Erosive Osteoarthritis
Conditions
Brief summary
It is hypothesized that effervescent alendronate will be able to maintain bone turnover markers within the pre-menopausal reference range and thereby reducing the likelihood of bone turnover associated changes (rebound effect), after discontinuation of denosumab treatment in a non-osteoporotic population.
Detailed description
Denosumab discontinuation is associated with a rebound effect in bone turnover and loss in bone mass density. These changes resulted in an increase of fracture incidence in patients with postmenopausal osteoporosis back to background levels. However, no excess in fracture incidence was observed. Amongst patients who presented with vertebral fractures after treatment discontinuation, there was a slightly higher incidence of multiple vertebral fractures in patients discontinuing Prolia versus those who discontinued the placebo treatment. A 2 year, randomized, crossover study demonstrated that alendronate intake after discontinuing denosumab treatment, lead to remaining stable bone mass densitometry (BMD) values in postmenopausal women. In a study within a non-osteoporotic study population, ongoing at our department, increases in bone turnover are to be expected as soon as patients end study participation (i.e. open label treatment with denosumab, Prolia, anti-RANK ligand inhibition). It is currently recommended that alternative anti-resorptive therapy may be warranted after Prolia discontinuation. One study describes the use of oral alendronate after denosumab therapy to maintain bone mineral density. However, gastro-intestinal upset and tolerability, as well as difficulty in swallowing pills may limit oral alendronate compliance. To attenuate this concern, buffered soluble (effervescent) alendronate 70 mg, developed with the aim to improve the gastrointestinal tolerability through full dissolution of alendronate in buffered palatable solution before ingestion, will be used. This study wants to provide a follow up and study wether the use of effervescent alendronate after previous denosumab treatment can prevent a rebound effect in bone turnover that is to be expected when denosumab is discontinued. Subjects that completed our erosive hand osteoarthritis (OA) study and therefore discontinued denosumab 60 mg/every 3 months, will receive alendronate. Moreover, the study wants to asses if there is difference between using alendronate for six or twelve months, starting at the earliest three months but no later than four months after the last injection of denosumab.
Interventions
DRUGAlendronate Effervescent Oral Tablet
At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for either 24 or 48 weeks
Sponsors
Amgen
EffRx Pharmaceuticals SA
University Hospital, Ghent
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
40 subjects randomized in 2 groups (n=20). 1 group will receive effervescent alendronate treatment for 24 weeks, the other group will receive the same treatment for 48 weeks.
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have completed the 48 weeks of the randomised placebo-controlled study phase followed by the 96 weeks open label denosumab 60 mg SC every 3 months phase. (EudraCT number: 2015-003223-53) * Last denosumab injection minimal 3 months or maximum 4 months before baseline * Able and willing to give written informed consent and to comply with the requirements of the study protocol
Exclusion criteria
* Patients with clinically significant hypersensitivity to any of the components of effervescent alendronate. * Patient who is pregnant or planning pregnancy * Female subjects who are breast-feeding. * History of osteonecrosis of the jaw, and/or recent (within 3 months) tooth extraction or other unhealed dental surgery; or planned invasive dental work during the study * Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures * Hypocalcaemia. * Oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within the previous year) of major gastro-intestinal disease such as peptic ulcer, or active gastro-intestinal bleeding, or surgery of the upper gastro-intestinal tract other than pyloroplasty. * Abnormalities of the oesophagus and other factors which delay oesophageal emptying such as stricture or achalasia. * Inability to stand or sit upright for at least 30 minutes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels | 48 weeks | Difference in bone turnover marker C-terminal telopeptide of type I collagen (CTX-I) after 48 weeks. Comparisons made within and between both treatment arms |
| PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels | 48 weeks | Difference in Bone Turnover Marker N-terminal propeptide of type I procollagen (PINP) After 48 Weeks. Comparisons are made both within and between both treatment arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With CTX-I (C-terminal Telopeptide of Type I Collagen )Levels Above the Reference Range at Week 48 | 48 weeks | The number of patients that do not maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the bone turnover marker reference range at week 48. |
| The Number of Patients PINP (N-terminal Propeptide of Type I Procollagen) Above Reference Range at Week 48 | 48 weeks | The number of patients that do not maintain N-terminal propeptide of type I procollagen (PINP) levels within the bone turnover marker reference range at week 48 |
| Bone Mass Density at the Spine After 48 Weeks | 48 weeks | Difference in bone mass density at the spine after 48 Weeks. Comparisons are made both within and between both treatment arms |
| Bone Mass Density at the Hip After 48 Weeks | 48 weeks | Difference in Bone Mass Density at the hip After 48 Weeks. Comparisons are made both within and between both treatment arms. |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Alendronate 70 mg Weekly for 24 Weeks Subject receiving alendronate treatment for 24 weeks (n = 15)
Alendronate Effervescent Oral Tablet: At the earliest three months but no later than four months after the last denosumab injection, subjects were randomized to effervescent alendronate administered for 24 weeks | 15 |
| Treatment Alendronate 70 mg Weekly for 48 Weeks Subject receiving alendronate treatment for 48 weeks (n = 15)
Alendronate Effervescent Oral Tablet: At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for 48 weeks | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment Alendronate 70 mg Weekly for 24 Weeks | Total | Treatment Alendronate 70 mg Weekly for 48 Weeks |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 7.7 | 64.0 years STANDARD_DEVIATION 8.2 | 64.7 years STANDARD_DEVIATION 8.9 |
| Bone mineral density hip | 0.85 g/cm2 STANDARD_DEVIATION 0.1 | 0.83 g/cm2 STANDARD_DEVIATION 0.11 | 0.80 g/cm2 STANDARD_DEVIATION 0.08 |
| Bone mineral density spine | 1.16 g/cm2 STANDARD_DEVIATION 0.11 | 1.14 g/cm2 STANDARD_DEVIATION 0.13 | 1.11 g/cm2 STANDARD_DEVIATION 0.16 |
| C-terminal telopeptide of type I collagen (CTX-I) | 0.057 ng/ml STANDARD_DEVIATION 0.03 | 0.064 ng/ml STANDARD_DEVIATION 0.05 | 0.071 ng/ml STANDARD_DEVIATION 0.06 |
| mean time since last denosumab injection (days) | 89 days STANDARD_DEVIATION 7 | 91 days STANDARD_DEVIATION 8 | 94 days STANDARD_DEVIATION 8 |
| mean treatment duration with denosumab (days) | 813 days STANDARD_DEVIATION 165 | 782 days STANDARD_DEVIATION 170 | 751 days STANDARD_DEVIATION 174 |
| N-terminal propeptide of type I procollagen (PINP) | 10.15 microgram/L STANDARD_DEVIATION 5.5 | 9.56 microgram/L STANDARD_DEVIATION 8.3 | 8.97 microgram/L STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 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 | 15 Participants | 30 Participants | 15 Participants |
| Sex: Female, Male Female | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 10 / 15 | 12 / 15 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 |
Outcome results
Primary
CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels
Difference in bone turnover marker C-terminal telopeptide of type I collagen (CTX-I) after 48 weeks. Comparisons made within and between both treatment arms
Time frame: 48 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 24 Weeks | CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels | Baseline | 0.05 ng/ml | Standard Error 0.06 |
| 24 Weeks | CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels | Week 48 | 0.63 ng/ml | Standard Error 0.33 |
| 48 Weeks | CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels | Baseline | 0.06 ng/ml | Standard Error 0.06 |
| 48 Weeks | CTX-I (C-terminal Telopeptide of Type I Collagen ) Bone Turnover Marker Levels | Week 48 | 0.33 ng/ml | Standard Error 0.33 |
Comparison: linear mixed models were used to compare bone turnover markers (CTX-I) between both treatment groups. These models were performed with an intention to treat approach, where drop-outs were considered as non-responders. The models accounted for repeated measures.p-value: <0.01Mixed Models Analysis
Primary
PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels
Difference in Bone Turnover Marker N-terminal propeptide of type I procollagen (PINP) After 48 Weeks. Comparisons are made both within and between both treatment arms.
Time frame: 48 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 24 Weeks | PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels | Baseline | 8.1 microgram/L | Standard Error 0.41 |
| 24 Weeks | PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels | Week 48 | 78.9 microgram/L | Standard Error 0.44 |
| 48 Weeks | PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels | Baseline | 4.6 microgram/L | Standard Error 0.41 |
| 48 Weeks | PINP (N-terminal Propeptide of Type I Procollagen) Bone Turnover Marker Levels | Week 48 | 39.5 microgram/L | Standard Error 0.44 |
Comparison: linear mixed models were used to compare bone turnover markers (PINP) between both treatment groups. These models were performed with an intention to treat approach, where drop-outs were considered as non-responders. The models accounted for repeated measures.p-value: 0.05Mixed Models Analysis
Secondary
Bone Mass Density at the Hip After 48 Weeks
Difference in Bone Mass Density at the hip After 48 Weeks. Comparisons are made both within and between both treatment arms.
Time frame: 48 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 24 Weeks | Bone Mass Density at the Hip After 48 Weeks | Baseline | 0.85 g/cm2 | Standard Error 0.03 |
| 24 Weeks | Bone Mass Density at the Hip After 48 Weeks | Week 48 | 0.85 g/cm2 | Standard Error 0.03 |
| 48 Weeks | Bone Mass Density at the Hip After 48 Weeks | Baseline | 0.80 g/cm2 | Standard Error 0.03 |
| 48 Weeks | Bone Mass Density at the Hip After 48 Weeks | Week 48 | 0.81 g/cm2 | Standard Error 0.03 |
Secondary
Bone Mass Density at the Spine After 48 Weeks
Difference in bone mass density at the spine after 48 Weeks. Comparisons are made both within and between both treatment arms
Time frame: 48 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 24 Weeks | Bone Mass Density at the Spine After 48 Weeks | Baseline | 1.16 g/cm2 | Standard Error 0.03 |
| 24 Weeks | Bone Mass Density at the Spine After 48 Weeks | Week 48 | 1.10 g/cm2 | Standard Error 0.03 |
| 48 Weeks | Bone Mass Density at the Spine After 48 Weeks | Baseline | 1.11 g/cm2 | Standard Error 0.03 |
| 48 Weeks | Bone Mass Density at the Spine After 48 Weeks | Week 48 | 1.11 g/cm2 | Standard Error 0.03 |
Secondary
Number of Patients With CTX-I (C-terminal Telopeptide of Type I Collagen )Levels Above the Reference Range at Week 48
The number of patients that do not maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the bone turnover marker reference range at week 48.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 24 Weeks | Number of Patients With CTX-I (C-terminal Telopeptide of Type I Collagen )Levels Above the Reference Range at Week 48 | 5 Participants |
| 48 Weeks | Number of Patients With CTX-I (C-terminal Telopeptide of Type I Collagen )Levels Above the Reference Range at Week 48 | 0 Participants |
Comparison: A Fisher's exact test was used to assess differences in patient numbers exceeding reference ranges between both treatment groups at week 48p-value: 0.042Fisher Exact
Secondary
The Number of Patients PINP (N-terminal Propeptide of Type I Procollagen) Above Reference Range at Week 48
The number of patients that do not maintain N-terminal propeptide of type I procollagen (PINP) levels within the bone turnover marker reference range at week 48
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 24 Weeks | The Number of Patients PINP (N-terminal Propeptide of Type I Procollagen) Above Reference Range at Week 48 | 5 Participants |
| 48 Weeks | The Number of Patients PINP (N-terminal Propeptide of Type I Procollagen) Above Reference Range at Week 48 | 0 Participants |
Comparison: A Fisher's exact test was used to assess differences in patient numbers exceeding reference ranges between both treatment groups.p-value: 0.042Fisher Exact