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SUMMARY
Indolent systemic mastocytosis (ISM) is a subtype of mastocytosis that is characterized by a
mild proliferation and accumulation of pathological mast cells in extracutaneous tissues, with
or without cutaneous involvement. Accumulation and degranulation of mast cells in the bone
may cause symptoms of bone involvement, the most important symptoms being fragility
fractures and osteoporosis.
These patients are generally treated with bisphosphonates, according to the guidelines for the
regular, postmenopausal osteoporosis population with increased fracture risk. However,
considering the different pathophysiological mechanism causing the symptoms and the
different composition of the ISM population compared to the postmenopausal population,
questions on the effectiveness of bisphosphonates as a treatment for patients with ISM and
osteoporosis and/or fragility fractures can be raised.
This study is the largest study to evaluate the effectiveness of bisphosphonates in 50 ISM
patients with symptoms of bone involvement with regards to fracture rate, bone mineral density
(BMD) and zCTx scores during five years of follow-up. Bisphosphonates significantly
increased the lumbar BMD and decreased bone turnover, considering the decrease in zCTx
scores. A decrease in fracture rate prior to and after treatment was found when assuming that
fractures prior to treatment are detected within two years. Interpretation of this fracture rate is
difficult, since a proper control group is lacking. Therefore, final conclusions on the
effectiveness of bisphosphonates as a treatment for patients with ISM and bone involvement in
the form of fragility fractures and osteoporosis cannot be made. However, considering the large
number of fractures in this patient population, proper treatment is necessary and future
randomized studies are highly recommended to further evaluate this treatment option.
SAMENVATTING
Indolente systemische mastocytose (ISM) is een subtype van mastocytose. Het wordt
gekarakteriseerd door een milde proliferatie en opeenstapeling van pathologische mestcellen in
extracutane weefsels, met daarnaast nog eventuele betrokkenheid van het cutane weefsel. De
ophoping en degranulatie van mestcellen in het bot kan symptomen als het ontstaan van laag
energetische fracturen dan wel osteoporose veroorzaken.
Deze patiënten worden over het algemeen, in navolging van de richtlijnen van de reguliere,
postmenopauzale osteoporose populatie met een verhoogd fractuurrisico, behandeld met
bisfosfonaten. Echter, gelet op de verschillen in onderliggende pathofysiologie en de
verschillen in samenstelling van de populatie, is het de vraag of deze behandeling wel effectief
is voor de ISM populatie.
Deze studie is de grootste studie die de effectiviteit van bisfosfonaten evalueert. 50 patiënten
met ISM en botbetrokkenheid met betrekking tot fractuurfrequentie, botmineraaldichtheid
(BMD) en zCTx scores zijn gevolgd gedurende een follow-up van vijf jaar. Bisfosfonaten
verhoogden de lumbale BMD en zorgden voor een verlaagde bot turnover, wat af te lezen is in
een daling van zCTx scores. De fractuurfrequentie nam af na behandeling als aangenomen
wordt dat fracturen voor start van behandeling binnen twee jaar gedetecteerd worden.
Interpretatie van deze gegevens is gecompliceerd, aangezien er geen goede controlegroep
beschikbaar is. Samenvattend kunnen we geen definitieve conclusies trekken wat betreft de
effectiviteit van bisfosfonaten in de behandeling van patiënten met ISM en LE fracturen in de
vorm van LE fracturen en osteoporose. Desalniettemin behoeft deze groep wel goede
behandeling gelet op het grote aantal fracturen. Daarom is vervolgonderzoek in de vorm van
een randomized clinical trial sterk aanbevolen.
3
CONTENTS
English and Dutch summary p. 2
Abbreviations p. 4
Introduction p. 5
Materials and methods p. 7
Results p. 11
- Flowchart
- Baseline results
- General results
- Fractures
- Lumbar BMD
- Femoral BMD
- zCTx
Discussion p. 21
Conclusion p. 24
References p. 25
Appendices p. 27
- Appendix 1
- Appendix 2
- Appendix 3
- Appendix 4
- Appendix 5
- Appendix 6
4
ABBREVIATIONS
SM = systemic mastocytosis
BMD = bone mineral density
CTx = cross-linked telopeptide of type I collagen
HE = high energetic
ISM = indolent systemic mastocytosis
IQR = interquartile range
LE fractures = low energetic fractures/ fragility fractures
MPR = medication possession rate
zCTx = age and sex linked z score of CTx
5
INTRODUCTION
Mast cells are commonly known for their role in allergic reactions. They can be activated by
various triggers, though usually they are activated after cross-linking of antigens to IgE attached
to the Fc epsilon receptor on the mast cell membrane, causing subsequent degranulation of the
cell. The release of mediators such as histamine and heparin causes a wide variety of symptoms,
e.g. flushing, pruritis, urticaria, nasal congestion and hypotension. (1)
Mastocytosis is a rare disease. The systemic variant of the disease has an estimated prevalence
of 1 in 10,000 (2,3). It is characterized by abnormal proliferation and accumulation of
pathological mast cells in various tissues of the body (4-6). Common sites of accumulation are
the skin, bone marrow, liver, spleen, lymph nodes and the gastro-intestinal system.
Due to pathological abnormalities of mast cells in patients with mastocytosis, stem cell factor
is not required for mast cell differentiation, activation and survival. The most common mutation
that causes this abnormal cell function is the D816V mutation of the KIT gene. This mutation
is found in approximately 80% of patients with systemic mastocytosis. (1,7)
The WHO distinguishes seven types of mastocytosis. Cutaneous mastocytosis, systemic
mastocytosis (SM) and mast cell tumours are the three main groups. Cutaneous mastocytosis,
with characteristic urticaria pigmentosa laesions, is restricted to the skin. There are two types
of mast cell tumours, mast cell sarcoma and extracutateous mastocytoma. Systemic
mastocytosis (SM) presents itself in extracutaneous tissues and is diagnosed when a patient
meets the major criterion and at least one minor criterion or three minor criteria. SM may
present itself with or without cutaneous involvement.
The major criterion for systemic mastocytosis is met when multifocal dense aggregates of mast
cells, with more than 15 cells per aggregate, are found in an extracutaneous tissue. The four
minor criteria are respectively more than 25% of morphologically abnormal mast cells in bone
marrow or extracutaneous tissues, detection of a D816V Kit mutation in laesional tissue or in
the peripheral blood, the expression of CD25 and/ or CD2 by KIT+ mast cells, and serum
baseline tryptase levels higher than 20 ng/mL. (4)
Depending of the severity of proliferation and organ involvement, SM can be further
differentiated in indolent systemic mastocytosis (ISM), smouldering systemic mastocytosis
(SSM), aggressive systemic mastocytosis (ASM) and systemic mastocytosis with an associated
clonal haematological non-mast-cell-lineage disease (SM-AHNMD).
The vast majority (90%) of patients with SM suffers from indolent systemic mastocytosis. ISM
is characterized by a mild proliferation of mast cells, an indolent course and a good prognosis,
with a normal life expectancy. The percentage of mast cells in the bone marrow is usually below
5%. (7,8)
The clinical presentation of ISM is varies, partly due to the variation in sites of accumulation
of mast cells. Patients may suffer from symptoms like flushing, gastro-intestinal complaints or
anaphylaxis (due to various triggers, of which stings of wasps and bees are most life
threatening).
One of the extracutaneous sites in which the disease manifests itself is the bone. Manifestation
of ISM in the bone can cause a variety of symptoms, ranging from bone pain to osteoporosis,
osteosclerosis and fragility fractures (fractures caused by low energetic trauma).
Osteoporosis, defined by a decreased bone mineral density (BMD) of a T-score of < -2.5 in the
lumbar spine or the hip, is a frequent manifestation in patients with ISM. So far, the reported
6
prevalence of osteoporosis in patients with ISM ranges from 18 to 31%. (7, 9-12) One study
showed a high prevalence of 54% of osteoporotic fractures in ISM patients (10).
Osteoporosis is normally found in postmenopausal women as a result of hormonal changes.
However, the mastocytosis population with osteoporosis or low energetic (LE) fractures has a
different composition than the ‘regular’ osteoporosis population. Thus far, studies show that
approximately 50% of the patients with osteoporosis or fragility fractures were male.
Furthermore, this bone involvement regularly manifest itself in patients under the age of 50.
(10,11)
There is increasing evidence that the mediators released by mast cells mediators interfere with
the natural mechanism of demolition and construction of the bone, causing bone loss and
therefore contributing to the development of osteoporosis. (10,11,13)
According to Dutch guidelines, patients in the postmenopausal osteoporosis population with a
high fracture risk are generally treated with bisphosphonates plus calcium and vitamin D, in
order to increase bone mineral density and therefore decrease the chance of fragility fractures.
(14) Bisphosphonates have a high affinity for bone mineral, resulting in a selective uptake by
the osteoclasts. Furthermore, they have a strong inhibitory effect on osteoclasts. Therefore they
are highly suitable for the treatment of osteoporosis in postmenopausal women. (15)
Considering the assumed differences in underlying pathophysiological mechanisms of the
occurrence of osteoporosis and/ or fragility fractures in the postmenopausal and mastocytosis
populations questions can be raised about the effectiveness of bisphosphonates as a treatment
for patients with SM with bone involvement. Since mast cell release is local, the subsequent
damage to the bone is local as well. General inhibition of osteoclasts caused by bisphosphonates
may not be as effective as it is in the postmenopausal population in the prevention of fragility
fractures.
So far, only small studies have looked at the effect of bisphosphonates as a treatment of
osteoporosis. These studies had only a small number of participants and/or a short duration of
follow-up. (9,16-21)
The two studies with the largest number of participants provided data of respectively 25 patients
with a follow-up of only 1 year and 9 patients with an average duration of follow-up of 65
months. (9,16) In these studies bisphosphonates did appear to be effective in increasing BMD
and the prevention of fragility fractures.
Since Groningen is the national centre for expertise on mastocytosis, we have a large population
of patients with mastocytosis and osteoporosis and/ or fragility fractures who have been treated
with bisphosphonates. Furthermore, the duration of follow-up is relatively high, compared to
previous studies. This allows us to give a more elaborate assessment of the effectiveness of
bisphosphonates in preventing the occurrence of fragility fractures and in increasing the bone
mineral density of patients suffering from indolent systemic mastocytosis.
7
MATERIALS AND METHODS
This retrospective cohort study evaluates the effectiveness of bisphosphonates on preventing
fragility fractures and increasing bone mineral density (BMD) after five years of treatment in
patients suffering from indolent systemic mastocytosis (ISM) and osteoporosis and/ or fragility
fractures.
Subjects
For this study the list of patients of all 693 patients who had visited the UMCG because of a
suspicion of mastocytosis was used. Furthermore, a database containing information on 53
ISM patients who were known to have used bisphosphonates prior to 2011 was used. This
database was last updated in 2011. Using the patient list of 693 patients we were able to identify
an additional 11 patients that had been treated with bisphosphonates.
Patients known to have used bisphosphonates at the present or in the past were approached to
participate in this research.
The medical ethical committee judged that all necessary guidelines were met. Subsequently,
patients were approached. They were asked for their informed consent for using data from their
medical records. Furthermore, they were asked for informed consent for requesting a history of
drugs supplied by their pharmacist. This only concerned drugs relevant to the study
(bisphosphonates, calcium, vitamin D). Finally, they were asked to report if, when and under
which circumstances they ever fractured any bones.
Patients who did not initially respond to the send letter were contacted by telephone. The
pharmacists of patients who agreed to participate were contacted by telephone and provided
with a copy of the patient’s informed consent. Correspondence with the medical ethical
committee, patients and pharmacists can be found in appendix 1-3.
Available data (medical records, previous response to a questionnaire about fractures) of
patients who were deceased were used. No informed consent was asked from relatives of the
deceased and no further data were requested from either pharmacists or relatives.
Patients diagnosed with ISM who were treated with bisphosphonates were included,
irrespective of start of bisphosphonate treatment prior to or after ISM diagnosis. Patients who
started treatment in or after January 2011 were excluded based on a too short duration of follow-
up. Patients who were given mast cell eradication therapy, e.g. interferon alpha, imatinib or
cladribine, before or during bisphosphonate treatment, were also excluded. If ISM progressed
to SSM during the first five years of bisphosphonate treatment, their follow-up data was
excluded. However, their baseline data were included. The BMD and CTx (cross-linked
telopeptide of type I collagen, a bone resorption marker) data of one transwoman were excluded,
since BMD and CTx are sex related. Her fracture outcomes were included.
Treatment characteristics and baseline data
Moment of start of treatment was determined by data in patient’s medical records and the data
provided by the pharmacists. The data provided by the pharmacists were considered to be
leading, unless this data was incomplete or unclear.
The number and types of bisphosphonates used per patient were noted, as well as the average
duration of treatment, adverse events and reasons for terminating treatment.
Data from the medical records (in case of intravenous administration) and data provided by the
pharmacists were used to determine duration of treatment and medication possession rate
8
(MPR). MPR was determined for the first five years of treatment, since the evaluation of
treatment was also based on this period. MPR of the period after these 5 years was not
determined. If patients were not treated for five years, the MPR for the duration of treatment
was evaluated. Based on previous studies with bisphosphonates in osteoporotic women patients
with a MPR of ≥ 80% were considered to be compliant(22-25). Patients with a MPR ≥ 80% and
a duration of treatment of ≥ five years were defined as having been treated per protocol.
The collected baseline data can be found in Table 1 of the results. Indication of treatment was
assessed; were patients started on bisphosphonates shortly after LE fractures were detected or
shortly after low BMD values were measured? Parameters of disease activity were measured in
blood (tryptase) or urine (MH, MIMA). Fractures were inventoried by using patients response
to the questionnaire and data in their medical records. If digital medical records were not
elaborate enough or were lacking paper medical records were requested. BMD was measured
with the use of DEXA scans. zCTx scores prior to bisphosphonate treatment were noted. zCTx
levels are the age and sex matched scores of CTx levels measured in the blood. Only CTx levels
measured in the afternoon were used, given the circadian pattern of this parameter. Furthermore
use of H1 and H2 antagonists as well as calcium and/or vitamin at start of bisphosphonate
treatment was noted. Also smoking and alcohol habits at baseline were inventoried. Patients
who had given up smoking for at least a year at baseline were considered to have quit. Alcohol
abuse was defined as >2 units of alcohol per day, alcohol intolerance was noted if patients
reported discomfort after consumption of small amounts of alcohol. Patients were screened for
the presence of co-morbidities and use of medication (for ≥ 3 months) that influence the bone
metabolism using information in their medical records. Co-morbidities include hypo- and
hyperthyroidism, celiac disease, renal insufficiency, hypogonadism, premature menopause and
acromegaly. Medications include anti-epileptics, corticosteroids (inhaled or systemic,
excluding eye drops), thiazides and furosemide.
Measurement and statistical analysis of follow-up data
During follow-up fractures, BMD and zCTx were assessed. Disease activity was not assessed
during follow-up, for bisphosphonate treatment does not interfere with this and therefore no
changes were expected.
Fractures were noted at three moments in time. A history and total number of fractures at start
of treatment, occurrence and total number of fractures within the first year of treatment and
occurrence and total number of fractures up to 5 years of follow-up (with a range of 4 to 6
years). In the latter group a differentiation between patients who were and were not treated per
protocol was made.
Fractures were assessed using medical records, patient’s response to the questionnaire and the
results of DEXA scans and vertebral fracture assessment (VFA). The vertebral fractures in the
reports had been assessed by a nuclear medicine physician, using the criteria by Genant. These
criteria consider a reduction of at least 20% in anterior, middle, and/or posterior height (relative
to the same or adjacent vertebrae) accompanied by a reduction in area of at least 10% to be a
fracture.(26) In case of doubt or incomplete reports we reassessed the scans using the same
criteria.
Fractures were classified as vertebral and non-vertebral fractures. Furthermore, they were
divided as high (HE) and low energy (LE) fractures. LE fractures were defined as fractures as
a results of a mechanical impact that would normally not result in a fracture. (27)
The fractures in the first year of treatment were recorded separately, for the duration of
bisphosphonate treatment would then have been too short in order to be able to effectively in
9
prevent fractures. Furthermore, some patients did not have a recent DEXA scan and VFA at
start of treatment, meaning fractures detected during the first year of treatment could also have
occurred prior to start of treatment.
A survival analysis (Kaplan Meier curve) of LE vertebral fractures was made to evaluate the
moment of occurrence of the first fracture during follow-up. The fractures that occurred in the
first year of treatment were excluded in this analysis, for previously explained reasons. If
fractures were noted by the patient, the date the patient mentioned was used for the survival
curve. If the fracture was measured on a DEXA scan, but had not been observed before, the
date of the DEXA scan was used as the moment of fracture. If patients did not have a DEXA
scan in the range of 4 to 6 years after start of treatment the date of the last DEXA scan prior to
the 4 to 6 year period was used as the moment of loss to follow-up, even if DEXA scans after
more than 6 years showed absence of fractures. This was done to prevent the occurrence of a
positive bias in our data. Patients who showed no fractures at DEXA scans in the range of 4 to
6 years were all recorded as a censored case at 5 years exactly. Patients who showed fractures
on the DEXA scan between 5 and 6 years were all recorded to have fractures at 5 years exactly.
This was done because if the exact dates would be used an unrealistic drop would be seen at
the end of the curve, due to the great number of drop-out cases before the full 6 years.
Changes of BMD between baseline and follow-up were measured at the lumbar spine and the
proximal femur. For BMD at baseline a range of 1 year prior to and 1 year after start of
bisphosphonate treatment was used. For follow-up the range of 4-6 years was used. BMD was
measured both in T and Z scores, as well as in absolute numbers (g/cm3). T scores were
considered to be the most important outcome measure of the three, since these scores are most
commonly used in clinical care. Lumbar BMD was considered to be a more important outcome
measure than femoral BMD, since osteoporosis has more often been found in the lumbar spine
than in the femur in the ISM population, meaning the mastocytosis is presumably more active
at this site(11).
For assessment of lumbar and femoral BMD changes, plots of T and Z scores were made. The
number of measurements for all outcome units were inventoried. Some patients had
measurements at baseline and between 4 to 6 years of follow-up. Others only had measurements
at one of the two moments of measurement. Medians and interquartile ranges (IQR) were given
of the group with both measurements and of the group as a whole (in other words, including
patients with only one measurement). Results of BMD were found to be non-parametric, hence
two-tailed Wilcoxon Matched-Pairs Signed-Ranks Tests were performed to determine whether
changes in BMD prior and after treatment were significant. Analysis of absolute scores was not
performed here, for these scores are age and sex linked, therefore overall median and IQR scores
are not of additional value, as opposed to Δ scores of these absolute numbers.
Due to the low number of patients in our population and the wide variety in T and Z scores at
baseline, medians may be deceptive. Therefore these analyses (median, IQR, Wilcoxon) were
also performed on the Δ T, Z and g/cm3 scores.
Furthermore, subanalyses of median, IQR and Wilcoxon Matched-Pairs Signed-Ranks Tests
on T scores and Δ T scores of lumbar BMD were performed for the subgroups men and women,
per protocol and not per protocol, start of treatment prior to 2005 and after 2005, the presence
or absence of lumbar fractures prior to treatment and the presence or absence of lumbar fractures
during follow-up. These subanalyses were only performed on T scores of lumbar BMD, since
this outcome measurement was considered to be most important. The baseline variables zCTx
(for compliance), tryptase (disease activity), BMI (general condition) and femoral BMD
10
(general level of osteoporosis) of these groups were compared to see if there were any large
differences between the groups that could explain differences in effectiveness.
The differentiation between start of treatment prior to 2005 and after 2005 was made because
in 2004 changes in the settings of the DEXA scan equipment were made, which may potentially
influence the results.
Finally, changes in zCTx were assessed. zCTx levels should decrease when adequate
bisphosphonate treatment is used. Due to the rapid decrease of zCTx shortly after start of
treatment only zCTx levels before start of treatment (max. 1 year) were used as baseline
variables. In case of doubt over the exact date of start of treatment and multiple available zCTx
data in this period, the oldest zCTx measurement was taken, to be sure that the values represent
the bone turnover prior to treatment.
11
RESULTS
Flowchart
Out of the 693 patients known in the UMCG, 243 patients had ISM. A total number of 64
patients were identified as ISM patients were/ had been treated with bisphosphonates. Five of
these patients were deceased. A total number of 59 patients was approached by mail. 17 non-
responders were approached by phone in an attempt to increase the response rate. We managed
to obtain informed consent of 53 patients. Four patients were excluded based on the moment of
start of treatment (after 1-3-2011). Two patients were excluded because on closer evaluation
their did not suffer from ISM but smouldering or aggressive systemic mastocytosis. Two
patients were excluded because they received mast cell eradication therapy. Aside from these
45 patients, the additional 5 deceased patients were included in the study, resulting in a total
number of 50 included patients.
Figure 1: flowchart in- and exclusion
Patients approached by mail
n=59
Non-responders to mail and subsequent
phone approach
n=6
Patients with obtained
informed consent
n=53
Exclusion
Start of treatment after 1-3-2011 (n=4)
Diagnosis other than ISM (n=2)
Current mast cell eradication therapy (n=2)
Patients after exclusion
n=45
Deceased patients included in the study
n=5
Included patients
n=50
Adult patients with ISM
n=243
12
Baseline results
Table 1 shows the baseline characteristics of the 50 ISM patients we were able to include. They
were all treated with bisphosphonates for their osteoporosis and/ or fragility fractures. Baseline
was defined as the moment of start of treatment with bisphosphonates. Numbers are given in
means or medians, depending on whether or not the data were normally distributed.
At start of treatment the patients had an average age of 55 years. A relatively equal number of
men and women was included. The vast majority of the women was postmenopausal at start of
treatment. On average, women were also older than men when they started treatment, 58.8 years
compared to 49.9 years. Low BMD scores were a more common indication for start of treatment
then the detection of fragility fractures. 26% and 12% of patients had a history of respectively
low or high energetic vertebral fractures at start of treatment, in 12% of the patients a vertebral
fracture was detected during the first year of treatment. Lumbar and femoral BMD had a median
T score of respectively -2.65 and -1.30.
Urticaria pigmentosa was present in the majority of patients. H1 and H2 antagonists were used
in a minority of patients at start of treatment, which may indicate that osteoporosis and fragility
fractures are an early presentation of ISM because regular treatment had not been initiated yet.
Calcium and/ or vitamin D was more commonly used at start of treatment, which is in
accordance with the guidelines.
Co-morbidities influencing and medications interfering with bone metabolism were found
rather frequently in this population.
Variable Participants
(n=50)
Age at start of treatment (yr) mean (sd) 54.7 (11.1)
Gender n (%)
Male
Female
Transwoman
23 (46%)
26 (52 %)
1 (2%)
Menopausal status in women n (%)*
Premenopausal
Postmenopausal
2 (8.3%)
24 (91.7%)
Indication for treatment n (%)
Low BMD
#
34 (68%)
16 (32%)
Urticaria pigmentosa n (%)
Absent
Present
20 (40%)
30 (60%)
BMI mean (sd)
<20 n (%)
20-25 n (%)
25-30 n (%)
30-35 n (%)
>35 n (%)
N of patients missing
25.6 (4.0)
4 (11%)
12 (33%)
15 (42%)
5 (14%)
0 (0%)
14
Parameters of disease activity median
(iqr)
Tryptase
MH
51.6 (24.9 – 94.0)
347 (261 – 587)
4.4 (2.8 – 7.1)
13
MIMA
Fracture history n (%)
Low energetic, vertebral
High energetic, vertebral
Low energetic, other
High energetic, other
13 (26%)
3 (6%)
4 (8%)
27 (54%)
Fractures during first year of treatment n
(%)
Low energetic, vertebral
High energetic, vertebral
Low energetic, other
High energetic, other
5 (10%)
0 (0%)
0 (0%)
1 (2%)
Lumbar BMD
T score median (iqr)
Z score median (iqr)
-2.65 (-3.35 to -1.80)
-1.65 (-2.68 to -0.60)
Femoral BMD mean (sd)
T score median (iqr)
Z score m mean (sd)
-1.30 (-1.90 to -0.55)
-0.57 (0.87)
zCTx mean (sd) 1.0 (1.8)
Use of H1 antagonists n (%)
Yes
No
N patients missing
17 (36.2%)
30 (63.8%)
3
Use of H2 antagonists n (%)
Yes
No
N patients missing
15 (32.6%)
31 (67.4%)
4
Use of calcium and or vitamin D n (%)
Yes
No
N patients missing
31 (67.4%)
15 (32.6%)
4
Alcohol n (%)
Intolerance
Tolerance
Abuse
N patients missing
5 (10.6%)
38 (80.9%)
4 (8.5%)
3
Smoking habits n (%)
Yes
No
Quit
N patients missing
17 (35.4%)
23 (47.9%)
8 (16.7%)
2
History of normal TSH n (%)
Yes
Not measured
Aberrant
29 (59.2%)
19 (38.8%)
1 (2%)
25(OH)Vit3 levels prior to treatment
median (iqr)
N patients missing
58.5 (42.5-98)
32
Co-morbidities that interfere with bone
metabolism n (%)
14
Yes
No
N patients missing
11 (22.4%)
38 (77.6%)
1
Medication used for > 3 months that
interferes with bone metabolism n (%)
Yes
No
N patients missing
7 (14.2%)
42 (85.7%)
1
*One transwoman was excluded from this analysis
Table 1: Baseline characteristics
15
General results
The mean duration of treatment was 6.97 years, with a standard deviation of 2.98 years.
The patients used a total of 6 different bisphosphonates. Risedronate was used most often (32
patients), followed by alendronate (n=20), zolendronate (n=8), ibandronate (n=6), etidronate
(n=3) and pamidronate (n=3).
34 patients used one type of bisphosphonates for the entire duration of treatment. 11 patients
used 2 different types, 3 patients used 3 different types and 1 patient used 4 different types.
18 patients were treated per protocol. Of the 32 patients who were not treated per protocol, 4
had both a duration of treatment of less than 5 years as well as an MPR below 0.80. 8 had only
a duration less than 5 years and 20 had an MPR below 0.80. In 6 of the 24 patients with a MPR
below 0.80 we were unable to determine the MPR. This was due to pharmacists who could not
retrieve data from the required period (n=5) or due to an unwilling pharmacist (n=1).
Reasons for termination of treatment varied, but were often unknown. Recorded reasons for
termination were the patient’s own initiative or compliance (n=2), duration of treatment (n=2)
(the physician questioned the effect of bisphosphonates after years of treatment), normal BMD
after treatment (n=1), occurrence of a new fracture during follow-up (n=1).
There were no patients where other treatments to improve BMD and prevent fractures, e.g.
denosumab and teriparatide, were used prior to bisphosphonate treatment or in the five years of
follow-up. Some patients did use these medications in a later stadium. Two patients did receive
oestrogen treatment for their osteoporosis prior to bisphosphonate treatment.
Serious adverse events were not reported. 3 patients suffered from musculoskeletal pains,
possibly as a result of the treatment. 1 patient suffered from fever and bone pain after
intravenous administration of zolendronate. 3 patients experienced “trouble” at intake of
bisphosphonates.
16
Results of fractures
Prior to start of treatment 75 high energetic (HE), and 7 low energetic (LE) non-vertebral
fractures were reported in respectively 27 and 4 patients. The HE fractures were mainly
childhood fractures. 4 HE and 28 LE vertebral fractures were found in respectively 3 and 13
patients. In the first year of treatment 1 HE non-vertebral fracture and 1 HE vertebral fracture
were noted. In 5 patients a total of 10 LE vertebral fractures was detected.
Treatment with bisphosphonates was always initiated within one year after detection of a LE
fracture.
In the remaining 1-6 years of follow-up 1 HE vertebral fracture was noted. 7 HE non-vertebral
fractures were noted in 6 patients. 22 LE vertebral fractures were detected in 14 patients. A
survival curve can be seen in Figure 2. No LE fractures of other bones were reported. 14 patients
were lost to follow-up. The remaining 22 patients showed no fractures at DEXA scans with
vertebral fracture assessment in the 4-6 year follow-up period.
Of the 14 patients with LE vertebral fractures in the 2 to 6 years follow-up period, 5 were treated
per protocol, 9 were not treated per protocol. The 5 patients who were treated per protocol had
a total of 9 fractures; one patient had 4 fractures, one 2, and the other three patients had 1
fracture each. The 9 patients who were not treated per protocol accounted for the remaining 13
fractures. Five patients had 1 fracture, four patients had 2 fractures each.
The average time of follow-up after which the first fracture in the per protocol group was
detected was 4.38 years. In the group not treated per protocol this was 2.37 years.
Figure 2: Survival analysis LE vertebral # after 1 year of treatment.
17
Results lumbar BMD
Plots of T and Z score, seen in Figure 3, showed an increase of BMD after treatment. The data
were all slightly left skewed, therefore non parametric tests were performed.
T score lumbar: baseline - 5 years
0 1-6
-4
-2
0
2 p=0.001
moment of measurement
T s
co
re lu
mb
ar
Z score lumbar: baseline - 5 years
0 1
-6
-1
4p=0.000
moment of measurement
lum
bar
Z s
co
re
Figure 3: plots of change of T and Z score of lumbar BMD
In the total population of 50 patients, 23 patients had T score and Z score and 25 patients had a
g/cm3 score measurement at baseline and in the 4-6 years range of follow-up. An additional 9
(T and Z) and 10 (g/cm3) patients only had a measurement at baseline and 8 patients only had
a follow-up measurement (all units). The remaining 10 (T & Z) and 7 (g/cm3) patients lacked
measurements at both measurement periods.
Analysing T and Z scores of patients with results at both moments of measurements resulted in
a significant increase of medians of -2.70 to -2.50 in T score and -2.00 to -1.10 in Z score after
5 years of follow-up.
Analysis of all T and Z scores of all patients also showed an increase in median score. Wilcoxon
analysis could not be performed here, since not all data were paired.
Baseline After 5 years P value Wilcoxon
T score, both
measurements
-2.70 (-3.50 to -1.80) -2.50
(-2.90 to -0.50)
0.000
Z score, both
measurements
-2.00 (-2.80 to -1.30) -1.10
(-2.30 to -0.20)
0.000
T score, all patients -2.65 (-3.35 to -1.80) -2.10
(-2.80 to -0.60)
Not applicable
Z score, all patients -1.65 (-2.68 to -0.60) -1.10
(-2.30 to -0.20)
Not applicable
Table 2 : Changes in lumbar BMD prior to and after treatment.
Analysis of Δ T, Z and g/cm3 scores resulted in a significant increase of lumbar BMD for all
three outcome measures. Median ΔT score increase was 0.65 (0.10-1.00) with a P value of
0.000, Z score 0.70 (0.33–1.10) with a P value of 0.000, g/cm3 0.08 (0.01- 0.12) with a P value
of 0.001.
For the subanalyses, plots of lumbar T scores for the different subgroups can be found in
appendix 4. Median and IQR outcomes mentioned in Table 3 are based only on the patients
18
with both baseline and follow-up data. The results of the Wilcoxon tests are only based on the
patients with both baseline and follow-up data.
A table with results of the several baseline characteristics of the subgroups can be found in
Appendix 5. Significant differences were found in tryptase levels between patients treated per
protocol and not treated per protocol (24.9 vs. 70.4, p-value 0.001). Furthermore significant
differences were found in BMI in patients with or without lumbar fractures during follow-up
(26.4 vs 25.4, p-value 0.000).The other differences in baseline values were not significant.
Table 3 shows that the differences in T scores at baseline and at 5 years of follow-up were
significant in all subgroups, except for the patients who started treatment prior to 2005.
Based on the medians of T scores, the subgroups in which patients were male, not treated per
protocol, started treatment after 2004, had lumbar fractures prior to treatment or during follow-
up, appeared to have higher increase in T scores of lumbar BMD. However, the medians of
delta T scores showed higher increase in the subgroups women, treated per protocol and no
lumbar fractures prior to treatment. Furthermore, remarkably no increase in median T score of
the group with start of treatment ≤2004 to treatment and in the group without lumbar fractures
prior to start of treatment was seen, whereas Δ median T scores were significantly increased.
N T score
median (IQR)
baseline
T score median
(IQR) follow-up
Δ T score
median
(IQR)
P-value
Men 12 -2.75
(-3.65 to -1.85)
-2.15
(-2.87 to -0.80)
0.40
(0.25 – 1.00)
0.005
Women 11 -2.70
(-3.40 to -1.50)
-2.50
(-3.20 to -0.20)
0.80
(0.25 – 1.08)
0.029
Per protocol 8 -2.70
(-3.48 to -1.58)
-2.55
(-2.80 to -0.75)
0.90
(0.05 – 1.00)
0.042
Not per protocol 15 -2.80
(-3.50 to -2.00)
-1.90
(-3.10 to -0.20)
0.50
(0.10 – 1.38)
0.004
Start of
treatment ≤
2004
5 -2.80
(-3.90 to -1.65)
-2.80
(-3.20 to -1.10)
0.40
(0.10 – 0.95)
0.068
Start of
treatment >
2004
18 -2.65
(-3.48 to -1.95)
-1.85
(-2.83 to -0.43)
0.70
(0.10 – 1.10)
0.002
Lumbar # prior
to of treatment
6 -1.90
(-3.70 to -1.73)
-1.20
(-2.00 to -0.73)
0.30
(0.00 – 0.93)
0.026
No lumbar #
prior to
treatment
17 -2.80
(-3.45 to -2.40)
-2.80
(-3.15 to -0.05)
1.00
(0.85 – 1.30)
0.005
Lumbar # in
follow- up
9 -2.80
(-3.70 to -1.00)
-1.80
(-3.15 to -0.05)
0.90
(0.05 – 1.45)
0.025
No lumbar # in
follow up
14 -2.65
(-3.13 to -1.95)
-2.50
(-2.95 to -0.73)
0.40
(0.10 – 1.00)
0.006
Table 3: T scores of lumbar BMD in subgroups
19
Results femoral BMD
Of the total 50 patients, 22 patients had T scores at baseline and in the 4-6 years range of follow-
up, 23 had Z scores at both time points, 25 had scores in (g/cm3). An additional 10 (T and
g/cm3) and 9 (Z) and 10 patients only had a measurement at baseline and 8 patients only had a
follow-up measurement (all units). The remaining 10 (T &Z) and 7 (g/cm3) patients lacked
measurements at both time points.
Plots of femoral T and Z score show a relatively stable femoral T and Z score before and after
treatment, as can be seen in Appendix 7.
Analysing T and Z scores of patients with results at both baseline and after 5 years resulted in
an increase of medians of -1.20 to -1.05 in T score and -0.90 to -0.50 in Z score after 5 years of
follow-up. The increase in Z score was significant, the increase in T score was not significant.
Analysis of all T and Z scores of all patients (including those with only 1 measurement) also
showed an increase in median score.
Baseline After 5 years P value Wilcoxon
T score, patients with
both measurements
-1.20 (-1.93 to -0.45) -1.05 (-1.73 to -
0.30)
0.081
Z score, patients with
both measurements
-0.90 (-1.3 to -0.20) -0.50 (-1.20 to 0.10) 0.019
T score, all patients -1.10 (-1.90 to -0.50) -1.05 (-1.73 to -
0.30)
Not applicable
Z score, all patients -0.60 (-1.10 to -0.25) -0.50 (-1.20 to 0.10) Not applicable
Table 4: Changes in femoral BMD prior to and after treatment.
Absolute increase of Δ femoral BMD score (in g/cm3) was 0.015 (-0.01 to 0.50) with a P-value
0.001. No significant increase in Δ median T and Z scores was found, with results of 0.15 (-
0.10 to 0.33), P value 0.081 and 0.10 (-0.10 to 0.30), P value 0.081 respectively.
20
Results zCTx
Of 50 patients, 15 patients had a zCTx measurement prior to start of treatment and in the 4-6
years range of follow-up. An additional 12 patients only had a zCTx measurement prior to
treatment and 13 patients only had a follow-up measurement. The other 10 patients lacked zCTx
scores at both measurement periods.
A plot was made of the change in zCTx values over time. 3 patients showed an increase in
zCTx, the other 12 patients had decreasing values. The 3 patients with an increase in zCTx were
all not treated per protocol.
Change in zctx: baseline - 5 years
0 1
-2
0
2
4 p=0.020
moment of measurement
zC
Tx
Figure 4: Plot of change in zCTx (n=15)
Median and interquartile range of the baseline and follow-up measurements were respectively
0.58 (-0.44 to 2.21) and -0.97 (-1.28 to 0.58), showing a descrease in zCTx after treatment. A
2-tailed Wilcoxon matched-pairs signed-ranks test analysis showed a significant P-value of
0.020.
Analysis of all 27 and 28 zCTx values prior and after treatment also showed a decrease in zCTx
scores after treatment, substantiating this finding. Median and IQR scores were respectively
0.51 (-0.43 to 2.21) and -0.97 (-1.55 to -0.24).
21
DISCUSSION
This is the first study evaluating the efficacy of treatment with bisphosphonates in patients with
ISM suffering from fragility fractures and/or osteoporosis. Considering the low prevalence of
ISM, we were able to evaluate a large group of patients with ISM and osteoporosis for a
relatively long duration of follow-up. High numbers of fragility fractures were found prior to
and after treatment. Lumbar BMD increased after treatment, femoral BMD did not.
We managed to obtain 5 year follow-up fracture data of 36 patients and complete baseline plus
5 year follow-up data of BMD of 23 patients, which makes this the largest study on the
effectiveness of bisphosphonates in patients with ISM with bone involvement.
Our study showed 28 LE vertebral fractures in 13 patients prior to start of treatment, compared
to 22 LE vertebral fractures in 14 patients during follow-up. Assuming that fractures are
detected within two years after the event the fracture rate has lowered from on average 14 per
year in 50 patients to 5.5 fractures per year in 36 patients. However, it has to be taken into
account that DEXA scans were not made regularly in all patients before detection of fractures.
Fractures may have been present for a much longer period of time. Also, the reduction in
fracture rate might also be due to other factors; patients may have altered their lifestyle after
previous fractures or diagnosis of osteoporosis.
Even though patients who were treated per protocol did not have less fractures per patient during
follow-up than the group who was not treated per protocol, fractures in this group did occur at
a later moment during follow-up. This indicates that bisphosphonates are effective in
postponing fractures.
Great effort was made to determine the MPR of the patients, for this is highly important in
evaluating the effectiveness of treatment and the subsequent outcomes of treatment. The
proportion of patients that was treated per protocol was, with 18 out of 50 patients, relatively
low. We think that this is an underestimation of the true proportion of patients treated per
protocol. Partly, this was due to incomplete or absent information provided by the pharmacists,
which made determining the (exact) MPR impossible. Furthermore, patients may have been
provided with bisphosphonates by other pharmacists or hospitals without our knowledge,
resulting in an underestimated MPR. However, compliance to oral bisphosphonates may be low
either way. A previous study in a postmenopausal osteoporotic population showed only 43% of
persistence to therapy after 1 year of treatment with various oral bisphosphonates (28). The
uncertainties in determining the MPR and thus the treatment per protocol may have been of
influence on the small differences found between the per protocol group and not per protocol
group, both in fracture outcomes as well as in BMD data.
The decrease in 12 of 15 of zCTx scores after treatment does imply a relatively good compliance
to therapy. In 3 patients an increase in zCTx was seen. These patients were not treated per
protocol. In 2 patient increase of zCTx was most likely caused by non-compliance, 1 patient
had a continuously low zCTx score, before and during treatment, which increased slightly.
Increase in median T score lumbar BMD was significant. The increase in Δ median T scores
was even higher. Therefore bisphosphonate treatment appears to be effective in increasing
BMD, though a control group is lacking.
A limitation of the lumbar BMD data that may have influenced our results is the fact that we
did not exclude vertebrae that were fractured before treatment of during follow-up when
calculating lumbar BMD. Patients with lumbar fractures during follow-up had a higher increase
in BMD scores than the patients without fractures. This is most likely due to the increase in
BMD due to the fractures and not due to the bisphosphonate treatment. Correction was
22
considered for fractures occurred during follow-up. However, not all original images of the
scans were available. Therefore we decided to use a consistent method not correcting for these
scores. In case of lumbar fractures prior to treatment we did not consider correction of these
data to be necessary, as we thought fractures prior to treatment will not influence the effect of
the bisphosphonates on BMD, as long as fractures do not worsen. However, based on the results
this may have had influence after all as the Δ median T score increased more in the group with
no fracture prior to treatment. Perhaps increase in BMD was not possible in this extent in the
group with a fracture, as the BMD at baseline was already increased due to these fractures.
Changes in femoral BMD were small and not significant. However, strikingly, generally
patients did not suffer from symptoms at the femur either, not at baseline and not after treatment,
in contrast to the lumbar spine region. Femoral BMD T scores were not in the osteoporotic
range of T scores below -2.50 and only one patient reported a hip fracture, which was the result
of a HE trauma.
Only one study previously discussed prevalence of LE fractures in ISM patients (10). This study
was also performed in the UMCG, so there is overlap in the patients evaluated in these studies.
Patients already using bisphosphonates at moment of ISM diagnosis were excluded. In this
study a prevalence of 37% of LE fractures was found, 62% of which were LE vertebral
fractures. This prevalence is comparable to the ratio of patients with or without LE fractures
found during our follow-up period in our study, with fractures in 14 out of 36 patients (39%).
Proper comparison to a control group of ISM patients with bone involvement without treatment
was not possible. In order to put our results slightly into perspective we have made a comparison
with two large studies in postmenopausal osteoporosis populations. (29,30) These studies aimed
to evaluate the effect of alendronate and risedronate on the occurrence of fractures and change
in BMD compared to placebo.
In both studies follow-up was 2 to 3 years. In the first study, at baseline approximately 20% of
patients suffered from fractures. Occurrence of new vertebral fractures during these periods of
follow-up varied largely, with 3.2% in one study and 18.1% in the other, compared to 6.2% and
29% in controls treated with placebo, though in the latter study only patients with a history of
vertebral fractures at baseline (3 to 4 fractures on average) were included which might indicate
that this population is more prone to have fractures in follow-up as well. (29,30) Our study
showed new vertebral fractures in 39% of patients in the five year period of follow-up. After 2
to 3 years the percentage of survival in our survivalcurve is approximately 80 to 90%, which
is comparable to the second study. However, in our study, at baseline, 28% of patients showed
vertebral fractures. Therefore, our population appears to be much more prone to the
development of vertebral fractures than the postmenopausal osteoporosis population.
Concerning lumbar BMD: the increase in BMD was only given in percentages in above
mentioned studies, with increases of approximately 7% and 8% after 2 or 3 years of treatment.
This data is comparable with the increase in median T score in our population after 5 years of
treatment. However, the Δ median T score of our population showed a higher increase. These
differences in our results can be explained by the large variety of BMD between the patients.
This variety has a relatively large influence on the results, due to the low number of patients.
Unfortunately these Δ scores cannot be compared to the postmenopausal studies, for absolute
increase in T scores were not given in these studies, so Δ scores cannot be calculated.
Furthermore, the large variation between changes in median T scores and ΔT scores makes
interpretation of the increase in BMD shown in our data more difficult. In contrast to our study,
these two postmenopausal studies did find an increase in femoral BMD.
23
Overall comparison to the postmenopausal population tells us that bisphosphonates appear to
increase lumbar BMD in our ISM population to a comparable extent as they do in the
postmenopausal population. However, fracture rate is higher in our population.
Finally, the reported number of adverse events in our population was low, but is likely to be
underestimated. Since patients were usually only seen in the UMCG once every one or two
years, or even less regularly, day-to-day care was provided by the GP or other hospitals.
Adverse events may have only been reported there. Considering that a large proportion of
patients switched type of bisphosphonate at least once may indicate that patients may have
suffered from adverse events more often than is known to us.
For future research a prospective study on the effectiveness of bisphosphonates would be useful
in order to obtain a more complete dataset than we managed to obtain in this study. We are
planning to conduct a international multicentre randomized controlled trial that compares the
effects of bisphosphonates to the effect of denosumab in patients with ISM and bone
involvement. Denosumab is a treatment option that is increasingly used in the postmenopausal
osteoporosis population, that may also be of value in this population. The use of two groups
ISM will also simplify the interpretation of the data for changes in outcome measurements can
be compared to a similar patient population.
24
CONCLUSION
We evaluated a relatively large group of ISM patients with bone involvement in the form of
osteoporosis and/ or fragility fractures.
Assuming LE fractures prior to treatment are detected within two years of the event, we can
conclude that the fracture rate of LE vertebral fractures decreases after treatment with
bisphosphonates. Furthermore a significant increase lumbar BMD was found. No significant
changes in femoral BMD were found, though no LE fractures or low (T score < -2.5) BMD
were detected at the femur either. It is important to realise that an increase in lumbar BMD is
only relevant when this prevents the occurrence of fragility fractures.
Final conclusions on the effectiveness of bisphosphonates as a treatment in patients with ISM
and fragility fractures and/or osteoporosis cannot be made, since a control group with similar
patient characteristics is lacking.
Considering the large proportion of fragility fractures prior to treatment and during follow-up,
this population is clearly in need of proper treatment. Therefore future research is required.
25
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28
APPENDICES
Appendix 1
Letter to METc
Geachte heer/ mevrouw,
Bij dezen verzoeken wij u te beoordelen of het volgende onderzoek wel of niet WMO-plichtig
is.
Momenteel zijn wij bezig met een retrospectieve studie naar het effect van bisfosfonaten op
osteoporose en/of laag energetische fracturen in patiënten met mastocytose.
Bij patiënten met mastocytose wordt verondersteld dat de osteoporose en/ of laag energetische
fracturen veroorzaakt worden door de release van mediatoren afkomstig uit mestcellen.
Vanwege de veronderstelde verschillen met de reguliere osteoporose populatie
(postmenopauzale vrouwen) is het van belang om de effectiviteit van bisfosfonaten in deze
patiëntenpopulatie te evalueren.
Voor dit onderzoek maken wij gebruik van een database met patiëntgegevens van patiënten die
bij ons onder behandeling zijn of zijn geweest en van wie bekend is dat zij momenteel of in het
verleden met bisfosfonaten zijn behandeld.
Er wordt gebruik gemaakt van een subpopulatie uit de generieke mastocytose database, en het
gaat om ongeveer 60 patiënten. Baselinegegevens en follow-up gegevens zijn sinds het begin
van de bisfosfonaatbehandeling bijgehouden. De patiënten zijn op zijn vroegst in 1995
begonnen met de behandeling. De duur van follow-up varieert, aangezien niet alle patiënten
meer in het UMCG onder behandeling zijn. Meestal betreft het een periode van omstreeks tien
jaar. Bijgehouden variabelen zijn onder andere parameters van ziekte-activiteit, resultaten van
botdichtheidsmetingen en uitslagen van biopten.
Bisfosfonaten worden veelal langdurig (gedurende jaren) voorgeschreven. Om de
therapietrouw van deze patiënten zo goed mogelijk in kaart te brengen willen wij deze patiënten
aanschrijven om toestemming vragen om de data van afhalen en hoeveelheid afgehaalde
medicijnen bij hun apothekers op te vragen. De medicatie betreft kalktabletten, vitamine D
tabletten en bisfosfonaten, zoals alendronaat.
In afwachting van uw antwoord, bij voorbaat hartelijk dank.
Hoogachtend,
Namens Dr. J.N.G. Oude Elberink, internist-allergoloog, hoofd mastocytose werkgroep
Merel Onnes
Student-onderzoeker
29
Appendix 2
Letter to patients
Geachte heer / mevrouw,
U heeft mastocytose en u bent daarvoor bij ons in het UMCG onder behandeling of u bent dat
in het verleden geweest. Het UMCG is sinds 2015 officieel een Expertise centrum, erkend door
de Nederlandse Federatie van Universitair Medische Centra (NFU).
Een van de redenen dat wij van de overheid deze erkenning hebben gekregen is dat wij naast
het bieden van een optimale behandeling aan mensen met mastocytose ook veel onderzoek doen
naar de verschillende aspecten van dit ziektebeeld.
Waarom wij sturen wij u deze brief?
1. Algemeen
In het kader van het onderzoek naar mastocytose zouden wij graag enkele gegevens uit uw
medisch dossier gebruiken, zoals labwaarden en resultaten van botdichtheidsmetingen. Wij
mogen deze gegevens volgens de huidige wetgeving gebruiken zonder hiervoor speciaal
toestemming van de betreffende persoon nodig te hebben. De wetgeving wordt echter steeds
strenger en daarom vinden wij het netter om u officieel om toestemming te vragen om deze
gegevens te gebruiken. Voor u betekent dit dat wij uw gegevens, uiteraard volledig
geanonimiseerd, gebruiken om meer kennis en inzicht te vergaren in de verschillende aspecten
van dit ziektebeeld, om uiteindelijk voor nog betere behandelingsmogelijkheden te kunnen
zorgen. Dit kost u geen extra bezoeken of onderzoeken.
2. Specifiek: onderzoek naar botontkalking
Bijna de helft van de mensen met mastocytose heeft ernstige osteoporose (botontkalking), wat
dus veel meer is dan in de algemene bevolking.
Mensen met botontkalking zonder mastocytose worden behandeld met medicijnen die wij
bisfosfonaten noemen. Of deze medicijnen ook goed werken bij botontkalking door
mastocytose is nooit onderzocht. Wij zijn nu aan het bekijken of deze medicijnen goed werken.
Voor betrouwbare conclusies hebben wij gedetailleerde informatie nodig. Ten eerste is het
belangrijk zo precies mogelijk de dosering en de start- en stopdatum te weten Hiervoor zijn
gegevens van de apotheek nodig en daarvoor hebben wij uw toestemming nodig. Ten tweede
is het belangrijk precies te weten of en wanneer u iets heeft gebroken en onder welke
omstandigheden. Het is goed mogelijk dat wij u dit in 2009 ook al gevraagd hebben. Op grond
van de gegevens van 2009 konden we helaas nog niet goed conclusies trekken. We hopen dat
nu, bijna 7 later wel te kunnen. Als u destijds al uw gegevens heeft opgestuurd vragen wij u
de enquête in te vullen vanaf 2009 tot nu. Wij zouden deze extra moeite enorm waarderen.
Samenvattend: wat vragen wij u?
1. Toestemming voor het gebruik van uw gegevens voor onderzoeken naar
mastocytose, zoals hierboven omschreven.
30
2. Toestemming voor het opvragen van uw apothekersgegevens in het kader van het
botontkalkingsonderzoek. Uiteraard worden ook deze gegevens volledig
geanonimiseerd verwerkt en ook dit kost u geen extra bezoeken of onderzoeken.
3. Ten slotte willen wij u vragen of u voor ons een korte enquête m.b.t. eventuele
botbreuken in zou willen vullen.
Wij vragen u vriendelijk om uw toestemming voor de algemene gegevens, de toestemming voor
de apotheekgegevens en de ingevulde enquête over botbreuken op te sturen in bijgaande
antwoordenvelop. U helpt ons en andere mastocytose patiënten enorm mee.
Bij voorbaat hartelijk dank!
Hoogachtend,
Mede namens Dr. J.N.G. (Hanneke) Oude Elberink, internist-allergoloog
Merel Onnes
Student-onderzoeker
31
Bijlage 1 van 3
Toestemmingsformulier voor het gebruik van gegevens voor mastocytose-onderzoek
Met dit formulier geeft u om toestemming om gegevens uit uw medisch dossier beschikbaar te
stellen voor medisch-wetenschappelijk onderzoek naar mastocytose.
Het gaat hierbij om algemene gegevens als leeftijd en geslacht en om uitslagen van medische
testen, zoals labwaarden, röntgenfoto’s en uitslagen van biopten. Alle gegevens zullen te allen
tijde volledig geanonimiseerd gebruikt worden. U behoudt altijd het recht om uw toestemming
weer in te trekken.
Met uw gegevens kunnen wij de kennis over deze relatief zeldzame ziekte vergroten om zo
uiteindelijk tot betere behandelmogelijkheden te komen.
Ik verklaar het bovenstaande begrepen te hebben en geef de onderzoeksgroep mastocytose van
het Universitair Medisch Centrum Groningen toestemming om mijn gegevens te gebruiken
voor medisch-wetenschappelijk onderzoek naar mastocytose.
Naam:
Geboortedatum:
Datum:
Handtekening:
32
Bijlage 2 van 3
Toestemming voor het opvragen van apothekersgegevens voor mastocytose-onderzoek
Met dit formulier geeft u de onderzoekers van de mastocytose werkgroep van het Universitair
Medisch Centrum Groningen toestemming om uw apothekersgegevens op te vragen en te
gebruiken voor medisch wetenschappelijk onderzoek.
Het gaat hierbij om data waarop de medicijnen zijn opgehaald en in welke hoeveelheden dit
gebeurt is. Het betreft de volgende medicatiegroepen: bisfosfonaten, calcium en vitamine D.
Met behulp van deze gegevens willen wij het gebruik van deze medicatie zo goed mogelijk in
beeld brengen. Hierdoor kunnen wij vervolgens de effectiviteit van deze medicatie beter kunnen
evalueren. Wij zullen ons hierbij vooral richten op het effect van deze medicatie op het
voorkomen van fracturen.
Ik verklaar het bovenstaande begrepen te hebben en geef de onderzoeksgroep mastocytose van
het Universitair Medisch Centrum Groningen toestemming om bovengenoemde
apothekersgegevens op te vragen en te gebruiken voor het omschreven onderzoek.
Naam:
Geboortedatum:
Datum:
Handtekening:
33
Bijlage 3 van 3
Enquête over botbreuken
Datum van invullen:
Naam:
Geboortedatum:
Heeft u ooit één of meerdere botten gebroken?
o Ja
o Nee
Zo ja, wilt u dan hieronder aangeven welk(e) bot(ten) u heeft gebroken, wanneer u deze heeft
gebroken en waardoor u deze heeft gebroken?
Voorbeeld:
Welk bot: rechterbovenbeen
Wanneer: maart 1984
Waardoor: val van 3 meter hoog
Welk bot Wanneer (maand + jaartal,
evt. bij benadering)
Waardoor
34
Appendix 3
Letter to pharmacists
Geachte heer/ mevrouw,
Momenteel evalueert de mastocytose-werkgroep van het UMCG de behandeling van
osteoporose bij systemische mastocytose. Daarom ontvang ik graag van u een overzicht van het
gebruik van bisfosfonaten, calcium en vitamine D, m.n. een overzicht van alle afhaaldata en
geleverde hoeveelheden, vanaf de start van de behandeling van deze medicamenten van dhr./
mw. geboren dd-mm-jjjj. De patiënt in kwestie heeft ons schriftelijk toestemming verleent tot
het opvragen van deze gegevens.
Ons faxnummer is 050-3619308. Mocht u vragen hebben dan kunt u ons ook bellen of mailen.
Bij voorbaat hartelijk dank voor uw medewerking,
Hoogachtend,
Merel Onnes
Student-onderzoeker
Mede namens
Dr. J.N.G. (Hanneke) Oude Elberink
Internist-allergoloog
35
Appendix 4
Plots of T scores lumbar BMD subgroups
per protocol
0 1-6
-4
-2
0
2 p=0.004/0.042
moment of measurement
T s
co
re lu
mb
ar
Black: male, red: female Black: not per protocol, red: per protocol
start until 2005 / after 2005
0 1-6
-4
-2
0
2 p=0.002/0.068
moment of measurement
T s
co
re lu
mb
ar
Black: start ≥ 2005, red: start < 2005
lumb#follow-up
0 1-6
-4
-2
0
2 p=0.006/0.025
moment of measurement
T s
co
re lu
mb
ar
lumb# at start of treatment
0 1-6
-4
-2
0
2 p=0.008/0.026
moment of measurement
T s
co
re lu
mb
ar
Black: no fracture, red: fracture Black: no fracture, red: fracture
male female
0 1-6
-4
-2
0
2 p=0.005/0.036
moment of measurement
T s
co
re lu
mb
ar
36
Appendix 5
Baseline variables of subgroups
zCTx
mean
(sd)
P T femur
BMD
median
(IQR)
p BMI
mean
(sd)
P Tryptase
median
(IQR)
P
Men 0.47
(1.56)
0.139 -1.1
(-1.75 to
-0.55)
0.32 26.1
(3.6)
0.464 39.8
(27.2 to
73.4)
0.47
Women 1.54
(1.97)
-1.45
(-2.08 to
-0.55)
25.1
(4.3)
63.7
(21.2 to
124)
Per
protocol
-0.01
(1.19)
0.085 -1.50
(-1.95 to
-0.55)
0.746 25.7
(4.1)
0.930 24.9
(16.8 to
39.1)
0.001
Not per
protocol
1.38
(1.91)
-1.15
(-1.90 to
-0.55)
25.6
(4.1)
70.4
(33.0 to
121.8)
Early start
of
treatment
1.46
(2.69)
0.721 -1.00
(-1.85 to
-0.70)
0.840 23.7
(2.2)
0.081 51.3
(35.6 to
157.5)
0.175
Late start
of
treatment
0.97
(1.81)
-1.35
(-1.90 to
-0.50)
26.4
(4.3)
51.9
(20.0 to
83.5)
Lumbar #
prior to
start of
treatment
0.93
(1.97)
0.835 -1.20
(-1.90 to
-0.63)
0.840 24.5
(3.3)
0.578 51.3
(27.0 to
94.5)
0.643
No lumbar
# prior to
start of
treatment
1.16
(1.56)
-1.40
(-1.95 to
-0.50)
30.2
(3.5)
53.5
(17.8 to
97.2)
Lumbar #
during
follow-up
0.85
(1.10)
0.775 -1.50
(-1.80 to
-1.10)
0.390 26.4
(3.6)
0.000 29.5
(27.2 to
53.5)
0.483
No lumbar
# during
follow-up
1.04
(1.98)
-0.95
(-1.93 to
-0.50)
25.4
(4.1)
52.9
(21.2 to
95.3)
37
Appendix 6
Plot of T and Z score femoral BMD
T score femur: baseline - 5 years
0 1-3
-2
-1
0
1 p=0.081
moment of measurement
T s
co
re f
em
ur
z femur
0 1
-2
0
2
p = 0.019
moment of measurementZ s
co
re f
em
ora
l
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