Oral salmon calcitonin reduces Lequesne's algofunctional index scores and decreases urinary and serum levels of biomarkers of joint metabolism in knee osteoarthritis.

OBJECTIVE: To evaluate the effects of oral salmon calcitonin (sCT) on Lequesne's algofunctional index scores and on biomarkers of joint metabolism in knee osteoarthritis. METHODS: In this randomized, double-blind trial, patients received either placebo (n = 18), 0.5 mg of sCT (n = 17), or 1 mg of sCT (n = 18) daily for 84 days. Biomarkers included C-telopeptide of type II collagen (CTX-II), type II collagen neoepitope C2C, collagenases (matrix metalloproteinase 1 [MMP-1], MMP-8, and MMP-13), stromelysin (MMP-3), tissue inhibitors of metalloproteinases 1 and 2, and hyaluronan. Statistical analysis included nonparametric tests. RESULTS: A total of 41 patients completed the study (13 in the group receiving 0.5 mg of sCT and 14 in each of the other 2 other groups). Although, on day 84, patients in both the placebo group and the group receiving 1 mg of sCT exhibited a similar significant decrease in pain scores, a significant reduction in the function score was observed only in the 2 sCT groups. On day 84, there was no significant decrease in biomarker levels in the placebo group, whereas significant reductions in the levels of both MMP-3 and hyaluronan were observed in the 2 sCT groups. The group of patients receiving 1 mg of sCT exhibited significant decreases in the levels of CTX-II, C2C, and MMP-13. CONCLUSION: By improving functional disability and by reducing levels of biomarkers that are thought to be predictive of joint space narrowing (and thus cartilage loss), oral sCT at a dose of 1 mg might be a useful pharmacologic agent in human knee OA

AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women

Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women.The first study, examined single ascending doses (4 to 120. mg) and limited multiple doses (60 or 120. mg. q.d. for 12. days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60. mg AXT914, placebo, 20. μg Forteo/teriparatide/PTH(1-34) fragment).AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4. weeks of 45 or 60. mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60. mg AXT914 treatment groups (8.0 % and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose-limiting effects on serum calcium.In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations. © 2014

Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib

Background: In a multicenter clinical trial in North America and Europe that tested the cathepsin K (catK) inhibitor balicatib for the treatment of osteoporosis, several patients developed hardening of the skin. Objective: We sought to characterize these observed adverse events. Methods: Patients with skin hardening were examined by a local dermatologist. All of those patients except one had at least one biopsy specimen taken from affected skin, which was read by local and two central dermatopathologists. Workup was directed for consideration of systemic scleroderma. Results: Nine patients of 709 treated with balicatib developed skin hardening and were given a diagnosis of morphea-like skin changes. No such events were observed in patients taking placebo or the lowest balicatib dose. After discontinuation of balicatib, skin changes resolved completely in 8 and partially in one patient. Limitations: Each patient was seen by a different dermatologist in 6 different countries. Conclusions: These observations are likely dose-related adverse effects of balicatib. Although catK was originally thought to be expressed only in osteoclasts, it has more recently also been found in lung and dermal fibroblasts and been implicated in the degradation of the extracellular matrix in the lung and the skin. It is therefore plausible that the observed dermal fibrosis in balicatib-treated patients is a result of impaired degradation of extracellular matrix proteins and may represent a class effect of catK inhibitors. We recommend that further exploration of catK inhibition for the treatment of osteoporosis or cancer should include monitoring for similar adverse effects

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. 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 vitarnin 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 (-60.8% to -81.8% 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 = 0.78, p < 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 (-18.9% and -20.5%, respectively, p < 0.05). The placebo-corrected change in OC was - 8.6 (p = 0.09), whereas the change in BSALP was -7.3 (p = 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