Osteoporosis, Osteoporosis, Age-Related, Osteoporosis Fracture, Osteoporosis Localized to Spine, Osteoporosis of Vertebrae, Osteoporosis, Postmenopausal, Osteoporosis Risk, Osteoporosis Senile, Osteoporosis Vertebral
Conditions
Keywords
BA058, abaloparatide, TYMLOS®, Bone metabolism, Osteoporosis, Fracture, Bone loss
Brief summary
The objective of this study is to measure the early effects of abaloparatide on tissue-based bone formation using samples obtained by transiliac crest bone biopsy after quadruple fluorochrome labeling.
Detailed description
This was an open-label, single-arm study of postmenopausal women with osteoporosis treated with 80 micrograms (μg) abaloparatide for 3 months. Transiliac bone biopsies were taken at 3 months after quadruple fluorochrome labeling. The treatment duration of 3 months was determined to be the optimal time when biochemical markers of bone turnover peak and are predictive of subsequent changes in bone mineral density (BMD). The main study was conducted for a 3-month treatment period with a 1-month follow up. A sub-study was conducted at 1 site to collect peripheral quantitative computed tomography (pQCT) data. Study treatment for participants in the sub-study was extended for an additional 3 months of study drug administration for a total of 6 months of treatment.
Interventions
DRUGAbaloparatide
Abaloparatide is a novel, synthetic, 34 amino acid peptide designed to be a potent and selective activator of the PTH/PTH-related protein (PTHrP) type 1 receptor (PTHR1) signaling pathway with 41% homology to PTH\[1-34\] and 76% homology to human PTHrP\[1-34\].
Sponsors
Radius Health, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following criteria to be eligible to participate in this study: 1. The participant is a healthy ambulatory postmenopausal female from 50 to 85 years of age (inclusive) with osteoporosis. 2. The participant has been postmenopausal for at least 5 years. Postmenopausal status will be established by a history of amenorrhea for at least 5 years and by an elevated follicle stimulating hormone (FSH) value of ≥30 international units(IU)/liter (L). 3. The participant has a BMD T-score ≤-2.5 at the lumbar spine (L1-L4) or hip (femoral neck or total hip) by dual-energy x-ray absorptiometry (DXA) or lumbar spine or hip BMD T-score ≤-2.0 with a history of low trauma vertebral, forearm, humerus, sacral, pelvic, hip, femoral, or tibial fracture sustained within 5 years prior to enrollment. These fractures must be documented by radiograph or hospital report. 4. The participant is in good general health as determined by medical history and physical examination (including vital signs), has a body mass index (BMI) of 18.5 to 33, inclusive, and is without evidence of clinically significant abnormality in the opinion of the Investigator. 5. The participant has serum calcium (albumin-corrected), parathyroid hormone (PTH) (1-84), phosphorus, and alkaline phosphatase levels all within the normal range during the Screening Period. Any participant with an elevated alkaline phosphatase value, and who meets all other entry criteria, is required to have a normal bone-specific alkaline phosphatase result to be enrolled. 6. The participant has serum 25-hydroxyvitamin D values ≥ 20 nanograms (ng)/milliliter (mL) and within the normal range. Participants with serum 25-hydroxyvitamin D levels \< 20 ng/ml may be treated with vitamin D3 and re-tested once. 7. The participant's resting 12-lead electrocardiogram (ECG) obtained during screening shows no clinically significant abnormality. 8. The participant has read, understood, and signed the written informed consent form.
Exclusion criteria
Participants with any of the following characteristics are not eligible to participate in the study: 1. Presence of abnormalities of the lumbar spine that would prohibit assessment of lumbar spine BMD, defined as having at least 2 radiologically evaluable vertebrae within L1-L4. 2. Unevaluable hip BMD or participants who have undergone bilateral hip replacement (unilateral hip replacement is acceptable). 3. History of bone disorders (for example, Paget's disease) other than postmenopausal osteoporosis. 4. Clinically significant abnormality of serum hemoglobin, hematocrit, white blood cells (WBC) and platelets, coagulation, or usual serum chemistry: electrolytes, renal function, liver function and serum proteins. 5. Unexplained elevation of serum alkaline phosphatase. 6. History of radiotherapy (radiation therapy), other than radioiodine. 7. History of bleeding disorder that would preclude a bone biopsy, in the opinion of the Investigator. 8. History of chronic or recurrent renal, hepatic, pulmonary, allergic, cardiovascular, gastrointestinal, endocrine, central nervous system, hematologic or metabolic diseases, or immunologic, emotional and/or psychiatric disturbances to a degree that would interfere with the interpretation of study data or compromise the safety of the participant. 9. History of Cushing's disease, hyperthyroidism, hypo- or hyperparathyroidism, or malabsorptive syndromes within the past year. 10. History of significantly impaired renal function (serum creatinine \> 177 micromoles \[µmol\]/L or \>2.0 milligrams \[mg\]/deciliter \[dL\]). If the serum creatinine is \>1.5 and ≤ 2.0 mg/dL, the calculated creatinine clearance (Cockcroft-Gault) must be ≥ 30 mL/minute (min). 11. History of any cancer within the past 5 years (other than basal cell or squamous cell cancer of the skin). 12. History of osteosarcoma at any time or a history of hereditary disorders which could predispose the participant to osteosarcoma. 13. History of nephrolithiasis or urolithiasis within the past 5 years. 14. Participant known to be positive for hepatitis B, hepatitis C, or human immunodeficiency virus infection (HIV-1 or HIV-2). Testing is not required in the absence of clinical signs and symptoms suggestive of HIV infection or acute or chronic hepatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mineralizing Surface/Bone Surface (MS/BS) in the Cancellous Envelope at Month 3 | Baseline (Day 1), Month 3 | Change in dynamic histomorphometry indices was assessed in the cancellous envelope. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bone Formation Rate/Bone Surface (BFR/BS) in the Cancellous Envelope at Month 3 | Baseline (Day 1), Month 3 | Change in dynamic histomorphometry indices was assessed in the cancellous envelope. BFR/BS was reported as cubic millimeter/square millimeter/year (mm\^3/mm\^2/year). |
| Change in Serum Procollagen Type I N-terminal Propeptide (s-P1NP) From Baseline at Month 1 and Month 3 | Baseline (Day 1), Months 1 and 3 | Blood samples were taken to measure efficacy related markers of bone metabolism at Day 1, Month 1, and Month 3. |
| Change in Serum Carboxy-Terminal Cross-Linking Telopeptide of Type I Collagen (s-CTX) From Baseline at Month 1 and Month 3 | Baseline (Day 1), Months 1 and 3 | Blood samples were taken to measure efficacy-related markers of bone metabolism at Day 1, Month 1, and Month 3. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abaloparatide Participants self-administered a single daily dose of 80 µg of abaloparatide SC during the treatment period. Participants were instructed to use a new injection pen after each 30-day period. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Protocol Deviation | 1 |
Baseline characteristics
| Characteristic | Abaloparatide |
|---|---|
| Age, Continuous | 67.4 years STANDARD_DEVIATION 8.59 |
| Body Mass Index (BMI) | 23.92 kilogram (kg)/square meter (m^2) STANDARD_DEVIATION 3.629 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Lumbar Spine Bone Mineral Density (BMD) T-Scores Femoral Neck BMD T-Score | -2.530 T-Score STANDARD_DEVIATION 0.5708 |
| Lumbar Spine Bone Mineral Density (BMD) T-Scores Lumbar Spine BMD T-Score | -2.232 T-Score STANDARD_DEVIATION 1.3098 |
| Lumbar Spine Bone Mineral Density (BMD) T-Scores Total Hip BMD T-Score | -2.392 T-Score STANDARD_DEVIATION 0.6363 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized White | 22 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 23 |
| other Total, other adverse events | 18 / 23 |
| serious Total, serious adverse events | 2 / 23 |
Outcome results
Primary
Change From Baseline in Mineralizing Surface/Bone Surface (MS/BS) in the Cancellous Envelope at Month 3
Change in dynamic histomorphometry indices was assessed in the cancellous envelope.
Time frame: Baseline (Day 1), Month 3
Population: The Bone-Biopsy Population included all participants who received an evaluable biopsy (defined as a biopsy sample that can be analyzed in the laboratory). Here, 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abaloparatide | Change From Baseline in Mineralizing Surface/Bone Surface (MS/BS) in the Cancellous Envelope at Month 3 | Baseline | 5.74 percentage of MS/BS | Standard Deviation 3.978 |
| Abaloparatide | Change From Baseline in Mineralizing Surface/Bone Surface (MS/BS) in the Cancellous Envelope at Month 3 | Change at Month 3 | 18.66 percentage of MS/BS | Standard Deviation 12.114 |
p-value: <0.0001Paired t-test, 2 sided
Secondary
Change From Baseline in Bone Formation Rate/Bone Surface (BFR/BS) in the Cancellous Envelope at Month 3
Change in dynamic histomorphometry indices was assessed in the cancellous envelope. BFR/BS was reported as cubic millimeter/square millimeter/year (mm\^3/mm\^2/year).
Time frame: Baseline (Day 1), Month 3
Population: The Bone-Biopsy Population included all participants who received an evaluable biopsy (defined as a biopsy sample that can be analyzed in the laboratory). Here, 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abaloparatide | Change From Baseline in Bone Formation Rate/Bone Surface (BFR/BS) in the Cancellous Envelope at Month 3 | Baseline | 0.011 mm^3/mm^2/year | Standard Deviation 0.0076 |
| Abaloparatide | Change From Baseline in Bone Formation Rate/Bone Surface (BFR/BS) in the Cancellous Envelope at Month 3 | Change at Month 3 | 0.034 mm^3/mm^2/year | Standard Deviation 0.0245 |
Secondary
Change in Serum Carboxy-Terminal Cross-Linking Telopeptide of Type I Collagen (s-CTX) From Baseline at Month 1 and Month 3
Blood samples were taken to measure efficacy-related markers of bone metabolism at Day 1, Month 1, and Month 3.
Time frame: Baseline (Day 1), Months 1 and 3
Population: The Bone-Biopsy Population included all enrolled participants who received an evaluable biopsy (defined as a biopsy sample that can be analyzed in the laboratory). Here, 'Number Analyzed' signifies participants evaluable for the specified categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Abaloparatide | Change in Serum Carboxy-Terminal Cross-Linking Telopeptide of Type I Collagen (s-CTX) From Baseline at Month 1 and Month 3 | Change at Month 1 | 0.052 ng/mL |
| Abaloparatide | Change in Serum Carboxy-Terminal Cross-Linking Telopeptide of Type I Collagen (s-CTX) From Baseline at Month 1 and Month 3 | Change at Month 3 | 0.311 ng/mL |
| Abaloparatide | Change in Serum Carboxy-Terminal Cross-Linking Telopeptide of Type I Collagen (s-CTX) From Baseline at Month 1 and Month 3 | Baseline | 0.460 ng/mL |
Secondary
Change in Serum Procollagen Type I N-terminal Propeptide (s-P1NP) From Baseline at Month 1 and Month 3
Blood samples were taken to measure efficacy related markers of bone metabolism at Day 1, Month 1, and Month 3.
Time frame: Baseline (Day 1), Months 1 and 3
Population: The Bone-Biopsy Population included all enrolled participants who received an evaluable biopsy (defined as a biopsy sample that can be analyzed in the laboratory). Here, 'Number Analyzed' signifies participants evaluable for the specified categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Abaloparatide | Change in Serum Procollagen Type I N-terminal Propeptide (s-P1NP) From Baseline at Month 1 and Month 3 | Baseline | 54.990 nanograms (ng)/milliliter (mL) |
| Abaloparatide | Change in Serum Procollagen Type I N-terminal Propeptide (s-P1NP) From Baseline at Month 1 and Month 3 | Change at Month 1 | 119.155 nanograms (ng)/milliliter (mL) |
| Abaloparatide | Change in Serum Procollagen Type I N-terminal Propeptide (s-P1NP) From Baseline at Month 1 and Month 3 | Change at Month 3 | 141.130 nanograms (ng)/milliliter (mL) |