Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model.
The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. We used a rodent model of vitamin D depletion to quantify the 25-hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10-wk-old male Sprague-Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D(3) for 4 mo to achieve stable mean serum 25D levels ranging between 10 and 115 nM. At 7 mo of age, animals were killed, and the histomorphometry of distal and proximal femora and L(2) vertebra was analyzed. Total RNA was extracted from whole femora for real-time RT-PCR analyses. In the distal femoral metaphysis, trabecular bone mineral volume (BV/TV) showed a significant positive association with circulating 25D levels (r(2) = 0.42, p < 0.01) in the animals with serum 25D levels between 20 and 115 nM. Osteoclast surface (Oc.S) levels were positively associated with RANKL:OPG mRNA ratio, higher in groups with lower serum 25D levels, and were independent of serum 1,25D levels. Serum 25D levels <80 nM gave rise to osteopenia as a result of increased osteoclastogenesis, suggesting that levels of 25D >80 nM are needed for optimal bone volume. These data indicate that serum 25D levels are a major determinant of osteoclastogenesis and bone mineral volume and are consistent with the levels of 25D recommended to reduce the risk of fracture in humans.
Anderson
Paul H
PH
School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia. paul.anderson@imvs.sa.gov.au
Sawyer
Rebecca K
RK
Moore
Alison J
AJ
May
Brian K
BK
O'Loughlin
Peter D
PD
Morris
Howard A
HA
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000097:blood / Q000150:complications* / Q000503:physiopathology*; D002113:Calcification, Physiologic; D004195:Disease Models, Animal; D005269:Femur / Q000033:anatomy & histology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D009929:Organ Size; D010012:Osteogenesis; D010018:Osteomalacia / Q000097:blood / Q000150:complications / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000097:blood; D053245:RANK Ligand / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014808:Vitamin D Deficiency / Q000097:blood / Q000150:complications* / Q000503:physiopathology*
D010281:Parathyroid Hormone; D053245:RANK Ligand; D012333:RNA, Messenger; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase