Hypercalcemia After Paraffin Oil Injection

April 2, 2025 updated by: Martin Blomberg Jensen

Hypercalcemia After Paraffin Oil Injection: Aetiology, Pathogenesis and Possible Treatment Options

Today, there is an increased use of non-medical, invasive cosmetic treatments globally without sufficient awareness of possible health risks. A particular problem is young men injecting large amounts of paraffin oil into skeletal muscles especially on upper arms and chest to increase the visible size of the muscles. Several case reports have suggested that intramuscular injection of paraffin oil induces foreign body reaction and granuloma formation and subsequently hypercalcemia. Our hypothesis is that increased generation of activated vitamin D (1,25(OH)2D3) in the marcrophages may be responsible for the persistent hypercalcemia. Now trhe investigators want to include a large group of men who injected 100-10.000 ml paraffin oil to identify risk factors for developing hypercalcemia and try to understand the pathogenesis of the disease. Additionally, granuloma tissue from selected patients will be cultured ex vivo to investigate whether they produce 1,25(OH)2D3 or PTHrP and to test which drugs can most effectively be used to lower calcium levels in these men. Subsequently, we will try to stratify the men according to the severity of the changes in calcium homeostasis as we suggest that this stratification will be the basis for future intervention trials

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Today, there is an increased use of non-medical, invasive cosmetic treatments globally without sufficient awareness of possible health risks. A particular problem is young men injecting large amounts of paraffin oil into skeletal muscles especially on upper arms and chest to increase the visible size of the muscles. Several case reports have suggested that intramuscular injection of paraffin oil induces foreign body reaction and granuloma formation. The formation of granuloma probably precedes the marked hypercalcemia that often develops and appears to be difficult to treat. The largest study to date included 14 men and showed that practically all men developed serious hypercalcemia, but the etiology was unclear. Foreign body granulomas are like other granulomatous diseases such as Tuberculosis or sarcoidosis rich in macrophages, (ref) and it has been proposed that increased generation of activated vitamin D (1,25(OH)2D3) in the marcrophages may be responsible for the persistent hypercalcemia.

Calcium homeostasis is tightly regulated primarily by vitamin D, Parathyroid hormone (PTH) and Fibroblast growth factor 23 (FGF23) that rapidly modifies intestinal absorption, renal excretion and calcium mobilization from the skeletal compartment in response to immediate changes in serum calcium (ref). Vitamin D (cholecalciferol) is normally formed by UV-B radiation of the skin and requires two enzymatic reactions before it can bind and activate the vitamin D receptor (VDR). Conversion of cholecalciferol to 25-hydroxydvitamin (25OHD) is the first activation step; it is un-regulated and generally exerted by the hepatic CYP2R1. 25OHD is not biologically active and must undergo 1-alpha hydroxylation by renal CYP27B1 to form the active metabolite 1,25(OH)2D3. The main actions of 1,25(OH)2D3 is to promote calcium and phosphate absorption and decrease calcium excretion until inactivated by CYP24A1. 1,25(OH)2D3 is also a powerful inhibitor of PTH and inducer of FGF23, which ensures an important feedback-loop to maintain an adequate vitamin D status (ref). PTH which is a potent inducer of CYP27B1, mobilizes calcium and phosphate from the skeleton and increases phosphate excretion. In contrast, FGF23 that inhibits CYP27B1, induces the in-activating CYP24A1 and promotes phosphate excretion. Almost all organs has the ability to activate, respond to, and inactivate vitamin D because CYP27B1, VDR and CYP24A1 are expressed also in most non-renal tissues. However, regulation of CYP27B1 and CYP24A1 is strikingly different in these organs where high intracellular levels of 1,25(OH)2D3 activates VDR that induces transcription of CYP24A1 and thereby increases in-activation to restore normal intracellular levels of all vitamin D metabolites. This autoregulatory control of vitamin D metabolites secures under normal circumstances that high concentrations of 1,25(OH)2D3 are not released into circulation. Regulation of vitamin D homeostasis is different in the macrophages present in granulomas because they retain a splice variant of CYP24A1 that is not upregulated in response to high 1,25(OH)2D3 levels, which in part explains the increased release of 1,25(OH)2D3 in granulomatosis disease. Another important issue is aberrant regulation of CYP27B1 in macrophages, which is induced by inflammatory signals such as interleukin-2 and TNF-alpha rather than PTH. Previous case reports have detected CYP27B1 expression in granuloma tissue by immunohistochemistry. However, these findings have to our knowledge never been corroborated by a more comprehensive analysis of enzyme activity and a recent study questioned the etiology because most men with granulomas had normal levels of 1,25(OH)2D3 in serum (ref).

In the present study the investigators want to include a large group of men who injected 100-10.000 ml paraffin oil to identify risk factors for developing hypercalcemia and try to understand the pathogenesis of the disease. Additionally, granuloma tissue from selected patients will be cultured ex vivo to investigate whether they produce 1,25(OH)2D3 or PTHrP and to test which drugs can most effectively be used to lower calcium levels in these men. Subsequently, elucidate whether it is possible to stratify the men according to the severity of the changes in calcium homeostasis as such a stratification may be required prior to and form the basis for future intervention trials

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Denmark
      • Herlev, Denmark
        • Recruiting
        • Herlev Hospital
        • Contact:
          • Ebbe Eldrup
          • Phone Number: +4538683868
        • Contact:
          • Martin Blomberg Jensen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Up to 200 people (predominantly men) <80 years will be included. Inclusion takes place at Endocrinological Section, Medical Department O, Herlev Hospital in connection with an outpatient visit. After initial discussions, reflection time and acceptance of participation in the study, extended blood tests are taken in connection with the pre-planned outpatient visits.

Description

Inclusion Criteria: - previous injection of paraffin oil into the body

-

Exclusion Criteria: - inability to walk

  • inability to understand the consequences of inclusion
  • incurable cancer disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Foreign body granuloma
men injecting paraffin oil
Diagnostic test: Biochemical observational
no intervention - observational

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Hypercalcemia
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
the number of men with elevated ionized calcium (above 1.32 mmol/l)
determined 2-10 years after paraffin oil injection (first visit)
production of 1,25OHD3
Time Frame: ex vivo culture experiments of human granuloma tissue for 48 to 72 hours
production of 1,25OHD3 determined in media from granuloma tissue culture compared with kidney culture by ELISA platform
ex vivo culture experiments of human granuloma tissue for 48 to 72 hours

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
hypercalciuria
Time Frame: determined 2-10 years after paraffin oil injection
calcium excretion determined by spot or 24 hour urine
determined 2-10 years after paraffin oil injection
change in serum 1,25OH2D3
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
differences in calcitriol production or conversion rate 1,25OH2D3/25OHD that reflects how active the enzyme is
determined 2-10 years after paraffin oil injection (first visit)
nephrolithiasis
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
obtained by interview -anamnesis and preferably supported by jorunal of CT report on nephrolithiasis
determined 2-10 years after paraffin oil injection (first visit)
Overall change in calcium homeostasis
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
changes in calcium, PTH, alkaline phosphatase and 1,25OHD depending on oil injected, varm/cold
determined 2-10 years after paraffin oil injection (first visit)
inflammatory response
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
changes in inflammatory markers IL2R, ferritin, ACE
determined 2-10 years after paraffin oil injection (first visit)
Bone formation and resorption
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
Serum levels of alkaline phosphatase, C-terminal telopeptide of type I collagen (CTX-I) and N-terminal propeptide of type I procollagen (PINP)
determined 2-10 years after paraffin oil injection (first visit)
renal function
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
change in GFR, creatinine, Urea
determined 2-10 years after paraffin oil injection (first visit)
calciphylaxis
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
risk determined by Calcium - phosphate product
determined 2-10 years after paraffin oil injection (first visit)
Suppressed PTH
Time Frame: determined 2-10 years after paraffin oil injection (first visit)
PTH lower than lower reference (2)
determined 2-10 years after paraffin oil injection (first visit)
suppression of 1,25OHD3 production
Time Frame: ex vivo culture experiments of human granuloma tissue exposed to treatments for 48 and 72 hours
production of 1,25OHD3 released into the media from granuloma culture suppressed by different treatments in vitro
ex vivo culture experiments of human granuloma tissue exposed to treatments for 48 and 72 hours
production of PTHrP
Time Frame: ex vivo culture experiments of human granuloma tissue for 48 and 72 hours
PTHrP production in granuloma determined by ELISA platform
ex vivo culture experiments of human granuloma tissue for 48 and 72 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Martin Blomberg Jensen

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Herlev Hospital

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Ebbe Eldrup, Herlev

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2019

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2029

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 26, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 27, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 3, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 6, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 2, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • H-19010297

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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