Pamidronate for pain in adult chronic nonbacterial osteitis (PAM-CNO): a randomized, double-blind, placebo-controlled trial

Chronic nonbacterial osteitis (CNO) is a rare inflammatory disorder of the
axial skeleton, mainly affecting sternum, clavicles and upper ribs. Patients
present with swelling and pain in the affected areas and impaired movement of
the shoulder girdle. Disease burden is high, and impaired quality of life
common. Radiological features include sclerosis and hyperostosis, with
increased radioactive isotope uptake on skeletal scintigraphy. Awareness for
SCCH is low and diagnosis often delayed, associated with progressive pain,
increasingly impaired quality of life, and difficulties in remaining in the
workforce.

There is no approved therapy for CNO. The precise trigger for the underlying
inflammation associated with local increases in bone turnover is not known.
NSAIDs are mostly effective in controlling symptoms in early stages of the
disorder (own observations). Literature data on the use of intravenous
bisphosphonates or TNF a inhibitors, are scarce and none available from
randomised placebo-controlled trials (RCTs).
The rationale for using bisphosphonates in SCCH, is based on the likelihood of
pain to be due to the local increase in bone turnover, which should respond to
treatment with these agents, although a potential direct anti-inflammatory
effect of bisphosphonates is also possible. In our Center, we have been
effectively and safely treating patients with SCCH with intravenous
bisphosphonates for over two decades, with an observed favourable outcome of
reduction in pain, improvement in shoulder mobility, and prevention of disease
progression in a majority of patients (unpublished observations). However,
there is a need to confirm these promising observations by means of RCTs, using
validated tools for evaluation of changes in pain, shoulder girdle function and
quality of life in response to treatment, which is the reason for this study.

This study has been transitioned to CTIS with ID 2023-510309-16-00 check the CTIS register for the current data.

The primary objective to demonstrate that in CNOpatients with pain 3-monthly
treatment with pamidronate will result in significant decrease in maximum pain
score (as measured with BPI) as compared to placebo.

Secondary objectives:
• To study the number of patients with mild pain (maximal pain 4 or below 4)
after 3-monthly treatment with pamidronate
• To study the number of patients with 50% reduction in maximal pain (VAS score
in BPI)
• To study change in shoulder rating questionnaire (SRQ) and facets of Shoulder
function assessment (SFA) score (among which is ability to dress)
• To study change in range of motion
• To study improvement in general health as measured with Short Form Health
Survey (Sf-36), work activity score, and physical activity International
Physical Activity Questionnaire (IPAQ, short form, previous 7 days)
• To investigate partner burden before and after therapy using Care-related
Quality of Life Instrument (CarerQol)
• To study a change in standard dose of analgesics possible during course of
the study as evidence for efficacy of treatment
• Evaluation of confounding factors for outcome of treatment such as delay in
diagnosis and the amount of baseline tracer uptake, pain and range of motion
• Significant alteration of inflammation and quantifiable decrease in
Na18F-PET/CT tracer uptake of SCCH lesions after pamidronate therapy, and its
relation to disease symptoms as measured using above mentioned questionnaires
and SFA
• Evaluation of a possible neuropathic component of the reported pain (pain
detect)
• To estimate the number of CNOpatients exhibiting signs of central pain
sensitization by Central Sensitization Inventory (CSI) (18)
• To determine the association between central sensitization symptomatology and
patient reported outcomes (pain) after treatment with pamidronate/placebo,
amongst which the primary outcome measure (maximal pain)
• To evaluate cost-effectiveness of therapy in an economic evaluation
• To assess spinal involvement of SCCH-lesions

Adult patients with an established diagnosis of CNO with a reported maximum
pain score >= 6/10, signs of disease activity on imaging,
and no treatment with bisphosphonates for the previous 6 months will be
included in the study.
Female patients should be warned of the need to use contraceptives during the
study because of
absence of data on possible teratogenic effect of bisphosphonates.

The design of the first 6 months of the study is double-blind
placebo-controlled. Randomization
(computer based) will be performed for either pamidronate or placebo infusions.
Treatment with
intravenous pamidronate (30 mg/day on 3 consecutive days) or placebo (saline
0.9%) will be given
at time point 0 and after 3 months. The hospital pharmacy will prepare the
active
and placebo study medication. Placebo will be similar in appearance as
pamidronate and the
research nurse will be blinded to its nature while administering it, as will be
patients, doctors and
researchers.

Patients are allowed to use analgesics. NSAIDs may be continued or decreased
during the study, but increase is not preferred. If necessary to achieve pain
control, patients are instructed to report increase of NSAIDs to the
researcher. All analgesics are recorded in the patient diary and thus available
for the researcher. Patients are allowed to use analgesics, for which NSAIDs
will be fixed to the dosage used before
start of the trial. Patients can continue using their normal own medication
after providing a list of
these medications. Study medication (pamidronate or placebo) will only be
started if vitamin D level
is adequate, with serum calcium and levels within the normal range. If
necessary, calcium
and vitamin D will be started or dosage will be increased. During infusion of
study medication
patients will be advised to use paracetamol 1000 mg QD during one to three days
depending on
symptoms of acute phase reaction. They are allowed to start or continue
physiotherapy.

After the first 6 months, the study will stop being double-blind
placebo-controlled and will follow an
open label design. Patients can choose between pamidronate treatment in the
same schedules at month 6 and month 9, or only analgesic treatment.

Every 3 months patients will be requested to complete the following
questionnaires:
- BPI to assess pain and interference of pain with daily life
- Pain-DETECT to assess neuropathic pain
- S,shoulder rating questionnaire and shoulder function assessment to assess
shoulder complaints.
- Work activity (work activity score) to assess work activity
- IPAQ will be used to evaluateto assess physical activity both during work and
leisure time (short form, last 7 days)
- sf-36 for general health
- ,MVI-20 for fatigue
- EQ-5D for quality of life
- CarerQol for partner burden
- Patient Global Impression of Change (PGIC, score 0-7) will be used to
evaluate changes in well-being.
- Central Sensitization Inventory (CSI) to assess symptoms of pain
sensitization (only at baseline, month 6 and month 12)
- For economic evaluation the iMCQ questionnaire, and iPCQ questionnaire will
be evaluated every 3 months to measure healthcare use and productivity
respectively


Expected results
It is expected that 3-monthly pamidronate courses will decrease the locally
increased bone turnover, to be confirmed by a quantifiable decrease in
radioisotope uptake on Na18FD-PET/CT scans and that this will be associated
with a measurable decrease in pain scores (primary endpoint), improvement in
shoulder girdle function, quality of life, and physical and work activity
(secondary endpoints) in the active treatment arm compared to placebo.

Conclusion
CNO is a rare bone disease of unknown aetiology, with to date no approved
treatment. The objectives of our proposed RCT are three-fold: to confirm our
long-term experience spanning more than two decades on the favourable outcome
of 3-monthly intravenous pamidronate on the clinical manifestations of SCCH; to
evaluate the potential contribution of an anti-inflammatory effect of
bisphosphonates to the outcome of treatment; and to explore the potential use
of quantification of radioisotope uptake on sequential Na18FD-PET/CT scans to
monitor disease activity and thus outcome of treatment.

Pamidronate infusion 30 mg/day (diluted in 0.9% saline) or placebo (0.9%
saline) on 3 consecutive days, at start of the study and after 3 months (double
blind randomized phase) and possibly during open label phase pamidronate 30
mg/day (diluted in 0.9% saline) at month 6 and month 9.

Burden and risks of participation are minimal, since care is similar to
standard care, and pamidronate is used for decades for osteoprosis and
metabolic bone diseases. The only differences between this study and Standard
Care Path are questionnaires every 3 months (20 minutes for all questionnaires)
and keeping a pain/fatigue and analgesic use diary 2x per week. Risks for
pamidronate are well known: possible acute phase respons after first
application (fever, myalgia and arthralgia up to several days after
application), hypocalcemia although this can be prevented if serum
calcium/vitamine D and PTH are normal before infusion (which will be checked),
and the very rare complication of osteonecrosis of the jaw (ONJ) and atypical
femur fracture (AFF). ONJ is hardly ever seen in case of this dosage, and
mainly if dental hygiene is poor; in case of poor dental hygiene patients will
only get pamidronate after maxillary surgeon consultation. Every visit patients
will be asked for complaints pointing at AFF.

The radiation exposure does not constitute an additional risk as well. For this
study, 2 total body low dose Na18F PET-CT scans will be performed at t=0 and
t=12. This is part of the standard care as currently available at the
LUMC/Alrijne Ziekenhuis for CNO . Until recently, standard care encompassed
99mTc+SPECT-CT scans. The radiation exposure of a single PET-scan is lower than
this conventinal SPECT-CT: 3.4mSv +7.1 mSv (99mTc+SPECT-CT) versus 1.7 +
(5.5+1.7) mSV for the newly introduced Na18F PET-CT. At t=6 months not a total
body CT will be performed, but a Na18F PET-CT of the sternum solely. The
radiation exposure for the scans at T0 and T12 = 1.7 mSv for PET + 5.5mSv for
LDCT TB= 7.2 mSv. The scan at T=6 = 1.7 mSv (PET) + 3.5 mSv (CT sternum) = 5.2
mSv. The total radiation exposure for this study is therefore 7,s x 2 + 5,2 =
19.6 mSv. As only the scan at T=6 is additional in comparison to standard care,
the extra radiation exposure is 5,2 mSv. The study therefore falls into the
risk category of 1-10 mSvdetr.