Moise Azria

Effects of Salmon Calcitonin on Trabecular Microarchitecture as Determined by Magnetic Resonance Imaging: Results From the QUEST Study

The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT‐NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT‐NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or μCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT‐NS and placebo.

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 Pagets 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 preparations chondroprotective effect in osteoarthritis.

Safety and Efficacy of a Novel Salmon Calcitonin (sCT) Technology‐Based Oral Formulation in Healthy Postmenopausal Women: Acute and 3‐Month Effects on Biomarkers of Bone Turnover

Oral administration of calcitonin could improve compliance to long‐term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months.

The effect of rectal and nasal administration of salmon calcitonin in normal subjects

SummaryIn order to ascertain the blood levels and the biologic responses obtained after administration of two noninjectable forms of salmon calcitonin (SCT) (i.e., a nasal spray and a suppository), two doses of 200 IU each were administered at 3 hour intervals nasally to 8 normal subjects, and rectally to 9 normal subjects. Five untreated subjects served as controls. All were given a standardized diet for 2 days before the test. Plasma salmoncalcitonin, ionized calcium, phosphate, sodium, proteins, creatinine, and alkaline phosphatase were measured repeatedly after the administration of the drug. Modifications in fractionated urinary calcium, phosphate, sodium, and creatinine excretions (and hydroxyproline for the 8 subjects treated by the nasal spray) were compared with the values measured on the previous day. Plasma concentrations of SCT were found to increase sharply with both routes of administration, the peaks being high and short after rectal administration, low but more sustained after nasal application. Despite these differences, almost similar biologic effects could be demonstrated: transient hypocalcemia, increased calciuria, phosphaturia, and natriuria. Urinary hydroxyproline excretion decreased. Plasma sodium did not increase, whereas it did in the controls. In conclusion, nasal sprays and suppositories of SCT appear to exert the known biologic effects of SCT, and might be favored for long-term treatment in diseases representing indications for calcitonin therapy.

The Analgesic Role of Calcitonin Following Osteoporotic Fracture

Abstract: 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.

Bioavailability and Biological Efficacy of a New Oral Formulation of Salmon Calcitonin in Healthy Volunteers

Salmon calcitonin (SCT) is a well‐tolerated peptide drug with a wide therapeutic margin and is administered parenterally for long‐term treatments of bone diseases. Its clinical usefulness would be enhanced by the development of an orally active formulation. In this randomized crossover double‐blinded phase I trial, controlled by both a placebo and a parenteral verum, we have tested a new oral formulation of SCT associated with a caprylic acid derivative as carrier. Eight healthy volunteers received single doses of 400, 800, and 1200 μg of SCT orally, a placebo, and a 10‐μg (50 IU) SCT intravenous infusion. SCT was reliably absorbed from the oral formulation, with an absolute bioavailability of 0.5–1.4%, depending on the dose. It induced a marked, dose‐dependent drop in blood and urine C‐terminal telopeptide of type I collagen (CTX), a sensitive and specific bone resorption marker, with the effects of 1200 μg exceeding those of 10 μg intravenously. It also decreased blood calcium and phosphate, and increased the circulating levels of parathyroid hormone (PTH) and, transiently, the urinary excretion of calcium. It was well‐tolerated, with some subjects presenting mild and transient nausea, abdominal cramps, diarrheic stools, and headaches. This study shows that oral delivery of SCT is feasible with reproducible absorption and systemic biological efficacy. Such an oral formulation could facilitate the use of SCT in the treatment of osteoporosis and other bone diseases.

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.

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 CTs 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.

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 calcitonins analgesic effect is probably a direct central action, but that this is further supported by peripheral mechanisms that may also improve bone status locally.

Femoral neck trabecular microstructure in ovariectomized ewes treated with calcitonin: MRI microscopic evaluation.

Ovariectomy induces deterioration of the trabecular structure in the femoral neck of ewes, as depicted by MR microscopic imaging. This structural deterioration is prevented by salmon calcitonin treatment.