A New Diphosphonate: Dissociation Between Effects on Cells and Mineral in Rats and a Preliminary Trial in Paget’s Disease

Lemkes, H. H. P. J.; Reitsma, Pieter H.; Frijlink, W. B.; Verlinden-Ooms, H.; Bijvoet, O. L. M.

doi:10.1007/978-1-4684-7758-0_47

Cited by 23 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The minimum dose of EHDP that gave histological osteomalacia was determined by King et al [9] in rats of a body weight comparable to that in the present study, and is in the order of 16/zmol/kg/ day. Direct comparison of EHDP with APD confirmed that EHDP is twice as potent as APD in this respect [14]. King et al [9] found that when mineral content of the whole femur was measured chemically, reduction was observed at higher doses than when osteomalacia was assessed histologically, In the present study such a discrepancy was absent.…”

Section: Mineralization When the Dose Of Apd Exceeded 40supporting

confidence: 79%

“…Preliminary experiments comparing a third bisphosphonate, APD, with EHDP and Ci2MDP showed that APD had an even more potent inhibitory effect on bone and cartilage resorption than the others, while the doses affecting bone resorption were lower than the doses affecting mineralization [14]. Because of the high potency of APD, we have extended these studies.…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in rats

et al. 1980

Self Cite

View full text Add to dashboard Cite

Dose-related effects of APD on bone metabolism and Ca homeostasis were studied in rats. The experimental approach consisted of longitudinal and cross-sectional observations, aiming at a kinetic interpretation. Bone and cartilage resorption was inhibited with 2--8 days at doses between 0.16 and 16 mumol/kg body weight/day. This was followed by changes in bone apposition that needed at least 23 days for a maximal effect. The time lag created a transient dissociation between resorption and apposition resulting in excess Ca and P retention, adding to increased metaphyseal bone mass. At high doses of APD (greater than or equal to 40 mumol/kg/day)the mineral content of new matrix decreased, associated with impairment of longitudinal growth of long bones. It is concluded that the lower doses of APD inhibited resorption of bone and cartilage, possibly by physicochemical stabilization of bone mineral, whereas the effect on bone apposition was due to a cellular homeostatic mechanism. Inhibition of growth and of matrix calcification, requiring much higher doses, may be due to a direct, toxic effect on bone cells. The modes of action of APD are discussed in relation to EHDP and Cl2MDP.

show abstract

Section: Mineralization When the Dose Of Apd Exceeded 40supporting

confidence: 79%

Section: Introductionmentioning

confidence: 94%

Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in rats

et al. 1980

Self Cite

View full text Add to dashboard Cite

show abstract

“…The inhibitory effect of bisphosphonates on osteoblast function in vitro has been suggested previously (16,17,20,21,65). However, it is not clear if such inhibition is due to direct effects on osteoblasts or not, because the cul ture systems included not only osteoblasts but also other cell types.…”

Section: Discussionmentioning

confidence: 96%

“…However, there appears to be less information regarding the direct effect of bisphosphonates on bone formation. Indeed there seem to be some controversial findings in this regard showing that the bisphosphonates may stimu late alkaline phosphatase (ALP) activity (15,16), prosta glandin E2 (PGE2) synthesis (17), collagen synthesis (18) and mineralization (16,19) or inhibit ALP activity (16,20), PGE2 synthesis (17), collagen synthesis (21) and mineralization (16,21) of osteoblasts. This controversy may be a reflection of the problems associated with the use of varied and different model systems, including rat bone fragment (ex vivo) (21), rat calvaria cells (15,17,18), human osteoblast cells (20), chick periosteal osteo genesis model (in vitro) (16) and chick osteoblast cells (19).…”

mentioning

confidence: 99%

Alendronate Modulates Osteogenesis of Human Osteoblastic Cells In Vitro

Tsuchimoto

Azuma

Higuchi

et al. 1994

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

ABSTRACT-The bisphosphonates, which are carbon-substituted pyrophosphates, have been studied exten sively both in vivo and in vitro to elucidate their effects on bone tissues and cells. However, because these agents were shown to have a potent inhibitory effect on bone resorption, the majority of studies have focused on only this aspect of bone metabolism. There appears to be less information regarding the direct effect of bisphosphonates on bone formation, so thus we undertook experiments to investigate the effects of bisphosphonates, especially alendronate, on the mineralization and matrix protein synthesis of human osteoblastic cells in vitro. The data show that the bisphosphonates, alendronate, etidronate and pamidronate, suppressed 1,25-dihydroxycholecalciferol (1,25(OH)2D3)-stimulated mineralization of human osteoblastic cells at high concentrations, while relatively lower concentrations of alendronate and etidronate potentiated mineralization of the cells in the presence of 1,25(OH)2D3. The potentiation of mineralization with alendronate was accompanied by increased synthesis of bone matrix proteins, osteocalcin and col lagen, and the mRNA of pro a(I) collagen. These findings show that in addition to their well-known effects on bone resorption, bisphosphonates have significant and direct effects on osteogenesis in osteoblasts in vitro. The actual mechanism remains to be further investigated.

show abstract

“…Diphosphonates stabilize bone mineral and reduce the rate at which calcium is mobilized by osteoclastic resorption. Most diphosphonates, however, also reduce the rate of mineralization of new osteoid so that osteomalacia may result [ 14]; C12MDP does not interfere with bone formation as readily and so may be a more satisfactory drug for chronic treatment of hypercalcemic states [15,16].…”

mentioning

confidence: 97%

Human parathyroid hormone 1-34-mediated hypercalcemia in a rat model, and its inhibition by dichloromethane diphosphonate

Doppelt

Neer²,

Potts³

1981

Calcif Tissue Int

View full text Add to dashboard Cite

Summary. The purpose of these experiments was twofold: (a) to see if a continuous hPTH-(1-34) infusion could sustain hypercalcemia for 1-2 weeks; and (b) to test the efficacy of dichloromethane diphosphonate (CI2MDP) in controlling the hypercalcemia of bone origin. First, 150-g SpragueDawley rats underwent parathyroid transplantthyroidectomy and were equilibrated on a calcium-free diet prior to treatment. To evaluate the model, animals received either the hPTH-(1-34) infusion (12 units/rat/h), or 0.1 cc 0.9% NaC1 per 100 g body weight (b.w.) per day. Thereafter, similar animals received 1 of 4 treatments: (a) hPTH-(1-34); (b) C12MDP (10 mg drug per kg b.w. per day); (c) hPTH-(1-34) plus ClzMDP; or (d) saline (controls). The peptide was administered by subcutaneously implanted osmotic minipumps; the CI2MDP and saline by once-daily subcutaneous injections. Plasma calcium and inorganic phosphate were measured for up to 15.5 days.In all studies the hPTH-(1-34) infusion alone promptly resulted in a hypercalcemic state (mean plasma calcium rise of 3-4 mg/dl), which was sustained for 11.5 days. Hypophosphatemia (mean decrement of 3 mg/dl) was seen for the duration of the infusion. Pretreatment with C12MDP blocked the plasma calcium response to the hPTH-(1-34) infusion. When ClzMDP was started shortly after the hPTH-(1-34) infusion began, the drug had no apparent effect on the magnitude of the hypercalcemia for 12 h, but thereafter effected a continuous decline in plasma calcium to normal levels. The phosphate response to hPTH-(1-34) infusion was unchanged by CI2MDP treatment. Cessation of the hPTH-(1-34) infusion caused the plasma calcium to fall 3-5 mg/dl in all animals receiving the peptide, either alone or in combination with C12MDP. Both Send off)grint requests to S. H. Doppelt at the above address.groups showed a trend toward normalization of their plasma calcium 48 hr later.

show abstract

A New Diphosphonate: Dissociation Between Effects on Cells and Mineral in Rats and a Preliminary Trial in Paget’s Disease

Cited by 23 publications

References 7 publications

Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in rats

Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in rats

Alendronate Modulates Osteogenesis of Human Osteoblastic Cells In Vitro

Human parathyroid hormone 1-34-mediated hypercalcemia in a rat model, and its inhibition by dichloromethane diphosphonate

Contact Info

Product

Resources

About