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Novel Precision Medicine Approach to Treatment of Osteoporosis Based on Bone Turnover

Primary Purpose

Age-Related Osteoporosis

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Teriparatide
Alendronate
Sponsored by
Hartmut Malluche, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Age-Related Osteoporosis

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Diagnosed Osteoporosis by DXA (BMD t-score ≤ -2.5 with or without fragility fractures);
  2. Age ≥ 40 years;
  3. Females;
  4. White race;
  5. Normal levels of Vitamin D, and
  6. Absence of all exclusion criteria on clinical workup.

Patients diagnosed as osteoporotic due to the presence of fragility fractures, but without osteoporotic t-scores, will not be included because they would require fractures as a study endpoint which would entail a multi-center approach. Moreover, abnormal bone quality has been shown to be present in these patients, which requires bone histology for assessment.

Exclusion Criteria:

  1. Malignancy within the prior 5 years metastatic to bone or requiring chemotherapy (except non-melanoma skin cancers or cervical carcinoma in situ);
  2. Metabolic bone diseases (including osteomalacia, primary hyperparathyroidism and other hypercalcemic disorders, Osteogenesis Imperfecta, Paget's disease, etc.);
  3. Endocrinopathy (e.g., current hyperthyroidism, untreated hypothyroidism, Cushing's syndrome;
  4. Other medical diseases (e.g., eating disorders, end stage liver, heart or lung disease, intestinal malabsorption, chronic kidney disease stages 2-5D);
  5. Any use of antiresorbers (e.g., alendronate, actonel, denosumab) or use within the last two years of anabolic agents (e.g., teriparatide, abaloparatide);
  6. Use within the prior year of glucocorticoids, hormone replacement therapy, calcitonin, selective estrogen receptor modulators or phenytoin;
  7. Pregnancy, desire to get pregnant, or nursing;
  8. Allergy to tetracycline;
  9. prior external beam or implant radiation therapy;
  10. use of non-aspirin anticoagulants that cannot be safely stopped for the biopsy;
  11. prisoners; and
  12. radius BMD t-score ≤ -3.5.

Sites / Locations

  • University of KentuckyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Group 1 Low Turnover

Group 2 Low Turnover

Group 3 Normal-High Turnover

Arm Description

Teriparatide (anabolic) For 1 Year

Standard of Care - Control: Treated with Alendronate (antiresorber) For 1 Year

Standard of Care Treatment with Alendronate (antiresorber) For 1 Year

Outcomes

Primary Outcome Measures

Mineral Bone Density of the lumbar spine
Percent change in mineral bone density absolute values of the lumbar spine measured by DXA at baseline and at one year.
Measure of serum osteocalcin levels to predict bone turnover
Diagnostic Utility of serum osteocalcin level measurements by ELISA at baseline and at one year to predict bone turnover. Area under the receiver operating characteristic curve analysis will be used to determine the discriminative power of osteocalcin levels for determination of low versus non-low bone turnover.

Secondary Outcome Measures

Full Information

First Posted
November 17, 2021
Last Updated
June 21, 2023
Sponsor
Hartmut Malluche, MD
Collaborators
National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT05151484
Brief Title
Novel Precision Medicine Approach to Treatment of Osteoporosis Based on Bone Turnover
Official Title
Novel Precision Medicine Approach to Treatment of Osteoporosis Based on Bone Turnover
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 21, 2022 (Actual)
Primary Completion Date
August 31, 2026 (Anticipated)
Study Completion Date
August 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Hartmut Malluche, MD
Collaborators
National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Osteoporosis affects 24.5% of women over 65 and results in fracture-related hospital admissions exceeding those of heart attacks, strokes and breast cancer combined. Current treatment options do not account for differences between age-related and estrogen deficiency related osteoporosis, because of the need for bone biopsies for determination. This study will establish a paradigm-shifting individualized treatment protocol for age-related osteoporosis and a non-invasive method for its determination, thereby reducing the major health problems and enormous burden on society and the elderly related to this disease.
Detailed Description
Osteoporosis is a health problem of major proportions. It affects more than 40 million Americans and results in more than 2 million fractures annually among Medicare patients alone. Hospital admissions for osteoporotic fractures exceed those of heart attacks, strokes and breast cancer combined. Osteoporosis is commonly considered a disease associated with menopause. This estrogen deficiency related bone loss is characterized by high bone turnover with increased resorption without commensurate changes in bone formation. It is in contrast to age-related bone loss, which starts as early as in the fourth decade of life and continues with increasing age. Age-related bone loss is usually associated with lower bone turnover and decreased bone formation is the main abnormality. Current therapies do not address age-related bone loss and the special needs of the age-related osteoporosis population is currently ignored. This is to a great degree due to difficulties associated with the bone biopsy necessary for determination of bone turnover status. Thus, the current standard of care relies on starting with an antiresorber, which is less effective in age-related osteoporosis, and in fact impedes the effectiveness in this population of the appropriate anabolic medication. The investigators study seeks to achieve two specific aims: Aim 1) to establish a novel precision medicine approach to treatment of age-related osteoporosis based on recognition of low bone turnover and initial treatment with anabolics, and Aim 2) to find a non-invasive method for diagnosing low bone turnover in osteoporotic patients by measurements of serum carboxylated osteocalcin with validation via the "gold standard" bone biopsy and histomorphometry. The investigators approach will be to enroll female participants who have been diagnosed with osteoporosis in a prospective, proof of concept study. Patients will undergo bone biopsy and blood draws at baseline. Bone turnover status will be assessed employing histomorphometry. In addition, blood levels of carboxylated osteocalcin will be measured in order to determine their validity - alone or in combination with other bone markers - for diagnosing low bone turnover prevailing in age-related bone loss. Participants will be grouped according to turnover status. Low-turnover participants will be randomized (1:1) either to treatment with the anabolic teriparatide (Group 1) or with the standard of care antiresorber alendronate (Group 2) for one year. In order to provide the necessary comparison group for the non-invasive assessment of turnover, normal-high turnover participants (Group 3) will be treated with standard of care alendronate for one year. At baseline and at one-year bone mineral density measurements will be performed by DXA and 1-year changes in BMD will be compared between groups. The investigators central hypothesis is that low turnover, age-related osteoporosis needs to be diagnosed and treated differently from estrogen deficiency related osteoporosis. The results will provide a paradigm shift in the treatment of osteoporosis.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Age-Related Osteoporosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1 Low Turnover
Arm Type
Active Comparator
Arm Description
Teriparatide (anabolic) For 1 Year
Arm Title
Group 2 Low Turnover
Arm Type
Active Comparator
Arm Description
Standard of Care - Control: Treated with Alendronate (antiresorber) For 1 Year
Arm Title
Group 3 Normal-High Turnover
Arm Type
Active Comparator
Arm Description
Standard of Care Treatment with Alendronate (antiresorber) For 1 Year
Intervention Type
Drug
Intervention Name(s)
Teriparatide
Intervention Description
Participants will receive 20 μg teriparatide per day via subcutaneous injections. Participants, and if needed a caregiver, will be trained in the subcutaneous administration of teriparatide according to the manufacturer's guidelines. The investigators will measure serum calcium, BSAP and TRAP-5b levels via blood draws at quarterly monitoring visits. If BSAP or TRAP-5b do not increase compared to baseline or decrease after any quarter, participants will be contacted and correct administration will be reviewed. Serum calcium is measured for safety to avoid hypo- and hypercalcemia. Participants will also be given a daily dose of Vitamin D of 800 IUs to prevent development of Vitamin D deficiency.
Intervention Type
Drug
Intervention Name(s)
Alendronate
Intervention Description
Participants will receive 70 mg alendronate p.o. once per week. Participants will be carefully instructed to follow the manufacturer's recommendations for administration. Compliance will be assessed by measurement of the bone turnover markers BSAP and TRAP-5b from blood drawn at quarterly monitoring visits. These markers have been shown to be useful for assessment of turnover changes with treatment. If these markers do not decrease compared to baseline or rise after any quarter, participants will be contacted and correct administration will be reviewed. Participants will also be given a daily dose of Vitamin D of 800 IUs to prevent development of Vitamin D deficiency.
Primary Outcome Measure Information:
Title
Mineral Bone Density of the lumbar spine
Description
Percent change in mineral bone density absolute values of the lumbar spine measured by DXA at baseline and at one year.
Time Frame
1 Year
Title
Measure of serum osteocalcin levels to predict bone turnover
Description
Diagnostic Utility of serum osteocalcin level measurements by ELISA at baseline and at one year to predict bone turnover. Area under the receiver operating characteristic curve analysis will be used to determine the discriminative power of osteocalcin levels for determination of low versus non-low bone turnover.
Time Frame
1 Year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosed Osteoporosis by DXA (BMD t-score ≤ -2.5 with or without fragility fractures) Treatment naive with respect to with anabolic or antiresorptive bone drugs. Premenopausal, menopausal, and post-menopausal females. 45 years old and older. Presence or absence of diabetes Normal levels of Vitamin D Absence of all exclusion criteria on clinical workup Patients diagnosed as osteoporotic due to the presence of fragility fractures, but without osteoporotic t-scores, will not be included because they would require fractures as a study endpoint which would entail a multi-center approach. Moreover, abnormal bone quality has been shown to be present in these patients, which requires bone histology for assessment. Exclusion Criteria: Pregnant or trying to become pregnant or are breastfeeding. Participation in a study of an investigational drug during the past 30 days. Treatment with anabolic or antiresorptive bone drugs. Use of systemic anticoagulation (blood thinner) Planned or anticipated oral surgery within the next 12 months. Allergy to the antibiotics demeclocycline or tetracycline. Planning to move out of the area within 18 months of the study. Inability to stand or sit upright for at least 30 minutes. Chronic alcoholism and/or drug addiction. Prior radiation therapy (external beam or implant radiation) involving the skeleton (only if randomized to the bone forming drug (anabolic Forteo®)). Systemic illnesses or organ diseases that may affect bone (except type 1 or type 2 Diabetes Mellitus). Clinical condition that may limit study participation (e.g., heart diseases (unstable angina), lung diseases (severe COPD), other infections). Abnormalities of the esophagus (tube connecting the mouth to the stomach) which delay esophageal emptying such as stricture (narrowing) or achalasia (a condition that prevents normal swallowing). Have other bone diseases that are not linked to age or menopause. Have a history of malignancy (cancer), not including non-melanoma skin cancer. Vitamin D (Calcidiol) level below the normal range (below 20ng/mL). AFTER RANDOMIZATION: If randomized to Group 1 Teriparatide and radius BMD t-score is less than -3.5 and does not sign consent to continue in the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hartmut H Malluche, MD
Phone
859-323-2637
Email
hhmall@uky.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Paul F Netzel, DNP
Phone
859-323-2672
Email
pfnetz2@uky.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
hartmut h Mallluche, md
Organizational Affiliation
University of Kentucky
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hartmut H Malluche, MD
Phone
859-323-2637
Email
hhmall@uky.edu

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Novel Precision Medicine Approach to Treatment of Osteoporosis Based on Bone Turnover

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