Experience of long-term use of denosumab in women with osteoporosis and various concomitant diseases

Background: Possible differences in the results of planned RCTs and real clinical practice were the reason for the analysis of long-term therapy with denosumab in patients with osteoporosis (OP) of various origins on an outpatient basis.Aim: To assess the effectiveness of long-term administration of denosumab in terms of the effect on BMD and markers of bone metabolism, tolerance and consequences of drug withdrawal in patients with OP of various etiologies.Materials And Methods: A retrospective analysis of the outpatient records of women with OP of various etiology, who were observed at the FSBI «NMRC TPM» from 1 to 10 years and regularly received denosumab 60 mg once every 6 months subcutaneously (at least 2 injections), was carried out. All completed examination and anthropometric research; DXA of the lumbar spine and proximal femur (PF); laboratory tests: marker of bone resorption CTx (β-crosslaps) in blood serum; survey on the presence of adverse events.Results: The study included 148 patients who were divided into 2 groups: 1 (N=98) - did not take anti-osteoporotic therapy (AT), 2 (N=50) - who took AT before the appointment of denosumab. Long-term therapy with denosumab was associated with a steady and reliable increase in BMD in the spine and PF, as well as a decrease in the concentration of CTx of both those who didn’t take and who previously took AT. In 54% of patients BMD in the spine reached values of osteopenia, in 43.4% of women target BMD values in the femoral neck were determined. During the first year of therapy, there was a decrease in the concentration of CTx by 67% in those who didn’t take AT and by 58% in those who had previously taken AT. Discontinuation of denosumab therapy without subsequent administration of AT was associated with a significant decrease in BMD in the spine (by 4.4-8.2%) during the first year after discontinuation of the drug.Conclusion: Denosumab therapy effectively increases BMD in the spine and PF and decreases CTx levels both in untreated patients and in those who previously received AT. It is necessary to discontinue therapy, further management of the patient should be discussed to prevent «withdrawal syndrome».

Federal clinical guidelines for diagnosis, treatment and prevention of osteoporosis

Due to continuous aging of population and increase in the number of elderly people, osteoporosis became socially significant disease leading to disability, increasing mortality and thereby putting an additional burden on the public healthcare system.Screening to identify groups with a high probability of fracture is recommended using the FRAX® Tool for all postmenopausal women and men over 50 years old (А1). In the presense of major pathological fractures (hip, spine, multiple fractures) it is recommended to diagnose osteoporosis and prescribe treatment regardless of the results of spine and hip double X-ray absorptiometry (DXA) or FRAX® (B2).It is recommended to evaluate C-terminal telopeptide when prescribing antiresorptive therapy and procollagen type 1 N-terminal propeptide (P1NP) when prescribing anabolic therapy to patients receiving osteoporosis treatment at baseline and 3 months after the start of therapy in order to assess the effectiveness of treatment early and adherence to the therapy (А2). It is recommended to diagnose osteoporosis and prescribe treatment to patients with high individual 10-year probability of major pathological fractures (FRAX®) regardless of the results of spine and hip DXA (В3).It is recommended to diagnose osteoporosis and prescribe treatment with a decrease in BMD, measured by DXA, by 2.5 or more T-score standard deviations in femoral neck, and/or in total hip, and/or in lumbar vertebrae, in postmenopausal women and men over 50 years old (А2).It is recommended to prescribe bisphosphonates, denosumab or teriparatide to prevent pathological fractures and increase BMD in patients with postmenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis (А2). When the clinical effect of therapy in osteoporotic patients without pathological fractures is achieved (BMD T-score > -2.0 SD in femoral neck and absence of new fractures), it is recommended to interrupt bisphosphonates therapy for 1-2 years with subsequent follow-up (B2). In patients with vertebral fractures, hip fractures or multiple fractures, it is recommended to continue ceaseless long-term treatment of osteoporosis (В3).All drugs for the treatment of osteoporosis are recommended to be prescribed in combination with calcium and cholecalciferol (А2). In order to reduce the risk of recurrent fractures by prescribing osteoporosis therapy timely and maintaining long-term follow-up of patients over 50 years old with pathological fractures, it is recommended to create Fracture Liaison Services (В2).

Effect of empagliflozin on phosphorus and calcium metabolism in patients with type 2 diabetes mellitus with preserved kidney function

Background: Sodium glucose co-transporter type 2 inhibitors (iSGLT2) are antihyperglycemic drugs approved for the treatment of type 2 diabetes mellitus (T2DM). Clinical trials with these drugs have shown evidence of an increased risk of fractures and an effect on phosphorus, vitamin D and parathyroid hormone (PTH) levels.Aim: The aim of this study was to investigate the effect of the most selective iSGLT2 empagliflozin on the calcium and phosphorus metabolism in patients with T2DM and preserved kidney function.Materials and methods: Thirty-nine T2DM patients were received empagliflozin 10 mg in addition to their antihyperglycemic drugs for 12 weeks. Before starting treatment, a dual-energy X-ray absorptiometry (DXA) with an assessment of the trabecular bone score (TBS) was performed. The concentration of phosphorus (P), total (tCa) and ionized calcium (Ca++), fibroblast growth factor 23 (FGF-23), 25(OH)D and PTH were assessed.Results: According to the DXA results, only 2 patients had osteoporosis, 10 (25.6%) patients had bone mineral density (BMD) values below 1.35 g /cm2 on the TCI scale. Treatment with empagliflozin for 12 weeks was lead to significant increase in FGF-23. Compared to the baseline level, there were no statistically significant differences in the concentrations of P, oCa, Ca++, PTH and 25(OH)D after 12 weeks of treatment. The level of FGF-23 did not correlate with the level of glomerular filtration rate either before or after treatment (r = 0.31, p = 0.27 and r = 0.39, p = 0.55, respectively). In addition, baseline BMD adjusted for TBS and baseline 25(OH)D did not correlate with Ca, F, FGF-23, and PTH concentrations (p>0.05).Conclusion: Thus, empagliflozin has increased the level of FGF-23 without significant changes in the concentration of phosphorus, calcium, 25 (OH) D, and PTH after 12 weeks of treatment in patients with T2DM and preserved renal function. The obtained data confirmed the necessity to assess the TBS in patients with T2DM, because it’s provide additional information on the quality of bone tissue.

Parathyroid hormone-independent hypercalcemia and hypercalciuria of a patient with nephrolithiasis and nephrocalcinosis and impaired vitamin D metabolism due to a defect in the CYP24A1 gene

Hypercalcemia associated with impaired vitamin D metabolism is a rare autosomal recessive disorder. The mechanism of this pathology is the impairment of inactivation of active metabolites of vitamin D because of mutations in the CYP24A1 gene, which leads to an increase of calcium absorption and the development of hypercalcemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. The phenotype of the disease ranges from severe forms which are diagnosed in early infancy (severe hypercalcemia associated with dehydration, vomiting, nephrocalcinosis, and sometimes death) to milder forms, that often are diagnosed in adulthood and manifested with recurrent nephrolithiasis and nephrocalcinosis. Differential diagnosis is carried out with the most common causes of hypercalcemia: primary hyperparathyroidism and malignant neoplasms. To diagnose, the determination of vitamin D metabolites and genetic research are used. As a treatment for mild forms, it is recommended to limit dairy products, to keep a drinking regimen, to refuse taking vitamin D and calcium preparations, and use of sunscreens. The article presents a clinical case of parathyroid hormone-independent hypercalcemia due to mutation of the CYP24A1 gene of a 20-year-old patient suffering from nephrolithiasis and nephrocalcinosis since the age of 16 with a confirmed violation of vitamin D metabolism.

Polypharmacy in elderly patients with falls

Background: Falls in elderly–a multifactorial syndrome. One of the modifiable factors is polypharmacy. STOPP/START criteria are used for correction of polypharmacy in geriatrics.Aim: Assessment of the prevalence of polypharmacy, analysis and correction of pharmacotherapy using STOPP/START criteria in patients with falls.Materials and methods: The study included 655 patients hospitalized in the geriatric department over 60 years of age, who were divided into two groups. Group 1 (n=332, 50.7%)–patients with 1 or more falls, group 2 (n=323,49.3%)–patients without falls. The analysis of the received therapy before hospitalization was performed. After that, based on the indications, contraindications and STOPP/START criteria, drug therapy was corrected in patients with falls.Results: Patients of group 1 took 4.5±2.18 drugs, group 2–4.3±2.6. Polypharmacy was diagnosed in 150 (45.2%) patients with falls and in 122 (37.8%) patients without falls. Patients with falls were more likely to receive sleeping pills, NSAIDs. Univariate analysis showed that falls were associated with NSAIDs (OR 2.15, 95% CI 1.38–3.35, p=0.001) and sleeping pills (OR 2.03, 95% CI 1.02–4.02, p=0.047). An audit and correction of therapy was performed: in 108 (32.5%) patients the number of prescribed drugs was reduced. Patients with falls were prescribed statins, antidementia drugs, anticonvulsants and antidepressants as components of therapy for chronic pain syndrome, chondroitin sulfate and glucosamine sulfate for the treatment of osteoarthritis, calcium and antiresorbtive therapy, antianemic drugs, vitamin D. Antiplatelet agents, digoxin, sleeping pills and NSAIDs were less frequently prescribed. STOPP/START criteria and their frequency in patients with falls were analyzed. 141 cases of potentially non-recommended but prescribed medications were identified. STOPP criteria were for the administration of NSAIDs (n=53, 37.6%) and acetylsalicylic acid (n=62, 44%). There were 458 cases of potentially recommended but not prescribed medications. The most common START criteria were not for the administration of vitamin D and statins.Conclusion. Half of elderly patients with falls have polypharmacy. These patients are more likely to take sleeping pills and NSAIDs. STOPP criteria most often concerned the appointment of NSAIDs and acetylsalicylic acid, and the START criteria revealed the absence of the appointment of vitamin D and statins.

Ivan I. Dedov (on the occasion of his 80th birthday)

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Vitamin D imbalance effects on dentoalveolar system: a review

Vitamin D is a fat-soluble secosteroid that plays an important role in the human body. There are two main native forms – vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). The regulation of calcium-phosphate metabolism and ensuring adequate bone remodeling are the most studied function of vitamin D. In recent years, researchers have found out the «extra-bone» effects of vitamin D and it allows us to be convinced of the great role of this compound. The participation of active forms of vitamin D in the processes of immunomodulation, anti-inflammatory, antimicrobial, antiproliferative effects and stimulation of cell differentiation are reflected in diseases of the maxillofacial region.In this article, we examined the main functions of vitamin D in the human body, the mechanisms of its action and influence on the occurrence and course of oral diseases. The discovery of the relationship between vitamin D deficiency and the processes of osseointegration, bone remodeling, the severity of chronic recurrent aphthous stomatitis, squamous cell carcinoma and periodontitis allow us to conclude that it is advisable to diagnose vitamin D deficiency in appropriate time and correction its serum level in dental patients.

Burden of Osteoporosis in the Countries of the Eurasian Region

The public health burden of osteoporosis estimated by the results of clinical and population-based researches in most of the former USSR is uncertain for today. The objective of this audit (Audit-2020) was the epidemiological, medico-social and economic analyse of current and future osteoporosis challenges for the future years for eight countries of the Eurasian region.Methods. We did a search and critical analysis of the publications, including of regional in English, Russian or national languages, did organize a structured survey among national osteoporosis societies members in Armenia, Belarus, Georgia, Kazakhstan, Moldova, Uzbekistan, Kyrgyz Republic, Russia, as well as explored the demographic trends in these countries.Results. Scientific researches including the wide population-based EVA project discovered that the expected number of patients with osteoporosis varies from 240,000 in Armenia to 16 million in Russia. All the countries should be categorized as a moderate risk of hip fractures for women (200–300 cases /100,000 per year). Belarus, Moldova, Armenia, Georgia and Kyrgyzstan have moderate risk for men (100–150/100,000), as well as Russia, Uzbekistan and Kazakhstan are distinguished by a high risk for men (over 150 cases/100,000). Population aging trends are predicting the future growth in the osteoporosis-associated health challenges throughout the region. It is likely the number of osteoporotic fractures to rise in Uzbekistan, Kazakhstan and Kyrgyzstan the most: 2.5–3.5 times by 2050. However current hospitalization rates for hip fracture persons are low in most countries (33–80%), the diagnostic equipment is insufficient (0.2–1.3 per million), DXA testing are expensive. Although modern treatments are available, the cure expenses remain high. Hereby, immediate action is required in each country of audit, including admit osteoporosis is a priority public health problem.Conclusion. Osteoporosis is a challenge for the countries of the Eurasian region. Its burden is about to get worse due to the expected demographic changes.

The relationship of bone mineral density with the of the intima-media thickness in premenopausal women

Background: Osteoporosis and cardiovascular disease (CVD) are among the most common causes of morbidity, disability and death worldwide. In recent years, more and more data have been accumulating on the presence of an age-independent relationship and general pathogenetic mechanisms of a decrease in bone mineral density (BMD) and the development of CVD. It has been shown that a decrease in BMD is an important independent predictor of the risk of atherosclerosis of the great arteries and is associated with increased calcification of the aorta and other vessels. The strongest relationship between these parameters was observed in the study of the female population, in connection with which we selected a group of middle-aged women for analysis.Objective: to investigate the association between bone mineral density and carotid intima-media thickness in middle-aged women.Results: 35 women were included in the study. The mean age was 44,74±4,32 years. We found the following changes in arterial wall characteristics: atherosclerosis — 21,9% women, increased carotid intima thickness — 15,7% women. Low bone mineral density for chronological age (Z-criteria -2,0 and less) was found in 7 patients at the age of 35±2,7 years. We discovered a negative correlation between the markers of subclinical atherosclerosis and bone mass: Ccarotid intimamedia thickness negatively correlated with bone mineral density in hip (p<0,05), and presence of atherosclerosis plaques was associated with lower bone mineral density in the proximal part of hip (p<0,05).Conclusion: The findings about negative association between bone mineral density of hip with preclinical markers of atherosclerosis allow us to make a conclusion about their interaction.

Prevalence of vitamin D deficiency in various regions of the Russian Federation: results of the first stage of the multicenter cross-sectional randomized study

Background. A vitamin D deficiency is a global wide health problem. Inadequate vitamin D status leads to serious medical, social and economic consequences and requires timely diagnosis and adequate correction.Aim: to assess the incidence of vitamin D deficiency among the population living in regions of the Russian Federation located at latitudes from 45° to 70° and to study its relationship to various factors (demographic, socio-economic, geographical, etc.).Materials and methods. A multicenter, cross-sectional, randomized study of individuals of both sexes aged 18 to 50 years. The study of 25ОНD level in the blood serum was carried out by INVITRO LLC laboratories using chemilumescent analysis in two stages: in the period from March to May 2020 and from October to November 2020. The first stage of the study involved 500 volunteers (77% women, 23% men). Demographic and socioeconomic characteristics, factors associated with vitamin D levels, were assessed using a specially designed questionnaire.Results. In this article we present the results of the first stage. A countrywide high prevalence of vitamin D deficiency (56.4%) and insufficiency (27.9%) was revealed, that is, 84.3% of the population aged 18–50 years requires cholecalciferol supplementation. The lowest vitamin D status was found in St. Petersburg, Arkhangelsk, Kyzyl and Rostov-on-Don (over 90% of participants had inadequate levels). A decrease in the level of 25ОНD was observed to a greater extent in men than in women (p <0.05), as well as in young people aged 18–25 years (p <0.05). No major association of vitamin D status with anthropometric parameters, the number of days of disability, were not found. However, those who went to tanning beds or were in direct sunlight for at least 30 days a year had higher levels of 25ОНD, and those using sunscreens had lower levels.Conclusion. The data obtained confirms the widespread prevalence of vitamin D deficiency and insufficiency in the country (84.3% of participants), generally not related to the geographical latitude of residence, which indicates the need for vitamin D supplementation in a significant part of the population.