Time-evolution and reversibility of strontium-induced osteomalacia in chronic renal failure rats.
BACKGROUND
Patients with impaired renal function can accumulate strontium in the bone, which has been associated with the development of osteomalacia. A causal role for strontium in the development of the disease was presented in chronic renal failure (CRF) rats. Strontium-ranelate has been put forward as a therapeutic agent in the treatment of osteoporosis. Since the target population for strontium treatment consists mainly in postmenopausal osteoporotic women, who may have a reduced renal function, the risk for osteomalacia should be considered.


METHODS
To determine the time evolution and reversibility of the strontium-induced mineralization defect, CRF rats were loaded with strontium (2 g/L) (+/- 200 mg/kg/day) during 2, 6, and 12 weeks, followed by a washout period of 0, 2, 4, or 8 weeks.


RESULTS
Histologic examination of the bone of the animals treated with strontium revealed signs of osteomalacia already after 2 weeks. Animals that received strontium during 6 and 12 weeks had a significantly higher osteoid perimeter, area and thickness as compared to CRF controls. After 12 weeks, the mineralization was significantly affected, as evidenced by a lower double-labeled surface, mineral apposition and bone formation rate in combination with an increased osteoid maturation time and mineralization lag time. The osteoblast perimeter was significantly lower in the strontium-treated animals. After the washout periods, these effects were reversed and the bone lesions evolved to the values of CRF controls. This went along with an 18% reduction of the bone strontium content. A significant rise in serum alkaline phosphatase (ALP) activity was apparent in the strontium-treated animals as compared to CRF controls. This was not only due to higher levels of the bone ALP but also to those of the liver and the intestinal isoenzymes. Serum parathyroid hormone (PTH) levels decreased during strontium treatment. After cessation of the treatment, the serum ALP activity and PTH concentration reversed to control levels.


CONCLUSIONS
In this study evidence is provided for the rapid development of a mineralization defect in strontium-loaded CRF rats, accompanied by a reduced osteoblast number, reduced PTH synthesis or secretion, and increased serum ALP levels. These effects can be rapidly reversed after withdrawal of the compound.
Oste
Line
L
Department of Nephrology-Hypertension, University of Antwerp, Antwerp, Belgium.
Bervoets
An R
AR
Behets
Geert J
GJ
Dams
Geert
G
Marijnissen
Rita L
RL
Geryl
Hilde
H
Lamberts
Ludwig V
LV
Verberckmoes
Steven C
SC
Van Hoof
Viviane O
VO
De Broe
Marc E
ME
D'Haese
Patrick C
PC
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism*; D008297:Male; D010006:Osteoblasts / Q000187:drug effects; D010018:Osteomalacia / Q000139:chemically induced*; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013324:Strontium / Q000097:blood / Q000633:toxicity*; D013997:Time Factors
D010281:Parathyroid Hormone; D000469:Alkaline Phosphatase; D013324:Strontium