Intended for healthcare professionals


Recombinant human parathyroid hormone

BMJ 2002; 324 doi: (Published 23 February 2002) Cite this as: BMJ 2002;324:435

Osteoporosis is proving amenable to treatment

  1. Jonathan Reeve, head of bone research group
  1. University Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ

    On 27 July the US Food and Drug Administration held a public hearing on an application for a licence for the use of recombinant human parathyroid hormone in the treatment of postmenopausal osteoporosis. The application, from Eli Lilly, is for teriparatide (Forsteo), the N-terminal fragment rhPTH(1-34). The hearing's advisory panel voted unanimously in favour of the parathyroid hormone and approval could be expected after resolution of a few technical concerns. The application was partly based on solid evidence that parathyroid hormone, given as a daily injection for several weeks or months in experimental animals, increases bone mass and strength.1 This evidence led to a multicentre randomised controlled trial in women with osteoporosis, which showed that treatment with parathyroid hormone reduced spine fractures by 66% to 90% (according to whether smaller fractures and those causing minor symptoms were counted) and other fractures by 50%.2

    The first experiments showing an anabolic effect of parathyroid hormone on bone in young rats took place in various North American laboratories between 1929 and 1937. Despite the stature of the investigators (including Fuller Albright and Hans Selye), these experiments were almost forgotten in the controversy over alternative biochemical theories for parathyroid hormone's mode of action.3 Edith Bülbring, who had been expelled from Berlin when Adolf Hitler came to power, had done a thesis on parathyroid hormone.4 She retained her early interest and encouraged others to pursue her previous work done in Berlin. When parathyroid hormone and calcitonin had both been purified, it was possible to determine that it was parathyroid hormone and not calcitonin that had an anabolic effect on bone in young rats.5

    The first studies on osteoporosis in humans were undertaken on a small group of severely affected patients who consented to an array of methods designed to monitor progress and safety.6 It was shown that the effect of parathyroid hormone depended on large increases in bone formation. Increases in cancellous (trabecular) bone of 70% above baseline in the ilium and 50% in the vertebral bodies were possible, with very small changes in radial or femoral shaft bone. 3 7 8 There was concern that parathyroid hormone had no discernible effect on dietary calcium absorption in patients whereas increased absorption was found in animals. This concern led to a number of randomised studies in which parathyroid hormone was used along with oestrogen or calcitriol—and to prevarication by a drug industry committed to calcitonin and vitamin D metabolites. 1 9

    A decade ago two related events occurred. Firstly, the US National Institutes of Health sponsored trials of sodium fluoride that showed big effects on bone mass without prevention of fractures.10 The Food and Drug Administration responded by establishing tougher standards for approving drugs to treat osteoporosis. These included the requirements firstly to show increased bone strength in two animal models and then to provide proof of efficacy against fractures in humans. Eventually, data from animal studies permitted the launch of the Lilly multicentre trial. Simultaneously, Lilly undertook a study in which rats were given extremely large doses of parathyroid hormone for well over a year—more than half a rat's lifespan. Some animals developed osteosarcomas, and consequently the human trial was stopped at just over the halfway point. The Food and Drug Administration concluded that the rat studies were not a realistic model of human treatment, because of the huge doses and long duration of treatment. Thus we may now have a treatment that needs to be given for only half the time originally expected. Careful monitoring will be needed to check that the incidence of osteosarcomas is not increased by treatment.

    What can we hope of parathyroid hormone for the future? Currently it seems to be the most effective treatment for osteoporosis, although this apparent advantage will certainly be contested by the promoters of bisphosphonates of proved effectiveness. Side effects have been few and mild. The need to inject the hormone with a penlike device, as used for insulin, is a slight nuisance, though perhaps preferable to the dyspepsia caused in some by bisphosphonates. A licence application for Europe is pending. We still need to evaluate the effectiveness of parathyroid hormone in other forms of osteoporosis, and already data indicate that it is effective in steroid induced osteoporosis and osteoporosis in men. 11 12 Undoubtedly, the minimum duration of treatment will be studied. We also need to know whether antiresorptive treatment should be started when parathyroid hormone treatment is stopped, to prevent subsequent loss of bone. 13 14

    Parathyroid hormone's biggest untested impact might be in the prevention of hip fractures, because it expands the bony envelope in the hip and elsewhere.5 From being one of medicine's most untreatable disorders, osteoporosis is following in the footsteps of hypertension and proving amenable to treatment through several targets: oestrogen receptors, osteoclasts (by targeting them with bisphosphonates), and now parathyroid hormone receptors. A fourth target just over the horizon might be the promotion of local nitric oxide synthesis in bone by statins.15


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    View Abstract