The Efficacy of Denosumab in Patients With Rheumatoid Arthritis: A Systematic Review and Pooled Analysis of Randomized or Matched Data

ObjectiveThe purpose of this study was to evaluate the efficacy of denosumab treatment in patients with rheumatoid arthritis (RA).MethodsThe Medline, Embase and Cochrane Library databases were searched for relevant clinical studies. Studies that assessed the efficacy of denosumab in patients with RA were identified. The primary endpoints were the percent changes in bone mineral density (BMD), and the changes in modified total Sharp score (mTSS), modified Sharp erosion score and joint space narrowing (JSN) score. Pooled analyses were calculated using random-effect models.ResultsAfter searching the literature and performing further detailed assessments, 10 studies with a total of 1758 patients were included in the quantitative analysis. Pooled analyses showed that denosumab treatment significantly increased the percent changes in lumbar spine BMD [mean difference (MD): 5.12, confidence intervals (CI): 4.15 to 6.09], total hip BMD (MD: 2.72, 95% CI: 1.80 to 3.64) and femoral neck BMD (MD: 2.20, 95% CI: 0.94 to 3.46) compared with controls. Moreover, denosumab treatment significantly decreased the changes in mTSS (MD: -0.63, 95% CI: -0.86 to -0.41) and modified Sharp erosion score (MD: -0.62, 95% CI: -0.88 to -0.35). Subgroup analysis indicated that denosumab was superior to bisphosphonates for the improvement of BMD and the mitigation of joint destruction.ConclusionDenosumab treatment was associated with increased BMD and alleviated progression of joint destruction in RA patients, even when compared with bisphosphonates.

17p-estradiol (1 mg daily) in continuous combination with dydrogesterone (5.10 or 20 mg daily) increases bone mineral density in postmenopausal women

Although the minimal dose of 17/3-estradiol in hormone replacement regimens was originally considered to be 2 mg a day, it is now increasingly accepted that a lower dose of 1 mg a day is effective in protecting women from the detrimental effects of the menopause. A 1-year, multicentre, double-blind, randomized study was conducted in 214 healthy postmenopausal women in order to assess the effect of 17(3-estradiol (1 mg a day) continuously combined with dydrogesterone (5,10 or 20 mg/day) in preventing bone loss. Bone mineral density (BMD) was evaluable in 177 women who completed the study. In all women, a statistically significant increase from baseline in lumbar vertebrae (L.2~L4) BMD was seen after 6 months (+ 2,4%; p0,01); this increase was somewhat greater after 12 months (+ 3,6%;p 0,01). Similar effects were seen in the hip. After 6 months, BMD in the femoral neck, Wards triangle and trochanter had increased by 0,20% (not significant [n.s.]), 0,32% (n.s.)and 1,08% (p0,01), respectively, compared with baseline. Greater increases were again seen after 12 months (+1,16%, + 1,62% and +2,83%, respectively), all of which were statistically significant (p0,01) compared with baseline. The change in BMD from baseline did not diff er significantly between the three dydrogesterone dosages for either L.2~L4 or hip. All dosages were well tolerated and amenorrhoea was achieved in over 70%. In conclusion, 17(3-estradiol (1 mg/day) continuously combined with dydrogesterone (5, 10 or 20 mg/day) results in a significant increase in lumbar vertebrae and hip BMD in postmenopausal women. The lower dose of oestrogen and the avoidance of cyclical bleeding make this a particularly suitable regimen for the prevention and treatment of osteoporosis in older women.

Composition of the body in male patients with rheumatoid arthritis with account of androgenic status

Aim. To evaluate alterations in body composition and bone mineral density (BMD) in male patients with rheumatoid arthritis (RA) taking into account their androgen status. Materials and methods. The single-stage study included 96 male RA patients. The mean age of patients was 59 [54; 64.75] years. The control group included 30 healthy men of comparable age. The androgen status assessment was based on sex hormone binding globulin (SHBG), total and free testosterone levels determination. Body composition and BMD measurements were performed using dual-energy X-ray absorptiometry (DXA) on the Stratos dR device (DMS, France) with the program “Whole Body”. Depending on the combination of BMD, lean- and fat-mass parameters, phenotypes of body composition were determined. The study was approved by Pirogov Russian National Research Medical University Local Ethics Committee. All patients signed informed consent.Results. Generally, lumbar spine, femoral neck and total hip BMD in RA patients was significantly less than in the control group (p<0.05). In 69 (71.9%) patients with RA osteopenic syndrome was detected. It was represented by osteopenia and osteoporosis (OP) in 60.4% and 11.5% of cases respectively. The spine and femoral neck BMD correlated negatively with SHBG level, and positive correlation was detected between BMD and free testosterone level. The RA patients had significantly less lean mass than the control group. Low lean mass was found in 48.9% of patients in the main group and was not detected in the control group. Appendicular lean mass (ALM) correlated positively with total and free testosterone levels. According to DXA data, the adipose tissue content (%) corresponded to obesity in 63.3% of patients. Adipose tissue indicators correlated negatively with SHBG, total and free testosterone levels. The BMD of various skeleton parts correlated positively with trunk lean mass, and the femoral neck and total hip BMD had positive relationships with body mass index (BMI). Body composition alterations were revealed in 93.2% of RA patients. The most common phenotypes were osteosarcopenic obesity (25%), osteopenic obesity (21.6%) and osteopenic sarcopenia (14.8%). Conclusion. Our study shows that RA course in men is associated with the development of osteopenic syndrome in 71.9% of cases and ALM decrease to diagnostic values of sarcopenia in 48.9% of cases. This fact should be considered in the development of a gender approach to RA patients management and rehabilitation.

Reduction in femoral neck and total hip bone mineral density following hospitalisation for diabetes-related foot ulceration

Management of diabetes-related foot ulceration (DFU) includes pressure offloading resulting in a period of reduced activity. The metabolic effects of this are unknown. This study aims to investigate changes in bone mineral density (BMD) and body composition 12 weeks after hospitalisation for DFU. A longitudinal, prospective, observational study of 22 people hospitalised for DFU was conducted. Total body, lumbar spine, hip and forearm BMD, and total lean and fat mass were measured by dual-energy X-ray absorptiometry (DXA) during and 12 weeks after hospitalisation for DFU. Significant losses in total hip BMD of the ipsilateral limb (− 1.7%, p < 0.001), total hip BMD of the contralateral limb (− 1.4%, p = 0.005), femoral neck BMD of the ipsilateral limb (− 2.8%, p < 0.001) and femoral neck BMD of the contralateral limb (− 2.2%, p = 0.008) were observed after 12 weeks. Lumbar spine and forearm BMD were unchanged. HbA1c improved from 75 mmol/mol (9.2%) to 64 mmol/mol (8.0%) (p = 0.002). No significant changes to lean and fat mass were demonstrated. Total hip and femoral neck BMD decreased bilaterally 12 weeks after hospitalisation for DFU. Future research is required to confirm the persistence and clinical implications of these losses.

Efficacy and Safety of Oral Ibandronate versus Intravenous Zoledronic Acid on Bone Metabolism and Bone Mineral Density in Postmenopausal Japanese Women with Osteoporosis

There are no published clinical reports comparing ibandronate (IBN) treatment and zoledronic acid (ZOL) treatment in Japanese postmenopausal osteoporotic patients. This investigation therefore compared the efficacy and safety of the drugs on improving bone metabolism and bone mineral density (BMD) in Japanese postmenopausal women with primary osteoporosis. Eighty-two treatment-naïve primary osteoporotic female patients were randomly divided into IBN-treated or ZOL-treated groups. Bone turnover markers and BMD were examined immediately prior to treatment (baseline) and at 6, 12, 18, 24, and 30 months of therapy. Compared with baseline levels, the values of type 1 procollagen N-terminal propeptide, bone-specific alkaline phosphatase (BAP), urinary type-I collagen amino-terminal telopeptide (NTX), and tartrate-resistant acid phosphatase 5b were all significantly decreased at every time point in both groups apart from BAP at 30 months in the ZOL group, urinary NTX at 12 months in the ZOL group and at 24 and 30 months in both groups. Lumbar BMD values were significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6 and 12 months in the ZOL group compared with pre-treatment levels. Hip BMD values were also significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6, 12, and 18 months in the ZOL group compared with baseline values. The percentage changes of hip BMD at 18 and 24 months in the ZOL group were significantly higher than those in the IBN group (both p < 0.05). No remarkable adverse events were noted in either group. In conclusion, both IBN and ZOL significantly and safely improved bone turnover markers and BMD during 30 months of treatment in Japanese osteoporosis patients. The ZOL group tended to exhibit greater gains in BMD as compared with the IBN group, which merits further investigation.

Association of Decreased Muscle Mass with Reduced Bone Mineral Density in Patients with Graves’ disease

Background The bone mineral density (BMD) did not increase significantly after the normalization of serum thyroid hormone levels. Studies on the effect of muscle mass on BMD in patients with Graves’ disease are scarce. This study aimed to determine the association of decreased muscle mass with reduced bone mineral density in patients with Graves’ disease. Methods A total of 758 patients with Graves’ at diagnosis (mean age 41.2 years) were enrolled for a cross-sectional study; of these, 287 patients were enrolled for a cohort study with a median follow-up of 24 months. Meanwhile, 1164 age- and sex-matched healthy controls participants were recruited. All participants underwent dual-energy x-ray absorptiometry and muscle mass index (ASMI) measurements. The changes in ASMI and BMD were calculated from the measurements made at a gap of 2 years. Results Compared with healthy controls participants, the BMD was still significantly lower after normalizing serum thyroid hormone levels (1.131 ± 0.268 vs. 1.07 ± 0.133, p < 0.05). ASMI was positively related to BMD in patients with Graves’ disease(lumbar BMD, r = 0.210; femoral neck BMD, r = 0.259;hip BMD, r = 0.235;P < 0.001) and this relationship still existed after successful anti-thyroid therapy(lumbar BMD, r = 0.169; femoral neck BMD, r = 0.281;hip BMD, r = 0.394;P < 0.001). Low muscle mass was associated with low BMD (OR, 1.426; 95% CI, 1.019–1.994). Moreover, improving the muscle mass led to changes in the bone mass of the femoral neck (OR, 0.420; 95% CI, 0.194–0.911) and hip (OR, 0.217; 95% CI, 0.092–0.511) during the follow-up period. However, this phenomenon was not observed in lumbar, and bone turnover markers. Conclusions The recovery of bone mass might be related to the recovery of muscle mass. Improving muscle mass might bring about changes in the bone mass of the femoral neck and hip. A site-related discrepancy was also observed. Patients with Graves’ disease should be helped in recovering muscle mass while administering anti-thyroid therapy.

Four-Year Teriparatide Followed by Denosumab vs. Continuous Denosumab in Glucocorticoid-Induced Osteoporosis Patients With Prior Bisphosphonate Treatment

ObjectivesIn our previous 24-month study, we observed that teriparatide had some advantages over denosumab for bone mineral density (BMD) in glucocorticoid-induced osteoporosis (GIO) patients with prior bisphosphonate treatment. We conducted this extension study to investigate whether the advantage of teriparatide obtained in the first 2 years would be maintained after the switch to denosumab.Materials and MethodsWe switched patients who had completed 24-month daily teriparatide treatment to denosumab (switch group, n=18) and compared their BMD every 6 months up to 48 months with the group who continued to receive denosumab (denosumab group, n=16).ResultsAt 48 months, the lumbar spine BMD was significantly increased from baseline in both groups (denosumab: 10.4 ± 8.7%, p&lt;0.001; switch: 14.2 ± 6.8%, p&lt;0.001). However, a significant increase in femoral neck BMD from baseline occurred only in the switch group (11.2 ± 14.6%, p&lt;0.05); denosumab (4.1 ± 10.8%). The total hip BMD increased significantly from baseline in both groups (denosumab: 4.60 ± 7.4%, p&lt;0.05; switch: 7.2 ± 6.9%, p&lt;0.01). Femoral neck BMD was significantly increased in the switch versus the denosumab group (p&lt;0.05).ConclusionIn GIO patients with prior bisphosphonate treatment, the advantage of teriparatide may be maintained after the treatment period. A continuous increase in BMD can be expected with teriparatide followed by denosumab.

Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study

Background. Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. Methods. Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. Results. The RA + osteoporosis group had elevated sRANKL levels ( p = 0.005 ), higher sRANKL/OPG ratio ( p = 0.017 ), decreased DKK-1 ( p = 0.028 ), and lower SOST levels ( p < 0.001 ). Low total hip BMD correlated with high sRANKL ( p = 0.001 ) and sRANKL/OPG ratio ( p = 0.005 ). Total hip and lumbar spine BMD correlated with DKK-1 ( p = 0.009 and p = 0.05 , respectively) and SOST levels ( p < 0.001 and p < 0.001 , respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures ( p = 0.003 and p = 0.003 , respectively) and hip fracture ( p = 0.002 and p = 0.006 , respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture ( p = 0.003 ) and hip fracture ( p = 0.009 ). Conclusion. High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Efficacy of Romosozumab for Osteoporosis in a Patient With Osteogenesis Imperfecta: A Case Report

ABSTRACT The efficacy of romosozumab for severe osteoporosis is uncertain in patients with osteogenesis imperfecta (OI). This report introduced a severe osteoporotic case of OI to examine the effect of romosozumab on bone fragility. A 64-year-old man with OI was referred to our department for finding out the cause of his repeated fractures. He was medicated with alendronate for only one year, eight years ago, but it did not prevent repeated fractures, and thus he had not received any treatments for osteoporosis since then. However, recently, the frequency of fractures had become increased. At presentation, his lumbar and bilateral total hip bone mineral density (BMD) values were severely decreased at 0.546 and 0.209 g/cm2, respectively. Because of his severe osteoporosis, we started romosozumab treatment with eldecalcitol. Romosozumab (210 mg) was injected subcutaneously every month. At 12 months after drug initiation, his lumbar and total hip BMD increased by 22.0% and 136.4% versus pre-treatment levels, respectively. Bone formation markers increased, and bone resorption markers decreased at 12 months of the therapy. Neither hypocalcemia nor any other severe adverse effects were observed in this severe osteoporotic case. This study revealed good responses of BMD and bone turnover markers to romosozumab treatment, which can be considered as an effective treatment option for osteoporotic OI patients.

Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis

Background Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk with associated disability, morbidity and mortality. This Bayesian network meta-analysis compared the effects of current anti-osteoporosis drugs on bone mineral density. Methods The present systematic review and network meta-analysis follows the PRISMA extension statement to report systematic reviews incorporating network meta-analyses of health care interventions. The literature search was performed in June 2021. All randomised clinical trials that have investigated the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. The network comparisons were performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. The inverse variance method with standardised mean difference (SMD) was used for analysis. Results Data from 64 RCTs involving 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. Denosumab resulted in a higher spine BMD (SMD −0.220; SE 3.379), followed by pamidronate (SMD −5.662; SE 2.635) and zoledronate (SMD −10.701; SE 2.871). Denosumab resulted in a higher hip BMD (SMD −0.256; SE 3.184), followed by alendronate (SMD −17.032; SE 3.191) and ibandronate (SMD −17.250; SE 2.264). Denosumab resulted in a higher femur BMD (SMD 0.097; SE 2.091), followed by alendronate (SMD −16.030; SE 1.702) and ibandronate (SMD −17.000; SE 1.679). Conclusion Denosumab results in higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab had the highest influence on hip and femur BMD. Level of evidence Level I, Bayesian network meta-analysis of RCTs