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  string(1597) "Background. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is a new treatment for type 2 diabetes mellitus (T2DM). In the approval process, the FDA Advisory Committee reviewed data suggesting that canagliflozin increased the incidence of bone fractures. It is not known if these treatment-emergent fractures were more frequent in certain populations (e.g., post-menopausal women). Objective. To identify predictors of fractures to determine whether 1) bone-related baseline variables correlate with fracture rate and 2) changes in bone-specific variables can predict treatment-emergent fractures. Participants. Subjects from in 9 clinical trials who have sustained fractures as compared to matched controls. Study Design. Retrospective analysis of risk factors and fracture data from multiple clinical trials focusing on fractures after 1 year of therapy. Main Outcome Measures(s). The primary outcome variables are time to first fracture and time to first low trauma fracture. Statistical Analysis. We will use Cox regression to compare the fracture risk among treatment groups and to evaluate the effect of baseline and on-treatment risk factors on fracture risk. Caveats. Statistical power may be limited due to the small sample size. Ultimately, our goal is to gain information that may assist clinicians to risk-stratify patients who may be most vulnerable to developing drug-induced bone fractures. With continued studies, we may be able to suggest therapeutic approaches to minimize the fracture risk (e.g. vitamin D repletion if vitamin D deficiency is a risk factor)."
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  string(3215) "SGLT-2 inhibitors improve glycemia, induce modest weight loss and lower blood pressure, but may increase the risk of bone fractures. This is particularly relevant for individuals with diabetes since fracture risk is increased in those with T2DM, especially older individuals (e.g., postmenopausal women). Younger persons with T2DM may also be at higher risk due to the long duration  of exposure. Furthermore, we have learned important lessons from the ADOPT trial which demonstrated that thiazolidinediones (TZDs) increase the risk of bone fractures (1). After a 1- year lag for women and 3 years for men, rosiglitazone-treated patients experienced an increase in bone fractures (2, 3). This knowledge helps prescribers monitor and risk stratify appropriate patients for TZD use. Identifying modifiable risk factors (e.g., low vitamin D) may help us propose interventions that mitigate this risk, guide optimal patient selection, and contribute to improved safety of this class of medications.
Background. At the FDA advisory committee meeting on dapagliflozin in July 2011, a disproportionate, dose-dependent fracture rate was noted after 104 weeks in diabetes patients with moderate renal impairment: 9.4% fractures (10 mg dose), 6% (5 mg dose), and no fractures on placebo (4). In patients with normal renal function, there was a 2-fold increase.
At the FDA advisory committee meeting on canagliflozin in January 2013, pooled data from 8 clinical trials (68-weeks) showed a ~30% increase in bone fractures in canagliflozin-treated patients (5). This increase was observed only after 1 year on therapy (6).
Both, fracture location and trauma classification demonstrated an imbalance in upper limb fractures (not favoring canagliflozin), which persisted in low trauma upper limb fractures and spine fractures. In a pooled analysis of all treatment arms, females on canagliflozin had a higher incidence of upper limb fractures (1.2% [31/2608]) compared to placebo (0.4% [5/1338]) (7). The location of distal extremity fractures resembled fracture sites found in other diseases, e.g., primary hyperparathyroidism (8). Subsequently, the FDA required one of five post-marketing studies on canagliflozin to include a study on bone fracture risk (9).
The following observations support potential pathophysiological mechanisms: In a pooled analysis of studies conducted for 26 weeks (n=2,313), serum phosphate increased by 5.1% at the highest dose of canagliflozin (300 mg) compared to placebo (6). In patients with renal impairment (treatment duration 26 weeks), serum phosphate also increased (+7.8%) and 1,25-hydroxyvitamin D decreased (-8.1%) from baseline (10). The most acute changes in serum phosphate occurred within a few weeks of study initiation, suggesting feedback mechanisms maintaining homeostasis (e.g. possible increases in parathyroid hormone which is known to induce phosphaturia). In fact, a small increase in mean PTH (+7.9%) had been observed with canagliflozin (6). If the data were to follow a normal distribution, then ~15% of canagliflozin-treated patients would experience a >47% increase in PTH (mean + 1 SD), a change that could be clinically significant (11)." ["project_specific_aims"]=> string(1313) "Specific Aim #1. To evaluate baseline predictors of fracture risk.
Our goal is to investigate if baseline characteristics can predict fracture risk on canagliflozin. Certain factors are known to be related to bone health, including hormonal status (menopause, hypogonadism ), age, Vitamin D deficiency, low bone mineral density, previous fractures, etc. We expect that individulas with more risk factors at baseline will have a higher fracture rate on canagliflozin than comparable individuals who were not treated with canagliflozin.
Specific Aim #2. To investigate if any treatment-emergent changes before or after 1 year can predict fracture rate.
It is plausible that treatment induced changes over time could predict an increased fracture risk. The KM curve in Figure 1 demonstrates an increase in treatment emergent fractures occurred after 1 year. It begs the question: what treatment-emergent bone-specific factors could predict fracture risk after 1 year of therapy? Even small reductions in 1,25-dihydroxyvitamin D or increases in PTH can have detrimental long-term changes in bone metabolism (12, 13). Furthermore, persistent reductions in blood pressure or weight loss may also predict fracture rates. Therefore, we hope to analyze the patient level data before and after 1 year." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(1226) "Retrospective analysis of fracture risk in canagliflozin treated patients will be assessed by evaluating individual participant level data from the following studies: NCT01137812, NCT01106690, NCT01106651, NCT00968812, NCT01106677, NCT01081834, NCT01064414, NCT01106625, NCT00642278. In addition, we are asking (via a separate data request) for any additional information from NCT01032629, which is currently in progress. If we were able to have access to un-blinded individual participant level data that has already been made available to the FDA and presented at the FDA advisory committee, we could further identify which patients may be at the highest risk for fractures after 1-2 years of therapy, given this study is the longest study available for canagliflozin.
Inclusion criteria:
1. Men and women, any age, race, baseline BMI
2. Type 2 Diabetes diagnosis, any HbA1c
3. Fracture, any location
4. Treatment group (canagliflozin, any dose) or placebo group
Exclusion criteria:
1. Unavailable demographic information regarding sex, age
2. Unavailable information on fracture (trauma level, location)
3. Unavailable information on treatment or placebo group" ["project_main_outcome_measure"]=> string(594) "The primary outcome measures are time from randomization to first fracture and time from randomization to first low trauma fracture. Fracture is defined as an event that has been diagnosed and reported previously, including prospectively adjudicated fractures presented at the FDA advisory committee by data cutoff July 1st 2012 plus any additional data available from the participant level data. Low trauma fracture is defined as a fracture resulting from falls from standing height or less; falls on stairs, steps, or curbs; moderate trauma other than falls; minimal trauma other than falls." ["project_main_predictor_indep"]=> string(813) "The predictor variables for this study will dependent on the availability of baseline data to predict fracture risk. Age, sex, race, and baseline BMI, will be included in all analyses. The following will be included if available:
1. PTH
2. 1, 25 dihydroxyvitamin D and 25-OH vitamin D
3. Bone biomarkers (e.g. C-telopeptide, P1NP, osteocalcin, N-Telopeptide)
4. Alkaline phosphatase (bone specific, if available)
5. Serum calcium, iCa
6. Phosphate
7. Urinary calcium, phosphate, creatinine
Because of the relatively small number of events we will use continuous predictor variables when possible. Categorical variables may be created depending on the distribution of the baseline variables. This decision will be made prior to analyzing the fracture data." ["project_other_variables_interest"]=> string(178) "Other variables of interest include: LH, FSH, estradiol, testosterone levels. If available, these variables are also important in the evaluation of bone health and fracture rate." ["project_stat_analysis_plan"]=> string(1263) "We will first perform life-table analyses of time to first fracture and time to first low trauma fracture in order to determine the unadjusted event rates for each treatment group. We will then evaluate the baseline data to determine the amount of missing data. We will examine the correlations among the other variables and will select predictors with the least amounts of missing data. Data will be transformed or grouped into categories if appropriate. We will also evaluate the rates within individual studies.
We will use Cox regression to evaluate the effect of baseline predictors. Treatment group, age, sex, and BMI will be included in all analyses. We will add each of the other variables individually to select the ones that are predictive. If there are sufficient events we will then perform a stepwise Cox regression analysis.
For the second primary aim we will use time dependent Cox regression to evaluate the effect of changes in BMI and bone-specific parameters on fracture risk. Analyses will be performed using SAS 9.3.
The power of these analyses will depend on the number of events. We have not performed power analyses at this time because we need more information about the number of events in the available data." ["project_timeline"]=> string(250) "Yoda application submission: February 2015
Project start date: March 2015
Analysis completion date: June 2015
Date manuscript drafted and ready for submission: Fall2015
Date results reported back to YODA project: Fall 2015" ["project_dissemination_plan"]=> string(158) "We anticipate the target audience of this publication to be general medical journals and sub-specialty journals, which will be determined after data analysis." ["project_bibliography"]=> string(2381) "

1. Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G 2008 Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31:845-851
2. Schwartz AV 2008 TZDs and Bone: A Review of the Recent Clinical Evidence. PPAR research 2008:297893
3. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR 2007 The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 92:1305-1310
4. Kohan DE, Fioretto P, Tang W, List JF 2013 Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney international
5. www.invokanahcp.com/prescribing-information.pdf IPI
6. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting KHCceasEaMDACM, Materials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336234.pdf
7. Kwon Hyon P, MPH 2013 Medical Clinical Review Application number 204042Orig1s000. In: FDA CfDEaR ed.
8. Khosla S, Melton LJ, 3rd, Wermers RA, Crowson CS, O’Fallon W, Riggs B 1999 Primary hyperparathyroidism and the risk of fracture: a population-based study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 14:1700-1707
9. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. In:
10. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G 2013 Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes, obesity & metabolism 15:463-473
11. Taylor SI, Blau JE, Rother KI 2015 Possible adverse effects of SGLT2 inhibitors on bone. The lancet Diabetes & endocrinology 3:8-10
12. Cianferotti L, Marcocci C 2012 Subclinical vitamin D deficiency. Best practice & research Clinical endocrinology & metabolism 26:523-537
13. Haroon M, FitzGerald O 2012 Vitamin D deficiency: subclinical and clinical consequences on musculoskeletal health. Current rheumatology reports 14:286-293

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2015-0416

General Information

How did you learn about the YODA Project?: Data Holder (Company)

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT00642278 - A Randomized, Double-Blind, Placebo-Controlled, Double-Dummy, Parallel Group, Multicenter, Dose-Ranging Study in Subjects With Type 2 Diabetes Mellitus to Evaluate the Efficacy, Safety, and Tolerability of Orally Administered SGLT2 Inhibitor JNJ-28431754 With Sitagliptin as a Reference Arm
  2. NCT01106625 - A Randomized, Double-Blind, Placebo-Controlled, 3-Arm, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Pioglitazone Therapy
  3. NCT01064414 - A Randomized, Double-Blind, Placebo-Controlled, 3-Arm, Parallel-Group, 26-Week, Multicenter Study With a 26-Week Extension, to Evaluate the Efficacy, Safety and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus Who Have Moderate Renal Impairment
  4. NCT01081834 - A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin as Monotherapy in the Treatment of Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Diet and Exercise
  5. NCT01106677 - A Randomized, Double-Blind, Placebo and Active-Controlled, 4-Arm, Parallel Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin Monotherapy
  6. NCT00968812 - A Randomized, Double-Blind, 3-Arm Parallel-Group, 2-Year (104-Week), Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-28431754 Compared With Glimepiride in the Treatment of Subjects With Type 2 Diabetes Mellitus Not Optimally Controlled on Metformin Monotherapy
  7. NCT01106651 - A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin Compared With Placebo in the Treatment of Older Subjects With Type 2 Diabetes Mellitus Inadequately Controlled on Glucose Lowering Therapy
  8. NCT01106690 - A Randomized, Double-Blind, Placebo-Controlled, 3-Arm, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Sulphonylurea Therapy
  9. NCT01137812 - A Randomized, Double-Blind, Active-Controlled, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin Versus Sitagliptin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Sulphonylurea Therapy
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

Request Clinical Trials

Data Request Status

Status: Concluded

Research Proposal

Project Title: Bone safety of canagliflozin, aSGLT2 inhibitor, in type 2 diabetes: A retrospective analysis to evaluate fracture risk

Scientific Abstract: Background. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is a new treatment for type 2 diabetes mellitus (T2DM). In the approval process, the FDA Advisory Committee reviewed data suggesting that canagliflozin increased the incidence of bone fractures. It is not known if these treatment-emergent fractures were more frequent in certain populations (e.g., post-menopausal women). Objective. To identify predictors of fractures to determine whether 1) bone-related baseline variables correlate with fracture rate and 2) changes in bone-specific variables can predict treatment-emergent fractures. Participants. Subjects from in 9 clinical trials who have sustained fractures as compared to matched controls. Study Design. Retrospective analysis of risk factors and fracture data from multiple clinical trials focusing on fractures after 1 year of therapy. Main Outcome Measures(s). The primary outcome variables are time to first fracture and time to first low trauma fracture. Statistical Analysis. We will use Cox regression to compare the fracture risk among treatment groups and to evaluate the effect of baseline and on-treatment risk factors on fracture risk. Caveats. Statistical power may be limited due to the small sample size. Ultimately, our goal is to gain information that may assist clinicians to risk-stratify patients who may be most vulnerable to developing drug-induced bone fractures. With continued studies, we may be able to suggest therapeutic approaches to minimize the fracture risk (e.g. vitamin D repletion if vitamin D deficiency is a risk factor).

Brief Project Background and Statement of Project Significance: SGLT-2 inhibitors improve glycemia, induce modest weight loss and lower blood pressure, but may increase the risk of bone fractures. This is particularly relevant for individuals with diabetes since fracture risk is increased in those with T2DM, especially older individuals (e.g., postmenopausal women). Younger persons with T2DM may also be at higher risk due to the long duration of exposure. Furthermore, we have learned important lessons from the ADOPT trial which demonstrated that thiazolidinediones (TZDs) increase the risk of bone fractures (1). After a 1- year lag for women and 3 years for men, rosiglitazone-treated patients experienced an increase in bone fractures (2, 3). This knowledge helps prescribers monitor and risk stratify appropriate patients for TZD use. Identifying modifiable risk factors (e.g., low vitamin D) may help us propose interventions that mitigate this risk, guide optimal patient selection, and contribute to improved safety of this class of medications.
Background. At the FDA advisory committee meeting on dapagliflozin in July 2011, a disproportionate, dose-dependent fracture rate was noted after 104 weeks in diabetes patients with moderate renal impairment: 9.4% fractures (10 mg dose), 6% (5 mg dose), and no fractures on placebo (4). In patients with normal renal function, there was a 2-fold increase.
At the FDA advisory committee meeting on canagliflozin in January 2013, pooled data from 8 clinical trials (68-weeks) showed a ~30% increase in bone fractures in canagliflozin-treated patients (5). This increase was observed only after 1 year on therapy (6).
Both, fracture location and trauma classification demonstrated an imbalance in upper limb fractures (not favoring canagliflozin), which persisted in low trauma upper limb fractures and spine fractures. In a pooled analysis of all treatment arms, females on canagliflozin had a higher incidence of upper limb fractures (1.2% [31/2608]) compared to placebo (0.4% [5/1338]) (7). The location of distal extremity fractures resembled fracture sites found in other diseases, e.g., primary hyperparathyroidism (8). Subsequently, the FDA required one of five post-marketing studies on canagliflozin to include a study on bone fracture risk (9).
The following observations support potential pathophysiological mechanisms: In a pooled analysis of studies conducted for 26 weeks (n=2,313), serum phosphate increased by 5.1% at the highest dose of canagliflozin (300 mg) compared to placebo (6). In patients with renal impairment (treatment duration 26 weeks), serum phosphate also increased (+7.8%) and 1,25-hydroxyvitamin D decreased (-8.1%) from baseline (10). The most acute changes in serum phosphate occurred within a few weeks of study initiation, suggesting feedback mechanisms maintaining homeostasis (e.g. possible increases in parathyroid hormone which is known to induce phosphaturia). In fact, a small increase in mean PTH (+7.9%) had been observed with canagliflozin (6). If the data were to follow a normal distribution, then ~15% of canagliflozin-treated patients would experience a >47% increase in PTH (mean + 1 SD), a change that could be clinically significant (11).

Specific Aims of the Project: Specific Aim #1. To evaluate baseline predictors of fracture risk.
Our goal is to investigate if baseline characteristics can predict fracture risk on canagliflozin. Certain factors are known to be related to bone health, including hormonal status (menopause, hypogonadism ), age, Vitamin D deficiency, low bone mineral density, previous fractures, etc. We expect that individulas with more risk factors at baseline will have a higher fracture rate on canagliflozin than comparable individuals who were not treated with canagliflozin.
Specific Aim #2. To investigate if any treatment-emergent changes before or after 1 year can predict fracture rate.
It is plausible that treatment induced changes over time could predict an increased fracture risk. The KM curve in Figure 1 demonstrates an increase in treatment emergent fractures occurred after 1 year. It begs the question: what treatment-emergent bone-specific factors could predict fracture risk after 1 year of therapy? Even small reductions in 1,25-dihydroxyvitamin D or increases in PTH can have detrimental long-term changes in bone metabolism (12, 13). Furthermore, persistent reductions in blood pressure or weight loss may also predict fracture rates. Therefore, we hope to analyze the patient level data before and after 1 year.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.:

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Retrospective analysis of fracture risk in canagliflozin treated patients will be assessed by evaluating individual participant level data from the following studies: NCT01137812, NCT01106690, NCT01106651, NCT00968812, NCT01106677, NCT01081834, NCT01064414, NCT01106625, NCT00642278. In addition, we are asking (via a separate data request) for any additional information from NCT01032629, which is currently in progress. If we were able to have access to un-blinded individual participant level data that has already been made available to the FDA and presented at the FDA advisory committee, we could further identify which patients may be at the highest risk for fractures after 1-2 years of therapy, given this study is the longest study available for canagliflozin.
Inclusion criteria:
1. Men and women, any age, race, baseline BMI
2. Type 2 Diabetes diagnosis, any HbA1c
3. Fracture, any location
4. Treatment group (canagliflozin, any dose) or placebo group
Exclusion criteria:
1. Unavailable demographic information regarding sex, age
2. Unavailable information on fracture (trauma level, location)
3. Unavailable information on treatment or placebo group

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The primary outcome measures are time from randomization to first fracture and time from randomization to first low trauma fracture. Fracture is defined as an event that has been diagnosed and reported previously, including prospectively adjudicated fractures presented at the FDA advisory committee by data cutoff July 1st 2012 plus any additional data available from the participant level data. Low trauma fracture is defined as a fracture resulting from falls from standing height or less; falls on stairs, steps, or curbs; moderate trauma other than falls; minimal trauma other than falls.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: The predictor variables for this study will dependent on the availability of baseline data to predict fracture risk. Age, sex, race, and baseline BMI, will be included in all analyses. The following will be included if available:
1. PTH
2. 1, 25 dihydroxyvitamin D and 25-OH vitamin D
3. Bone biomarkers (e.g. C-telopeptide, P1NP, osteocalcin, N-Telopeptide)
4. Alkaline phosphatase (bone specific, if available)
5. Serum calcium, iCa
6. Phosphate
7. Urinary calcium, phosphate, creatinine
Because of the relatively small number of events we will use continuous predictor variables when possible. Categorical variables may be created depending on the distribution of the baseline variables. This decision will be made prior to analyzing the fracture data.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Other variables of interest include: LH, FSH, estradiol, testosterone levels. If available, these variables are also important in the evaluation of bone health and fracture rate.

Statistical Analysis Plan: We will first perform life-table analyses of time to first fracture and time to first low trauma fracture in order to determine the unadjusted event rates for each treatment group. We will then evaluate the baseline data to determine the amount of missing data. We will examine the correlations among the other variables and will select predictors with the least amounts of missing data. Data will be transformed or grouped into categories if appropriate. We will also evaluate the rates within individual studies.
We will use Cox regression to evaluate the effect of baseline predictors. Treatment group, age, sex, and BMI will be included in all analyses. We will add each of the other variables individually to select the ones that are predictive. If there are sufficient events we will then perform a stepwise Cox regression analysis.
For the second primary aim we will use time dependent Cox regression to evaluate the effect of changes in BMI and bone-specific parameters on fracture risk. Analyses will be performed using SAS 9.3.
The power of these analyses will depend on the number of events. We have not performed power analyses at this time because we need more information about the number of events in the available data.

Narrative Summary: Diabetes increases the risk for bone fractures. Therefore, when providers choose medications, understanding the safety profile is very important. We want to address whether a recently approved medication called InvokanaTM may further increase bone fracture risk. We will evaluate clinical trial data to identify which patients may be more susceptible to fractures after 1 year of taking this medication.

Project Timeline: Yoda application submission: February 2015
Project start date: March 2015
Analysis completion date: June 2015
Date manuscript drafted and ready for submission: Fall2015
Date results reported back to YODA project: Fall 2015

Dissemination Plan: We anticipate the target audience of this publication to be general medical journals and sub-specialty journals, which will be determined after data analysis.

Bibliography:

1. Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G 2008 Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31:845-851
2. Schwartz AV 2008 TZDs and Bone: A Review of the Recent Clinical Evidence. PPAR research 2008:297893
3. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR 2007 The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 92:1305-1310
4. Kohan DE, Fioretto P, Tang W, List JF 2013 Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney international
5. www.invokanahcp.com/prescribing-information.pdf IPI
6. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting KHCceasEaMDACM, Materials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336234.pdf
7. Kwon Hyon P, MPH 2013 Medical Clinical Review Application number 204042Orig1s000. In: FDA CfDEaR ed.
8. Khosla S, Melton LJ, 3rd, Wermers RA, Crowson CS, O’Fallon W, Riggs B 1999 Primary hyperparathyroidism and the risk of fracture: a population-based study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 14:1700-1707
9. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. In:
10. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G 2013 Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes, obesity & metabolism 15:463-473
11. Taylor SI, Blau JE, Rother KI 2015 Possible adverse effects of SGLT2 inhibitors on bone. The lancet Diabetes & endocrinology 3:8-10
12. Cianferotti L, Marcocci C 2012 Subclinical vitamin D deficiency. Best practice & research Clinical endocrinology & metabolism 26:523-537
13. Haroon M, FitzGerald O 2012 Vitamin D deficiency: subclinical and clinical consequences on musculoskeletal health. Current rheumatology reports 14:286-293