Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model

J Bone Miner Res. 2008 Nov;23(11):1789-97. doi: 10.1359/jbmr.080616.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
  • Animals
  • Bone Resorption / blood
  • Bone Resorption / complications*
  • Bone Resorption / physiopathology*
  • Calcification, Physiologic
  • Disease Models, Animal
  • Femur / anatomy & histology
  • Femur / enzymology
  • Gene Expression Regulation, Enzymologic
  • Male
  • Organ Size
  • Osteogenesis*
  • Osteomalacia / blood
  • Osteomalacia / complications
  • Osteomalacia / physiopathology
  • Parathyroid Hormone / blood
  • RANK Ligand / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Regression Analysis
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • Vitamin D Deficiency / blood
  • Vitamin D Deficiency / complications*
  • Vitamin D Deficiency / physiopathology*


  • Parathyroid Hormone
  • RANK Ligand
  • RNA, Messenger
  • Vitamin D
  • 25-hydroxyvitamin D
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase