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

Abstract

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. Introduction: We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population. Materials and Methods: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays. Results: After the first dose, sCT evoked dose-dependent decreases in serum CTx (Ϫ60.8% to Ϫ81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r ϭ 0.78, p Ͻ 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (Ϫ18.9% and Ϫ20.5%, respectively, p Ͻ 0.05). The placebo-corrected change in OC was Ϫ8.6 (p ϭ 0.09), whereas the change in BSALP was Ϫ7.3 (p ϭ 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups. Conclusion:The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.

Safety concerns over the use of intestinal permeation enhancers: A mini-review

“…GI disturbances such as nausea, diarrhea, abdominal pain, vomiting, loose stools and constipation were also shown in a study with 5-CNAC involving 277 postmenopausal women with 32% reporting at least one event. 28 Similar effects were seen in another 5-CNAC study which included over 2000 participants and concluded that there were more adverse GI reports in the patients receiving 0.8mg sCT formulated in the 5-CNAC carrier orally compared to the matched placebo (26-30% compared to 46%). 29 It was thought that these adverse events were related to sCT as they were comparable to those observed with subcutaneous injection of sCT.…”

“…A number of clinical studies have been published involving SNAC and also the related enhancer, 5-CNAC. 21,[27][28][29] One study was carried out in which sCT was administered orally with 200mg 5-CNAC twice daily over 2 weeks to 36 men and 37 postmenopausal women. 21 Fortyfour mild adverse events were observed, some of which were in the placebo group.…”

Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

“…The two most commonly reported side effects with injectable sCT were a transient nausea with or without vomiting and a local site injection inflammatory response. Both of these side effects occur with a frequency of 10% in treated patients, while "loss of appetite" or "reduced body weight" has not been extensively reported with sCT treatments for osteoporosis (Miacalcin, Novartis product literature, 2002) (35,39). More preclinical research is needed to clarify the discrepancy between the potent anorexigenic effect produced with low doses of sCT and the decrease in hypercalcemia and suppression of bone resorption shown with hundred-or thousand-fold higher doses of sCT used to treat bone maladies.…”

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

“…(45) The presence of inhibition of bone resorption with limited effect on bone formation has also been shown with oral calcitonin. (46) A third question is an apparent anabolic effect of CT-NS on trabecular microarchitecture (significant improvement in apparent BV/TV, and apparent trabecular number and spacing, at region 1 of the radius, but not when the means of regions 1-4 were assessed). Whereas Farley et al (47) and Furuichi et al (48) have suggested in vitro, or in vivo animal, effects of CT-NS on bone formation, such findings have been relatively unique, and a possible anabolic effect remains hypothetical.…”