BACKGROUND-Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.

BACKGROUND Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations. METHODS We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed. RESULTS The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced. CONCLUSIONS The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men.

BACKGROUND Unlike most chronic diseases, approved osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of most osteoporosis drugs remains controversial due to efficacy and safety concerns. Thus, many patients are treated with the sequential use of two or more therapies. Discontinuing teriparatide and denosumab, two of our most potent agents, results in rapidly declining bone mineral density (BMD). It is unknown if switching from one therapy to another prevents this decline or further increases BMD. METHODS This study is a pre-planned extension of the Denosumab and Teriparatide Administration study (DATA), a 24-month study in which 94 postmenopausal osteoporotic women were randomized to receive 24-months of teriparatide (20-μg-daily), denosumab (60-mg-every-6-months), or both drugs. In this extension trial, women originally assigned to 24-months of teriparatide received 24-months of denosumab whereas subjects originally randomized to 24-months of denosumab received 24-months of teriparatide. Subjects who originally received both drugs, received an additional 24-months of denosumab alone. BMD at the hip, spine and wrist were measured 6,12,18, and 24 months after the drug transitions as were biochemical markers of bone turnover. FINDINGS Transitioning from teriparatide or combination therapy to denosumab further increases BMD whereas switching from denosumab to teriparatide results in transient bone loss at the spine and hip and progressive loss at the radius shaft. After 48-months, spine BMD increased by18.3±8.5%, 14.0±6.7%, and 16.0±4.1% in the teriparatide-to-denosumab, denosumab-to-teriparatide, and combination-to-denosumab groups, respectively (P=NS for between-group comparisons). Conversely, total hip BMD increased most in the combination-to-denosumab group (8.6±3.0%), intermediately in the teriparatide-to-denosumab group (6.6±3.3%) and least in the denosumab-to-teriparatide group (2.7±3.3%), (P<0.05 for all between-group comparisons). Femoral neck BMD changes resembled those at the total hip. After 48-months, radius BMD was unchanged in the teriparatide-to-denosumab group (0.0±2.9%), decreased by −1.8±5.9% in the denosumab-toteriparatide group, and increased by 2.8±3.2% in the combination-to-denosumab group (P<0.01 combination-to-denosumab versus both other groups). INTERPRETATION In postmenopausal osteoporotic women switching from teriparatide to denosumab, BMD continued to increase whereas switching from denosumab to teriparatide results in progressive or transient bone loss. Combination denosumab/teriparatide therapy followed by denosumab alone results in the largest 4-year increases in hip and wrist BMD. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients.

Context Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone. Objective The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent. Design Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 μg daily), denosumab (60 mg every 6 months), or both medications for 24 months. Participants Participants were 94 postmenopausal women with osteoporosis. Outcome Measures Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured. Results At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy. Conclusions Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.

Compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. Moreover, the abaloparatide-induced BMD increases at the total hip are greater than with the marketed dose of teriparatide. These results support the further investigation of abaloparatide as an anabolic therapy in postmenopausal osteoporosis.

Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.

The physiologic role of androgens and estrogens in the maintenance of normal bone turnover in men is a fundamental issue in bone biology. To address this question, we randomized 70 men between the ages of 20 and 44 yr to receive one of three treatment regimens. Group 1 (n = 25) received a GnRH analog (goserelin acetate 3.6 mg by sc injection every 4 wk) alone for 12 wk to suppress endogenous gonadal steroids to prepubertal levels. Group 2 (n = 22) received goserelin plus transdermal testosterone (Androderm 5 mg topically daily) to normalize circulating testosterone and estradiol levels. Group 3 (n = 23) received goserelin plus testosterone plus an aromatase inhibitor (anastrozole 1 mg orally daily) to induce selective estrogen deficiency. The selective effects of androgens and estrogens on skeletal homeostasis were then assessed by measuring changes in biochemical markers of bone turnover and analyzing the between-group differences. Bone resorption markers increased in both the hypogonadal group (group 1) and in the group with selective estrogen deficiency (group 3). Urinary deoxypyridinoline excretion increased more in group 1 than in group 3 (P = 0.023), suggesting a significant effect of androgens on bone resorption, whereas serum N-telopeptide levels increased more in group 3 than in group 2 (P = 0.037), suggesting a significant effect of estrogen on bone resorption. Bone formation markers initially declined in all groups and then increased in groups 1 and 3. The between-group comparisons were consistent for all formation markers. Bone formation markers increased more in group 1 than in group 2 (P = 0.001, 0.037, 0.005 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Bone formation markers also increased more in group 1 than in group 3 but these differences were not statistically significant (P = 0.065 0.073, 0.099 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Taken together, these data suggest that both androgens and estrogens play independent and fundamental roles in regulating bone resorption in men. These data also suggest that androgens may play an important role in the regulation of bone formation in men.

METHODS.One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS.As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS.Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION. ClinicalTrials.gov, NCT00114114.FUNDING. AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.