Miyazaki et al. 2016 

Fingolimod suppresses bone resorption in female patients with multiple sclerosis

Japan

Cohort

N_Initial=83, N_Final=83

Population: Fingolimod group (n=29): Mean age=37.4yr; Gender: males=9, females=20; Disease course: RRMS=24, SPMS=5; Mean EDSS=2.3; Mean disease duration=10.7yr. Untreated group (UT; n=29): Mean age=37.3yr; Gender: males=9, females=20; Disease course: RRMS=26, SPMS=3; Mean EDSS=2.1; Mean disease duration=7.7yr. Healthy controls (HC; n=25): Mean age=36.8yr; Gender: males=8, females=17.

Intervention: Participants received fingolimod or no treatment (UT). Fingolimod was administered at 0.5mg/d for a mean of 12.9mo. The UT group received no pharmacological agents or immunosuppressants that could modify MS symptoms for at least 3mo. HC were also used for comparison. Samples were collected once in the morning on the day of testing.
Outcomes/Outcome Measures: Bone turnover markers (BTM) in serum and urine samples; urinary type 1 collagen cross-linked N-telopeptide (N-Tx); tartrate-resistant acid phosphatase (TRACP) 5b in serum; bone-specific alkaline phosphatase (BAP) in serum; procollagen type 1 amino-terminal propeptide (P1NP); creatinine in serum; serum free thyroxine; 25(OH)D in serum.

1.      Serum concentrations for a resorption BTM (N-Tx) was significantly decreased in fingolimod compared to HC and UT (p<0.05).

2.      The other bone resorption marker (TRACP5b) and two formation markers (BAP/P1NP) did not significantly differ between groups (p>0.05).

3.      Females, but not males, taking fingolimod had lower N-Tx levels compared to females in UT (p<0.01).

4.      The BTM N-Tx was significantly positively correlated with EDSS for ambulatory females in the UT (p=0.0264), but not fingolimod group (p=0.3198).

5.      TRACP5b, BAP, AND P1NP did not differ between the different study groups (healthy control, untreated-MS, fingolimod-MS) (p<0.01).

6.      In males that were fully ambulatory (EDSS ≤ 3.5), TRACP5b and P1NP had a significant negative correlation with EDSS in UT (p=0.0458; p=0.0072), but not fingolimod group (p=0.7131; p=0.3956).

7.      Treatment duration was significantly positively correlated with level of BAP, a BTM, in females. No significant correlation existed with males.

Varoglu et al. 2010 

The effect of interferon beta 1B on bone mineral density in multiple sclerosis patients

Turkey

Cohort

N_Initial=32, N_Final=32

Population: Interferon Beta (IFN-β) group (n=17): Mean age=36.2yr; Gender: males=5, females=12; Disease course: PPMS or SPMS; Mean EDSS=2.64; Mean disease duration=4.2yr. Control group (CG; n=15): Mean age=34.1yr; Gender: males=7, females=8; Disease course: PPMS or SPMS; Mean EDSS=2.80; Mean disease duration=3.4yr.

Intervention: Participants in the IFN-β group received IFN-β 1b treatment, while participants in the CG did not receive IFN-β. The IFN-β group received treatment for at least 1yr.
Outcomes/Outcome Measures: Bone mineral density (BMD) of the lumbar spine (L1-L4, anteroposteriorly) and total left hip by DXA using Hologic QDR 4500.

1.      Lumbar BMD in IFN-β group was 0.90 ± 0.13 g/cm². Lumbar BMD in CG was 0.96 ± 0.12 g/cm².

2.      Left hip (total) BMD was 0.76 ± 0.13 g/cm². Left hip (total) BMD was 0.73 ± 0.20 g/cm².

3.      After treatment there was no significant difference between IFN-β and CG groups in the femoral neck (p=1) or lumbar spine (p=0.3).

Shuhaibar et al. 2009

Favorable effect of immunomodulatory therapy on bone mineral density in multiple sclerosis

Ireland

Case Control

N_Initial=37, N_Final=37

Population: Mean age=38.8yr; Gender: males=13, females=24; Disease course: Unspecified; Mean EDSS=3.1; Mean disease duration=5.8yr.

Intervention: Individuals receiving immunomodulatory therapy (IMT) for an average of 3.1yr underwent bone mineral density (BMD) tests. BMD was measured at both the hip and lumbar spine. Outcomes were compared to age and sex-matched BMD scores. Types of IMT administered included: Interferon β-1a (70%), Interferon β-1b (27%), and Glatiramer (3%). Intravenous steroid treatment (methylprednisolone 500mg) was administered in 81% of individuals.

Outcomes/Outcome Measures: Bone mineral density (BMD) was measured via DXA at the lumbar spine (L1-L4) and left total femur site using a Hologic QDR4000 Elite Densitometer.

1.      BMD Z-scores at the spine (p=0.0084) and at femur (p=0.0001) were significantly greater than age and sex-matched BMD scores.

2.      There was no difference between men and women in regards to BMD z-scores.

Weinstock-Guttman et al. 2006 

Interferon-beta modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients

USA

Cohort

N_Initial=18, N_Final=18

Population: MS participants (n=9): Mean age=46.5yr; Gender: males=3, females=6; Disease course: RRMS; Mean EDSS=2.44; Mean disease duration: Unspecified. Healthy Controls (n=9): Mean age=44.5yr; Gender: males=2, females=7.

Intervention: All MS participants received an intramuscular injection of 30mg interferon-β (IFN-β-1a). Healthy controls did not receive any treatment. Outcomes were measured at 8hr, 24hr, and 6mo.
Outcomes/Outcome Measures: Osteoprotegerin (OPG) plasma protein; free, uncomplexed RANKL protein in plasma; osteocalcin; plasma levels of C-telopeptides of type 1 collagen; osteocalcin.

1.      Significant changes from pre-treatment levels occurred at the 8 and 24hr time points in treated MS patients but not in controls; there was a significant decrease in OPG levels at 8hr post treatment (p<0.001), and a significant increase in OPG levels at 24hr post treatment (p=0.007).

2.      The OPG levels at the six-month time point were not significantly different from baseline.

3.      Levels of the bone formation marker osteocalcin were lower in MS participants compared to untreated healthy controls at baseline (p=0.007) and increased to 142 ±17% of pre-treatment levels after 1yr of IFN-β-1a treatment.