Long-Term Oral Toxicity and Anti-osteoporotic Effect of Sintered Dicalcium Pyrophosphate in Rat Model of Postmenopausal Osteoporosis

Abstract

Sintered dicalcium pyrophosphate (SDCP), a synthetic pyrophosphate analog, has shown potential for the management of osteoporosis. The long-term oral toxicity and anti-osteoporotic effect of SDCP in a postmenopausal osteoporosis rat model were evaluated in this study. SDCP was orally administered to bilateral ovariectomized (OVX) Wistar rats at a dose of 0.75 mg/kg daily for 24 weeks following by 2 weeks of observation. There were no abnormal findings in clinical signs of toxicity, food consumption, body weight, blood examination, necropsy, and histological inspection attributable to the ingestion of SDCP. The serum level of type I collagen fragments, a bone resorption marker, decreased in SDCP-treated rats, and the bone formation markers alkaline phosphatase, osteocalcin, and osteopontin significantly decreased. These findings indicate that the bone turnover rate decreased in SDCP-treated animals. Relative to OVX rats, the increase in serum tartrate-resistant acid phosphatase 5b level represents an increase in bony tissues in the SDCP-treated rats. Histological examinations of distal femoral metaphyses further revealed that the ingestion of SDCP improved the trabecular bone architecture and decreased bone porosity. Analysis of limb bone ashes showed a significant increase in bone mineral content. Our results show that SDCP inhibits bone resorption to restore bone mass in OVX rats without deleterious effects, and therefore that SDCP has potential in the management of osteoporosis.

Keywords: Bone turnover markers; Oral toxicity; Osteoporosis; Pyrophosphate analog; Sintered dicalcium pyrophosphate.

Fig. 1

Body weight changes of rats. There was no significant difference between OVX + SDCP and OVX + ALN groups. Body weights of these two groups were heavier than that of sham group and lower than that of OVX group

Fig. 2

After ovariectomy, serum levels of bone formation markers a ALP, b OC, and c OPN in OVX group increased significantly. d Level of TRACP-5b significantly decreased in OVX group. e CTX-1 also increased in OVX group. In contrast, administration of SDCP significantly decreased levels of ALP, OC, OPN, and CTX-1, but increased level of TRACP-5b. Similar findings were observed in OVX + ALN group. f Serum level of intact PTH increased in OVX + ALN group. There were no significant differences among sham, OVX, and OVX + SDCP groups

Fig. 3

a Histological sections (Goldner’s trichrome stain) of distal femur showed intervening trabecular bone with connectivity of trabeculae elements in sham group. b After ovariectomy (OVX group), there was significant thinning and disconnection of trabeculae in the femur compared with sham group. c Administration of SDCP and d ALN partial restored bony architecture of healthy cancellous bone

Fig. 4

Ratio of bone ash to dry weight (w_f/w_i) of limbs decreased significantly post-ovariectomy (OVX group). Ingestion of SDCP and ALN significantly increased w_f/w_i ratios of all limbs compared with OVX group. There were no significant differences in w_f/w_i ratios of humerus and forearm among sham, OVX + SDCP, and OVX + ALN groups. However, w_f/w_i ratios of femur and tibia in OVX + SDCP group were significantly lower than that of OVX + ALN group (both p < 0.05)