Shapiro et al. (2016): Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)

Reference ↗
Title	Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
Topic	Vitamin D
Author	Shapiro, AC, Adlis, SA, Robien, K, Kirstein, MN, Liang, S, Richter, SA, Lerner, RE
Year	2016
Journal	Breast cancer Research and Treatment
DOI	https://doi.org/10.1007/s10549-016-3710-6

Brief summary

This study investigated the efficacy of high-dose vitamin D3 with regard to muscular symptoms associated with aromatase inhibitors. No significant differences were found between the arms that received high-dose vitamin D and the control arm that only received standard vitamin D therapy. A positive aspect of this study is the consideration of the vitamin D level and the high rate of patients who took the medication as prescribed.

In dieser Studie wurde die Wirksamkeit von hochdosiertem Vitamin D3 hinsichtlich mit Aromatasehemmer assoziierter muskulärer Symptome untersucht. Es fanden sich keine bedeutsamen Unterschiede zwischen den Armen, die hochdosiertes Vitamin D bekam und der Kontrollarm, die nur eine Vitamin-D-Standardtherapie erhielt. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Medikation wie vorgegeben eingenommen haben.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Post-menopausal women >18 years of age, with stage I-IIIA breast cancer, being treated with anastrozole, letrozole or exemestane for at least 30 days and experiencing aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) at enrollment (prior to the run-in period)
Exclusion criteria	Received previous aromatase inhibitor treatment, had a history of rheumatoid arthritis, hypercalcemia or were taking excluded medications, unwilling to discontinue other oral supplements containing D3 and/or calcium; patients with osteoporosis in some cases
N randomized	116
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	NI
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Basline T1: after 1.5 months T2: after 3 months T3: after 6 months

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage
Specifications on cancer stages	n=53 (46.9%) stage I, n=45 (39.8%) stage II, n=15 (13.3%) stage IIIA
Comorbidities	NI
Current cancer therapies	Chemotherapy, Hormone therapy, Radiation therapy
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 60.9 (8.8)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	57
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Cholecalciferol (D3)
Dosage and regime	All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize Usual care dose of 600 IU D3 capsules daily + all participants: 1,000 mg calcium carbonate
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	168
Side effects / Interactions	Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
Number of participants (arm) N randomized	59
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Dropped out during run-in period
Intervention	Usual Care
Dosage and regime	All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize High-dose of 4,000 IU D3 capsules daily + all participants: 1,000 mg calcium carbonate
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	168
Side effects / Interactions	Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences

Outcomes

Musculoskeletal symptoms

Outcome type As specificed by the authors	Primary
Outcome specification	Aromatase inhibitor-associated musculoskeletal symptoms
Type of measurement	AUSCAN (Australian/Canadian Osteoarthritis Hand Index), BCPT (Breast Cancer Prevention Symptom Scales), HGST Maximum (Handgrip Strength Test), PROMIS (Patient-Reported Outcomes Measurement Information System), Western Ontario and McMaster Osteoarthritis Index
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No statistically significant differences in the change in BCPT-MS scores between arms; The subscales for pain, stiffness, and physical function on the AUSCAN, WOMAC, PROMIS and the HGST did not show any differences between arms for the change from baseline to 6 months; Exploratory analyses within each arm did not show clinically significant correlations between free or total serum 25(OH)D and BCPT-MS scores, hand-grip strength or estradiol concentrations
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	Serum 25(OH)D
Type of measurement	Chemiluminescent immunoassay
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After the run-in period, the mean baseline serum total 25(OH)D level for all participants was 36.6 (13.0) ng/mL (mean (SD)), and free serum 25(OH)D was 8.0 (3.2) pg/mL, 5 participants in the intervention arm and 4 participants in the control arm had insufficient 25(OH)D levels of ≤ 20ng/mL and no participants were vitamin D deficient; At 6 months, all participants were vitamin D sufficient, statistically significant difference in the change in serum 25(OH)D between arms (a decrease of 2.6 (7.6) ng/mL in control arm vs an increase of 9.3 (10.4) in the intervention arm, p < 0.0001).
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	NA
Bias due to deviation from intended intervention (assignment to intervention)	NA
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	NA
Bias in measurement of the outcome	NA
Bias in selection of the reported result	NA
Other sources of bias	NA
Overall RoB judgment	NA

Interaction with cancer treatment

Outcome type As specificed by the authors	Secondary
Outcome specification	Interactions between D3 and anastrozole and letrozole
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	High-dose vitamin D3 did not affect steady-state concentrations of anastrozole and letrozole, neither serum total nor free 25(OH)D was significantly associated with the steady-state concentrations
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Hormone level

Outcome type As specificed by the authors	Secondary
Outcome specification	Reproductive hormone concentrations for estrone, estradiol, testosterone (free and total) and sex-hormone binding globulin
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences in the change from baseline to 6 months
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding

Research relating to this analysis was funded by grants from the: National Cancer Institute (R21 CA149934), National Institutes of Health Office of Dietary Supplements and the Park Nicollet Institute and Park Nicollet Foundation. This work was supported in part by NIHP30CA77598, using the following University of Minnesota Masonic Cancer Center resource: Clinical Pharmacology and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH UL1TR000114)

Conflicts of Interest

No conflicts of interest reported by any of the authors

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	No
- Reasons for insufficient sample size based on power analysis	NI
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	Yes
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	No
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	NA

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	Yes
Correction for multiple testing	No
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	Yes
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	Yes
Side effects considered in result interpretation	No
Ethics votum	Yes

Additional Notes

PRO:

• Ethics vote
• High compliance (<95%)
• Intention-to-treat analysis, only low dropout (A: 5%, B: 3%)
• Change in vitamin D levels examined; A significant more change than B (total vitamin D: p < 0.0001; free vit. D: p < 0.0001)

CONTRA:

• Sample too small according to power analysis (< 58 per group)