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Principal Investigator: Luke Joseph Peppone
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2024
Award: $607,140
Funding agency: National Cancer Institute
ABSTRACT:
Use of androgen deprivation therapy (ADT), which causes near-total loss of testosterone, has increased
dramatically in elderly prostate cancer patients over the last decade. ADT is associated with a significant increase
in bone mineral density (BMD) loss (2-5% annually) and bone fractures, combined with a significant decrease in
skeletal muscle mass (2-5% annually) compared to age-matched prostate cancer patients not on ADT and men
without cancer. The loss of BMD and muscle mass results in a high prevalence of falls, reduced muscular
strength, and decreased balance. Despite the high incidence of ADT-related side effects, treatment options are
limited. Bisphosphonate therapy is commonly used for ADT-induced bone loss, but is associated with significant
side effects and poor compliance. Vitamin D protects against BMD loss and fractures, but its effects are strongly
dose-dependent. Current IOM recommended supplementation (600-800 IU/day) and serum 25-OH levels (20
ng/mL) are inadequate to protect against bone loss in a high risk population such as prostate cancer patients on
ADT. In addition, RCT interventions of 400-500 IU/day of vitamin D fail to prevent ADT-induced bone loss. High-
dose vitamin D supplementation (e.g., 50,000 IU/week) is a promising intervention that significantly increases
25-OH vitamin D to levels shown to improve BMD in other populations. Vitamin D has also been shown to
increase muscular strength, reduce falls, and improve balance. In preparation for this R01, we conducted a
Phase II randomized controlled trial (RCT) investigating the feasibility, safety, and preliminary efficacy of HDVD
versus placebo for 24 weeks in 59 prostate cancer patients receiving ADT (NCI R21CA185678; PI: Peppone).
Compelling evidence from our pilot study showed: 1) 50,000 IU/week of vitamin D (HDVD) was safe with no
increase in toxicity versus low-dose vitamin D, 2) compliance was excellent at 94%, and 3) HDVD significantly
increased 25-OH vitamin D levels. Those randomized to HDVD lost 1.9% BMD at the total hip versus 3.7% loss
in the placebo group (p=0.03). Stratified analyses showed the HDVD group lost 2.3% BMD at the total hip vs
7.1% for the placebo group for those with baseline vitamin D <27 ng/ml (p<0.01). Based on our preliminary data,
we propose to conduct a definitive, multi-center, phase III RCT in which 366 prostate cancer patients ≥65 years
old starting ADT with vitamin D <27 ng/ml will be randomized to 1) 50,000 IU/week vitamin D or 2) a matching
placebo for 52 weeks. All participants will receive a daily supplementation (800 IU vitamin D/1,000 mg calcium)
to ensure a minimum of 100% RDA. The primary outcomes is the change in BMD, while secondary outcomes
include changes in the clinically relevant outcomes of falls, balance, quality of life and fractures. We also plan to
explore the biological pathways of ADT-induced bone loss and response to HDVD using bone biomarkers. If
found to be efficacious, HDVD would be a safe, low-cost, widely-available OTC treatment that could revolutionize
management of ADT-induced bone loss and change clinical practice paradigms.
Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ASCO><Age><Aged 65 and Over><Agonist><Alcohol Chemical Class><Alcohols><American Society of Clinical Oncology><Biological><Biological Markers><Bisphosphonates><Blood Serum><Bone Density><Bone Mineral Density><CCOP><Calciol><Calcium><Cancer Center><Cancer Patient><Cancer Survivor><Cancers><Cholecalciferol><Clinical><Clinical Practice Guideline><Community Clinical Oncology Program><Community Oncology><Country><Coxa><DEXA><DXA><Data><Distal><Dose><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Dual-Energy X-Ray Absorptiometry><Dual-Energy Xray Absorptiometry><Elderly><Ensure><Equilibrium><Exercise><Femur><Fracture><GNRH><GNRH1><GNRH1 gene><Gonadotropin Releasing Hormone 1><High Prevalence><Hip><Hip Fractures><Hip region structure><Hypercalcemia><Incidence><Initiation Factors><Intervention><Intervention Strategies><Intervention Trial><Interventional trial><Investigation><LNRH><Luteinizing Hormone-Releasing Hormone><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Metastatic Prostate Cancer><Morbidity><Morbidity - disease rate><Muscle><Muscle Atrophy><Muscle Tissue><Muscular Atrophy><Neck><Non-metastatic><Non-pharmacologic Therapy><Nonmetastatic><Nonpharmacologic Intervention><Nonpharmacologic Therapy><Nonpharmacologic approach><Nonpharmacologic treatment><Oncologist><Osteoporosis><Outcome><Participant><Pathway interactions><Patients><Pelvic Bones><Peptide Initiation Factors><Phase><Pilot Projects><Placebos><Population><Preparation><Preventative treatment><Prevention><Preventive treatment><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><Publishing><QOL><Quality of life><Radial><Radius><Randomized><Randomized, Controlled Trials><Recommendation><Regimen><Research><Safety><Serum><Sham Treatment><Site><Skeletal Muscle><Smoking><Spinal Column><Spine><Supplementation><Supplementation with vitamin D><Testosterone><Therapeutic Testosterone><Toxic effect><Toxicities><Trans-Testosterone><Translation Initiation Factor><Translational Initiation Factor><Universities><VIT D><Vertebral column><VitD3><Vitamin D><Vitamin D 3><Vitamin D supplementation><Vitamin D3><Voluntary Muscle><above age 65><advanced age><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><ages><androgen ablation therapy><androgen blockade therapy><androgen deprivation therapy><androgen deprivation treatment><antagonism><antagonist><arm><backbone><balance><balance function><bio-markers><biologic><biologic marker><biomarker><biphosphonate><bisphosphonate><bone><bone cell><bone fracture><bone health><bone loss><clinical practice><clinical practice and guidelines><clinical relevance><clinically relevant><community setting><cost><design><designing><diphosphonate><efficacy testing><elderly patient><falls><fracture risk><geriatric><high risk><high risk group><high risk individual><high risk people><high risk population><hip bone><human old age (65+)><improved><interventional strategy><machine learning based method><machine learning method><machine learning methodologies><malignancy><men><mortality><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle strength><muscle wasting><muscular><neoplasm/cancer><non-drug therapy><non-drug treatment><nondrug therapy><nondrug treatment><novel><old age><older patient><over 65 years><pathway><pharmacologic><pilot study><placebo group><preparations><prevent><preventing><primary outcome><programs><prostate cancer treatment><randomisation><randomization><randomized control trial><randomly assigned><response><sarcopenia><sarcopenic><secondary outcome><senior citizen><sham group><sham therapy><side effect><vitamin D supplement><≥65 years>