Among postmenopausal women with osteoporosis and a high risk of fracture, treatment with the monoclonal antibody romosozumab for 12 months followed by alendronate resulted in a significantly lower ...risk of fracture than alendronate for 12 months followed by alendronate.
Summary Background Unlike most chronic diseases, 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 osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments. Methods This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to teriparatide received denosumab (teriparatide to denosumab group), those originally assigned to denosumab received teriparatide (denosumab to teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00926380. Findings Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18·3% (95% CI 14·9–21·8) in 27 women in the teriparatide to denosumab group, 14·0% (10·9–17·2) in 27 women the denosumab to teriparatide group, and 16·0% (14·0–18·0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0·13 for the teriparatide to denosumab group vs the denosumab to teriparatide group, p=0·30 for the teriparatide to denosumab group vs the combination to denosumab group, and p=0·41 for the denosumab to teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the teriparatide to denosumab group (6·6% 95% CI 5·3–7·9) than in the denosumab to teriparatide group (2·8% 1·3–4·2, p=0·0002), but had the greatest increase in the combination to denosumab group (8·6% 7·1–10·0; p=0·0446 vs the teriparatide to denosumab group, p<0·0001 vs the denosumab to teriparatide group). Similarly, femoral neck bone mineral density increased more in the teriparatide to denosumab group (8·3% 95% CI 6·1–10·5) and the combination to denosumab group (9·1% 6·1–12·0) than in the denosumab to teriparatide group (4·9% 2·2–7·5; p=0·0447 for teriparatide to denosumab vs denosumab to teriparatide, p=0·0336 for combination to denosumab vs denosumab to teriparatide). Differences between the combination to denosumab group and the teriparatide to denosumab group did not differ significantly (p=0·67). After 48 months, radius bone mineral density was unchanged in the teriparatide to denosumab group (0·0% 95% CI −1·3 to 1·4), whereas it decreased by −1·8% (−5·0 to 1·3) in the denosumab to teriparatide group, and increased by 2·8% (1·2–4·4) in the combination to denosumab group (p=0·0075 for the teriparatide to denosumab group vs the combination to denosumab group; p=0·0099 for the denosumab to teriparatide group vs the combination to denosumab group). One participant in the denosumab to teriparatide group had nephrolithiasis, classified as being possibly related to treatment. Interpretation In postmenopausal osteoporotic women switching from teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients. Funding Amgen, Eli Lilly, and National Institutes of Health.
This study shows that in postmenopausal women with low bone mineral density, the monoclonal antibody romosozumab, which binds to sclerostin, an osteoblast-activity inhibitor, was associated with ...increased bone mineral density and bone formation and decreased bone resorption.
Osteoporosis is characterized by low bone mass and defects in microarchitecture that are responsible for decreased bone strength and increased risk of fracture.
1
Antiresorptive drugs for osteoporosis increase bone mineral density and prevent the progression of structural damage but may not restore bone structure. Stimulation of bone formation is necessary to achieve improvements in bone mass, architecture, and strength.
Sclerostin, encoded by the gene
SOST,
is an osteocyte-secreted glycoprotein that has been identified as a pivotal regulator of bone formation. By inhibiting the Wnt and bone morphogenetic protein signaling pathways, sclerostin impedes osteoblast proliferation and function, thereby decreasing bone formation. . . .
Summary
We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There ...was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication.
Introduction
Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers.
Methods
Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53–84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35–40 years).
Results
Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI −63 % (difference 13 %, 95 % CI 0 to 27.1,
P
= 0.049) and good compliance −67 % (difference 15.9 %, 95 % CI 6.3 to 25.5,
P
= 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3,
P
= 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate.
Conclusions
Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.
This multicenter trial evaluated zoledronic acid versus placebo in men with osteoporosis for a primary end point of new morphometric vertebral fracture over 24 months. Zoledronic acid was associated ...with a significantly reduced risk of vertebral fracture.
Osteoporosis is an important cause of morbidity and mortality among men.
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,
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Among persons older than 50 years of age, approximately 40% of all osteoporotic fractures worldwide occur in men.
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Mortality after osteoporotic fracture is higher among men than among women.
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,
4
Previous studies involving men with osteoporosis have focused on the surrogate outcomes of bone mineral density and bone-turnover markers,
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–
9
but data from double-blind, randomized studies assessing antifracture efficacy are lacking. In addition, given the low awareness of the disease,
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the development of guidelines for the detection and treatment of osteoporosis in men has been limited.
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Hence, there . . .
Romosozumab binds sclerostin, increases bone formation, and decreases bone resorption. Postmenopausal women with osteoporosis were assigned to romosozumab or placebo for 1 year, followed by 1 year of ...denosumab. Romosozumab was associated with lower vertebral and clinical fracture risk.
Osteoporosis can lead to fragility fractures, which result in clinical burden and increased mortality.
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,
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Even after a fracture, fewer than 25% of patients receive pharmacologic treatment for osteoporosis.
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–
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After the discovery that sclerostin deficiency causes rare genetic conditions that are characterized by high bone mass and resistance to fracture,
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,
7
sclerostin became a therapeutic target for the treatment of osteoporosis. Sclerostin, a negative regulator of bone formation that is secreted by osteocytes,
8
inhibits Wnt signaling, down-regulating this stimulus for osteoblast development and function.
9
Romosozumab (Amgen and UCB Pharma) is a monoclonal antibody that binds and inhibits sclerostin, with . . .
: Considerable attention has recently focused on dietary protein's role in the mature skeleton, prompted partly by an interest in nonpharmacologic approaches to maintain skeletal health in adult ...life.
The aim was to conduct a systematic review and meta-analysis evaluating the effects of dietary protein intake alone and with calcium with or without vitamin D (Ca±D) on bone health measures in adults.
Searches across 5 databases were conducted through October 2016 including randomized controlled trials (RCTs) and prospective cohort studies examining
) the effects of "high versus low" protein intake or
) dietary protein's synergistic effect with Ca±D intake on bone health outcomes. Two investigators independently conducted abstract and full-text screenings, data extractions, and risk of bias (ROB) assessments. Strength of evidence was rated by group consensus. Random-effects meta-analyses for outcomes with ≥4 RCTs were performed.
Sixteen RCTs and 20 prospective cohort studies were included in the systematic review. Overall ROB was medium. Moderate evidence suggested that higher protein intake may have a protective effect on lumbar spine (LS) bone mineral density (BMD) compared with lower protein intake (net percentage change: 0.52%; 95% CI: 0.06%, 0.97%,
: 0%;
= 5) but no effect on total hip (TH), femoral neck (FN), or total body BMD or bone biomarkers. Limited evidence did not support an effect of protein with Ca±D on LS BMD, TH BMD, or forearm fractures; there was insufficient evidence for FN BMD and overall fractures.
Current evidence shows no adverse effects of higher protein intakes. Although there were positive trends on BMD at most bone sites, only the LS showed moderate evidence to support benefits of higher protein intake. Studies were heterogeneous, and confounding could not be excluded. High-quality, long-term studies are needed to clarify dietary protein's role in bone health. This trial was registered at www.crd.york.ac.uk as CRD42015017751.
Summary
The 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.
Introduction
This 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.
Methods
Women 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.
Results
Throughout 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.
Conclusions
Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.
In this trial, women between the ages of 60 and 90 with low bone mineral density received twice-yearly subcutaneous injections of denosumab, a fully human monoclonal antibody against the receptor ...activator of nuclear factor-κB ligand, which inhibits the development and activity of osteoclasts, or placebo. Denosumab was associated with a reduced risk of vertebral, nonvertebral, and hip fractures.
Women between the ages of 60 and 90 with low bone mineral density received twice-yearly subcutaneous injections of denosumab, which inhibits the development and activity of osteoclasts, or placebo. Denosumab was associated with a reduced risk of vertebral, nonvertebral, and hip fractures.
Fractures are a major cause of disability and health care costs.
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,
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The use of denosumab is a novel approach to fracture prevention. It is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), a cytokine that is essential for the formation, function, and survival of osteoclasts.
3
By binding RANKL, denosumab prevents the interaction of RANKL with its receptor, RANK, on osteoclasts and osteoclast precursors and reversibly inhibits osteoclast-mediated bone resorption.
4
In previous trials, the subcutaneous administration of 60 mg of denosumab every 6 months reduced bone turnover and increased bone mineral density.
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–
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We . . .
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