Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17.
OBJECTIVE
Aromatase inhibition depletes estrogen levels and may be associated with accelerated bone resorption. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study MA.17B evaluated bone turnover markers and bone mineral density (BMD) in postmenopausal women randomly assigned to MA.17, a placebo-controlled trial of letrozole after standard adjuvant tamoxifen.


METHODS
Eligible women had a baseline BMD T score of at least 2.0 in either the hip or L2-4 spine; all received calcium 500 mg and vitamin D 400 U daily. Percentage change in BMD (L2-L4 spine and hip) at 12 and 24 months, rate of osteoporosis, and change in markers of bone formation (serum bone alkaline phosphatase) and resorption (serum C-telopeptide and urine N-telopeptide) at 6, 12, and 24 months were compared.


RESULTS
Two hundred twenty-six patients (122 letrozole, 104 placebo) were enrolled. Baseline characteristics were similar in the two groups, including BMD, median age of 60.7 years (81% < 70 years), and median follow-up of 1.6 years. At 24 months, patients receiving letrozole had a significant decrease in total hip BMD (-3.6% v -0.71%; P = .044) and lumbar spine BMD (-5.35% v -0.70%; P = .008). Letrozole increased urine N-telopeptide at 6, 12, and 24 months (P = .054, < .001, and .016, respectively). No patient went below the threshold for osteoporosis in total hip BMD, whereas at the L2-L4 (posteroanterior view), more women became osteoporotic by BMD while receiving letrozole (4.1% v 0%; P = .064).


CONCLUSIONS
After 5 years of adjuvant tamoxifen, subsequent letrozole causes a modest increase in bone resorption and reduction in bone mineral density in the spine and hip compared to placebo. Further follow-up is necessary to evaluate the long-term clinical implications of this difference.
Perez
Edith A
EA
St Michael's Hospital, Toronto, Canada. perez.edith@mayo.edu
Josse
Robert G
RG
Pritchard
Kathleen I
KI
Ingle
James N
JN
Martino
Silvana
S
Findlay
Brian P
BP
Shenkier
Tamara N
TN
Tozer
Richard G
RG
Palmer
Michael J
MJ
Shepherd
Lois E
LE
Liu
Shifang
S
Tu
Dongsheng
D
Goss
Paul E
PE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015519:Bone Density / Q000187:drug effects*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D002170:Canada; D017024:Chemotherapy, Adjuvant; D024042:Collagen Type I / Q000097:blood / Q000652:urine; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use*; D010455:Peptides / Q000097:blood / Q000652:urine; D013629:Tamoxifen / Q000008:administration & dosage*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D015415:Biomarkers; D024042:Collagen Type I; D020847:Estrogen Receptor Modulators; D009570:Nitriles; D010455:Peptides; D014230:Triazoles; C052929:collagen type I trimeric cross-linked peptide; D013629:Tamoxifen; D000077289:Letrozole; D000469:Alkaline Phosphatase