Is it time to combine osteoporosis therapies?

www.thelancet.com Published online May 15, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60984-8 1 Some therapies licensed to treat osteoporosis work by inhibiting bone turnover (anticatabolic agents) and some by stimulating bone formation (anabolic agents). In The Lancet, Joy Tsai and colleagues report an exciting new approach in which an anticatabolic drug, denosumab, is combined with an anabolic drug, teriparatide. Teriparatide comprises the fi rst 34 aminoacids of parathyroid hormone, and when given as a daily injection leads to an increase in bone-mineral density (BMD) of the spine and a reduction in spinal and nonspinal fracture risks. It was licensed in the UK in 2003, and is recommended by the National Institute for Health and Clinical Excellence for use in women who have severe osteoporosis and fragility fractures and in whom bisphosphonates have not been tolerated or have been ineff ective. Loss of BMD from the hip, however, is frequently seen in the fi rst 6 months of treatment, especially in patients who have previously been treated with bisphosphonates, although BMD does eventually increase over the recommended 2-year period of treatment. Avoidance of early bone loss in the hip would be preferable in order to prevent increased risk of hip fracture. A seemingly obvious way to prevent bone loss from the hip would be to combine teriparatide with a bisphosphonate. This approach has been tried with oral alendronic acid given at a dose of 10 mg per day, but the overall increase in BMD at the spine and hip was reduced in women with established osteoporosis. Similar results were seen in men who were given alendronic acid and teriparatide and when a similar anabolic drug, intact parathyroid hormone, was given with alendronic acid in women with established osteoporosis. These fi ndings were puzzling and led to the hypothesis that the inhibition of osteoclast survival by bisphosphonates also inhibits the secretion of an osteoclast-derived coupling factor that is necessary for the anabolic eff ect of teriparatide on osteoblasts. Zoledronic acid is a bisphosphonate administered as a 5 mg infusion once per year. It suppresses bone resorption more rapidly and to a greater extent than alendronic acid (table). Greater attenuation of the eff ect of teriparatide than of alendronic acid would, therefore, be expected. The opposite, however, has been noted. In a 1-year study of zoledronic acid and teriparatide, alone or combined, zoledronic acid prevented early bone loss at the hip, but no additional benefi t was seen at the spine compared with the eff ects of teriparatide alone. Thus, the hypothesis that the eff ect of teriparatide will be weakened might have to be altered to state that it applies only to anticatabolic therapies given orally on a daily basis. Denosumab is an anticatabolic drug that is given every 6 months by subcutaneous injection. It is an antibody to the receptor activator of nuclear factor κ B, and inhibits the key pathway by which osteoblasts and osteocytes regulate osteoclast activity. Bone resorption is more rapidly inhibited (within 24 h) than with zoledronic acid (table). Tsai and colleagues describe a study in which 100 postmenopausal women with osteoporosis were randomly assigned to treatment with teriparatide and denosumab, alone or combined. As judged by the trial’s primary endpoint, posterior-anterior lumbar spine BMD, combination therapy was better than either drug alone, yielding an increase of 9·1% (SD 3·9) at 12 months as compared with an increase of 6·2% (4·6) with teriparatide and 5·5% (3·3) with denosumab. Femoral-neck and total-hip BMD also improved more with combination treatment than with teriparatide or denosumab alone. Therefore, the Is it time to combine osteoporosis therapies?