The effects of low magnitude high frequency mechanical stimulation

(LMS) on bone density in childhood cancer survivors (CCS).

Kirsten K. Ness, PT, PhDAPTA Combined Sections Meeting

February 2015

Low bone density in survivors of childhood cancer

• 29.5% of adult survivors of acute lymphoblastic leukemia have low bone mineral density (BMD) (Gurney 2014)

• 26% of adult survivors of sarcoma have low BMD (Kaste 2008)

• 47% of adult survivors of CNS malignancies have low BMD (Barr 1998, Kaste 2006)

Bone density decreases during chemotherapy

(Unpublished data, Inaba 2015)

Current treatment options

• Bisphosphonates– Decrease recruitment of osteoclasts, reducing bone

absorption – also stimulate osteoblasts to produce an inhibitor of bone resorption

– Side effect profile • Fever, hypocalcemia, bone pain, transient iritis and uveitis,

impaired mineralization of bone, impaired linear growth and nephrocalcinosis

• Weight bearing exercise– Has been tested in healthy children (pending results from

ongoing trial (R01CA129384, Cox PI))

• Nutritional supplements– Vitamin D and Calcium (Bone II, Kaste PI)

Low magnitude, high frequency mechanical stimulation (LMS)

• LMS– Based on the mechanical strain theory - has been

applied in cellular, animal and human models to evaluate its effects on bone accretion.

• The effective intervention– 0.3 g (1 g=9.8 m/s2=gravity)– 1/1000 of the force required to fracture bone– Frequency of 30-40 Hertz– Treatment applied by having participant stand on the

oscillating plate for 10 minutes 1-2 times per day – Duration from 6 – 12 months

Effects of LMS mechanical stimulation on bone in humans (randomized trials)

• Post-menopausal women– 2.2% relative increase in femoral and 1.5% relative

increase in lumbar BMD after 1 year of 10 minute twice per day LMS mechanical stimulation (Rubin 2004)

• Young people (15 – 20 year old females)– 2.3% relative increase in lumbar BMD after 1 year of 10

minutes per day LMS mechanical stimulation (Gilsanz 2006)

• Disabled children– 17.7% relative increase in BMD in tibia and 5.2% relative

increase in lumbar spine BMD in a six month trial of 10 minutes per day of LMS mechanical stimulation (Ward 2004)

Vibration intervention for bone enhancement

• To evaluate the effects of LMS on bone mineral content, BMD, and bone strength in childhood cancer survivors

• To evaluate the effects of LMS on markers of bone turnover in childhood cancer survivors

Eligibility criteria

• Children 7 – 17 years old previously treated for childhood cancer at SJCRH

• 5+ years from diagnosis and not currently receiving treatment for cancer

• Age and gender matched whole body BMD z-score of -1.0 or less

• Could stand independently (may use supports)

• All received vitamin D and calcium supplements according to Children’s Oncology Group Guidelines

Study design• Participants stood on a “vibrating”

platform for 10 minutes twice a day for one year

• Participants in the control arm stood on a placebo device that mimics the sound of the active device

• Baseline and post-intervention imaging and laboratory evaluations were used to determine the effects of the intervention on BMD and markers of bone turnover

Participant eligible for study

Randomization

Placebo Intervention

12 month intervention

Two ten minute sessions per day

Follow-up measurements:

(BMD, bone turnover biomarkers)

Follow-up measurements:

(BMD, bone turnover biomarkers)

Baseline measurements (BMD,

bone turnover biomarkers)

Consort diagram

Intervention(N=22)

Placebo(N=26)

% %

Sex Male 54.5 53.8Race Non-white 13.6 19.2

Tanner stage 3+ 54.5 53.8

Diagnosis

ALL 11 (50.0) 16 (61.5)CNS 9 (40.9) 6 (23.1)Ewing 1 (4.5) 0NHL 0 3 (11.5)Neuroblastoma 0 1 (3.8)Wilms Tumor 1 (4.5) 0

Characteristics of the study population

Characteristics of the study population

Intervention(N=22)

Placebo(N=26)

Mean (SD) Mean (SD)Age at baseline (years) 13.4 (2.7) 13.5 (2.8)Age at diagnosis (years) 3.1 (1.6) 4.5 (2.4)Time since diagnosis (years) 10.3 (2.7) 9.1 (2.8)Body mass index percentile 64.2 (28.8) 68.1 (33.5)

Adherence

• Completion of twice daily, 10 minute prescribed sessions– 70.1% intervention

group– 63.9% placebo group– p=0.43

Mean change BMD from baseline to 12 months

Intervention Placebo

Mean* SD Mean* SD p-value*(N=22) (N=26)

Total body BMD Z-score 0.25 0.78 -0.19 0.79 0.05Lumbar BMD Z-score 0.15 0.51 0.08 0.51 0.82% tibial cortical bone 3.00 4.69 1.77 4.90 0.16% tibial trabecular bone 4.86 16.58 -3.68 16.92 0.08% lumbar bone volume 5.64 10.83 5.30 11.06 0.91*Adjusted for sex and Tanner stage

Mean change markers of bone turnover from baseline to 12 months

Intervention Placebo

Mean* SD Mean* SD p-value*Bone formationAminoterminal propeptide of type I procollagen -0.11 0.51 -0.29 0.34 0.18Osteocalcin -0.06 0.30 -0.27 0.41 0.08Alkaline phosphatase-skeletal (Bone specific) -0.18 0.34 -0.31 0.30 0.17*Adjusted for sex and Tanner stage

Mean change markers of bone turnover from baseline to 12 months

Intervention PlaceboMean* SD Mean* SD p-value*

Bone resorptionCarboxyterminal telopeptide of type I collagen -0.11 0.30 -0.19 0.31 0.38Collagen cross linked N-telepetide -0.30 0.56 -0.28 0.43 0.88Bone tunroverReceptor activator nuclear factor kB ligand/Osteoprotegerin index 0.14 0.44 -0.14 0.50 0.06*Adjusted for sex and Tanner stage

Thank you!

• Collaborators– Sue Kaste– Robert Ferry Jr.– Rona Mogil– Carrie Howell– Robyn Karlage– Kristin Scobey

• Funding– NICHD HD059292– Gabrielle’s Angels

Foundation– NIH CA21765– ALSAC