Tag Archives: trial

Romosozumab Phase I Trial Increased Bone Density

Abstract

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody.

Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation.

Padhi D, Jang G, Stouch B, Fang L…
J. Bone Miner. Res. Jan 2011
PMID: 20593411

Blosozumab Phase 2 Trial Increased Bone Density

Abstract

A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density.

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.

Recker RR, Benson CT, Matsumoto T, Bolognese MA…
J. Bone Miner. Res. Feb 2015
PMID: 25196993 | Free Full Text

Blosozumab: Eli Lilly’s New Sclerostin Inhibitor

Blosozumab is a new sclerostin inhibitor developed by Eli Lilly. According to Wikipedia:

Phase II trial of a monoclonal human antibody to sclerostin from Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group.

Romosozumab: Amgen’s New Sclerostin Inhibitor

Romosozumab is a new Sclerostin Inhibitor from Amgen. Specifically it is a humanized monoclonal antibody that targets sclerostin for the treatment of osteoporosis. According to Wikipedia:

Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys. In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated. In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than bisphosphonate and teriparatide treatment….

The Amgen drug is expected to be on the market in 2017 and is predicted to be the gold standard in osteoporosis treatment by 2021.

Review: Sclerostin Inhibition: A New Approach

Abstract

Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis.

Osteoporosis and osteoporosis-related fractures are growing problems with the aging population and are associated with significant morbidity and mortality. At this time, other than parathyroid hormone analogs, all therapies for osteoporosis are antiresorptive. Therefore, researchers have focused efforts on development of more anabolic therapies. Understanding of the Wnt signaling pathway, which is critical for skeletal development, and the role of sclerostin in inhibition of Wnt signaling has led to the discovery of a novel therapeutic approach in the treatment of osteoporosis – sclerostin inhibition. In this review, we discuss the biology of Wnt signaling and sclerostin inhibition. We then discuss human disorders of decreased sclerostin function and animal models of sclerostin inhibition. Both have served to elucidate the effects of decreased sclerostin levels and function – increased bone mass and strength and fewer fractures. In addition, we review data from Phase I and II studies of the two humanized sclerostin monoclonal antibodies, romosozumab and blosozumab, both of which have had positive effects on bone mineral density. We conclude with a discussion of the ongoing Phase III studies of romosozumab. The available data support the potential for neutralizing sclerostin monoclonal antibodies to serve as anabolic agents in the treatment of osteoporosis.

Shah AD, Shoback D, Lewiecki EM
Int J Womens Health 2015
PMID: 26082665

High-Protein Short-Term Diets are Not Detrimental to Bone

Abstract

Calcium homeostasis and bone metabolic responses to high-protein diets during energy deficit in healthy young adults: a randomized controlled trial.

Although consuming dietary protein above current recommendations during energy deficit (ED) preserves lean body mass, concerns have been raised regarding the effects of high-protein diets on bone health. The objective was to determine whether calcium homeostasis and bone turnover are affected by high-protein diets during weight maintenance (WM) and ED.

In a randomized, parallel-design, controlled trial of 32 men and 7 women, volunteers were assigned diets providing protein at 0.8 [Recommended Dietary Allowance (RDA)], 1.6 (2 × RDA), or 2.4 (3 × RDA) g · kg(-1) · d(-1) for 31 d. Ten days of WM preceded 21 d of ED, during which total daily ED was 40%, achieved by reduced dietary energy intake (∼30%) and increased physical activity (∼10%). The macronutrient composition (protein g · kg(-1) · d(-1) and % fat) was held constant from WM to ED. Calcium absorption (ratio of (44)Ca to (42)Ca) and circulating indexes of bone turnover were determined at day 8 (WM) and day 29 (ED).
Regardless of energy state, mean (±SEM) urinary pH was lower (P < 0.05) at 2 × RDA (6.28 ± 0.05) and 3 × RDA (6.23 ± 0.06) than at the RDA (6.54 ± 0.06). However, protein had no effect on either urinary calcium excretion (P > 0.05) or the amount of calcium retained (P > 0.05). ED decreased serum insulin-like growth factor I concentrations and increased serum tartrate-resistant acid phosphatase and 25-hydroxyvitamin D concentrations (P < 0.01). Remaining markers of bone turnover and whole-body bone mineral density and content were not affected by either the protein level or ED (P > 0.05).
These data demonstrate that short-term consumption of high-protein diets does not disrupt calcium homeostasis and is not detrimental to skeletal integrity.

Cao JJ, Pasiakos SM, Margolis LM, Sauter ER…
Am. J. Clin. Nutr. Feb 2014
PMID: 24284444

Oral Calcitonin Phase 3 Trail

Abstract

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial.

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2  mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000  mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis.

Binkley N, Bolognese M, Sidorowicz-Bialynicka A, Vally T…
J. Bone Miner. Res. Aug 2012
PMID: 22437792

From Tarsa Therapeutics’ web site:

Tarsa Therapeutics in conjunction with Unigene Laboratories has developed a once-daily oral tablet version of calcitonin. This proprietary technology prevents the degradation of calcitonin in the gastrointestinal system and assists its transit across the cells lining the intestine and into the bloodstream.

Nitroglycerin Modestly Increases Bone Density and Decreased Resorption in Postmenopausal Women

Abstract

Effect of nitroglycerin ointment on bone density and strength in postmenopausal women: a randomized trial.

Nitroglycerin stimulates bone formation and inhibits bone resorption, is inexpensive, and is widely available. Its effects on bone density, bone structure, and bone strength are unknown. To determine if nitroglycerin increases lumbar spine bone mineral density (BMD) and to evaluate changes in hip BMD, bone geometry, and density at the radius and tibia, and markers of bone turnover.

A single-center, double-blind, placebo-controlled randomized trial conducted in Toronto, Ontario, Canada, for 24 months starting in November 2005 and completed in March 2010, of 243 postmenopausal women with lumbar spine T scores of between 0 and -2.0 who completed a 1-week run-in period taking nitroglycerin ointment. Intervention Nitroglycerin ointment (15 mg/d) or placebo applied at bedtime for 24 months.
Areal BMD at the lumbar spine, femoral neck, and total hip. Secondary outcomes included indices of bone geometry and strength at the distal radius and tibia, and biomarkers of bone formation (bone-specific alkaline phosphatase) and bone resorption (urine N -telopeptide).
At 2 years, women randomized to the nitroglycerin group had significant increases in areal BMD at the lumbar spine (from 1.05 to 1.14 g/cm(2) vs placebo from 1.06 to 1.08 g/cm(2); percentage change, 6.7%; 95% confidence interval [CI], 5.2%-8.2%; P < .001); total hip (from 0.92 to 0.97 g/cm(2) vs placebo from 0.93 to 0.92 g/cm(2); 6.2%; 95% CI, 5.6%-7.0%; P < .001); and femoral neck (from 0.88 to 0.93 g/cm(2) vs placebo from 0.87 to 0.86 g/cm(2); 7.0%; 95% CI, 5.5%-8.5%; P < .001). At 2 years, nitroglycerin also increased volumetric trabecular BMD (11.9% and 8.5%), cortical thickness (13.9% and 24.6%), periosteal circumference (7.4% and 2.9%), polar section modulus (10.7% and 9.8%), and polar moment of inertia (7.3% and 14.5%) at the radius and tibia, respectively (all P < .001); and increased bone-specific alkaline phosphatase by 34.8% and decreased urine N -telopeptide by 54.0% (P < .001). Incidence of serious adverse events did not differ between nitroglycerin (5 [4.2%]) and placebo (5 [4.3%]) groups. Among those women who continued treatment for 24 months, headaches were reported by 40 (35%) in nitroglycerin and 6 (5.4%) in placebo groups during the first month, decreasing substantially after 12 months.
Among postmenopausal women, nitroglycerin ointment modestly increased BMD and decreased bone resorption.

Jamal SA, Hamilton CJ, Eastell R, Cummings SR
JAMA Feb 2011
PMID: 21343579

There is a published comment on this study: Nitroglycerin needs more study.