Atypical Femoral Fracture, Osteoporosis
Conditions
Keywords
osteoporosis, atypical femoral fractures, prior bisphosphonate treatment, postmenopausal women, bone loss
Brief summary
This open label comparison study examines the hypothesis that teriparatide given immediately following repair of an atypical subtrochanteric or diaphyseal femoral shaft fracture will enhance healing and improve bone mineral density compared to delayed treatment (after six months) with teriparatide or no treatment with teriparatide (patients who refuse therapy or for whom teriparatide is contraindicated). Patients with up-front teriparatide in addition will have greater quality of life measures and less pain compared to those with delayed or no therapy.
Detailed description
Up to 24 postmenopausal women with osteoporosis who have been on bisphosphonate therapy for one year or more at any point prior to fracture and have sustained an atypical subtrochanteric or diaphyseal fracture will be enrolled. Subjects randomized to the two intervention arms will self-administer a daily SQ injection of the study medication for 12 months. The primary objective is to demonstrate greater radiologic evidence of healing at 10 weeks in patients on immediate teriparatide compared to those on delayed teriparatide who receive therapy six months after fracture. Secondary end points include (1) radiologic healing at 2, 6, 24, and 46 weeks; (2) increased bone density at 6 and 12 months as assessed by dual x-ray absorptiometry (DXA) at the spine, contralateral hip, and femoral neck; (3) quality of life improvements at 10 weeks and 6 months as assessed by quality of life questionnaire and pain score; and (4) differences in biochemical markers of bone turnover in patient with upfront therapy compared to patients with delayed therapy and patients who refuse therapy or for whom teriparatide is contraindicated.
Interventions
DRUGteriparatide
20 microgram once-daily subcutaneous injection
Sponsors
University of Pittsburgh
Eli Lilly and Company
Susan L. Greenspan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
* postmenopausal women * with osteoporosis who have been on bisphosphonate therapy for one year or more (all bisphosphonates will be included such as alendronate, risdedronate, ibandronate, or zoledronic acid). * Patients will also be included if they are on glucocorticoids or other medications known to affect bone mineral metabolism as these are often found in patients with these types of fractures. * sustain an atypical subtrochanteric or diaphyseal femoral shaft fracture as defined by the the 2010 ASBMR task force. An atypical fracture must include all of the following: (1) a location in the femur distal to lesser trochanter; (2) no trauma or minimal trauma as a fall; (3) transverse or short oblique configuration; (4) noncomminuted; and (5) complete fracture extends through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex. Patients who have an incomplete fracture can be included if they fall into the 2010 ASBMR task force definition.
Exclusion criteria
* men * children * those who have had radiation therapy * Paget's disease * treatment with teriparatide for two year in the past * metastatic bone disease * active cancer * hypercalcemia * hyperparathyroidism * metabolic disease other than osteoporosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiologic Evidence of Bone Healing | 6, 12 months of treatment | The radiologic indices of fracture healing included (1) cortical continuity on two of four cortices, (2) persistence of alignment, (3) decreased conspicuity of fracture line, and (4) increased callus formation. For each of these indices, healing was graded on a scale of 1 to 4 with 1 = no change (less than 25%), 2 = minimum healing (25-50%), 3 = moderate healing (50-75%), and 4 = complete healing (greater than 75%). A composite score was calculated by summing the subscale scores for the 4 indices. Composite score scale ranged from 4 to 16 with higher scores indicating more complete healing. The primary grading was performed by a radiologist with expertise in musculoskeletal radiology, then independently repeated by a second radiologist, both of whom were blinded to the study allocation. |
| Radiologic Evidence of Healing | at 10 weeks for immediate teriparatide group | Number of participants with persistence of alignment as determined by a radiologist. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Increased Bone Density | at 6 and 12 months | Percent change in Bone Mineral Density (BMD) as assessed by dual x-ray absorptiometry (DXA) at the spine, contralateral hip, distal 1/3 radius, and femoral neck |
| Radiologic Healing | at 2, 6, 24, and 48 weeks | — |
| Quality of Life Improvements | at 12 months | Assessed by quality of life questionnaire (SF-36). There are 8 subscales each ranging from 0-100 with higher scores indicating better quality of life. |
| Difference in Biochemical Markers of Bone Turnover | intervals over 12-18 months depending on treatment group | upfront therapy group compared to delayed therapy group and no therapy group |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Teriparatide Open label teriparatide given immediately following surgical repair of fracture
teriparatide: 20 microgram once-daily subcutaneous injection | 7 |
| Delayed Teriparatide Open label teriparatide given six months following surgical repair of fracture
teriparatide: 20 microgram once-daily subcutaneous injection | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Delayed Teriparatide | Total | Immediate Teriparatide |
|---|---|---|---|
| Age, Continuous | 69.8 years STANDARD_DEVIATION 8.085 | 74.2 years STANDARD_DEVIATION 9.094 | 78.0 years STANDARD_DEVIATION 8.66 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 11 Participants | 7 Participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 5 / 7 | 5 / 6 |
| serious Total, serious adverse events | 3 / 7 | 2 / 6 |
Outcome results
Primary
Radiologic Evidence of Bone Healing
The radiologic indices of fracture healing included (1) cortical continuity on two of four cortices, (2) persistence of alignment, (3) decreased conspicuity of fracture line, and (4) increased callus formation. For each of these indices, healing was graded on a scale of 1 to 4 with 1 = no change (less than 25%), 2 = minimum healing (25-50%), 3 = moderate healing (50-75%), and 4 = complete healing (greater than 75%). A composite score was calculated by summing the subscale scores for the 4 indices. Composite score scale ranged from 4 to 16 with higher scores indicating more complete healing. The primary grading was performed by a radiologist with expertise in musculoskeletal radiology, then independently repeated by a second radiologist, both of whom were blinded to the study allocation.
Time frame: 6, 12 months of treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Teriparatide | Radiologic Evidence of Bone Healing | 6 mo | 12.6 units on a scale | Standard Error 0.6 |
| Immediate Teriparatide | Radiologic Evidence of Bone Healing | 12 mo | 15.4 units on a scale | Standard Error 0.4 |
| Delayed Teriparatide | Radiologic Evidence of Bone Healing | 6 mo | 11.2 units on a scale | Standard Error 1.3 |
| Delayed Teriparatide | Radiologic Evidence of Bone Healing | 12 mo | 13.2 units on a scale | Standard Error 1.2 |
Primary
Radiologic Evidence of Healing
Number of participants with persistence of alignment as determined by a radiologist.
Time frame: at 10 weeks for immediate teriparatide group
Population: Based on orthopedic surgeons' assessment, x-rays were not deemed necessary in over 30% of patients at week 10. Results presented are for those who had x-rays at 10 weeks to assess persistence of alignment for safety purposes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Immediate Teriparatide | Radiologic Evidence of Healing | 5 Participants |
| Delayed Teriparatide | Radiologic Evidence of Healing | 4 Participants |
Secondary
Difference in Biochemical Markers of Bone Turnover
upfront therapy group compared to delayed therapy group and no therapy group
Time frame: intervals over 12-18 months depending on treatment group
Population: Funding unavailable for sample analysis.
Secondary
Increased Bone Density
Percent change in Bone Mineral Density (BMD) as assessed by dual x-ray absorptiometry (DXA) at the spine, contralateral hip, distal 1/3 radius, and femoral neck
Time frame: at 6 and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Teriparatide | Increased Bone Density | Femoral Neck (6 months) | -1.8 percentage change in BMD | Standard Error 2.1 |
| Immediate Teriparatide | Increased Bone Density | Total Hip (6 months) | -1.6 percentage change in BMD | Standard Error 1.5 |
| Immediate Teriparatide | Increased Bone Density | Femoral Neck (12 months) | -2.5 percentage change in BMD | Standard Error 3 |
| Immediate Teriparatide | Increased Bone Density | Spine-PA (6 months) | 2.1 percentage change in BMD | Standard Error 1.5 |
| Immediate Teriparatide | Increased Bone Density | Distal 1/3 Radius (6 months) | -0.6 percentage change in BMD | Standard Error 1.9 |
| Immediate Teriparatide | Increased Bone Density | Total Hip (12 months) | -0.3 percentage change in BMD | Standard Error 1.8 |
| Immediate Teriparatide | Increased Bone Density | Distal 1/3 Radius (12 months) | -1.9 percentage change in BMD | Standard Error 1.7 |
| Immediate Teriparatide | Increased Bone Density | Spine-PA (12 months) | 2.8 percentage change in BMD | Standard Error 2 |
| Delayed Teriparatide | Increased Bone Density | Distal 1/3 Radius (12 months) | -6.1 percentage change in BMD | Standard Error 2.1 |
| Delayed Teriparatide | Increased Bone Density | Spine-PA (6 months) | -0.6 percentage change in BMD | Standard Error 1.3 |
| Delayed Teriparatide | Increased Bone Density | Total Hip (6 months) | -0.8 percentage change in BMD | Standard Error 0.7 |
| Delayed Teriparatide | Increased Bone Density | Total Hip (12 months) | 1.5 percentage change in BMD | Standard Error 2.7 |
| Delayed Teriparatide | Increased Bone Density | Femoral Neck (6 months) | -2.7 percentage change in BMD | Standard Error 1 |
| Delayed Teriparatide | Increased Bone Density | Femoral Neck (12 months) | -1.9 percentage change in BMD | Standard Error 3.6 |
| Delayed Teriparatide | Increased Bone Density | Distal 1/3 Radius (6 months) | -0.7 percentage change in BMD | Standard Error 1.1 |
| Delayed Teriparatide | Increased Bone Density | Spine-PA (12 months) | 5.4 percentage change in BMD | Standard Error 2.8 |
Secondary
Quality of Life Improvements
Assessed by quality of life questionnaire (SF-36). There are 8 subscales each ranging from 0-100 with higher scores indicating better quality of life.
Time frame: at 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Teriparatide | Quality of Life Improvements | Physical functioning | 49.3 units on a scale | Standard Error 6.5 |
| Immediate Teriparatide | Quality of Life Improvements | Physical health limitations | 48.2 units on a scale | Standard Error 9.1 |
| Immediate Teriparatide | Quality of Life Improvements | Emotional health limitations | 75.0 units on a scale | Standard Error 9.1 |
| Immediate Teriparatide | Quality of Life Improvements | Energy/Fatigue | 54.5 units on a scale | Standard Error 7.4 |
| Immediate Teriparatide | Quality of Life Improvements | Emotional well-being | 80.7 units on a scale | Standard Error 4.1 |
| Immediate Teriparatide | Quality of Life Improvements | Social functioning | 92.9 units on a scale | Standard Error 4.6 |
| Immediate Teriparatide | Quality of Life Improvements | Pain | 72.9 units on a scale | Standard Error 9.7 |
| Immediate Teriparatide | Quality of Life Improvements | General health | 66.1 units on a scale | Standard Error 6.2 |
| Delayed Teriparatide | Quality of Life Improvements | General health | 67.2 units on a scale | Standard Error 12.1 |
| Delayed Teriparatide | Quality of Life Improvements | Physical functioning | 65.0 units on a scale | Standard Error 20.3 |
| Delayed Teriparatide | Quality of Life Improvements | Emotional well-being | 70.0 units on a scale | Standard Error 9.1 |
| Delayed Teriparatide | Quality of Life Improvements | Physical health limitations | 68.8 units on a scale | Standard Error 21.2 |
| Delayed Teriparatide | Quality of Life Improvements | Pain | 59.4 units on a scale | Standard Error 21.2 |
| Delayed Teriparatide | Quality of Life Improvements | Emotional health limitations | 72.9 units on a scale | Standard Error 19.7 |
| Delayed Teriparatide | Quality of Life Improvements | Social functioning | 65.6 units on a scale | Standard Error 23.6 |
| Delayed Teriparatide | Quality of Life Improvements | Energy/Fatigue | 59.4 units on a scale | Standard Error 15 |
Secondary
Radiologic Healing
Time frame: at 2, 6, 24, and 48 weeks
Population: Data not collected at 2 and 6 weeks. Twenty-Four week (6 months) data is presented in 6 month outcomes, and 48 week (12 months) data as 12 month outcomes (See primary outcomes section above).