Circulating microRNA Signatures in Primary Hyperparathyroidism
Conditions: Primary Hyperparathyroidism, Osteoporosis, Postmenopausal
Sponsor: University of Pennsylvania

Page 1 of 19 
 
 
 
DATE: 
07-Aug-2018 
Institutional Review Board 
TO: 
Heather Wachtel 
3800 Spruce St., First Floor Suite 151 
CC: 
RE: 
Philadelphia, PA 19104 
Phone: 215-573-2540 
(Federalwide Assurance # 00004028) 
IRB PROTOCOL#: 
829615 
PROTOCOL TITLE: 
  
Circulating microRNA signatures in primary hyperparathyroidism 
SPONSOR: 
NO SPONSOR NUMBER 
REVIEW BOARD: 
IRB #7 
 
IRB AMENDMENT: NOTICE OF APPROVAL 
Dear Dr. Wachtel, 
The documents noted below, for the above-referenced protocol, were reviewed by the Institutional Review Board 
using the expedited procedure set forth in 45 CFR 46.110 and approved on 06-Aug-2018. 
This study has been determined to pose minimal risk to subjects. IRB approval for the study will expire on 29-
May-2019. 
The documents included with the application noted below are approved: -HSERA Modification, 
confirmation code: cgjgbggf, submitted 7/31/2018 
ONGOING REQUIREMENTS: 
 You must obtain IRB review and approval under 45 CFR 46 if you make any changes to the protocol, 
consent form, or any other study documents subject to IRB review requirements. Implementation of any 
changes cannot occur until IRB approval has been given. 
 Reportable event, such as serious adverse events, deviations, potential unanticipated problems, and reports 
of non-compliance must be reported to the IRB in accordance with Penn IRB SOP RR 404. 
 When enrolling subjects at a site covered by the University of Pennsylvania’s IRB, a copy of the IRB 
approved informed consent form with the IRB approved from/to stamp must be used unless a waiver of 
written documentation of consent has been 
granted. 
 
 
 
 
 
 

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COMMITTEE APPROVALS: You are responsible for assuring and maintaining other relevant committee 
approvals. This human subjects research protocol should not commence until all relevant committee approvals 
have been obtained. 
If your study is funded by an external agency, please retain this letter as documentation of the IRB’s determination 
regarding your proposal. 
If you have any questions about the information in this letter, please contact the IRB administrative staff. A full 
listing of staff members and contact information can be found on our website: http://www.irb.upenn.edu 
***This letter constitutes official University of Pennsylvania IRB correspondence. *** 
 
 

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Modification 
Basic Info 
Confirmation Number: 
cgjgbggf 
Protocol Number: 
829615 
Created By: 
WACHTEL, HEATHER 
Principal Investigator: 
WACHTEL, HEATHER 
Protocol Title: 
Circulating microRNA signatures in primary hyperparathyroidism 
Short Title: 
miRNA in primary hyperparathyroidism 
Protocol Description: 
The goal of this study is to: 1. Analyze the expression levels of circulating (serum) miRNAs in 
primary hyperparathyroidism patients with and without osteoporosis, and patients with 
osteoporosis undergoing thyroidectomy, and to correlate with clinical markers of bone remodeling 
including biochemical and radiologic studies. 2. To evaluate serum miRNA levels after treatment 
with parathyroidectomy. 
Submission Type: 
Biomedical Research 
Application Type: 
EXPEDITED Category 2 
PennERA Protocol Status 
Approved 
Resubmission* 
No 
Are you submitting a Modification to this protocol?* 
Yes 
Current Status of Study 
Study Status 
Study has not begun (no subjects entered) 
If study is currently in progress, please enter the following 
Number of subjects enrolled at Penn since the study was initiated 
0 
Actual enrollment at participating centers 

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0 
If study is closed to further enrollment, please enter the following 
Number of subjects in therapy or intervention 
0 
Number of subjects in long-term follow-up only 
0 
IRB Determination 
If the change represents more than minimal risk to subjects, it must be reviewed and approved by the IRB 
at a convened meeting. For a modification to be considered more than minimal risk, the proposed change 
would increase the risk of discomfort or decrease benefit. The IRB must review and approve the proposed 
change at a convened meeting before the change can be implemented unless the change is necessary to 
eliminate an immediate hazard to the research participants. In the case of a change implemented to 
eliminate an immediate hazard to participants, the IRB will review the change to determine that it is 
consistent with ensuring the participant&prime;s continued welfare. Examples: Convened Board Increase 
in target enrollment for investigator initiated research or potential Phase I research Expanding inclusion or 
removing exclusion criteria where the new population may be at increased risk Revised risk information 
with active participants Minor risk revisions that may affect a subject&prime;s willingness to continue to 
participate Expedited Review Increase in target enrollment at Penn where overall enrollment target is not 
exceeded or potentially sponsored research Expanding inclusion or removing exclusion where the new 
population has the same expected risk as the previous, based on similarities of condition Revised risk 
information with subjects in long-term follow-up Minor risk revisions with no subjects enrolled to date 
Expedited Review 
Modification Summary 
Please describe any required modification to the protocol. If you are using this form to submit an exception 
or report a deviation, enter 'N/A' in the box below. 
This modification is to: 1. Make changes to the PRA template based on updated cost estimates for specimen 
processing. 2. Revise location of labs which are performing specimen processing. These will be processed 
in a deidentified manner at the Translational Core Lab at CHOP (Penn internal lab) as UPHS does not 
offer several of the tests internally and we would be required to send them to ARUP labs (external lab). 
Risk / Benefit 
Does this amendment alter the Risk/Benefit profile of the study? 
No 
Change in Consent 
Has there been a change in the consent documents? 
No 
If YES, please choose from the options below regarding re-consenting 
Deviations 
Are you reporting a deviation to this protocol?* 
No 

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Exceptions 
Are you reporting an exception to this protocol?* 
No 
Protocol Details 
Resubmission* 
Yes 
Study Personnel 
Principal Investigator 
Name: 
WACHTEL, HEATHER 
Dept / School / Div: 
4502 - SU-Surgery Administration 
Campus Address 
Mail Code 
6070 
Address: 
HARRISON - 313 STMLR 
3450 HAMILTON WK 
City State Zip: 
PHILADELPHIA PA 19104-6070 
Phone: 
215-519-8058 
Fax: 
215-662-7983 
Pager: 
Email: 
Heather.Wachtel@uphs.upenn.edu 
HS Training Completed: 
Yes 
Training Expiration Date: 
09/22/2018 
Name of course completed : 
CITI Protection of Human Subjects Research Training - ORA 
Study Contacts 
None 
Other Investigator 
Name: 
LEVINE, MICHAEL 
Dept / School / Div: 
7 - General University EB Pool 
Campus Address 
Mail Code 
4399 
Address: 
Suite 30 34th and Civic Cente 
11 Northwest Tower (CHOP) 
City State Zip: 
Philadelphia PA 19104-4399 

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Phone: 
215-590-3618 
Fax: 
- 
Pager: 
Email: 
levinem@email.chop.edu 
HS Training Completed: 
Yes 
Training Expiration Date: 
07/19/2018 
Name of course completed : 
CITI Protection of Human Subjects Research Training - ORA 
Responsible Org (Department/School/Division): 
4502 - SU-Surgery Administration 
Key Study Personnel 
Name: 
RAPAPORT KELZ, RACHEL 
Department/School/Division: 
SU-Surgery Administration 
HS Training Completed: 
Yes 
Training Expiration Date: 
09/29/2020 
Name of course completed: 
CITI Protection of Human Subjects Research Training - ORA 
Name: 
ERMER, JAE P 
Department/School/Division: 
SU-Surgery Administration 
HS Training Completed: 
Yes 
Training Expiration Date: 
12/03/2020 
Name of course completed: 
CITI Protection of Human Subjects Research Training - ORA 
Name: 
FRAKER, DOUGLAS L 
Department/School/Division: 
SU-Surgery Administration 
HS Training Completed: 
Yes 
Training Expiration Date: 
05/06/2019 
Name of course completed: 
CITI Protection of Human Subjects Research Training - ORA 
Name: 
AL MUKADDAM, MONA 
Department/School/Division: 
DM-Endocrinology, Diabetes & Metabolism 
HS Training Completed: 
Yes 
Training Expiration Date: 
03/28/2020 
Name of course completed: 
CITI Protection of Human Subjects Research Training - ORA 
Disclosure of Significant Financial Interests* 
Does any person who is responsible for the design, conduct, or reporting of this research protocol have a 
FINANCIAL INTEREST? No 

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Penn Intellectual Property* 
To the best of the Principal Investigator's knowledge, does this protocol involve the testing, development 
or evaluation of a drug, device, product, or other type of intellectual property (IP) that is owned by or 
assigned to the University of Pennsylvania? 
No 
Certification 
I have reviewed the Financial Disclosure and Presumptively Prohibited Conflicts for Faculty Participating 
in Clinical Trials and the Financial Disclosure Policy for Research and Sponsored Projects  with all 
persons who are responsible for the design, conduct, or reporting of this research; and all required 
Disclosures have been attached to this application. 
Yes 
Biomedical Research 
Clinical Trial* 
Is this a clinical trial? 
No 
Investigator Initiated Trial* 
Is this an investigator initiated trial? 
No 
Drugs or Devices* 
Does this research study involve Drugs or Devices? 
No 
IND Exemption 
For studies that fall under an IND exemption, please provide the number below 
For studies including IND or IDE's, please provide the number(s) below 
IDE Review* 
NOTE: For research involving investigational devices, you are required to review the guidance on 
Managing Research Device Inventory. Consult the Penn Manual for Clinical Research: https:// 
www.med.upenn.edu/pennmanual/secure/investigational-product-management-at-sites-not-
usinginvestigational-drug-services-(ids).html Please check the box Yes if you have reviewed the guidance. 
Yes 
Research Device Management* 
Please indicate how research device(s) will be managed. 
Not Applicable (no investigational devices) 
Drug, Herbal Product or Other Chemical Element Management * 
Please indicate how drugs, herbal products or other chemical entities will be managed. 
Not Applicable (no drugs, herbal products or other chemical entities) 
Radiation Exposure* 
Are research subjects receiving any radiation exposure (e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, 
FDG, Tc-99m, etc.) that they would not receive if they were not enrolled in this protocol? 
No 
Gene Transfer* 
Does this research involve gene transfer (including all vectors) to human subjects? 
No 

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Human Source Material* 
Does this research include collection or use of human source material (i.e., human blood, blood products, 
tissues or body fluids)? Yes 
CACTIS and CT Studies* 
Does the research involve Center for Advanced Computed Tomography Imaging Services (CACTIS) and 
CT studies that research subjects would not receive if they were not part of this protocol? 
No 
CAMRIS and MRI Studies* 
Does the research involve Center for Advanced Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) and MRI studies that research subjects would not receive if they were not part of this protocol? 
No 
Investigational Agent or Device within the Operating Room* 
Does the research project involve the use of an investigational agent or device within the Operating  
Room? 
No 
Cancer Related research not being conducted by an NCI cooperative group* 
Does this protocol involve cancer-related studies in any of the following categories? 
No 
Processing of Materials* 
Will the research involve processing (such as over encapsulating, or compounding)? 
No 
In-House Manufacturing of Materials* 
Will the research involve processing (such as over encapsulating, or compounding)? 
No 
Medical Information Disclosure* 
Does the research proposal involve the use and disclosure of research subject's medical information for 
research purposes? Yes 
If the answer is YES, indicate which items is is provided with this submission: 
Modified research informed consent document that incorporates HIPAA requirements 
CTRC Resources* 
Does the research involve CTRC resources? 
No 
Pathology and Laboratory Medicine Resources* 
Will samples be collected by hospital phlebotomy and/or processed or analyzed by any of the clinical 
laboratories of the University of Pennsylvania Health System? Yes 
Clinical Laboratory Services* 
Will samples be collected by UPHS phlebotomy and/or analyzed by the hospital laboratory? Yes 
Anatomic Pathology Services* 
Will tissue specimens (other than blood) be collected for clinical, diagnostic, or research purposes OR be 
processed through surgical pathology, cytopathology, neuropathology, or hematopathology? 
No 
Research Involves Apheresis, Cell Collection, and/or Blood Product Collection* 
Does this research involve collection of blood products in the Penn Donor Center and/or the use of 
apheresis for treatment or collection of cells or other blood components? 
No 

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Research involving blood transfusion or drug infusions* 
Will your research involve blood transfusion or infusion of study drug in 3 Ravdin Apheresis Unit for 
research purposes? 
No 
Trial in Radiation Oncology 
Is this research a prospective trial being done in Radiation Oncology, and if so, has this protocol been 
approved by the Radiation Oncology Protocol committee? 
N/A 
Study in Radiation Oncology 
Is this research a retrospective study being done in Radiation Oncology, and if so, has this project been 
reviewed by the Radiation Oncology Clinical Research Group? 
N/A 
Use of UPHS services* 
Does your study require the use of University of Pennsylvania Health System (UPHS) services, tests or 
procedures*, whether considered routine care or strictly for research purposes? 
Yes 
Primary Focus* 
Tissue/biospecimen 
Protocol Interventions 
Sociobehavioral (i.e. cognitive or behavioral therapy) 
Drug 
Device - therapeutic 
Device - diagnostic (assessing a device for sensitivity or specificity in disease diagnosis) Surgical 
Diagnostic test/procedure (research-related diagnostic test or procedure) 
x Obtaining human tissue for basic research or biospecimen bank 
Survey instrument 
None of the above 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
Sponsors 
Business Administrator 
Name: 
MERVIS, STEVEN 
Dept / School / Div: 
4502 - SU-Surgery Administration 
Phone: 
215-662-2806 
Fax: 
- 
Pager: 
Email: 
steve.mervis@uphs.upenn.edu 
Department budget code 

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400 - 400 - 1 - 461243 - XXXX - 2433 - 4498 
Funding Sponsors 
Funding sponsors billing address 
If you have selected a commercial or industry sponsor, please provide the appropriate address and contact 
information for the Sponsor for the purposes of billing for IRB review fees (initial review, continuing 
review and convened modification fees apply here). If the Sponsor is not industry/ commercial, this 
information is not necessary to provide with your application. 
Funding sponsors gift 
Is this research being funded by a philanthropic gift? 
Regulatory Sponsor 
IND Sponsor 
none 
400 - 400 - 1 - 461243 - XXXX - 2433 - 4498 
Industry Sponsor 
None 
Project Funding* 
Is this project funded by or associated with a grant or contract? 
No 
Sponsor Funding 
Is this study funded by an industry sponsor? 
Status of contract 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
Multi-Site Research 
Other Sites 
No other sites 
Management of Information for Multi-Center Research The 
following documents are currently attached to this item: 
There are no documents attached for this item. 
Protocol 
Abstract 
PHPT disproportionately effects post-menopausal women at elevated risk for osteoporosis. Surgery is 
indicated for asymptomatic patients with skeletal manifestations of osteoporosis and pathologic fractures, 
but not for those with osteopenia. However, more than a third of patients with asymptomatic PHPT 
demonstrate progressive disease, and meeting criteria for surgery at initial diagnosis is not predictive of 
disease progression. Although clinical tools are available to estimate the probability of major osteoporotic 

Page 11 of 19 
fracture, no biochemical markers for risk stratification exist. Serum miRNAs have both diagnostic and 
prognostic potential, to assist in identification of PHPT patients at elevated fracture risk and to determine 
subpopulations who may benefit from surgical parathyroidectomy. 
Objectives 
Overall objectives 
The goal of this study is to: 1. Analyze the expression levels of circulating (serum) miRNAs in primary 
hyperparathyroidism patients with and without osteoporosis, and to correlate with clinical markers of bone 
remodeling including biochemical and radiologic studies. 2. To evaluate serum miRNA levels after 
treatment with parathyroidectomy. 
Primary outcome variable(s) 
Primary outcome variable: Serum miRNA levels 
Secondary outcome variable(s) 
Secondary outcome variables: Clinical markers of bone remodeling, including serum levels of bonespecific 
alkaline phosphatase, osteocalcin, P1NP, CTX, calcium, phosphate, vitamin D metabolites, and PTH; urine 
calcium; and DXA scan. 
Background 
Osteoporosis and osteopenia are chronic diseases disproportionately affecting the elderly. In the United  
States, the prevalence of osteoporosis is projected to increase from 10 million in 2005 to 14 million in 
2025, due to population aging.1,2 Similarly, the economic cost of osteoporotic fractures is projected to 
increase to $25 billion by 2025. Primary hyperparathyroidism (PHPT) is one of the few reversible causes 
of osteoporosis and fragility fractures. PHPT is the third most common endocrine disorder, with an 
incidence of 27-30 per 100,000 person-years, and increasing with age; half of all patients with PHPT are 
post-menopausal women, a population at high risk for osteoporosis at baseline.3  All forms of PHPT are 
characterized by loss of the normal negative feedback relationship between serum calcium and parathyroid 
hormone (PTH) secretion, leading to hypercalcemia and hyperparathyroidism. Classic PHPT is 
characterized by skeletal, renal, gastrointestinal and neuropsychiatric manifestations. Skeletal 
manifestations of classic PHPT are mediated by osteoblast inhibition and osteoclast stimulation, leading 
to increased bone remodeling.4 The catabolic effects of chronic PTH excess may present as osteitis fibrosa 
cystica, brown tumors, pathologic fractures, bone pain, osteoporosis or osteopenia. Although frank osteitis 
fibrosa cystica is an increasingly rare presentation of PHPT in the United States, affecting 2% of patients, 
osteoporosis is reported in 39-63% of patients, with preferential loss of bone density in cortical sites.5 
Fragility fractures are significantly associated with PHPT, particularly in postmenopausal women.6,7 Both 
decreases in bone mineral density (BMD) and fragility fractures are considered indications for 
parathyroidectomy in patients with asymptomatic PHPT.8 Parathyroidectomy has been demonstrated to 
improve BMD in prospective studies of PHPT patients with osteoporosis; some studies suggest that more 
benefit may be seen in pre-menopausal women.9,10 Current research in bone remodeling has identified 
microRNAs (miRNAs), novel biomarkers with both diagnostic and therapeutic potential.11,12 miRNAs 
are short, single stranded, non-coding RNAs which regulate posttranscriptional expression of mRNA.13 
miRNAs have been extensively implicated in bone remodeling and homeostasis. Circulating miRNAs have 
been shown to correlate with fragility fractures, and are conserved across subpopulations of osteoporotic 
patients.14-16 miRNA panels have been suggested to have the potential to assist in diagnosis, prognosis, 
and are promising targets for directed therapy.13,15,17 Although miRNAs have been investigated in 
conjunction with pre-menopausal, postmenopausal, idiopathic and diabetic osteoporosis, no research to 
date has explored the miRNA profile of PHPT patients with osteoporosis. Similarly, although in vitro 
experiments have demonstrated miRNA response to bisphosphonates,18 no clear correlation has been 
established between therapeutic interventions and miRNA levels in vivo.15 The goal of this study is 
therefore two-fold; first, to analyze the expression levels of circulating miRNAs in PHPT patients with 
and without osteoporosis; and second, to evaluate miRNA levels after treatment with parathyroidectomy.   
References 1. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville MD2004. 2. 
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic 
burden of osteoporosis-related fractures in the United States, 2005-2025. Journal of bone and mineral 
research : the official journal of the American Society for Bone and Mineral Research 2007;22:465-75. 3. 
Fraser WD. Hyperparathyroidism. Lancet (London, England) 2009;374:145-58. 4. Lewiecki EM, Miller 
PD. Skeletal effects of primary hyperparathyroidism: bone mineral density and fracture risk. Journal of 

Page 12 of 19 
clinical densitometry : the official journal of the International Society for Clinical Densitometry 
2013;16:28-32. 5. Walker MD, Silverberg SJ. Primary hyperparathyroidism. Nature reviews 
Endocrinology 2017. 6. De Geronimo S, Romagnoli E, Diacinti D, D'Erasmo E, Minisola S. The risk of 
fractures in postmenopausal women with primary hyperparathyroidism. European journal of 
endocrinology 2006;155:415-20. 7. Vignali E, Viccica G, Diacinti D, et al. Morphometric vertebral 
fractures in postmenopausal women with primary hyperparathyroidism. The Journal of clinical 
endocrinology and metabolism 2009;94:2306-12. 8. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines 
for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth 
International Workshop. The Journal of clinical endocrinology and metabolism 2014;99:3561-9. 9. 
Lundstam K, Heck A, Godang K, et al. Effect of Surgery Versus Observation: Skeletal 5-Year Outcomes 
in a Randomized Trial of Patients With Primary HPT (the SIPH Study). Journal of bone and mineral 
research : the official journal of the American Society for Bone and Mineral Research 2017;32:1907-14. 
10. Lumachi F, Camozzi V, Ermani M, F DEL, Luisetto G. Bone mineral density improvement after 
successful parathyroidectomy in pre- and postmenopausal women with primary hyperparathyroidism: a 
prospective study. Annals of the New York Academy of Sciences 2007;1117:357-61. 11. Kim KM, Lim 
SK. Role of miRNAs in bone and their potential as therapeutic targets. Current opinion in pharmacology 
2014;16:133-41. 12. Garnero P. New developments in biological markers of bone metabolism in 
osteoporosis. Bone 2014;66:46-55. 13. Jing D, Hao J, Shen Y, et al. The role of microRNAs in bone 
remodeling. International journal of oral science 2015;7:131-43.  
14. Heilmeier U, Hackl M, Skalicky S, et al. Serum miRNA Signatures Are Indicative of Skeletal Fractures 
in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic 
Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro. Journal of bone and mineral 
research : the official journal of the American Society for Bone and Mineral Research 2016;31:2173-92. 
15. Kocijan R, Muschitz C, Geiger E, et al. Circulating microRNA Signatures in Patients With Idiopathic 
and Postmenopausal Osteoporosis and Fragility Fractures. The Journal of clinical endocrinology and 
metabolism 2016;101:4125-34. 16. Weilner S, Skalicky S, Salzer B, et al. Differentially circulating 
miRNAs after recent osteoporotic fractures can influence osteogenic differentiation. Bone 2015;79:43-51. 
17. Hackl M, Heilmeier U, Weilner S, Grillari J. Circulating microRNAs as novel biomarkers for bone 
diseases - Complex signatures for multifactorial diseases? Molecular and cellular endocrinology 
2016;432:83-95. 18. Zhou Q, Zhao ZN, Cheng JT, et al. Ibandronate promotes osteogenic differentiation 
of periodontal ligament stem cells by regulating the expression of microRNAs. Biochemical and 
biophysical research communications 2011;404:127-32. 
Study Design 
Phase* 
Not applicable 
Design 
This is a non-randomized cohort study. Subjects with and without osteoporosis, undergoing neck surgery 
or non-operative management will be recruited by one of two methods: 1. Prospectively identified and 
consented from the Endocrine Surgery and Endocrinology Clinics at the University of Pennsylvania Health 
System OR 2. Identified from the Penn Biobank (previously enrolled and consented).  Patients will be 
matched for age and gender. Groups will consist of 25 subjects each, for a total study population of 100 
subjects. Group 1: PHPT subjects with osteoporosis undergoing parathyroidectomy  Group 2: PHPT 
subjects without osteoporosis undergoing parathyroidectomy Group 3: Subjects with benign thyroid 
disease and osteoporosis undergoing thyroid surgery  Group 4: PHPT subjects with osteoporosis not 
undergoing surgery. 
Study duration 
Estimated length of time to enroll all subjects and complete the study: 2 years Length of a subject's 
participation time in study: 2 years Projected start date of the proposed study: April 1, 2018 
Resources necessary for human research protection 
Describe research staff and justify that the staff are adequate in number and qualifications to conduct the 
research. Describe how you will ensure that all staff assisting with the research are adequately informed 
about the protocol and their research related duties. Please allow adequate time for the researchers to 
conduct and complete the research. Please confirm that there are adequate facilities for the research. 

Page 13 of 19 
Subjects will be recruited in one of two methods: 1. Prospectively identified and consented from the 
Endocrine Surgery and Endocrinology Clinics at the University of Pennsylvania Health System OR 2. 
Identified from the Penn Biobank (previously enrolled and consented).  1. Prospective subject recruitment 
and consenting will take place in the Endocrinology or Endocrine Surgery clinics of the University of 
Pennsylvania Health System under the supervision of the PI. Research staff will be CITI and HIPAA 
trained and will be required to review study protocols and be added to the IRB prior to participation. Serum 
samples will be obtained in the clinical laboratories of the University of Pennsylvania Health System. 
Standard serum testing will be performed in the clinical laboratories of the University of Pennsylvania 
Health System. Serum specimens for miRNA will be assigned a study identifier, all PHI will be removed, 
and specimens will be stored in -80 freezers in the Harrison Department of Surgical Research. Deidentified 
serum specimens will be processed commercially for miRNA. 2. The Penn Medicine BioBank specimens 
are collected with informed consent consistent with previously approved IRB protocols (IRB#813913 & 
IRB#817977). Human subject protection relates to subject confidentiality because there is no direct patient 
contact for this study. All study personal have received the appropriate CITI training and are experiences 
in the conduct of research with human subjects. Appropriate computer security measures are in place; no 
PHI identifiers will be shared on these specimens. Data will be provided de-identified and specimens will 
be coded. 
Characteristics of the Study Population 
Target population 
This study is a non-randomized cohort study comparing serum miRNA levels in patients undergoing neck 
surgery (parathyroidectomy or thyroidectomy) or medical management, with or without osteoporosis. We 
aim to enroll 25 patients in each of 4 groups: Group 1: PHPT subjects with osteoporosis undergoing 
parathyroidectomy  Group 2: PHPT subjects without osteoporosis undergoing parathyroidectomy Group 
3: Subjects with benign thyroid disease and osteoporosis undergoing thyroid surgery  Group 4: PHPT 
subjects with osteoporosis not undergoing surgery. 
Subjects enrolled by Penn Researchers 
100 
Subjects enrolled by Collaborating Researchers 
0 
Accrual 
Study subjects will be identified by one of two methods: 1. Prospectively identified and consented from 
the Endocrine Surgery and Endocrinology Clinics at the University of Pennsylvania Health System OR 2. 
Identified from the Penn Medicine BioBank (previously enrolled and consented).  1. Prospective study 
recruitment and consenting will take place in the Endocrine Surgical clinics of Drs. Wachtel, Kelz and 
Fraker in the Division of Endocrine and Oncologic Surgery or Endocrinology Clinic of Dr. Mona Al 
Mukaddam, Director of the Penn Bone center. Approximately 40-50 new patients with thyroid/ parathyroid 
disorders are seen weekly in the combined surgical clinics. 2. Potential subjects from the Penn Medicine 
BioBank will be initially identified by data collected as part of the Penn Medicine BioBank protocols. The 
BioBank contains ~50,000 subjects. Future use of samples and personal health information has already 
been contemplated by participants of both parent protocols, thus there is no need to reconsent participants 
We aim to enroll 25 patients in each of the 4 groups. A minimum group size of 17 is calculated to detect a 
1 standard deviation difference in means assuming a two-sided alpha of 0.05 and beta 0.20, with equal 
variance of miRNA between groups; an enrollment of 25 patients will allow for potential attrition due to 
loss of follow up. 
Key inclusion criteria 
Inclusion criteria: Adult patients with primary hyperparathyroidism undergoing parathyroidectomy; adult 
patients with benign thyroid disease and osteoporosis, undergoing thyroid surgery. 
Key exclusion criteria 
Minors; vulnerable populations including adults unable to give consent; patients with thyroid malignancy; 
subjects with secondary osteoporosis including but not limited to renal osteodystrophy, hepatic 
dysfunction, glucocorticoid use, Cushings disease/syndrome, current or past use of bone active agents; use 
of estrogens or HRT; hyper- or hypothyroidism; vitamin d deficiency. 

Page 14 of 19 
Vulnerable Populations 
Children Form 
Pregnant women (if the study procedures may affect the condition of the pregnant woman or fetus) 
Form 
Fetuses and/or Neonates Form 
Prisoners Form 
Other x None of the above populations are included in the 
research study 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
Populations vulnerable to undue influence or coercion 
Although not directly targeted, mentally disabled persons, economically or educationally disadvantaged 
persons, and/or employees or students of the University of Pennsylvania will not be denied enrollment and 
any special protections and/or additional safeguards will be undertaken in order to protect the rights and 
welfare of these subjects from coercion or undue influence as appropriate 
Subject recruitment 
Study subjects will be identified by one of two methods: 1. Prospectively identified and consented from 
the Endocrine Surgery and Endocrinology Clinics at the University of Pennsylvania Health System OR 2. 
Identified from the Penn Medicine BioBank (previously enrolled and consented).  1. Prospectively 
identified and consented from the Endocrine Surgery and Endocrinology Clinics at the University of 
Pennsylvania Health System.  a. During the subject's initial clinical consultation, the treating physician 
will describe the study and its risks and benefits. b. The potential subject will be given a copy of the consent 
form to review and have all questions answered. If the subject decides to participate, the principal 
investigator or member of the study team will obtain consent.  c. The subjects will continue medical or 
surgical treatment with no alterations in their clinical care outside of venipuncture. 2. Subjects previously 
enrolled in the Penn Medicine BioBank will be assessed for eligibility. If meeting criteria for eligibility, 
they will be recontacted (recontact has previously been approved per BioBank protocol) for study 
enrollment. 
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does the 
study team plan to directly use social media to recruit for the research? 
No 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
Subject compensation* 
Will subjects be financially compensated for their participation? 
No 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
If there is subject compensation, provide the schedule for compensation per study visit or session and 
total amount for entire participation, either as text or separate document 
No cash compensation will be offered to subjects. Parking vouchers will be provided for parking at Penn 
garages on the day of study visits, up to a total cost of $13.00/day. 

Page 15 of 19 
Study Procedures 
Suicidal Ideation and Behavior 
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)? 
No 
Procedures 
Please see attached protocol. 
The following documents are currently attached to this item: 
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Deception 
Does your project use deception? 
No 
International Research 
Are you conducting research outside of the United States? 
No 
Analysis Plan 
Group comparisons will be performed to identify differences in clinical markers of bone remodeling and 
serum miRNA expression profiles in hyperparathyroid patients based on the presence of osteoporosis. 
Group comparisons will utilize the Students t test, Wilcoxon rank-sum test, and Fishers exact test, as 
appropriate. Pre- and postoperative clinical markers of bone remodeling and serum miRNA expression 
profiles will be compared using the chi-square test to identify treatment effect of parathyroidectomy or 
thyroidectomy. 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
Data confidentiality 
Paper-based records will be kept in a secure location and only be accessible to personnel involved in 
the study. 
x Computer-based files will only be made available to personnel involved in the study through the 
use of access privileges and passwords. 
x Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and confidentiality of identifiable information. 
x Wherever feasible, identifiers will be removed from study-related information. 
A Certificate of Confidentiality will be obtained, because the research could place the subject at risk 
of criminal or civil liability or cause damage to the subject's financial standing, employability, or 
liability. 
A waiver of documentation of consent is being requested, because the only link between the subject 
and the study would be the consent document and the primary risk is a breach of confidentiality. 
(This is not an option for FDA-regulated research.) 
Precautions are in place to ensure the data is secure by using passwords and encryption, because the 
research involves web-based surveys. 
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identification of subjects. 
Subject Confidentiality 
The identifiers used in this study are name, MRN, telephone number, date of birth, and date of surgery. 
Data will be deidentified (name and MRN removed from the dataset), and subjects will be assigned a study 
ID at the time of surgery. This will be kept on a secure, password protected, encrypted computer on the 

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Penn Medicine Server in a locking office in the Department of Surgery by the Principal Investigator. The 
linking dataset will be accessed to reidentify patients 1 year after surgery to obtain follow up clinical 
assessment and serum studies. Deidentified data will be entered into a REDCap database maintained by 
the University of Pennsylvania IT department. 
Sensitive Research Information* 
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record? 
No 
Subject Privacy 
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas confidentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact potential 
participants. The settings in which an individual will be interacting with an investigator. The privacy 
guidelines developed by relevant professions, professional associations and scholarly disciplines (e.g., 
psychiatry, genetic counseling, oral history, anthropology, psychology).  
Subjects will be identified and consented by HIPAA and CITI trained investigators listed under Personnel. 
Subject recruitment, consent discussion and study procedures will be performed in dedicated clinical space 
at the University of Pennsylvania, with existing private exam and procedure rooms consistent with clinical 
practice. Per study protocol, subjects will be contacted by indicated telephone preference, 1 year after 
treatment or surgery to schedule follow up clinical and biochemical assessment. 
Data Disclosure 
Will the data be disclosed to anyone who is not listed under Personnel? No 
data will be disclosed to anyone who is not listed under Personnel. 
Data Protection* 
x Name 
Street address, city, county, precinct, zip code, and equivalent geocodes x All elements of dates 
(except year) for dates directly related to an individual and all ages over 89 x Telephone and fax 
number 
Electronic mail addresses 
Social security numbers 
x Medical record numbers 
Health plan ID numbers 
Account numbers 
Certificate/license numbers 
Vehicle identifiers and serial numbers, including license plate numbers 
Device identifiers/serial numbers 
Web addresses (URLs) 
Internet IP addresses 
Biometric identifiers, incl. finger and voice prints 
Full face photographic images and any comparable images 
Any other unique identifying number, characteristic, or code 
None 
Does your research request both a waiver of HIPAA authorization for collection of patient information and 
involve providing Protected Health Information ("PHI") that is classified as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a recipient 
outside of the University of Pennsylvania covered entity? 

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No 
Tissue Specimens Obtained as Part of Research* Are 
Tissue Specimens being obtained for research? 
Yes 
Tissue Specimens - Collected during regular care* 
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)? Yes 
Tissue Specimens - otherwise discarded* 
Would specimens otherwise be discarded? 
No 
Tissue Specimens - publicly available* Will 
tissue specimens be publicly available? 
No 
Tissue Specimens - Collected as part of research protocol* Will 
tissue specimens be collected as part of the research protocol? Yes 
Tissue Specimens - Banking of blood, tissue etc. for future use* Does 
research involve banking of blood, tissue, etc. for future use? 
Yes 
Genetic testing 
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision of 
genetic counseling. Describe how subject confidentiality will be protected Note: If no genetic testing is to 
be obtained, write: "Not applicable." 
Not applicable 
Consent 
1. Consent Process 
Overview 
Prospective participant will be identified in Endocrinology or Endocrine Surgery clinics at the University 
of Pennsylvania Health System at the time of clinical consultation, or identified via the Penn Medicine 
BioBank. Subjects who are eligible for enrollment will be informed of the study and asked if they would 
like to participate by surgical staff. Sample consent language is below: "You are eligible for inclusion in a 
research study which examines the impact of surgery on bone health. Are you interested in hearing more 
information? Participation is completely voluntary, and will not change your medical or surgical care." If 
potential subjects are interested, formal consent form will be reviewed with patient (see attached 
document) by principle study investigator, Dr. Wachtel. This may be performed over the phone or in person 
at the time of the initial clinical consultation. Subjects who are incapable of consent will not be included 
in this study. Participants may choose to withdraw from the study at any time. 
Children and Adolescents 
Children and adolescents will not be included in this study. 
Adult Subjects Not Competent to Give Consent 
Adult subjects unable to give informed consent will not be included in this study. 
2. Waiver of Consent 
Waiver or Alteration of Informed Consent* 
No Waiver Requested 

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Minimal Risk* 
Impact on Subject Rights and Welfare* 
Waiver Essential to Research* 
Additional Information to Subjects 
Written Statement of Research* 
No 
If no written statement will be provided, please provide justificiation 
The following documents are currently attached to this item: 
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Risk / Benefit 
Potential Study Risks 
The primary risk of this study is associated with an additional blood draw. Whenever possible, the blood 
draw will be combined with other required laboratory work, such as preoperative blood work. The risks 
are limited to pain at the phlebotomy site, swelling, or minimal risk of infection.  The secondary risk of 
this study is a risk to loss of confidentiality, however the following measures will be taken to minimize 
this risk. The identifiers used in this study (MRN, name, DOS) will be used to identify the patient 
population of interest. During the identification of subjects, identifiers will be stored on a secure server on 
password-protected UPHS computers in a locking office in the Department of Surgery. After enrollment, 
data will be de-identified (MRN, name removed) and subjects will be assigned a study ID, and a linking 
dataset will be generated. This will be kept separately by PI on a password protected encrypted computer 
in a locking office in the Department of Surgery. De-identified data will be entered into a REDCap 
database. One year after surgery, subjects will be re-identified to facilitate contact for 1 year follow up 
visit. No patient information will be disclosed. 
Potential Study Benefits 
This study has no direct benefits to the individual subjects. This study has the potential to identify 
subpopulations who may benefit from early surgical intervention for primary hyperparathyroidism, and 
may change management guidelines for primary hyperparathyroidism. 
Alternatives to Participation (optional) 
Participation is entirely voluntary. Subjects may refuse to participate or withdraw from the study at any 
time with no repercussions. 
Data and Safety Monitoring 
This study will be monitored by the Principal Investigator. 
The following documents are currently attached to this item: 
There are no documents attached for this item. 
Risk / Benefit Assessment 
The risk of participation in this research is limited to an additional blood draw; whenever possible, this 
will be combined with other lab work to minimize discomfort to the subject. This study offers no direct 
benefit and only minimal risk to the subjects. There is significant societal benefit, however, as a better 
understanding of the genetic, molecular, and cellular events leading to the development of vascular disease 
will ultimately lead to the development of novel target strategies to prevent and treat vascular disease. As 
such, the minimal risk to the subjects is outweighed by the potential societal benefit. 

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General Attachments 
The following documents are currently attached to this item: 
Cover Letter (irbrevisionscoverletter7.30.18.docx) Additional forms 
(study_procedures_circulating_mirnas_phpt.july2018.docx) Additional forms 
(study_procedures_circulating_mirnas_phpt.july2018.cleancopy.docx) 
Additional forms (pra_template_non-drug_device_intervention.parathyroid.mirna.7.24.18.xls)