Nasal salmon calcitonin blunts bone microstructure alterations in healthy postmenopausal women.

UNLABELLED: In healthy postmenopausal women, nasal salmon calcitonin blunted distal radius and tibia bone microstructure degradation. INTRODUCTION: Nasal salmon calcitonin (NSC) has been reported to lower vertebral fracture risk by 33%, but to modestly increase spine areal bone mineral density (aBMD) by 1.5%. Thus, NSC may also influence bone microstructure, another known determinant of bone strength. METHODS: In a randomized, double-blind, placebo-controlled trial, we investigated the effects of 200 IU/day NSC on distal radius and tibia bone microstructure (by high-resolution 3-dimensional peripheral quantitative computerized tomography), aBMD (by dual-energy X-ray absorptiometry), and serum bone turnover markers in healthy postmenopausal women. RESULTS: Mean age was 57.6 ± 0.8 (±SEM) and 57.4 ± 0.7 in NSC (n = 45) and placebo groups (n = 45), respectively. Mean femoral neck T-score was in the osteopenic range; prevalent vertebral fracture was 4% in each group. There was no observed between-group difference in the primary outcome distal radius BV/TV (-2.8 ± 0.6% vs. -4.3 ± 1.0%, NS). By 2 years, the decrease in distal radius total density vs. baseline was 4.4 ± 0.7% in controls and 2.1 ± 0.6% in NSC-receiving patients (p < 0.05). Distal radius and tibia cortical thickness decreased by 3.7 ± 1.0 and 2.4 ± 0.5% in placebo (p < 0.05 vs. baseline for both), respectively, but not in the NSC group. Distal radius total density and cortical thickness changes were lower in NSC group than in placebo (p < 0.05 for both) in the subgroup with baseline C-terminal telopeptides (CTX) above the median. By 6 and 12 months, serum CTX decreased by 17.3 ± 6.2 and 19.1 ± 6.6% (both p < 0.05 vs. baseline), respectively, in NSC, but remained stable in controls (NS vs. baseline). There was no difference in aBMD. NSC was well tolerated, with less arthralgia than the placebo group (14 vs. 26, p < 0.05). CONCLUSION: Nasal salmon calcitonin blunted the degradation of distal radius and tibia bone microstructure in healthy postmenopausal women.

Lessons learned from the development of oral calcitonin: the first tablet formulation of a protein in phase III clinical trials.

Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life-9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations.

Salmon calcitonin: a review of current and future therapeutic indications.

Salmon calcitonin, available as a therapeutic agent for more than 30 years, demonstrates clinical utility in the treatment of such metabolic bone diseases as osteoporosis and Paget's disease, and potentially in the treatment of osteoarthritis. This review considers the physiology and pharmacology of salmon calcitonin, the evidence based research demonstrating efficacy and safety of this medication in postmenopausal osteoporosis with potentially an effect on bone quality to explain its abilities to reduce the risk of spine fracture, the development of an oral salmon calcitonin preparation, and the therapeutic rationale for this preparation's chondroprotective effect in osteoarthritis.

Rationale for the potential use of calcitonin in osteoarthritis.

This review provides evidence that osteoarthritis (OA) or a major subset of OA is not only a disease of cartilage but also a disorder of subchondral bone. This review also discusses the potential efficacy of a bone and cartilage active agent, calcitonin, and discusses how calcitonin might be useful in the pharmaceutical treatment of OA.

The analgesic role of calcitonin following osteoporotic fracture.

Osteoporosis is a systemic skeletal condition characterized by decreased bone strength with consequent increased susceptibility to bone fracture. Fragility fractures in osteoporosis are often painful and result in loss of quality of life and disability. Salmon calcitonin (SCT) is a natural hormone that may assist in the management of osteoporotic patients following fracture by reducing fracture risk and decreasing pain. SCT is an antiresorptive agent which has been shown to reduce the risk of vertebral fractures (by 36%) in postmenopausal women with osteoporosis and previous fractures, with a safety profile comparable to placebo over long-term use. Clinical evidence suggests that SCT (with either subcutaneous and intranasal delivery) is an analgesic for the acute pain following osteoporotic fracture. Pain relief with SCT occurs after 1 week or less of treatment. Associated with this pain relief, vertebral fracture patients receiving SCT have been observed to have earlier mobilization compared with those receiving a placebo. Both preclinical and clinical data suggest a central analgesic effect for SCT. The mechanism(s) by which SCT induces pain relief has (have) not been conclusively shown. Neither a direct receptor-mediated action nor an indirect endorphin-mediated effect can be ruled out.

Possible mechanisms of the analgesic action of calcitonin.

The analgesic activity of calcitonin is well established, both through clinical observation and specific experimental investigation. The mechanism involved, however, is still unclear, and the hypotheses that have been proposed range from a simple peripheral antiinflammatory action to a direct action on specific receptors in the central nervous system. The various hypotheses are briefly reviewed and some of the supporting evidence is presented. The conclusion is that the principal mechanism of calcitonin's analgesic effect is probably a direct central action, but that this is further supported by peripheral mechanisms that may also improve bone status locally.

Dyadic analyses of friendship in a sample of preschool-age children attending Head Start: correspondence between measures and implications for social competence.

Friendships among a large sample of preschool-age children (N = 471) attending Head Start were assessed. Based on sociometric data, friendship dyads were identified as reciprocated (mutual choice) or nonreciprocated (unilateral choice). Dyads were further classified with respect to gender composition as either same- or mixed-gender dyads. Older children were more likely to participate in a reciprocated friendship than were younger children and reciprocated dyads were more likely to be same-gender than were nonreciprocated dyads. Analyses of interaction between dyad partners revealed that reciprocated friends interacted more frequently across all categories of interaction coded and looked at each other more frequently than did members of nonreciprocated dyads. For the positive interaction subscore, the friendship status effect was modified by a significant interaction with gender composition such that significant effects of friendship status were obtained only for same-gender dyads. Additional analyses indicated that the average social competence level was greater for reciprocated dyads than for nonreciprocated dyads. The findings suggest that reciprocated friendships are meaningful for preschool-age children and may serve as special socialization contexts in which the repertoire of behavior can be exercised and perhaps improved. They also highlight the salience of same-gender friendships in the preschool classroom.

Friendship and social competence in a sample of preschool children attending Head Start.

Relations between friendship (operationalized as reciprocated or nonreciprocated sociometric choices) and social competence were studied for children (mostly African American) attending Head Start. Initial analyses showed that children with reciprocated friends had higher social competence scores than children without reciprocated friends. Correlations suggested that the number of reciprocated friendships was associated with the social competence indicators studied here. Beyond the cost of having no reciprocated friends, having nonreciprocated friendships was not a liability. Cross-time analyses suggested differing patterns of relations for boys and girls. Having versus not having a reciprocated friend was unstable across time, because there was a trend toward participating in reciprocated friendships from 3 to 4 years of age (most older children had at least 1 reciprocated friend). For girls there was a positive relation between the number of reciprocated friendships at Time 1 and at Time 2. No benefit (in terms of social competence) was found for children making the transition from 1 classroom to the next with a friend.

Effects of calcitonin on animal and in vitro models of skeletal metabolism.

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 effect of intranasal salmon calcitonin on postmenopausal bone turnover as assessed by biochemical markers: evidence of maximal effect after 8 weeks of continuous treatment.

Although treatment with intranasal salmon calcitonin (sCT) has been shown to effectively inhibit postmenopausal bone loss, there is still controversy over both timing and the duration of its application. In an open prospective study, we therefore assessed the effect of shortterm intranasal sCT on postmenopausal bone turnover, employing biochemical markers of bone metabolism. Ten early postmenopausal, previously untreated women (1-5 years after menopause) with biochemical evidence of increased bone resorption and a low bone mineral density at baseline were treated with intranasal sCT (100 IU B.I.D.) for a period of 3 months. Oral calcium (500 mg/day) was administered simultaneously, and during a further 3 month follow-up interval. Treatment with sCT resulted in a pronounced suppression of bone resorption markers with a maximum effect reached after 8 weeks of therapy: as compared to the respective baseline values, mean levels decreased by -26.2% +/- 3.4% (P < 0.001) for pyridinoline, -32.7% +/- 3.5% (P < 0.001) for deoxypyridinoline, -32.7% +/- 3.3% (P < 0.001) for hydroxyproline, and -24.1% +/- 8.2% (P < 0.001) for the amino-terminal telopeptide. In contrast, changes in bone formation markers of osteocalcin (-14.4% +/- 4.8%, P < 0.05) and C-terminal procollagen type I propetide (-7.9% +/- 3.9%, ns) were much less pronounced. Unexpectedly, after week 8 of the study all resorption markers showed a plateau and a trend to increase, although intranasal sCT was continued for a total of 12 weeks. This effect could not be attributed to the formation of anti-sCT antibodies. After cessation of treatment, both bone formation and resorption markers rapidly returned to baseline levels. Bone mineral density of both spine and hip showed no significant change during the observation period. Our results demonstrate that in postmenopausal women with a high bone turnover, intranasal treatment with 200 IU of sCT effectively reduces bone turnover and maintains bone mass, the maximum effect being reached after 8 weeks of treatment.

Comparison of the acute biological action of injectable salmon calcitonin and an injectable and oral calcitonin analogue.

In most countries, calcitonin is available in the form of injections, and less frequently as an intranasal spray. An oral route of administration should improve compliance. In a preliminary feasibility study, we have compared the acute biological action of injectable salmon calcitonin (50 IU), with the injectable calcitonin analogue ASC 710 (0.2 mg) and oral ASC 710 (20 mg) in 6 patients suffering from active Paget's disease of bone. The intensity and duration of the biological response were not significantly different in the 3 modes of therapy. In conclusion, the oral calcitonin analogue ASC 710 possesses an antiresorbing activity in Paget's disease comparable to that of an injection of salmon calcitonin which demonstrates that it can cross the intestinal barrier.

Lack of effect of ipriflavone on osteoclast motility and bone resorption in in vitro and ex vivo studies.

Using in vitro and ex vivo experimental procedures specifically designed to visualize pharmacological effects on parameters of bone resorption, studies were performed to elucidate whether ipriflavone's reported effect in osteoporosis is due to an effect on the motility and resorptive activity of osteoclasts, as has been shown to be the case with salmon calcitonin. Concentrations of ipriflavone used were higher by a factor of > 100 than peak blood levels measured in patients given standard therapeutic doses. Despite this, neither quantitative nor qualitative changes were observed in the motility of isolated rat osteoclasts or in their resorptive activity when incubated with bone slices. The conclusion is that ipriflavone does not possess antiosteoclastic and antiresorptive activity of the type documented for salmon calcitonin in the models employed and that further investigation of its mode of action is therefore necessary.

N-terminal truncation of salmon calcitonin leads to calcitonin antagonists. Structure activity relationship of N-terminally truncated salmon calcitonin fragments in vitro and in vivo.

Structural requirements for binding to the bone calcitonin (CT) receptor and for CT bioactivity both in vitro and in vivo were assessed for a series of N-terminally truncated, N alpha-acetylated, fragments of salmon calcitonin (sCT). Sequential deletion of amino acid residues from the amino-terminus of [Ala7]sCT-(2-32) peptide amide first led to partial agonists and, upon deletion of residues 1 to 7, to a high affinity antagonist, N alpha-acetyl-sCT-(8-32)-NH2. The presence of two separate domains within the sCT sequence is proposed: (I) a binding domain comprising residues 9-32 and (II) an activation domain requiring residues 3 to 6. N alpha-acetyl-sCT-(8-32)-NH2, in several bioassays including plasminogen activator release from LLC-PK1 cells (pA2 = 7.31), cAMP production in UMR-106-06 cells (pA2 = 7.81) and in the fetal rat long bone resorption assay showed potent antagonistic properties.

Endogenous production of specific antibodies does not decrease hypocalcemic response to calcitonin in young rabbits.

In order to evaluate the potential inhibition of the acute anti-osteoclastic activity of salmon calcitonin (SCT) by specific antibodies (Ab), we compared the SCT-induced hypocalcemic effect in young male rabbits with significant titers of high affinity Ab and in matched animals without Ab. Immunization of rabbits was performed by repetitive s.c. injections of SCT and Freund adjuvant. Ab were present in four-fifths of SCT-treated rabbits (Ab+). Their titer varied from 0.8 x 10(-9) to 30 x 10(-9) M/liter and their constant of affinity from 0.97 x 10(9) to 4.2 x 10(9) L/M. Intravenous injection of 1 IU/kg SCT to Ab+ rabbits induced a significant decrease (P less than 0.01) of ionized serum calcium (Ca2+) after 30 minutes (mean +/- SD: -9 +/- 0.6%) and until the 240th minute of the test (-16.7 +/- 4.7%), with a maximum after 120 minutes (-22.6 +/- 2%). This was not significantly different from the hypocalcemic effect measured after the same procedure performed in matched animals without Ab (Ab-): significant decrease in Ca2+ (P less than 0.01) after 30 minutes (-8.2 +/- 2.2%), maximal after 150 minutes (-23.2 +/- 4.9%), and lasting until 210 minutes (-14.5 +/- 3.7%). We conclude that, in the particular model of the male young rabbit, specific anti-SCT Ab do not block or reduce the acute anti-osteoclastic activity of SCT.

Disposition of sandostatin, a new synthetic somatostatin analogue, in rats.

The distribution, excretion, and metabolism of Sandostatin, a long-acting octapeptide analogue of somatostatin, have been studied in the rat after iv administration. Similar plasma levels and excretion values were observed by using radioimmunoassay and HPLC-liquid scintillation techniques. For the latter technique Sandostatin was radiolabeled with either 14C or 3H. The plasma pharmacokinetics of Sandostatin were as follows: Vdss = 0.4 liter/kg, C/t = 4.2 ml/min, and t1/2 2.0 hr; this half-life was by far longer than that of somatostatin. The in vitro protein binding amounted to 59% in rat plasma; no Sandostatin was taken up by blood cells. The tissue concentrations of Sandostatin were similar when determined either by radioimmunoassay or by quantitative whole-body autoradiography; this suggests that the distribution of 3H or 14C radioactivity observed 0.5 hr after iv administration mostly represented unchanged Sandostatin. Kidney and liver were the only tissues in which Sandostatin levels were higher than in blood; high radioactivity levels were observed in the blood vessel walls, whereas levels in brain were insignificant. Unchanged drug accounted for most of the radioactivity found in plasma, urine, and bile, whereas only traces of unchanged drug were detected in feces. These results demonstrated the metabolic stability of Sandostatin in the tissues, primarily in the liver, and suggested an extensive degradation in the intestinal tract. The degradation products consisted of smaller peptides and free amino acids. About 50% and 20% of the applied dose were excreted as unchanged Sandostatin in bile and urine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)