Abstract
Introduction
Osteoporosis is a skeletal disease characterized by loss of bone mass, reduced bone strength and increased bone fragility predisposing to fractures. This study was planned to evaluate the efficacy, safety and relative bioavailability of Microcore NESC® (Natural Egg Shell Calcium) in osteopenia and osteoporotic patients.
Methods
This was a randomized, open label, parallel group interventional clinical trial which included 60 study participants with osteopenia and osteoporosis who were randomized into three groups (20 each). Group 1—Microcore NESC®, Group 2—Shelcal and Group 3—CCM with 12 weeks treatment period. The participants were evaluated for relative oral bioavailability, bone mineral density (BMD), serum osteocalcin, change in VAS pain scale and quality of life—Questionnaires.
Results
There was significant improvement in the BMD T scores—post-treatment with MICROCORE NESC® and Shelcal. Higher percentage of improvement in calcium absorption as depicted by an increase in serum calcium levels (10.23%) in the MICROCORE NESC®-treated group when compared to Shelcal (7.7%) and CCM (7.2%). The relative bioavailability of MICROCORE NESC® with respect to Shelcal was 93%.
Discussion
MICROCORE NESC®, has shown a better oral relative bio availability of calcium (93%), better improvement of BMD T score compared to Shelcal and CCM. The general health status has improved to very good/excellent in 83% of patients in MICROCORE NESC®-treated group. Thus, MICROCORE NESC® can be considered a better and safe calcium supplement, as there are very few side effects observed without any clinically significant abnormalities in lab parameters.
Keywords: Natural Egg Shell Calcium, Osteoporosis, Osteopenia, Bioavailability, BMD, Bone health
Introduction
Osteoporosis is a skeletal disease characterized by loss of bone mass, reduced bone strength and increased bone fragility predisposing to fractures [1]. It is an important health problem in Western and developing countries; In the United States alone, an estimated 10 million people have osteoporosis, while 18 million people have low bone density (with osteopenia), putting them at risk for the disorder [1, 2]. Osteopenia is characterized predominantly by bone loss which is not as severe as in osteoporosis. Participants with osteopenia will sooner or later develop osteoporosis. If we are able to identify and treat osteopenia at an early stage, we can prevent the complications that occur as a result of osteoporosis.
Bone health is affected by many factors, but lack of calcium plays a role in the development of osteoporosis, in which bone is resorbed to maintain serum calcium levels when calcium excretion is not balanced by calcium absorption [2–4]. Calcium from the diet is mainly absorbed in the intestine and is an essential nutrient for reaching the peak of bone mass during adolescence and for the prevention and treatment of osteoporosis [1]. The recommended daily intake of calcium ranges from 400 to 1200 mg per day, depending on age and gender. This has been published by many governmental and non-governmental organizations in many countries [1, 5]. Because many of the modern diets we consume do not provide the recommended levels of calcium, calcium supplements have been recommended to prevent osteoporosis in the elderly. It is also recommended for other medical conditions including hypertension, hypercholesterolemia and cancer [6]. Many forms of calcium supplements are widely available on the market, but the most common are products containing calcium citrate malate and calcium carbonate [5–7]. Over the last 20 years, the absorption of calcium from various forms of dietary supplements has been studied using various methods. Few studies have shown that the more soluble calcium citrate and malate are better absorbed than the relatively insoluble calcium carbonate, while others have shown the opposite result and still others have found no significant difference [8–11]. Microcore NESC® Tablet is made of calcium carbonate from natural source (Natural Egg Shell Calcium) 1250 mg which is equivalent to elemental calcium 500 mg, cholecalciferol ID—600 IU, magnesium gluconate of 100mg (elemental magnesium at 16% which is 16 mg) and 42 mg of zinc citrate (Elemental zinc at 31% which is 13.2 mg) and natural strontium (0.31 mg/gm).
Objective
To study the efficacy and relative bioavailability of Microcore NESC® (Natural Egg Shell Calcium) in osteopenia and osteoporotic patients.
To assess the safety and tolerability of Microcore NESC® (Natural Egg Shell Calcium) by monitoring the occurrence of any adverse effects by clinical and laboratory evaluation.
Methodology
This was a Randomized, Open label, parallel group interventional clinical trial. The study was approved by the Institutional Ethics committee of a tertiary care medical college hospital and research center. The study was registered in CTRI (CTRI/2023/02/049901). The study included 60 study participants diagnosed to have osteopenia and osteoporosis. Screening procedures include demographic data (height, weight, Body Mass Index [BMI] and age), medical and medication history, physical examination, clinical laboratory tests (haematology, biochemistry, urine analysis and serology), urine microscopic examination, 12-lead electrocardiogram (ECG), BMD and chest X-ray. Male of female participants who were in the age group of 45–60 years with osteopenia and osteoporosis, diagnosed by BMD were enrolled (bone density that is between 1 and 2.5 SD below the mean is called osteopenia and a T score below 2.5 SDs indicates osteoporosis). The participants were not enrolled into the study if they had a history or the presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrinal, immunologic, dermatologic, neurological or psychiatric disease and who are allergic to investigational products. The participants who fulfilled the inclusion and exclusion criteria were enrolled in the study. The 60 participants were randomized into three groups with 20 in each group. Group 1—Participants with osteopenia and osteoporosis took two tablets daily of Microcore NESC® orally in the morning and night for 12 weeks, Group 2—Participants with osteopenia and osteoporosis took two tablets daily of Shelcal orally in the morning and night for 12 weeks and Group 3—Participants with osteopenia and osteoporosis took two tablets daily of CCM orally in the morning and night for 12 weeks. (Table 1, Fig 1).
Table 1.
Demographic details
| Gender | Group | Total | ||
|---|---|---|---|---|
| CCM | MICROCORE NESC® | Shelcal | ||
| Female | 13 | 11 | 12 | 36 |
| 68.40% | 61.10% | 70.60% | 66.70% | |
| Male | 6 | 7 | 5 | 18 |
| 31.60% | 38.90% | 29.40% | 33.30% | |
| Total | 19 | 18 | 17 | 54 |
| Age | 50.82 (6.56) | 56.0 (3.98) | 54.41 (5.21) | |
Fig. 1.
Participant flow diagram
In this study, all the participants fasted over night for at least 10.00 hours before test product administration. A standardized meal including dinner was provided to the participants at night of check-in. On day 1, eight blood samples were collected including pre-dose (00.00) blood sample of within 01.00 hour prior to dosing and post-dose blood samples of 2.5 ml each were collected at 30, 60, 90, 135, 180, 225 and 270 minutes following test product administration. Evaluation of the participants were done at baseline and the end of the study for Bone mineral density (BMD), serum osteocalcin, change in VAS pain scale and quality of life—Questionnaires, along with monitoring of adverse events.
Statistics
Descriptive statistics were given for baseline characteristics like age, sex and also any adverse events and tolerability profiles. All the results were evaluated and compared between the test and reference products using per protocol analysis, by SPSS software version 21.0. Scores and survey results of different participants were analysed by independent “t” test and ANOVA.
Results
There is a significant improvement in the BMD T scores—post-treatment with MICROCORE NESC® and Shelcal (on using paired t test). MICROCORE NESC® is showing a higher level of significance when compared to Shelcal (Fig. 2).
Fig. 2.
BMD (T score) levels
Reduction in osteocalcin (carboxylated) levels is a marker for reduced osteoporosis. Reduction in serum osteocalcin levels is observed in MICROCORE NESC® and Shelcal-treated group (paired t test). But there is no statistically significant reduction in any of the treatment groups (Tables 2, 3).
Table 2.
Improvement in BMD (T score)
| Group | BMD (T score) | N | Mean | Std. deviation | p value |
|---|---|---|---|---|---|
| MICROCORE NESC® | Baseline | 18 | − 2.01 | 0.82193 | 0.001 |
| Post-study | 18 | − 1.1694 | 0.82156 | ||
| Shelcal | Baseline | 17 | − 2.4829 | 0.91187 | 0.002 |
| Post-study | 17 | − 1.8535 | 1.1767 | ||
| CCM | Baseline | 19 | − 1.9933 | 1.69828 | 0.82 |
| Post-study | 19 | − 1.8961 | 0.75263 |
Table 3.
Changes in the osteocalcin levels
| Group | BMD | N | Mean | Std. deviation | p value |
|---|---|---|---|---|---|
| MICROCORE NESC® | Baseline | 18 | 11.5644 | 3.85392 | 0.374 |
| Post-study | 18 | 10.38 | 2.643 | ||
| Shelcal | Baseline | 17 | 9.3525 | 2.82222 | 0.95 |
| Post-study | 17 | 9.26 | 5.232 | ||
| CCM | Baseline | 19 | 10.0123 | 2.42534 | 0.269 |
| Post-study | 19 | 11.64 | 4.865 |
There is a significant improvement in the serum calcium levels from baseline up to 270 minutes in all the three groups on applying repeated measure ANOVA.
There is a higher percentage of improvement in calcium absorption as depicted by an increase in serum calcium levels (10.23%) in the MICROCORE NESC®-treated group when compared to Shelcal (7.7%) and CCM (7.2%)—Tables 4 and 5 and Fig. 3.
Table 4.
Serum calcium levels for relative absorption and bioavailability
| Group | Serum calcium | N | Mean | Std. deviation | p value |
|---|---|---|---|---|---|
| MICROCORE NESC® | Predosing | 18 | 8.1 | 0.766 | 0.0001 |
| 30 min | 18 | 7.964 | 0.7323 | ||
| 60 min | 18 | 8.06416 | 0.55 | ||
| 90 min | 18 | 8.26 | 0.572 | ||
| 135 min | 18 | 8.37 | 0.755 | ||
| 180 min | 18 | 8.39 | 0.613 | ||
| 225 min | 18 | 8.757 | 0.7345 | ||
| 270 min | 18 | 9.129 | 0.7237 | ||
| Shelcal | Predosing | 17 | 8.83 | 0.74 | 0.012 |
| 30 min | 17 | 8.769 | 0.7087 | ||
| 60 min | 17 | 8.785 | 0.7819 | ||
| 90 min | 17 | 8.85 | 0.647 | ||
| 135 min | 17 | 9.01 | 0.596 | ||
| 180 min | 17 | 9.38 | 0.971 | ||
| 225 min | 17 | 9.377 | 1.2807 | ||
| 270 min | 17 | 9.715 | 1.3662 | ||
| CCM | Predosing | 19 | 8.65 | 1.076 | 0.003 |
| 30 min | 19 | 8.533 | 1.0299 | ||
| 60 min | 19 | 8.608 | 0.8458 | ||
| 90 min | 19 | 8.71 | 0.977 | ||
| 135 min | 19 | 8.87 | 0.804 | ||
| 180 min | 19 | 8.84 | 0.776 | ||
| 225 min | 19 | 9.133 | 0.9119 | ||
| 270 min | 19 | 9.3 | 0.9544 |
Table 5.
Percentage improvement in Sr. calcium levels compared to baseline (Bioavailability)
| Sl. no. | Time point (min) | MICROCORE NESC® Sr. calcium (% improvement) |
Shelcal Sr. calcium (% improvement) |
CCM Sr. calcium (% improvement) |
|---|---|---|---|---|
| 1 | 0 | 8.1 (0) | 8.83 (0) | 8.65 (0) |
| 2 | 270 | 9.1 (10.23%) | 9.71 (7.76%) | 9.3 (7.27) |
Fig. 3.
Serum calcium levels—graphical representation
Relative bioavailability = AUC(T) * Dose (R) * 100/ AUC (R)* Dose (T)
Relative bioavailability of MICROCORE NESC® with respect to Shelcal = 38.15*500*100/40.75*500 = 93%. Thus, the relative bioavailability of MICROCORE NESC® with respect to Shelcal was 93% (Table 6).
Table 6.
Pharmacokinetic parameters
| Group | Cmax (mg/dl) |
AUC last | Tmax (h) |
|---|---|---|---|
|
MICROCORE NESC® |
9.341 | 38.1537 | 3.38 |
| Shelcal | 9.753 | 40.7559 | 3.46 |
| CCM | 9.183 | 38.9493 | 3.28 |
Changes from base line to post-study in quality of life—Feedback Questionnaires have shown that the general health status has improved to very good/ excellent in 83% of patients in MICROCORE NESC®-treated group compared to 76 % in Shelcal-treated group and 61% in CCM group. The limitation of activities has shown an improvement of around 72 % in MICROCORE NESC®-treated group compared to Shelcal with 70 % and CCM with 57.9%.
The improvement in physical health problems has shown an improvement of around 94.4 % in MICROCORE NESC®-treated group compared to Shelcal with 88.2 % and CCM with 94.7%.
The gastrointestinal side effects were common in all the groups. It was more in Shelcal treatment and the least with MICROCORE NESC® treatment. There were no clinically significant lab abnormalities (pre- and post-study) in any of the treatment groups, which proves the safety of the test compounds.
Discussion
Natural Egg Shell Calcium (MICROCORE NESC®) is a naturally rich source of calcium carbonate and has been studied as a treatment for management of symptoms related to osteoarthritis, osteopenia and osteoporosis [12, 13]. MICROCORE NESC® has shown a reduction in the production of pro-inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha [14]. MICROCORE NESC® has also shown to improve the recovery from exercise-induced joint pain, decrease stiffness and reduce discomfort immediately after exercise (stiffness) in post-menopausal women taking 500 mg once daily for 2 weeks [13]. Our study has also confirmed the same by showing a decrease in VAS pain scores and a good improvement in performance-related quality of life questionnaires [13, 14].
It has also been well documented that a positive correlation exists between cholecalciferol and total BMD improvement [15]. MICROCORE NESC® has natural Strontium in it. Strontium has a dual effect of stimulating new bone formation (Osteoblastic) and inhibiting bone resorption (osteoclastic) and also the biological behavior as well as the metabolism and distribution of strontium mimics that of calcium [12]. Studies have shown that Strontium supplements increases bone mass density and reduces the risk of vertebral and normal bone fracture [16].
A good magnesium homeostasis seems to be vital for bone health. On the basis of various experimental and epidemiological studies, both low and high magnesium have shown to have harmful effects on the bones. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting the secretion and the activity of parathyroid hormone and by promoting low grade inflammation.[17]
Oral zinc supplements helps to protect the bone from resorption in various conditions, such as aluminum toxicity, vitamin D deficiency, Ca deficiency, estrogen deficiency, diabetes and arthritis. Zinc improves bone mineral density [18, 19]. Microcore NESC® Tablet is made of calcium carbonate from natural source (Natural Egg Shell Calcium), 1250 mg which is equivalent to elemental calcium 500 mg, cholecalciferol ID—600 IU, magnesium gluconate of 100mg (elemental magnesium at 16% which is 16 mg) and 42 mg of zinc citrate (elemental zinc at 31% which is 13.2 mg) and natural strontium (0.31 mg/gm).
This novel combination of ingredients of calcium (along with cholecalciferol, magnesium and zinc) has shown a better oral relative bioavailability of calcium, better improvement of BMD while compared to other preparations like Shelcal and CCM. There is a significant improvement in the BMD (T score) post-treatment with MICROCORE NESC® and Shelcal. MICROCORE NESC® is showing a higher significance when compared to Shelcal. The magnesium and zinc supplementation along with Vitamin D 3 of NESC could be the reason for the better performance due to its synergistic effect. The progression from osteopenia to osteoporosis has been reduced, as serum carboxylated osteocalcin levels decreased from base line to post-study values, in MICROCORE NESC® treatment group. Reduction in osteocalcin (carboxylated) levels is a marker for reduced osteoporosis. Reduction in serum osteocalcin levels is observed in MICROCORE NESC® and Shelcal-treated group. However, there is no statistically significant reduction in any of the treatment groups. There is a higher percentage of improvement in calcium absorption as depicted by an increase in serum calcium levels (10.23%) in the MICROCORE NESC®-treated group when compared to Shelcal (7.7%) and CCM (7.2%) at 270 minutes after administration. The relative bioavailability of MICROCORE NESC® with respect to Shelcal was 93%. For calcium, which is an endogenous substance, measurement of absolute bioavailability of an oral dose requires the use of isotopic methods, but for assessing relative oral bioavailability, the pharmacokinetic method is a convenient and acceptable tool. Hence, the same was applied here. The literature reference shows that the absorption of calcium carbonate (Shelcal) is 22% and that of CCM is 42% considering its elemental calcium of 40% and 24%, respectively [11]. We also would like to put forth that there is an advantage with NESC with respect to the source of the calcium being used. Microcore NESC contains—egg shell calcium with zero or negligible heavy metal as it comes from living system, hence, it requires very minimal green chemistry processing and also naturally it is microgranular calcium that supports sustainable releases than any powder form of the calcium, whereas Shelcal is made from marine source which can have heavy metal from the source of the origin which requires high chemical refining and whereas the CCM is a synthetic product which is a derivate of the calcium with citrate maleate which falls under synthetic product which invites additional chemical refining.
There were no clinically significant lab abnormalities (pre- and post-study) in any of the treatment groups. There were no serious adverse events reported during the study period. All the participants tolerated the test products and the compliance was good. There is a significant reduction in total cholesterol and LDL levels, post-treatment with MICROCORE NESC® for a period of 12 weeks. Studies have shown that supplemental calcium alone or combined with vitamin D3 may reduce serum lipids and lipophilic micronutrients. The general health status has improved to very good/ excellent in 83% of patients in MICROCORE NESC®-treated group compared to 76 % in Shelcal-treated group and 61% in CCM group. Overall, the quality of life questionnaire has shown a better improvement in the general health, reduction in bodily pain, without any limitation of activities in all the three groups. There is also a better improvement in the emotional health, social activities and pain in MICROCORE NESC®, and Shelcal-treated group.
Conclusion
This novel combination of ingredients of MICROCORE NESC® has shown a synergistic effect and a better oral relative bio availability of calcium (93%), better improvement of BMD T score, over a treatment period of 12 weeks, while compared to other preparations like Shelcal and CCM. However, MICROCORE NESC® and Shelcal are showing a comparable performance in many other parameters, the absorption and side effect profile is better with MICROCORE NESC®. This study has also highlighted that MICROCORE NESC® treatment has shown to bring down osteocalcin levels, which is marker for reduction in osteoporosis. Thus, MICROCORE NESC® can be considered a better and safe calcium supplement, as there are very few side effects observed without any clinically significant abnormalities in lab parameters and patient compliance to the test product was exceptionally good, throughout the study.
Acknowledgements
We acknowledge the sponsor (Microcore) and the CRO (ki3 Pvt. Ltd).
Data availability
The data that supports the findings of this study will be available on request to the corresponding author.
Declarations
Conflict of Interest
The study was sponsored by Microcore.
Ethical Standard Statement
This article does not contain any studies with human or animal subjects performed by the any of the authors.
Informed Consent
Informed consent was obtained from the study participants.
Limitations
Sample size was small and only relative bio availability was calculated in our study. Baseline Vitamin D 3 and PTH levels could have been monitored to rule out other factors affecting calcium metabolism.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that supports the findings of this study will be available on request to the corresponding author.