A comparison of the skeletal effects of intermittent and continuous administration of calcitonin in ovariectomized rats

doi:10.1016/8756-3282(96)00014-2

Bone

Volume 18, Issue 4, April 1996, Pages 375-380

https://doi.org/10.1016/8756-3282(96)00014-2 Get rights and content

Abstract

The study was designed to compare the skeletal effects of intermittent and continuous administration of Calcitonin (CT) in ovariectomized (OVX) rats. Female rats were sham operated or OVX at 3 months of age and treated for 6 weeks with vehicle or salmon CT. Sham-operated control rats were injected subcutaneously with vehicle on alternate days. One group of OVX rats was treated with vehicle intermittently by subcutaneous injection or continuously via Alzet osmotic minipumps. The remaining OVX rats were treated with CT by either subcutaneous injections (16 U/kg) on alternate days or by continuous infusion via minipumps at a daily dose of 8 U/kg. OVX rats treated with CT continuously were mildly hypocalcemic compared with all other groups. The proximal tibial metaphyses of vehicle-treated OVX rats were osteopenic with a cancellous bone volume at only 28% of the vehicle-treated control level. This bone loss was associated with increased indices of bone turnover such as osteoclast surface, osteoblast surface, and bone formation rate. cancellous bone volume in OVX rats treated with CT either intermittently or continuously was significantly higher than that of vehicle-treated OVX rats, but lower than that of vehicle-treated control rats. Treatment of OVX rats with intermittent or continuous CT significantly decreased all indices of bone turnover compared with vehicle-treated OVX rats. However, osteoclast and osteoblast surfaces of OVX rats treated with CT continuously were still significantly higher than those of vehicle-treated control rats. These results indicate that intermittent and continuous administration of CT had similar skeletal effects in OVX rats. Both treatment regimens depressed bone turnover and partially prevented cancellous bone loss in the estrogen-deplete skeleton.

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Development and characterization of supramolecular calcitonin assembly and assessment of its interactions with the bone remodelling process
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Citation Excerpt :
Nevertheless, increased food intake due to estrogen deficiency does not affect bone mineral density of experimental OVX rats [37]. Treatment with calcitonin either intermittently or continuously (with Alzet osmotic pump) decreases the body weight of OVX rats significantly compared to vehicle treated rats [38]. In mammals bone resorption due to increased osteoclastic activity is characterized by high acid phosphatase activity, particularly tartarate resistance acid phosphatase 5b (TRAP5b) and CTX-I(C-terminal telopeptides, CTXI) as collagen degradation end product in serum.
Osteoporosis is the most common metabolic bone disease, which poses an immense socio-economic burden on the society. Human calcitonin, though safe, is not considered as a therapeutic option because of its high tendency to self-associate to form amyloid fibrils thereby affecting its potency. To circumvent this issue we harnessed the inherent capacity of aggregation and developed an assemblage of human calcitonin monomers, [Supramolecular Calcitonin Assembly (SCAI)], which releases biologically active calcitonin monomers in a sustained manner for a period of at least three weeks. AFM and FT-IR analysis showed that SCA-I is amorphous aggregates of calcitonin monomers. Both SCA-I and monomer released from it demonstrated superior anti-osteoclast activity and proteolytic stability in-vitro. SCA-I upon single injection significantly improved bone formation markers and reduced bone resorption markers in ovariectomized (OVX) rat model of postmenopausal osteoporosis. Micro-CT analysis revealed that calcitonin released from SCA-I exhibits its beneficial effect on cortical bone more profoundly compared to trabecular bone. This study demonstrates that SCA-I is more effective compared to the human calcitonin monomers on osteoclasts and has site-specific effect on bone in a model of post-menopausal osteoporosis. This approach opens up an innovative way to use and study the function of human calcitonin.
Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes
2006, Osteoarthritis and Cartilage
Citation Excerpt :
Salmon calcitonin is combined with the carrier 5-CNAC, which is an eligen-technology based carrier that protects the peptide during its gastrointestinal transition and facilitates its mucosal absorption19. The concentration of calcitonin was chosen based on previous reports to be in the higher end of doses used in rats20–23 taking into account the bio availability of oral calcitonin is approximately 1%24. The calcitonin formulations were freshly prepared daily, and immediately administered to the animals by oral gavage.
Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions.
Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-α (TNF-α) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001–1 μM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks.
The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-α and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P < 0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P < 0.01). TNF-α and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P < 0.001) decrease in CTX-II levels.
These results are the first evidence of calcitonin receptor expression on articular chondrocytes and that the chondroprotective effects of calcitonin might involve the inhibition of MMP expression.
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1999, Bone
During the 40 years since its discovery, calcitonin (CT) has been regarded primarily as an inhibitor of bone resorption and its therapeutic applications have been based on this property. A significant body of literature also indicates additional anabolic effects in animal and in vitro models. In a variety of bone loss histomorphometric models in the rat, CT, especially the salmon species, prevents or retards bone loss. In other species, similar results have been obtained, except in the beagle given human CT, in which a recent study reported increased bone resorption and bone loss. Consonant with the histomorphometric effects in several different species, bone mass (density) measured by a variety of methods increases, reversing the bone loss induced by the model. In related studies of mechanical properties, bone strength is increased by CT except in the beagle study which utilized human CT. In other species, experimentally induced fractures show either accelerated healing or heal normally, and there is no effect of CT to impair healing. Finally, studies of bone formation/mineralization strongly suggest an anabolic effect on cartilage formation, bone matrix synthetic activity, and bone growth. These animal effects are reflected by recent fracture prevention studies in humans. If its anabolic effects are ultimately found to be separable and additive to CT’s basic action to inhibit bone resorption, new approaches to osteoporosis prevention, and possibly other treatment situations such as cartilage regeneration, may evolve using novel CT-like molecules.
The biochemical and histological analysis of subcutaneous calcitonin and intramedullary methylprednisolone on bone repair after bone marrow ablation: an experimental comparative study in rats
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2015, BMC Musculoskeletal Disorders
The inhibitory effect of salmon calcitonin on intervertebral disc degeneration in an ovariectomized rat model
2015, European Spine Journal

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Original articleA comparison of the skeletal effects of intermittent and continuous administration of calcitonin in ovariectomized rats

Abstract

Metabolism

Bone

Pharmacol Res Common

Metabolism

Lancet

Bone

Recent Prog Horm Res

Bone

Calcitonin-physiology and pathophysiology

N Engl J Med

Processing of undecalcified bone specimens for bone histomorphometry

Prevention of ovariectomy osteopenia in rats after vaginal administration of hyaff 11 microspheres containing salmon calcitonin

Calcif Tissue Int

Bone turnover in postmenopausal osteoporosis: Effect of calcitonin treatment

J Clin Invest

Anabolic actions of parathyroid hormone on bone

Endocr Rev

Bone histomorphometry: Analysis of trabecular bone dynamics

An effective regimen of intranasal salmon calcitonin in early postmenopausal bone loss

Calcif Tissue Int

The effect of high-dose salmon calcitonin on bone mineral metabolism in the normal rat

Calcif Tissue Int

Effects of continuous and intermittent administration and inhibition of resorption on the anabolic response of bone to parathyroid hormone

J Bone Miner Res

Effects of salmon calcitonin suppositories on bone mass and turnover in established osteoporosis

Calcif Tissue Int

Original article
A comparison of the skeletal effects of intermittent and continuous administration of calcitonin in ovariectomized rats