A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial.
The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis.
Binkley N, Bolognese M, Sidorowicz-Bialynicka A, Vally T…
J. Bone Miner. Res. Aug 2012
From Tarsa Therapeutics’ web site:
Tarsa Therapeutics in conjunction with Unigene Laboratories has developed a once-daily oral tablet version of calcitonin. This proprietary technology prevents the degradation of calcitonin in the gastrointestinal system and assists its transit across the cells lining the intestine and into the bloodstream.
Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget’s disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen(®) 8-(N-2hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC) (Emisphere Technologies, Cedar Knolls, NJ). Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis) failed to meet key end points, and in December 2011, Novartis Pharma AG announced that it would not pursue further clinical development of oral calcitonin for postmenopausal osteoporosis or osteoarthritis. A unique feature of calcitonin is that it is able to uncouple bone turnover, reducing bone resorption without affecting bone formation and therefore increasing bone mass and improving bone quality. This effect, however, may be dose-dependent, with higher doses inhibiting both resorption and formation. Because so many factors affect the pharmacokinetics and pharmacodynamics of calcitonin, especially orally administered calcitonin, much work remains to be done to explore the full pharmacologic spectrum and potential of calcitonin and determine the optimum dose and timing of administration, as well as water and food intake.
Hamdy RC, Daley DN
Int J Womens Health 2012
PMID: 23071417 | Free Full Text
Another successful way of formulating oral calcitonin is by using an acid-resistant enteric coating that prevents dissolution in the stomach and adding citric acid to the tablet core to inhibit intestinal proteases and enhance paracellular transport across the intestinal mucosa. This formulation also has been tested in Phase III studies.
Salmon calcitonin (Miacalcic ns 200 IU) in prevention of bone loss after hip replacement.
Loosening of a hip prosthesis after total arthroplasty is related to periprosthetic bone loss. Calcitonin has been used in the treatment of bone loss in osteoporosis and prevention of fractures. The main purposes of the study were firstly to evaluate the effect of calcitonin on periprosthetic bone after total hip arthroplasty, secondly investigate possible loosening of the prosthesis and thirdly examine further clinical outcome.
60 patients who underwent total hip arthroplasty using cemented Exeter prosthesis were randomized in the treatment group (salmon calcitonin 200 IU nasal spray daily + calcium 500 mg) and the placebo group (inactive nasal spray + calcium 500 mg) for six months. Bone mineral density (BMD) was measured from different locations at the time of discharge and after six and 12 months. Dynamic histomorphometry on bone biopsies taken from femoral collum was performed. Serum bone-specific alkaline phosphatase (BAP), serum osteocalcine (OC) and cross-linked N-telopeptides (NTX) were measured after one week, one month, three months and 12 months. Clinical manifestations and the incidence of fractures and loosening of the prosthesis were followed up to eight years.
Statistically there was not significant difference in bone histomorphometry between the groups. In both groups there was a significant BMD decrease in periprosthetic bone. However, the difference between the groups was not statistically significant. In the biochemical analysis NTX increased more in the Miacalcic group than in the placebo group (p = 0.013). There were no significant differences between the groups in serum BAP or OC even though the changes within the groups were statistically significant. No loosening of the prosthesis was seen during the follow-up and there was no need for revision of any reason. Four fractures were recorded in three patients. One patient sustained a periprosthetic fracture. All the patients with fractures were allocated in the placebo group.
Nasal salmon calcitonin 200 IU on a daily basis does not promote any additional value on calcium substitution to prevent bone loss after hip replacement. The durability of the Exeter prosthesis was good.
Scand J Surg 2012
PMID: 23238499 | Free Full Text