Rastelli et al. (2011): Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial

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Title	Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial
Topic	Vitamin D
Author	Rastelli, AL, Taylor, ME, Gao, F, Armamento-Villareal, R, Jamalabadi-Majidi, S, Napoli, N, Ellis, MJ
Year	2011
Journal	Breast Cancer Research and Treatment.
DOI	https://doi.org/10.1007/s10549-011-1644-6

Brief summary

In this study, breast cancer patients who had already received aromatase inhibitor therapy for at least 8 weeks before the start of the study were examined with regard to typical side effects (musculoskeletal disorders, AIMSS) of this treatment. One arm received vitamin D2 in addition to the standard vitamin D/calcium treatment, initially weekly and then monthly, and the other arm received a placebo. The duration of the weekly dose differed depending on the vitamin D level at the start of treatment. After two months, there were significant differences between the two arms in terms of pain experienced in favor of the vitamin D2 arm, but not in terms of AIMSS symptoms. After four and six months, no differences were seen between the arms. In a further analysis, the group differences were considered separately for patients with higher vitamin D levels at the start of the study and those with lower levels. There were no differences between the vitamin D2 and placebo arms for patients with higher levels over the entire duration of the study, but significantly less pain was reported in the vitamin D2 arm for those with lower levels. A positive aspect of this study is the inclusion of vitamin D levels and the high rate of patients who took the medication as prescribed. However, due to the very small sample size and a high drop-out rate, especially in the vitamin D2 arm, this study has a significantly reduced validity.

In dieser Studie wurden Brustkrebspatientinnen, die vor Studienbeginn schon mind. 8 Wochen eine Aromatasehemmer-Therapie erhalten hatten hinsichtlich typischer Nebenwirkungen (Muskel-Skelett Erkrankungen, AIMSS) dieser Behandlung untersucht. Ein Arm bekam zusätzlich zur Vitamin-D/Kalzium Standardbehandlung anfangs wöchentlich und danach monatlich Vitamin D2 und der andere Arm bekam ein Placebo. Je nach Vitamin-D-Spiegel zu Beginn der Behandlung unterschied sich die Dauer der wöchentlichen Dosis. Nach zwei Monaten fanden sich bedeutsame Unterschiede zwischen den beiden Armen bezüglich des erlebten Schmerzes zugunsten des Vitamin-D2-Arms, aber nicht bezüglich der AIMSS-Symptome. Nach vier und sechs Monaten waren keine Unterschiede zwischen den Armen mehr zu sehen. In einer weiteren Analyse wurden die Gruppenunterschiede getrennt für Patienten mit höherem Vitamin D Spiegel zu Beginn der Studie und denen mit niedrigerem Spiegel betrachtet. Dabei zeigte sich bei Patientinnen mit höherem Spiegel über die gesamte Studiendauer keine Unterschiede zwischen Vitamin-D2- und Placebo-Arm, aber bei denen mit niedrigerem Spiegel wurde im Vitamin-D2-Arm bedeutsam weniger Schmerz berichtet. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Mediakation wie vorgegeben eingenommen haben. Diese Studie hat jedoch durch die sehr kleine Stichprobe und eine hohe Ausfallrate vor allem im Vitamin-D2-Arm eine deutlich geminderte Aussagekraft.

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	Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB), had completed at least 8 weeks of anastrozole as adjuvant therapy prior to study entry, and were experiencing new or worsening musculoskeletal pain unrelated to any history of trauma; serum 25OHD level between 10 and 29 ng/ml, serum calcium B10.3 mg/dl, and 24 h urine calcium excretion B250 mg/g creatinine
Exclusion criteria	Had known metastatic disease to the bone, kidney stones, primary hyperparathyroidism, Paget’s disease of the bone, severe arthritis, rheumatoid arthritis, severe neuropathy or 25OHD C 30 ng/ml; treatment on the trial was stopped if the patient developed hypercalciuria (C250 mg/g creatinine) or hypercalcemia (C10.3 mg/dl)
N randomized	60
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	NA
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: At 2 months T2: At 4 months T3: At 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, Adjuvant
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	Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB)
Comorbidities	NI
Current cancer therapies	Hormone therapy
Specifications on cancer therapies	Anastrozole
Previous cancer therapies	NI
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean (SD): 60 (8.8) Placebo arm: mean (SD): 63 (7.8)

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	30
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Never started treatment
Intervention	Vitamin D
Dosage and regime	Daily supplementation with 1,000 mg of calcium carbonate and 400 IU of Vitamin D3: Baseline 25OHD levels between 20 and 29 ng/ml were randomized to receive vitamin D2, one 50,000 IU capsule, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study; Baseline 25OHD levels between 10 and 19 ng/ml received Vitamin D2 50,000 IU capsule or a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
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.	-999
Side effects / Interactions	No toxicities or significant adverse events.

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	30
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	Placebo
Dosage and regime	Baseline 25OHD levels between 20 and 29 ng/ml got a placebo, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study; Baseline 25OHD levels between 10 and 19 ng/ml received a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
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.	-999
Side effects / Interactions	No.

Outcomes

Musculoskeletal symptoms

Outcome type As specificed by the authors	NI
Outcome specification	Syndrome may resemble arthritis, but may also mimic fibromyalg
Type of measurement	BPI-SF (Brief Pain Inventory - Short Form), FIQ (Fibromyalgia Impact Questionnaire), HAQ-DI (Health Assessment Questionnaire-Disability 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".	Pain decreased significantly at 2 months in the intervention arm compared to placebo, significant differences were found on several measures of pain intensity including FIQ pain (3.3 vs. 4.6, p = 0.0045), BPI worst pain (3.6 vs. 5.1, p = 0.04), BPI average pain (2.7 vs. 3.7, p = 0.0067), and BPI pain severity (2.7 vs. 3.5, p = 0.04), as well as on a measure of interference on subjects’ life activities (BPI interference, 1.8 vs. 2.5, p = 0.034); the effect on pain was not observed at 4 and 6 months when the majority of subjects were switched from weekly to monthly vitamin D supplementation; The improvement in pain severity and interference with daily activities was significant when averaging across all time points (2, 4, 6 months) for the patients with baseline vitamin D deficiency (10–19 ng/ml), but not in the patients with baseline insufficiency (20–29 ng/ml); No significant effect was found on the HAQ-DI questionnaire in the overall or strata analysis
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	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

BMD (Bone Mineral Density)

Outcome type As specificed by the authors	NI
Outcome specification	Bone Mineral Density of the lumbar spine, total femur, and femoral neck
Type of measurement	DXA (Dual energy X-ray Absorptiometry)
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 between the arms
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	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	mean serum 25OHD
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".	At the end of the study, mean serum 25OHD was higher in the intervention arm (p = 0.03) and a greater proportion of subjects normalized serum 25OHD (43% vs. 11.5%, p = 0.02); no linear relationship (r = 0.15, p = 0.5) was found between changes in vitamin D levels and changes in pain scores 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	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

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	NI

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	Some patients never started treatment
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	No
Ethnicity mentioned	Yes

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	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NI

Interpretation of results

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

Additional Notes

PRO:

• Double blinding
• High compliance rate (96%)
• Intention-to-treat
• Information on the development of vitamin D levels

CONTRA:

• Small sample (according to power analysis > 30 per group)
• High dropout rate after 6 months: A: 30%, B: 13%
• Multiple testing (all time points compared individually)
• Poor report quality