The Effect of Multi-faceted Intervention on Osteoporosis and Mineral and Bone Disorder (CKD-MBD)
Phase: NA
Conditions: Osteoporosis, Postmenopausal
Sponsor: National Taiwan University Hospital

Protocol 2019                                                            Dec 21,2019 
 
The effect of multi-faceted intervention on osteoporosis and CKD-MBD 
Identifiers: NCT04271605 
Unique Protocol ID: 201909060RINA 
Brief Title: Intervention on Osteoporosis and CKD-MBD 
 
Primary investigator 
Chirn-Bin Chang 
National Taiwan University Hospital Chu-Tung Branch 
Phone: 886-03-5943248 
 
Sponsor 
National Taiwan University Hospital Chu-Tung Branch 
Phone: 886-03-5943248 
 
 
 

Protocol 2019                                                            Dec 21,2019 
 
STUDY SUMMARY 
Title 
The effect of multi-faceted intervention on osteoporosis 
and CKD-MBD 
Methodology 
Prospective interventional cohort study 
Study Duration 
Estimated duration for the main protocol is from January 1, 
2020 to December 31, 2020. 
Study Center(s) 
Multi-center (National Taiwan University Hospital and 
National Taiwan University Hospital Chu-Tung Branch) 
Objectives 
To evaluate the effect of pharmacological therapy and 
behavioral interventions among patients with chronic 
kidney disease having risk of osteoporosis related fracture 
Number of Subjects 
60 subjects in a single arm  
Diagnosis and Main 
Inclusion Criteria 
Inclusion criteria 
1. Age > 50 years  
2. CKD stage 3-4, and eGFR >20 mL/min/1.73m2 
3. FRAX® screening threshold: risk of hip fracture (HF) and 
major osteoporotic fracture (MOF) (HF: men> 6%, women 
> 7%; MOF: men> 15%, women> 12.5%) 
Exclusion criteria 
1. Unable to consent (e.g. dementia)  
2. Have cancer under treatment  
3. Have acute coronary syndrome (unstable angina, non-ST 
elevation myocardial infarction, ST-elevation myocardial 
infarction) or stroke in 3 months.  
4. Limited cognitive or physical function for execute the 
intervention  
Interventions 
1. Pharmacological therapy for chronic kidney disease-
mineral bone disorder and osteoporosis 
2. Behavioral interventions including diet modification and 
exercise for bone and cardiovascular health 
Statistical 
Methodology 
Primary outcome: all-cause mortality, cardiovascular 
events, subsequent fracture rate, and fall rate 
Secondary outcome: biochemistry laboratory tests before 
and after multifaceted interventions 
 
 
 

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1 STUDY OBJECTIVES  
1.1 Primary Objective  
• Collect the baseline characteristics to screen for CKD-MBD and osteoporosis 
among CKD patients/ Deliver optimal care including pharmacological therapy and 
behavioral interventions for CKD, CKD-MBD, osteoporosis, and fragility fractures 
accordingly to the baseline characteristics. 
• Primary outcomes are all-cause mortality, cardiovascular events, subsequent 
fracture rates, and fall rate. 
1.2 Secondary Objectives  
• Secondary outcomes are changes of biochemistry laboratory data before and 
after interventions (pharmacological therapy and behavioral interventions). 
2 BACKGROUND AND RATIONALE  
2.1 Background on Condition, Disease, or Other Primary Study Focus  
Previous studies among CKD patients found the fracture incidence to 
progressively increase by 15.0, 20.5, 24.2, 31.2, and 46.3 per 1000 person-years for 
CKD stages 1 to 2, 3a, 3b, and 4, respectively1. The risk of fracture increases to 5 
times higher in patients with an estimated glomerular filtration rate (eGFR) <15 
versus >60 ml/min per 1.73 m2). Patients with CKD and older than 65 years of age 
have a higher rate of fractures during 3-years of follow-up2. It would be an important 
issue to prevent skeletal fracture among older adults with CKD since fracture can 
cause higher mortality and health resource utilization and loss of quality of life. 
Renal osteodystrophy is used previously to describe the histological changes of 
bone among CKD patients. However, these changes in mineral and bone metabolism 
were derived from dysregulation during renal function deterioration gradually. 
Therefore, the mineral and bone disorder associated with CKD is an evolving entity 
which caused abnormalities of mineral metabolism, bone turnover, and vascular 
calcification. The KDIGO CKD-MBD guideline suggests that a bone biopsy should be 
considered for patients with a presentation of bone pain or unexplained fracture3. A 
transiliac bone biopsy after tetracycline labeling is the gold-standard technique for 
diagnosis of CKD-MBD. However, this invasive measure might not be acceptable to 
many patients and only few centers have the expert histomorphometry analyzers4. 
In clinical practice, the primary osteoporosis is a more prevalent disease among 
older adults. The KDIGO CKD-MBD also suggested application of dual-energy x-ray 
absorptiometry (DXA) in evaluation the fracture risk among CKD patients3. In order 
to prevent fragility fracture, it would be reasonable to target abnormalities of 
mineral metabolism and primary osteoporosis. Further studies for CKD-MBD would 
be considered for those with unexplained factures or bone pain. Tools to evaluate 
osteoporosis and CKD-MBD are briefly described below.    

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Bone mineral density (BMD) 
The relevance of bone mineral density as measured by dual-energy X-ray 
absorptiometry (DXA) is limited in CKD patients because of interference of scoliosis, 
osteoarthritis at the lumbar spine, and the presence of vascular or joint 
calcifications. However, BMD measurement was also recommended for older adults 
with CKD in the 2017 KDIGO guidelines which were supported by several studies5.  
FRAX® 
The Fracture Risk Assessment Tool can be used to predict peripheral fractures in 
older patients with CKD stages 2 to 5. Clinical risk factors such as weight, height, 
prevalent fracture, family history of hip fracture, and steroid use are sufficient for 
10-year prediction and are as efficient alone as together with hip BMD.  
Serum biochemistry 
Vitamin D sterols.  
Circulating values of native vitamin D (25-hydroxyvitamin D [25OHD]) allow 
determination of vitamin D storage. But, the optimal circulating 25OHD level in CKD 
that protects against skeletal fractures is controversial. 2017 KDIGO guidelines 
recommend using the same 30 ng/ml cutoff value used for the CKD patient without 
dialysis. 
Phosphate.  
In previous study, serum phosphate levels are associated with higher fracture 
risk in both genders and in a subgroup of men with CKD6. Tubular reabsorption of 
phosphate (TRP) in patients with CKD stage 3 to 4 is an index of phosphaturic 
homeostatic mechanisms7.  
Parathyroid hormone.  
PTH is the best surrogate biomarker for bone histology in CKD in clinical 
practice8. 
Other biomarkers of mineral metabolism, such as calcium, and total ALP, are 
used as surrogate markers of high- or low-turnover bone disease. 
X-ray film.  
Lumbosacral spine anterior-posterior (AP) and lateral view will be used to 
evaluate aorta calcification and spinal compression fractures. 
2.2 Study Rationale 
A prospective intervention study is purposed to investigate whether the optimal 
therapy targeting those with risk of fragility fracture risk and CKD would lead to the 
better outcomes. Patients with CKD stage 3-4 (eGFR 60-20mL/min/1.73m2) are 
screened with FRAX®. If patients have high risk of osteoporotic fracture, they will be 
enrolled for serial examination and education to prevent complications of CKD and 
osteoporosis.  

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The primary outcomes are all-cause mortality, cardiovascular events, 
subsequent fracture rate, and fall rate. The secondary outcomes are changes of 
biochemistry laboratory data before and after interventions (pharmacological 
therapy and behavioral interventions). 
 
3 STUDY DESIGN 
The design is a pilot study with data collection through interviews, and medical 
records. There is one study arm: the intervention. A description of multi-faceted 
intervention on osteoporosis and CKD-MBD can be found in STUDY INTERVENTIONS. 
The pilot will take place at two primary clinical care practices in National Taiwan 
University Hospital and its Chu-Tung Branch in Taiwan. 60 patients will be enrolled 
and followed for up from January 1, 2020 to December 31, 2020 with interviews and 
medical record reviews. Participants will undergo a baseline and follow-up interview 
to collect patient reported baseline and outcome measures.  
 
4 SELECTION AND ENROLLMENT OF PARTICIPANTS  
Participants will be enrolled at two physicians in National Taiwan University and 
its Chu-Tung Branch. The intervention patient population will involve adults (age 
older than 50) with chronic kidney disease stage 3 or 4. Participants will be enrolled 
and identified using the inclusion/exclusion criteria. The physicians have been trained 
to conduct clinical trials. 
4.1 Inclusion Criteria  
1. Age > 50 years  
2. CKD stage 3-4, and eGFR >20 mL/min/1.73m2 
3. FRAX® screening: risk of hip fracture (HF) and major osteoporotic fracture (MOF) 
(HF: men> 6%, women > 7%; MOF: men> 15%, women> 12.5% which were based on 
the result of previous studies in Taiwan).   
4.2 Exclusion Criteria  
1. Unable to consent (e.g. dementia)  
2. Have cancer under treatment  
3. Have acute coronary syndrome (unstable angina, non-ST elevation myocardial 
infarction, ST-elevation myocardial infarction) or stroke in 3 months.  
4. Limited cognitive or physical function for execute the intervention  
 
5 STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
The elicitation of goals will be embedded into clinical programs routinely offered to 
patients with chronic kidney disease. Research coordinator will be trained to 

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complete the interviews.  
The core components of interventions 
 
For participants with abnormal biochemical markers, pharmacological therapy 
and diet modification are applied. 
 
Dietary education on phosphorus additives is applied specifically for retention 
of phosphorus or high serum phosphorus level. 
 
Exercise for bone and cardiovascular health. 
 
Osteoporosis medications are initiated according to the reimbursed criteria of 
National Health Insurance, otherwise medications are used with non-insurance 
payment.  
5.2 Handling of Study Interventions  
Research coordinator  
The Research coordinator will be a trained health professional (e.g. nurse, dietitian, 
case worker).  
Responsibilities  
1. Undergo training and preparation to elicit and document patients’ interview.  
2. Remind the participants to visit clinic on schedule.  
Physicians  
The clinician will be a licensed health care professional (MD).  
Responsibilities  
1. Know or review patient’s disease and care preferences.  
2. Review, discuss, and update patient’s health priorities on each visit.  
3.Prescribe medications for chronic kidney disease and osteoporosis according to the 
results of blood and urine examination, and bone density.  
 
6 STUDY PROCEDURES  
6.1 Schedule of Evaluation for Patient Population 
Time period 
Screening 
Informed 
Consent 
(Enrollment)
Clinic 
visit 
Interviews 
(Patient 
Reported 
Outcomes)
Blood and 
Urine 
Examination
Bone density 
and 
Thoracolumbar 
x-ray film 
Enrollment 
(Day 1) 
x 
x 
x 
 
x 
x 
Follow-up 
Evaluation 
 
 
x 
x 
x 
 

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(3,6,9,12th 
month) 
 
6.2 Description of Research Assessments and Evaluations  
6.2.1 Screening Evaluation  
Potentially eligible patients will first be identified by administrative data within 
the Electronic Health Record (EHR). In the intervention arm, the primary care 
clinician will review the list and refer patients to a Research Coordinator at the 
practice who will be responsible for obtaining informed consent to participate in the 
trial. Interviews will be conducted primarily through the primary clinic. In the case 
that a potential participant does not meet the inclusion criteria or meet the exclusion 
criteria, they will be excluded. Participants in the trial will not receive payment. 
6.2.2 Consent 
Although this study involves minimal risk, every effort will be made to ensure 
that all potential participants understand the details of the study. Additionally, it will 
be made clear that refusing to participate will not affect eligibility to receive services 
or benefits. Potential participants will be asked to demonstrate their understanding 
of what participation involves. If it is unclear that participants demonstrate full 
understanding of what is being asked of them, staff will continue the discussion until 
consent has been fully clarified. 
6.2.2 Assessments and Data Collection  
For interviews, the result of questionnaire will be transcribed and transcripts will be 
coded by investigator of the research study. Qualitative interviews are analyzed using 
the constant comparative methodology. All coded material will be de-identified and 
aggregated for data analysis.  
 
7 SAFETY ASSESSMENTS  
It is the responsibility of the PI to oversee the safety of the study. Research data 
will be reviewed in a timely manner; communication with the IRB will be 
documented in an open and timely manner in accordance with existing policies; 
source documentation will exist for all data fields/questions; explanations for 
deviations from the study protocol will be recorded; and all study files and 
documents will be maintained in organized files. The IRB will also determine whether 
currently or previously enrolled participants should receive notice of the 
unanticipated problem (and the potential for possible risk).  
7.1 Data Safety Monitoring Plan  
This protocol presents minimal risks to the subjects and Unanticipated Problems 
Involving Risks to Subjects or Others, including adverse events, are not anticipated. In 

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the unlikely event that such events occur, Reportable Events [which are events that 
are serious or life-threatening and unanticipated (or anticipated but occurring with a 
greater frequency than expected) and possibly, probably, or definitely related] or 
Unanticipated Problems Involving Risks to Subjects or Others that may require a 
temporary or permanent interruption of study activities will be reported immediately 
(if possible), followed by a written report within 5 calendar days of the Principal 
Investigator becoming aware of the event to the IRB.  
 
8 RISKS AND BENEFITS  
8.1 Risks  
The risk of participants in this study may have a minor risk in blood sampling. 
Except for a slight pain in the skin at the blood draw, the chance of bleeding from the 
puncture site or microbial infection at the puncture site is very small.0000  
8.2 Benefits  
The potential benefit of the evaluation of this integrated approach will be to 
disseminate optimal care of CKD-MBD and osteoporosis. We expect that this 
approach will result in better care for the participants with CKD. 
 
STATISTICAL CONSIDERATIONS  
9.1 Sample Size  
As this is a pilot study, we did not complete a formal sample size calculation. The 
chosen sample size is based upon the estimated number of patients that the funding 
supports their blood and urine examination, and bone density examination.  
 
9.2 Outcomes 
9.2.1 Primary outcomes  
The primary outcome measures will be all-cause mortality, cardiovascular 
events, subsequent fracture rate, and fall rate from January 1, 2020 to December 31, 
2020. The primary outcome measures will be collected during the baseline and 
follow-up (3-12 months) interviews in clinics. 
9.4.2 Secondary outcomes  
Secondary outcome measures will be biochemistry laboratory tests before and 
after multifaceted interventions. 
 
9.4 Data Analyses  
We will calculate descriptive statistics for participants’ baseline characteristics 
and primary and secondary outcomes. The bivariate analysis will be performed using 
the t-test or Mann-Whitney U test for continuous variables with normal or non-

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normal distribution, respectively. Chi-squared test for categorical variables will be 
used to test correlations between baseline characteristics, change of laboratory 
results and outcomes. The paired t-test will be used to examine the difference 
between before and after the interventions. Stepwise multivariate logistic regression 
models will be used to identify the correlates of outcomes after adjusting for 
potential confounders. All tests conducted will be two-tailed, and significance will be 
set at p < 0.05.   
 
10 DATA COLLECTION AND QUALITY ASSURANCE  
10.1 Data Collection Forms  
A trained research coordinator and investigators will be responsible for entry of 
screening, enrollment, and medical records. Data inconsistencies and data 
abstraction errors will be dealt with initially by telephone or email with the research 
coordinator. 
10.2 Data Management  
Data coordination and management will occur within the National Taiwan 
University Hospital and its Chu-Tung Branch. Data management procedures will 
ensure accurate and efficient data collection and analysis; confidentiality, on-demand 
study monitoring reports. All data will be maintained for participant confidentiality 
and privacy. Access to data resources will be strictly limited to research coordinator 
and investigators, and the medical records and paper materials of this project are 
based on the principle of not leaving the hospital. The typed information will only be 
the research number of the respondent. All data is locked or placed on an encrypted 
computer, and only authorized personnel have permission to interpret it. The 
information collected by this project is only for the project team's medical research 
and academic publication. 
 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent script and any subsequent modifications 
will be reviewed and approved by the Research Ethics committee of National Taiwan 
University Hospital responsible for oversight of the study.  
11.2 Participant Confidentiality and Security  
Information about study participants will be kept confidential. Any data, forms, 
reports, and other records will not leave the Hospital. All paper records will be kept 
in a locked file cabinet. For the qualitative interviews, at the completion of the coding 
and analysis the recordings and the link between study ID and identifying 
information will be destroyed, thus rendering the data anonymous. 

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12 RESULTS 
12.1 Number of Patients Screened 
A total of 249 patients in outpatient clinic of two investigators were screened for 
osteoporosis risk assessment. If FRAX® screening criteria for Hip fracture risk: men 
with risk > 6%, women > 7% or major fracture risk: men > 15%, Women > 12.5% were 
reached. Those with exclusion criteria were excluded. Finally, from January 1, 2020 to 
December 31, 2020, 5 participants were enrolled for multifaceted interventions. 
After the intervention, 5 people had laboratory testing, bone density examination 
and health education during follow-up but no one completed the study. The study 
was terminated because of funding was only for one year. A total of 133 patients 
were screened in National Taiwan University Hospital, and a total of 116 patients 
were screened in Chu-Tung Branch, with an average age of 75.7 years. A total of 138 
patients accounted for 55.4% of men. The average weight of men was 66.3kg, the 
average women were 57.3kg, and the average serum creatinine level 2.0 mg/dL for 
men and 1.8 mg/dL for women. The estimated glomerular filtration rate (eGFR) was 
41.9ml/min/1.73m2 for men and 38.1ml/min/1.73m2 for women (Table 1). In the 
analysis of the reasons for exclusion, the highest was the lower risk of fractures 
estimated by FRAX® which accounted for 128 (51.4%), followed by failure to 
perform behavioral interventions (17.7%) and patients’ refusal (15.7%). 
 
12.2 Baseline Status of Participants 
Among the 5 participants, 2 were women and 3 were men. The average age is 
85.2 years old, and the living situation is at most 40% living with foreign caregivers, 
indicating that this group may have higher care needs. For other comorbidities, all 5 
participants had hypertension, 4 had type 2 diabetes mellitus, and 3 had 
osteoarthritis. All are common chronic diseases of the older adults. In the baseline 
biochemistry tests, the average value of creatine level was 1.6 mg/dL, iPTH level was 
100.8 pg/mL, vitamin D level was 23.2 ng/mL, Alkaline phosphatase level was 65.3 
U/L, and hsCRP was 0.17 mg/ dL, total cholesterol was 168.3 mg/dL low-density 
lipoprotein cholesterol was 109.3 mg/dL, high-density lipoprotein cholesterol was 
40.3 mg/dL, blood calcium level was 2.3 mmol/L, blood phosphorus level was 3.5 
mg/dL, average tubular reabsorption of phosphate was 79. Among the 5 participants, 
no one was diagnosed as chronic kidney disease-mineral bone disorder according to 
serum biochemistry examination, and cholesterol and inflammation marker were not 
elevated significantly. 
 
12.3 Osteoporosis Related Variables  
Among the osteoporosis-related variables, the average height was 157.8 cm, the 

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average weight was 62.9 kg, and the average body mass was 25.1. There were 4 
participants with history of fractures before enrollment, 1 participant’s parent with 
hip fractures, and all participants did not have other risk factors. The risk of major 
fracture (excluding BMD) was 17.2%, the risk of major fracture (including BMD) was 
16.3%, the risk of hip fracture (excluding BMD) was 10.2%, and the risk of hip 
fracture (including BMD) was 9.4%. Only 1 participant was diagnosed with 
osteoporosis and received osteoporosis medication, 2 participants have exercise 
habits, and only 1 participant has the habit of supplementing calcium tablets and 
vitamin D. 
 
12.4 Fall-related Assessment and Medical History  
Before the enrollment, 2 participants had hip fracture, 2 participant had spine 
fracture, and 1 participant had ribs fracture. The residency before the fracture was 1 
participant living with spouse, 1 participant living with children, 1 person in nursing 
home, and others living with foreign caregivers. These results showed a higher 
proportion of participants in needs of care. After the fractures, the mobility of 2 
participants does not need assistive devices at all, and 3 participants need unilateral 
assistive devices to go out, which showed that hip fractures have a higher impact on 
walking ability. 
 
12.5 Baseline Health Literacy  
After explaining the impact of osteoporosis, behavioral intervention, medication 
use, and possible adverse reactions of medications, participant’ understanding of 
health education content was less than 25% for 1 participant, 25-49% for 1 
participant, and 50-74% for 2 participants, 75% or more is 1 participant. For 
information of medication use, the understanding level <25% was for 1 participant, 
25-49% for 1 participant, 50-74% for 2 participants, more than 75% for 1 participant. 
Oral health education alone has limited effect on increasing the awareness of the 
disease in our participants. 
Regarding the cause of chronic kidney disease and the signs of deterioration in 
renal function, what is glomerular filtration rate? What is urine protein? What are 
the choices of renal replacement therapies? Most participants do not understand. 
Only the impact of chronic kidney disease on your life, the goal of blood pressure 
control and the possible symptoms of chronic kidney disease would be the concern 
of participants, it showed that the participants have insufficient awareness of chronic 
kidney disease. 
 
12.6 Changes during Tracking and outcomes 

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The 5 participants all completed the follow-up visits. However, they did not complete 
the full follow-up visits because the trial was terminated because the funding was 
only for one year. 4 participants met the conditions for the treatment of osteoporosis 
by the National Health Insurance, and all 4 were prescribed medications. 3 of them 
started treatment after osteoporosis was found in trial, and 1 of them interrupted 
the treatment and restarted during the trial. Drug treatment showed that this group 
needs more active screening and intervention for osteoporosis, so as to reduce the 
impact of osteoporosis on its health. During the follow-up period, no subjects 
experienced new fractures, new cardiovascular events, falls or deaths. There is no 
significant change statistically in the serum biochemistry examination.