Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study

Previously we reported the results of a 4‐year extension of a 2‐year randomized placebo‐controlled trial showing that the antiresorptive effects of two annual 4‐mg doses of zoledronate in HIV‐infected men persisted for at least 5 years after the second dose. We set out to determine whether the effects on BMD and bone turnover persist beyond 10 years. We invited all participants in the original trial known to be alive and living in New Zealand to attend an additional visit approximately 12 years after trial entry and 11 years after their second dose of study medication. The outcome measures were BMD at the lumbar spine, proximal femur, and total body, and markers of bone turnover. Twenty‐five of the 43 men originally enrolled in the trial attended the final visit, representing 25 of 31 (81%) participants alive and residing in New Zealand at the time. The average duration of follow‐up was 12.4 years. At the final visit, BMD remained higher in the zoledronate group than the placebo group (lumbar spine 3.7%, 95% CI, 0.1 to 7.3; total hip 3.7%, 95% CI, 1.2 to 6.2; femoral neck 5.0%, 95% CI, 2.1 to 7.9; total body 2.4%, 95% CI, 0.7 to 4.0), and the between‐group differences in BMD remained stable between 6 and 12 years. Serum CTx remained lower in the zoledronate group than the placebo group between 6 and 12 years and, at the final visit, was 45% lower (95% CI, 25 to 64) than the placebo group. P1NP was 26% (95% CI, 4 to 48) lower in the zoledronate group than the placebo group at the final visit. In summary, two annual 4‐mg doses of zoledronate have effects on bone turnover and BMD in men that persist for at least 11 years after the second dose. © 2019 American Society for Bone and Mineral Research.

Section: Discussionmentioning

confidence: 88%

“…The persistence of effects of zoledronate also contrasts with changes after discontinuation of other osteoporosis agents. For example, after discontinuation of denosumab, odanacatib, romosozumab, oestrogen, and teriparatide, there are rapid increases in bone turnover and a rapid reduction in BMD to baseline levels …”

Section: Discussionmentioning

confidence: 99%

Effects of Intravenous Zoledronate on Bone Turnover and Bone Density Persist for at Least 11 Years in HIV-Infected Men

Bolland

Horne

Briggs

et al. 2019

“…Although the bone‐forming agents teriparatide and abaloparatide are US Food and Drug Administration (FDA) approved for the treatment of postmenopausal women with osteoporosis, agents with a different mechanism of action stand to offer additional therapeutic benefits. Patients receiving bone‐forming therapy should receive follow‐on therapy with an antiresorptive agent to maintain or further increase BMD, given that BMD increases attained with bone‐forming agents are reversible and osteoporosis—a chronic and progressive disease—requires ongoing management and, as reported, cessation of romosozumab therapy results in decrease in BMD toward baseline …”

Section: Introductionmentioning

confidence: 99%

One Year of Romosozumab Followed by Two Years of Denosumab Maintains Fracture Risk Reductions: Results of the FRAME Extension Study

Lewiecki

Dinavahi

Lazaretti‐Castro

et al. 2018

Self Cite

153

Romosozumab, a humanized monoclonal antibody that binds and inhibits sclerostin, has the dual effect of increasing bone formation and decreasing bone resorption. As previously reported in the pivotal FRActure study in postmenopausal woMen with ostEoporosis (FRAME), women with a T‐score of ≤ –2.5 at the total hip or femoral neck received subcutaneous placebo or romosozumab once monthly for 12 months, followed by open‐label subcutaneous denosumab every 6 months for an additional 12 months. Upon completion of the 24‐month primary analysis period, eligible women entered the extension phase and received denosumab for an additional 12 months. Here, we report the final analysis results through 36 months, including efficacy assessments of new vertebral, clinical, and nonvertebral fracture; bone mineral density (BMD); and safety assessments. Of 7180 women enrolled, 5743 (80%) completed the 36‐month study (2851 romosozumab‐to‐denosumab; 2892 placebo‐to‐denosumab). Through 36 months, fracture risk was reduced in subjects receiving romosozumab versus placebo for 12 months followed by 24 months of denosumab for both groups: new vertebral fracture (relative risk reduction [RRR], 66%; incidence, 1.0% versus 2.8%; p < 0.001), clinical fracture (RRR, 27%; incidence, 4.0% versus 5.5%; p = 0.004), and nonvertebral fracture (RRR, 21%; incidence, 3.9% versus 4.9%; p = 0.039). BMD continued to increase for the 2 years with denosumab treatment in both arms. The substantial difference in BMD achieved through 12 months of romosozumab treatment versus placebo was maintained through the follow‐up period when both treatment arms received denosumab. Subject incidence of adverse events, including positively adjudicated serious cardiovascular adverse events, were overall balanced between groups. In conclusion, in postmenopausal women with osteoporosis, 12 months of romosozumab led to persistent fracture reduction benefit and ongoing BMD gains when followed by 24 months of denosumab. The sequence of romosozumab followed by denosumab may be a promising regimen for the treatment of osteoporosis. © 2018 American Society for Bone and Mineral Research.

“…(3,4) Sclerostin, a key inhibitor of bone formation, was discovered through study of two rare syndromes of extreme high bone mass (HBM) due to mutations in SOST. (3,4) Sclerostin, a key inhibitor of bone formation, was discovered through study of two rare syndromes of extreme high bone mass (HBM) due to mutations in SOST.…”

Section: Introductionmentioning

confidence: 99%

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

Gregson

Bergen

Leo

et al. 2019

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.