Osteoporosis Therapy Pipeline Is Chock Full
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14 Osteoporosis R HEUMATOLOGY N EWS • October 2006 Osteoporosis Therapy Anastrozole Shaves Bone Density, Pipeline Is Chock Full But Wards Off Breast Ca Recurrence BY JANE SALODOF MACNEIL About a third of the anastrozole patients had BY ROBERT FINN an NDA is planned for 2007 for a Southwest Bureau not reached 5 years of follow-up, however. San Francisco Bureau combination of bazedoxifene and es- They were categorized as “not recorded” in Dr. trogen for osteoporosis treatment ATLANTA — Anastrozole decreased bone Coleman’s analysis. S AN F RANCISCO — “It’s a pret- and possible premenopausal use. Re- mineral density by an average of 6.1% in the In a discussion of the trial, Dr. Julie Gralow, ty exciting time for drug develop- sults from a phase III trial of arzox- lumbar spine and 7.2% in the hip over the 5 of the University of Washington, Seattle, ex- ment in osteoporosis,” Dr. Deborah ifene are not expected until 2010. years that postmenopausal breast cancer pa- cluded the 27 unrecorded patients, 6 of whom Sellmeyer said at a meeting on os- Tibolone is a drug that “likes every tients were enrolled in a study presented by Dr. started out with normal BMD, from a recal- teoporosis sponsored by the Uni- steroid receptor it ever met,” in Dr. Robert E. Coleman at the annual meeting of culation of the data. When she looked only at versity of California, San Francisco. Sellmeyer’s words. Its three metabo- the American Society of Clinical Oncology. patients for whom 5-year data were available, While joking that her information lites separately have affinities for es- Osteoporosis risk appeared limited to women she found that 53% of the women who start- was “sourced from Google and ru- trogen, progesterone, and androgen who were osteopenic before starting treatment ed with normal BMD became osteopenic on mor and various investment receptors. A recently completed 24- with anastrozole (Arimidex), an aromatase in- anastrozole. brochures,” Dr. Sellmeyer, director month prevention trial in 90 women hibitor. Less clear was the likelihood of pro- That anastrozole caused bone loss was no of the Center for Osteoporosis at showed no difference in vaginal spot- gression to osteopenia in women who started surprise to Dr. Coleman and his coinvestigators. the university, listed some of the ting between tibolone and placebo. out with normal bone mineral density (BMD). The 9,366-patient ATAC trial reported that the osteoporosis drugs in the pipeline. Interestingly, the women taking All the women who became osteoporotic— aromatase inhibitor was more effective than A fracture trial for a full-length placebo experienced a 12% weight four treated with anastrozole and one who was tamoxifen at preventing breast cancer recur- version of parathy- gain, while the women treated with tamoxifen—were osteopenic be- rences and had fewer side effects overall. Frac- roid hormone (PTH Tibolone is a taking tibolone experi- fore they began adjuvant hormonal therapy in tures were an exception, however, occurring in [1-84]) has been com- drug that ‘likes enced no average the Arimidex, Tamoxifen, Alone or in Combi- 11% of women on anastrozole but in only 7.7% pleted, and a new weight gain. A multi- nation (ATAC) trial. of those on tamoxifen (Lancet 2005;365:60-2). drug application every steroid national fracture study “No patient with normal bone at baseline be- “Anastrozole suppresses postmenopausal (NDA) was submit- receptor it ever involving 4,000 women came osteoporotic after 5 years of treatment,” estradiol levels by about 97%, so one would an- ted to the Food and is expected to conclude Dr. Coleman, a professor of medical oncolo- ticipate it would have an effect on bone health,” Drug Administration met,’ and was sometime in 2006. gy at Weston Park Hospital in Sheffield, Eng- Dr. Coleman said, noting that the bone-loss in July 2005. found in a recent It’s been known for land, said in his report on a subset of 167 study was planned when the trial was designed. Meanwhile, in- decades that stron- women who were tracked for bone loss. Tamoxifen increases estradiol levels and was haled-powder and study to not tium improves bone Among 81 patients tracked in the anastro- associated with significantly less bone loss for oral forms of PTH cause any mineral density zole arm of the trial, just 13 had normal BMD 86 women in the other arm of the study. Their are in phase I and (BMD), but it was nev- after 5 years. All but one had been classified as average BMD loss was just 2.8% in the lumbar phase II trials, and at average weight er developed for os- having normal bone before the study started. spine and 0.7% in the hip. least one PTH ana- gain. teoporosis prevention The group of patients identified as os- Despite greater bone loss with anastrozole, logue is in phase III. or treatment because teopenic after 5 years was more mixed, com- he said its “superior efficacy and better overall “Everyone’s looking for the magic it’s a nonpatentable chemical ele- prising 14 women who entered the study with tolerability, compared with tamoxifen” would combination that will be able to ment. Recently, however, a propri- normal BMD and 21 who were osteopenic at continue to give anastrozole the advantage in replicate the PTH skeletal effect and etary formulation of strontium— the outset. Dr. Coleman calculated that 17% of a risk-benefit analysis. get rid of the hypercalcemic effect,” strontium ranelate—has shown patients on anastrozole progressed from nor- AstraZeneca provided research funds and Dr. Sellmeyer said. some promise. A granular form has mal BMD to osteopenia during the study. honoraria. ■ Oral calcitonin preparations are in already been approved for use in phase I and phase II. And low-dose Europe and the United Kingdom, and ultralow-dose estrogen remain and a once-a-day pill finished a phase fertile areas of research. The hope is I trial in September 2005. Strontium Strontium Ranelate Shows 5-Year Benefit that these preparations will repli- ranelate is likely to complicate in- cate the beneficial bone effects of es- terpretation of BMD testing, since it T ORONTO — The extension phases of two which time treatment was associated with a trogen while avoiding its harmful has a higher density than calcium. large trials evaluating strontium ranelate for the 41% risk reduction for vertebral fractures (N. vascular effects. While two low-dose Denosumab, also known as AMG prevention of osteoporotic fractures have shown Engl. J. Med. 2004;350:459-68). patches and one low-dose pill have 162, is a monoclonal antibody that that the efficacy previously seen at 3 years holds In the second trial, the Treatment of Pe- already been approved for the pre- appears to decrease bone resorp- up during years 4 and 5, Dr. Jean-Yves Reginster ripheral Osteoporosis (TROPOS) study, treat- vention of osteoporosis and for the tion. Currently in a phase III fracture said at a world congress on osteoporosis. ment with 2 g/day strontium ranelate among treatment of vasomotor symptoms, trial on postmenopausal women, Efficacy of strontium ranelate was con- 5,091 postmenopausal women with osteo- no fracture data are yet available. denosumab will require two subcu- firmed for both vertebral and nonvertebral porosis was associated with a 16% relative risk Zoledronic acid, a once-a-year in- taneous injections per year. fractures, Dr. Reginster said. reduction for all nonvertebral fractures at 3 travenous bisphosphonate, is cur- Isosorbide mononitrate, long After 4 years of treat- years and a 39% reduc- rently approved for hypercalcemia of used for the pain of angina, appears ment, patients in the tion for vertebral frac- malignancy and is now in a phase III to improve several bone markers in Spinal Osteoporosis After 4 years, tures (J. Clin. En- trial to determine whether it pre- postmenopausal women. A BMD Therapeutic Interven- patients taking docrinol. Metab. 2005; vents osteoporotic fractures. This trial is currently underway. tion (SOTI) trial ran- strontium ranelate 90:2816-22). agent is likely to benefit people who β-Blockers constitute another domized to receive had a significant At 5 years, the rela- cannot tolerate oral bisphospho- class of drugs that may well have strontium ranelate had 33% reduction tive risk reduction for nates, people in assisted-living situa- bone effects. Most epidemiologic a significant 33% reduc- in risk. nonvertebral fractures tions, and people who have difficul- studies associate use of β-blockers tion in risk of new ver- was 15%, and for verte- ty remembering to take medication. with increases in BMD and decreas- tebral fractures com- DR. REGINSTER bral fractures the risk re- There are several new selective es- es in fractures. Randomized trials pared with on placebo, duction was 24%. trogen receptor modulators under are needed to determine whether β- said Dr. Reginster of the University of Liège, Patients in this study were older, averaging development, with three—lasofox- blockers actually have a place in os- Belgium. The trial included 1,649 women with 76.7 years, Dr. Reginster said. Mean femoral ifene, bazedoxifene, and arzoxifene— teoporosis prevention or treatment. postmenopausal osteoporosis whose mean age neck T score was –3.1. With regard to safety, in phase III or beyond. An NDA for Finally, there are several new was 69 years and whose mean lumbar spine no new concerns arose. “Among all patients at lasofoxifene was submitted to the agents with previously untried bone mineral density T score was –3.6. They the beginning of the trials there was a slight in- FDA in 2004, but the manufacturer mechanisms of action in the were recruited from 72 centers in 11 European crease in the incidence of deep vein thrombo- apparently received a nonapprovable pipeline.