Cacitonin-Salmon (Miacalcin, Fortical)
Calcitonin-salmon (Miacalcin, Novartis; Fortical, Upsher Smith) is a synthetic polypeptide of 32 amino acids found in salmon calcitonin. It is available in the U.S. in an intranasal form for daily use and in subcutaneous form for every-other-day use.
Calcitonin decreases bone resorption by reducing the activity and the number of osteoclasts. The antiresorptive activity of calcitonin is marked initially, but both antiresorptive and bone formation responses decrease over time. There is evidence in vitro that calcitonin may augment bone formation through increased osteoblast activity.
The efficacy and safety of intranasal calcitonin were established in the Prevent Recurrence of Osteoporotic Fractures (PROOF) trial. This large double-blinded, randomized, placebo-controlled study included 1,255 postmenopausal women who received 100 IU, 200 IU, 400 IU, or placebo daily for five years. Women receiving 200 IU, the approved dose in the U.S., experienced a 33% reduction in new vertebral fractures at five years (P = 0.03). The most commonly reported ADEs included rhinitis and back pain. eriacta 100 mg
Parathyroid Hormone (Teriparatide [Forteo])
Teriparatide (Forteo, Eli Lilly) contains the active 1-34 N-ter-minal amino-acid component of recombinant human PTH and is available as a subcutaneous injection for daily administra-tion. A bone anabolic agent, teriparatide encourages new bone formation on bone surfaces by stimulating osteoblast activity more than osteoclast activity. This agent appears to increase bone density and improve bone architecture.
The randomized, placebo-controlled Fracture Prevention Trial enrolled 1,647 postmenopausal women with a history of at least two mild vertebral fractures or one moderate vertebral fracture or BMD T-scores of less than -1.0 plus two or more moderate fractures.
Participants received teriparatide at 20 mcg daily, 40 mcg daily, or placebo. The women who received 20 mcg (the approved dose in the U.S.) had a 65% lower risk of one or more new vertebral fractures, compared with placebo, after an average follow-up period of 17 to 19 months (P < 0.05). The 20-mcg patients also had a 53% lower risk of nonvertebral fractures than women receiving placebo (P< 0.05).
In clinical studies, common ADEs associated with teriparatide included leg cramps and dizziness. Teriparatide was also associated with osteosarcoma in rats, and its labeling has a black-box warning against its use in patients with an increased risk of osteosarcoma. One case of osteosarcoma was reported in 300,000 patients treated with teriparatide worldwide, although an association between teriparatide and osteosarcoma was not established in this patient. Because of a potential risk of osteo-sarcoma and a lack of data on the drug’s long-term use, teri-paratide treatment should be limited to two years.
Products in Development
Strontium Ranelate (Protelos)
Strontium ranelate (Protelos, Servier), a compound consisting of the elemental metal, strontium, and ranelic acid, is approved in Europe and Australia for the treatment of PMO to reduce the risk of vertebral and hip fractures. A unique mechanism of action allows for continued bone formation while decreasing bone resorption. Two published clinical studies have shown its efficacy in the treatment of PMO.
In the Spinal Osteoporosis Therapeutic Intervention trial (SOTI), a three-year placebo-controlled, double-blinded study of 1,649 postmenopausal women with a history of one or more vertebral fractures and low BMD (below 0.840 g/cm2), subjects were randomly assigned to receive strontium ranelate 2 g daily or placebo. Over the three-year trial period, the strontium ranelate group of patients had a 41% lower risk of new vertebral fractures than the placebo group (P < 0.001).
The randomized, placebo-controlled Treatment of Peripheral Osteoporosis Study (TROPOS) included postmenopausal women aged 74 years or older with femoral neck T-scores of less than -2.5 or women 70 to 74 years of age but with at least one additional fracture risk factor. A total of 4,932 subjects received strontium ranelate 2 g daily or placebo for three years. Treatment was associated with a 39% reduction in vertebral fractures (P < 0.001) and a 16% reduction in the risk of nonvertebral fractures relative to placebo (P = 0.04). There was a 15% reduction in hip fracture risk with treatment, but the trend was not significant. However, the study was not powered to detect a difference in hip fracture.
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ADEs in clinical trials included transient nausea and diarrhea as well as dermatitis or eczema and headache. It is not known when approval for strontium ranelate will be sought.
Parathyroid Hormone (Preos)
PTH (1-84) (Preos, NPS Pharmaceuticals) is an anabolic agent under FDA review for the treatment of osteoporosis. Unlike teriparatide, it is a full-length human recombinant PTH. It increases bone density by stimulating bone formation and resorption, resulting in a net gain in bone formation.
Parathyroid Hormone (TOP) was a randomized, double-blind trial designed to study the efficacy of PTH (1-84) in preventing vertebral fractures in these groups of postmenopausal women:
In this study, 2,532 women were randomly assigned to receive PTH (1-84) 100 mcg/day or placebo. The treated women had a lower rate of new or worsened vertebral fractures than those taking placebo. The fracture rate was decreased by 58% (P < 0.05) with PTH (1-84), compared with placebo, if we assume that those who discontinued the trial early did not experience fractures. If we assume that the fracture rates in the group who discontinued equaled the rates for those who completed the trial, fractures were reduced by 40% with PTH (1-84), compared with placebo (P = 0.05). If we assume that those who discontinued the trial had fracture rates equal to those in the placebo group, PTH (1-84) reduced fractures by 38°% (P > 0.05). erectalis tablets
In clinical trials, ADEs reported with PTH (1-84) therapy at rates higher than placebo included injection-site reactions, transient hypercalcemia, hypercalciurea, and nausea. The FDA has issued an approvable letter for PTH (1-84), but approval has been delayed; the FDA is requesting more information about the incidence of hypercalcemia and the delivery device.