JFOA

Introduction

Osteoporosis is a chronic skeletal disorder defined by reduced bone mass and microarchitectural deterioration, which increases bone fragility and fracture risk [1]. Fractures due to osteoporosis are a major source of morbidity and mortality in older adults, imposing a substantial socioeconomic burden worldwide [2]. As the most common metabolic bone disease, osteoporosis is progressive and associated with pain, disability, and loss of independence [3,4]. Large population-based studies have shown excess mortality in individuals with osteoporosis compared with the general population, even when treated, partly due to fracturerelated complications [5].

The prevalence of osteoporosis is rising with global population aging. It affects ~10% of the general population and up to 30% of post-menopausal women [6]. In Asia and other high-income regions, including Japan, South Korea, Taiwan, Singapore, and Australia, the burden of osteoporotic fractures is particularly significant [7]. Racial and ethnic differences are evident; for example, Asian adults often have lower bone mineral density (BMD) than White counterparts, largely due to differences in skeletal size and body composition [8,9].

Pharmacological therapies, particularly bisphosphonates, are widely prescribed for patients at high fracture risk. Meta-analyses confirm that bisphosphonates reduce overall fracture incidence (odds ratio 0.62, p<0.001). Among several medication options, bisphosphonates are frequently prescribed as first-line therapy for patients with high fracture risk [10,11]. However, these agents do not fully halt disease progression, and residual fracture risk remains high. Adjunctive calcium and vitamin D supplementation are often recommended, although the optimal regimen remains uncertain [12]. Consequently, more effective and targeted treatment options for osteoporosis are urgently needed. Additionally, research results showed that even if osteoporosis is treated, the mortality rate and fractures still increase [5,13].

Calcium carbonate is a common supplement derived from natural sources such as oyster shell. Sigma Anti-Bonding Molecule Calcium Carbonate (SAC) is a modified form with weakened sigma antibonding, yielding higher bioavailability than conventional calcium carbonate [14]. In animal studies, SAC improved bone density by modulating osteocalcin, collagen, and mineral deposition without adverse effects [15]. Despite promising preclinical evidence, its efficacy in humans has not been evaluated. This study aimed to assess the effect of SAC supplementation on bone mineral density in an Asian population.

Materials and Methods

Study Design and Participants

This retrospective study was conducted at a medical clinic in Vancouver, Canada. Participants were recruited through newspapers, social media, and word-of-mouth advertisements. Participants received 7.6 mg SAC daily, administered as 5 ml of solution diluted in 500 ml of water per 70 kg body weight, taken twice daily on an empty stomach or between meals. Individuals were excluded if they had: 1) received osteoporosis treatment within the past year; 2) significant hepatic impairment (cirrhosis, active hepatitis); 3) impaired renal function or history of kidney/urinary stones; 4) inability to perform light exercise or maintain regular meals; 5) secondary osteoporosis requiring other treatments. After providing written informed consent, all participants underwent baseline bone density assessment using ultrasound and were prescribed SAC. The protocol was approved by the Institutional Review Board (Protocol no. MCC23681).

Bone Density Measurement

Bone density was assessed with a portable ultrasound device (BeamMed^™ MiniOmni^™). Daily calibration was performed using a standard block. Measurements were taken from the distal radius with the participant seated and forearm resting on the device [16].

Data Processing and Transformation

Ultrasound-derived speed of sound (SOS) values were converted to BMD and T-scores using Asian population reference standards from the World Health Organization (WHO) and regional epidemiological studies. Data conversion was validated to ensure consistency and minimize errors. The standard deviation (SD) of BMD in individuals compared to young adults is referred to as the T score. Based on this score, individuals were classified as normal (T-score > −1.0), osteopenia (−2.5 < T-score < −1.0), or osteoporotic (T-score ≤ −2.5) [4]. A T-score of 0 was defined as a BMD value of 1.2 g/cm².

Sample Size Calculation

The sample size was calculated using G^*Power 3.1 (HeinrichHeine-Universität Düsseldorf, Germany) to ensure adequate statistical power (0.80) at an alpha level of 0.05. For the chi-square test, an effect size of 0.6 (medium to large, based on prior literature) and 2 degrees of freedom were assumed, totalling 82 participants.

Statistical analysis

The efficacy of SAC was evaluated based on changes in bone mineral density (BMD), T-score, and speed of sound (SOS) of the distal radius after approximately 8 months of treatment.

Baseline Characteristics

Baseline characteristics of the study participants were compared across three clinical groups (normal, osteopenia, and osteoporosis). Numerical variables were analyzed using one-way analysis of variance (ANOVA) for comparisons across the three groups. Categorical variables were analyzed using the chi-square test or Fisher’s exact test when expected cell counts were less than 5.

Within-Group Changes: Changes in BMD, T-score, and SOS from baseline to post-treatment within the same group were analyzed using a paired t-test.

Between-Group Comparisons: Between-group differences in BMD changes after treatment were analyzed using analysis of covariance (ANCOVA), with baseline BMD as a covariate. For T-score and SOS, similar ANCOVA models were applied, with baseline T-score and SOS as respective covariates. To address multiple comparisons across BMD, T-score, and SOS, a Bonferroni correction was applied, adjusting the significance level to p < 0.0167 (0.05/3).

All statistical analyses were performed using IBM SPSS Statistics version 26 (IBM Corp., Armonk, NY, USA).

Results

Baseline characteristics

A total of 82 participants participated in this study. Table 1 presents the baseline characteristics of the participants, which showed no significant differences in the measured parameters except average age. The average age was approximately 54 for normal, 62 for osteopenia, and 64 for the osteoporosis group (p<0.0001).

Table 1: Characteristics of participants.

Changes of T-score, SOS, and BMD by clinical group, gender, and age group

T-scores, SOS, and BMDs were measured at baseline and ~8 months of SAC. As expected, the mean differences from baseline were statistically significant among clinical groups (p<0.0001, Figure 1). After treatment, SAC treatment significantly increased T score (-2.01 vs. -0.85, p<0.0001, Table 2), SOS (3,946 vs. 4,079, p<0.0001, Table 2), and BMD (0.95 vs. 1.10 g/cm2, p<0.0001, Table 3) regardless of gender and age groups. These improvements were more pronounced among participants with osteoporosis and in male subjects (p<0.0001) (Figure 1D). The efficacy of SAC was more evident in the men's group overall (Figure 1D, Table 2).

Figure 1: Baselines of T-Score, SOS, BMD, T Score Changes with 10^th, 25^th, median, 75^th, 90^th values in clinical groups. A: Median of T-scores are -0.11 (normal) vs -1.68 (osteopenia) vs. -3.34 (osteoporosis, p<0.0001). B: Median of SOS Scores are 4,153 vs 3,983 vs 3,798 (p<0.0001), and C: Median of BMD are 1.19 vs 1.00 vs 0.80 (p<0.0001). D. T score change after SAC treatment. Male and osteoporosis groups showed higher efficacy than female and other clinical groups (p<0.0001).

Table 2: Changes of T-score, SOS, and BMD by gender or menopausal status.

Table 3: T-score, SOS, BMD changes by gender and clinical groups.

The status of menopause is critical to bone health. As expected, participants with menopause showed significantly lower values of SOS (3,888 vs. 4,110, p<0.0001), T-score (-2.64 vs. -0.69, p<0,0001), and BMD (0.88 vs. 1.12, p<0.0001). The percentage increase in BMD after treatment was significantly higher in the menopausal group compared to the non-menopausal female group (15.1% vs. 8.1%, p=0.028). This association was not observed in changes of SOS (p=0.075) and T-score (p=0.288, Table 2).

Aging is a well-established risk factor for osteoporosis and plays a critical role in bone health deterioration. Significant inverse relations between age and bone health were observed on T-score (Pearson correlation with age, -0.41, p<0.0001), SOS (Pearson correlation with age, -0.43, p<0.0001), and BMD (Pearson correlation with age, -0.41, p<0.0001) (Figure 2). Efficacy of SAC was observed in all age groups. Therefore, there is no significant difference in efficacy among age groups (SOS change p=0.114, T-Score change p=0.324, BMD change p=0.124) (Figure 3).

Figure 2: Inverse relationship between age and bone health. A: T-score (p<0.0001), B: SOS (p<0.0001), C: BMD (p<0.0001)

Figure 3: Efficacy of SAC by age groups. Efficacy of SAC was observed in all age groups. There is no significant difference in efficacy among age groups. A: T-score change p=0.324, B: SOS change p=0.114, and C: BMD change p=0.124.

Among 82 participants, 65% of the osteopenia participants (20/31) improved to the normal range after 8 months of treatment, while 64% of participants with osteoporosis (21/33) were reclassified into the osteopenia group. Moreover, 12% of osteoporosis participants (4/33) improved to the normal range (Figure 4).

Figure 4: Distribution of clinical group before and after treatment based on T-score. 65% of participants with osteopenia (20/31) were improved to the normal group after treatment, while 64% of participants with osteoporosis (21/33) became the osteopenia group. Notably, 12% of osteoporosis participants (4/33) improved to the normal range.