SummaryThe FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile.IntroductionThis study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis.MethodsWomen who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively.ResultsThroughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed.ConclusionsDenosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.Electronic supplementary materialThe online version of this article (doi:10.1007/s00198-015-3234-7) contains supplementary material, which is available to authorized users.

We investigated the influence of menopause, age and sex on vitamin D metabolism in a large group of healthy women (n = 113) and men (n = 108) and in a group of early postmenopausal women (n = 124). Furthermore, we studied the vitamin D metabolism in 42 women with endometriosis. The vitamin D metabolites did not show dependence on age or on duration of menopause. The serum concentrations of vitamin D metabolites did not differ in normal men and women. There were highly significant seasonal oscillations for 25(OH)D and 24,25(OH)2D3 but not for 1,25(OH)2D. Women with endometriosis had significantly elevated serum 1,25(OH)2D compared to the normal women. Our study indicates that ageing is not associated with a significant depletion of 25(OH)D, 24,25(OH)2D or 1,25(OH)2D in normal men and women up to the age of 75 years. Furthermore, changes in vitamin D metabolism seem not to be an important factor in early postmenopausal bone loss. Our results on patients with endometriosis indicate that these patients may have some calcium-metabolic disturbances.

Hormone replacement therapy (HRT) prevents postmenopausal bone loss, but the prevalence of non-responders in healthy early postmenopausal women is not known. In order to study this, we reviewed data from three published studies, each carried out in a randomized, placebo-controlled, longitudinal design over 2 year, that used seven hormone replacement therapies. Bone mineral content (BMC) was measured in the distal forearm by single photon absorptiometry. A mathematical model for elimination of measurement errors was applied to published BMC data. After this correction, we found that only 1.2% of early healthy postmenopausal women who are receiving HRT in conventional doses will lose more than 1% of forearm BMC per year. In conclusion, most, if not all, healthy early postmenopausal women who might need HRT against loss of bone will respond positively in forearm BMC to such therapy.

The primary objective of this study was to investigate whether changes in the serum level of an endometrial secretory protein, placental protein 14 (PP14), can reflect endometrial adverse events induced by selective oestrogen receptor modulators (SERMs). A randomized, double-blind, placebo-controlled trial was used. Participants were healthy postmenopausal women aged 45-65 years, who received either various doses of raloxifene (30, 60 or 150 mg day-1) or levormeloxifene (1.25, 5, 10 or 20 mg day-1) or placebo for 12 months. Serum PP14 and endometrial thickness (ET) were monitored by radio-immunoassay and transvaginal ultrasonography, respectively. In the levormeloxifene trial, endometrial status at 12 months was assessed by hysteroscopy. Raloxifene induced only slight increases in serum PP14 and ET. Levormeloxifene, however, induced marked increases in both study parameters at all the does tested. The 6 month changes in PP14 showed a positive correlation with both the 6 and 12 month changes in ET (P < 0.001). Marked stromal oedema, pseudocysticity with or without hypervascularity and endometrial proliferation were seen on hysteroscopy in those showing the largest increases in serum PP14. These results suggest that the PP14 assay used on a group basis may provide useful information on the endometrial effects of SERMs administered in a given dose range, and thereby could assist future clinical trials aiming to find the optimal dose range of new SERMs.

Background Denosumab (DMAb) is an approved therapy for the treatment of postmenopausal women with osteoporosis at increased risk for fracture. The effects of DMAb treatment for up to 10 years are being evaluated in the 3-year FREEDOM study and its 7-year extension. Objectives To report the 5-year results of the FREEDOM extension study, representing up to 8 years of continued DMAb treatment. Methods During the extension, all women received 60 mg of DMAb every 6 months and daily calcium and vitamin D. In this analysis, women in the long-term group received 8 years of DMAb (3 years in FREEDOM and 5 years in the extension); women in the cross-over group received 5 years of DMAb (3 years of placebo in FREEDOM and 5 years of DMAb in the extension). Results Of the women who entered the extension, 66% completed the 5th year. With 8 years of DMAb treatment in the long-term group, mean bone mineral density (BMD) continued to increase from FREEDOM baseline for cumulative gains of 18.4% at the lumbar spine (LS) and 8.3% at the total hip (TH) (all p<0.0001). With 5 years of DMAb treatment in the cross-over group, there were mean BMD increases from extension baseline of 13.1% at the LS and 6.2% at the TH (all p<0.0001). Serum C-telopeptide was rapidly and similarly reduced after each DMAb dose, with the characteristic attenuation of effect at the end of the dosing period. Incidence of new vertebral and nonvertebral fracture continued to remain low throughout the extension; during year 8, hip fracture incidence was 0.2% and 0.1% for the long-term and cross-over groups, respectively. Overall incidences of adverse events (AEs) and serious AEs were consistent with data reported previously in the extension study. Conclusions DMAb treatment for up to 8 years was associated with continued increases in BMD, persistent reduction of bone turnover, and low fracture incidence. The benefit/risk profile for DMAb remains favorable. Disclosure of Interest C. Roux Grant/research support: Bongrain, Lilly, MSD, Consultant for: Amgen, MSD, Novartis, S. Papapoulos Consultant for: Amgen, Axsome, Gador, GSK, Merck, Speakers bureau: Amgen, Eli Lilly, GSK, Merck, Novartis, K. Lippuner Consultant for: Amgen, Eli Lilly, MSD, Takeda, UCB, C. Lin Shareholder of: Amgen Inc., Employee of: Amgen Inc., D. Kendler Grant/research support: Amgen, Astalis, Eli Lilly, Novartis, Pfizer, Consultant for: Amgen, Eli Lilly, Merck, Pfizer, Warner Chilcott, Speakers bureau: Amgen, Eli Lilly, Pfizer, E. M. Lewiecki Grant/research support: Amgen, Lilly, Merck, Consultant for: Agnovos, Amgen, Lilly, Merck, Radius Health, M. Brandi Grant/research support: Abiogen, Alexion, Amgen, Bruno, Eli Lilly, Farmaceutici, MSD, Servier, Shire, Stroder, Consultant for: Alexion, Servier, Speakers bureau: NPS, E. Czerwinski Grant/research support: Amgen Inc., Merck Serono, Servier, E. Franek Grant/research support: Amgen, Consultant for: Novartis, Speakers bureau: Amgen, MSD, Novartis, Servier, Teva, P. Lakatos Consultant for: Amgen, Lilly, Servier, Speakers bureau: Amgen, Lilly...