asked any
necessary questions regarding the study so that I have full
understanding of what is required in participating in the study.
2. I understand the purpose of this study, how my data will be used, and
my rights.
3. I understand that I will be required to attend the Manchester Royal
Infirmary for follow-ups two weeks after my discharge, and every three
months after discharge thereafter for a total of 24 months or until my
fracture has healed.
4. I understand that participation in this study is completely voluntary and
that I can withdraw from the study at any point throughout the study
period. If I withdraw, I will no longer receive further reimbursements and
my data may not be used.
5. I understand that my personal data will be used solely for the purpose of
the research study and that any information will be kept confidential and
anonymised, in accordance with the Data Protection Act 1998.
6. I promise that the information I provide throughout this study will be
accurate and to the best of my knowledge.
Name: Date:
Signature:
Contact details:
49. The impact of smoking and calorie intake on bone fracture healing
43
7.4 Appendix 4 – Self-completion
questionnaire
50. The impact of smoking and calorie intake on bone fracture healing
44
Self-completion questionnaire
N.B. this questionnaire is an example only. The questionnaire will be done
online via an electronic tablet.
BASELINE MEASUREMENT
ID number
Date of Birth
Sex M F I prefer not to answer
Which of the following best describes your Race?
White/Caucasian Asian Indian Japanese
Black, African
American
Chinese Korean
American Indian or
Alaska native
Filipino Vietnamese
Other race (please
specify)
Other Asian
(please specify)
I prefer not to answer
1. Smoking status
a. Have you ever smoked a cigarette, even for just a few puffs?
Yes [] No []
b. How often do you smoke? Please tick one box only
I have never smoked []
51. The impact of smoking and calorie intake on bone fracture healing
45
I am not a current smoker []
I have quit smoking []
At least once a day []
At least once a week []
At least once a month []
Less than once a month []
c. If you ticked ‘I have quit smoking’ (b), how long has it been
since you quit? Please tick one box only (otherwise leave
this section blank)
About a week ago []
Less than a month ago []
Less 3 months ago []
Less than 6 months ago []
Over 6 months ago []
Over a year ago []
Over 2 years ago []
d. If you have recently quit, are you on nicotine replacement
therapy?
Yes [] No[]
e. If the answer to (d) was ‘yes’, please specify what nicotine
replacement therapy you are on (otherwise leave this section
blank)
………………………………………………………………………..…
…………………………………………………………………………..