Abstract
Skeletal formation involves a tightly regulated sequence of osteoblast-driven matrix production (ossification) and subsequent mineral deposition (mineralization). Traditional bone therapies (e.g. hormones, bisphosphonates) can indiscriminately accelerate or freeze these processes, sometimes leading to suboptimal outcomes (e.g. premature growth plate closure or overly brittle bone). Botanical agents offer a nuanced approach, with evidence that certain herbs can stimulate osteoblastic activity while tempering osteoclastic resorption.
We present a theoretical pharmacological framework using two prototype botanical formulations – Osteva Red and Osteva Green – designed to temporally modulate bone mineralization and ossification. Osteva Red (20 g Daemonorops draco resin, 1 g Humulus lupulus hop cone, 1 g Camellia sinensis green tea leaf, in an ethanol-extract emulsion) is formulated to emphasize early-stage mineral deposition with restrained ossification. Osteva Green (10 g each of the same botanicals, ethanol-extract emulsion) provides a balanced matrix to promote later-stage ossification and bone maturation.
Daemonorops draco (“Dragon’s Blood” resin) has traditional use in healing fractures and osteoporosis. Its constituents (e.g. dracorhodin, loureirin) stimulate osteoblast differentiation (increasing ALP, Runx2, BMP-2) and inhibit osteoclastogenesis, potentially by modulating osteocalcin (OCN) levels. Humulus lupulus (hops) contains 8-prenylnaringenin, a potent phytoestrogen that can mimic estrogen’s bone-protective effects. Low doses transiently promote osteoblast activity without premature growth plate fusion, whereas higher doses exert stronger estrogenic (anti-resorptive) action. Camellia sinensis (green tea) provides catechins (e.g. EGCG) that enhance osteoblast differentiation and mineralization while reducing oxidative stress and bone resorption markers.
We hypothesize that Osteva Red, used in an initial phase, suppresses excessive OCN activity to delay full ossification, allowing robust matrix deposition and mineral accumulation. Subsequently, Osteva Green (with increased hops and green tea) would be introduced to enhance ossification, improve bone quality, and rebalance hormonal signaling for bone consolidation. The ethanol-extract emulsion delivery is chosen to maximize bioavailability of lipophilic phytochemicals and ensure consistent systemic exposure.
This framework outlines how botanical formulations might temporally modulate bone formation processes. We emphasize this is a conceptual strategy, not a clinically validated therapy. Rigorous experimental and clinical studies are needed to validate the safety and efficacy of Osteva Red/Green in modulating skeletal mineralization and ossification.
Introduction
Bone formation is a dynamic process involving osteoblast-mediated deposition of organic matrix (primarily collagen, known as ossification in a broad sense) followed by mineralization where hydroxyapatite and other minerals crystallize within the matrix. Proper skeletal development and remodeling require a balanced timing of these steps – too rapid mineralization without adequate matrix can yield brittle bones, whereas excessive matrix without timely mineralization can lead to poor bone strength. The distinction between ossification (bone tissue generation, including matrix synthesis) and mineralization (inorganic mineral deposition) is subtle yet crucial. Osteocalcin (OCN), a vitamin K-dependent protein secreted by mature osteoblasts, exemplifies this distinction: it is involved in organizing mineral in bone. High OCN activity is associated with the later stages of bone formation, aligning mineral crystals with collagen fibers for quality bone tissue. Manipulating OCN levels could thus influence the timing of mineralization relative to matrix production, offering a potential lever to separate these processes. Indeed, early genetic studies showed that mice lacking OCN had increased bone mass due to uninhibited mineral deposition, although later work found that OCN-deficient bone, while hyper-mineralized, had disordered mineral alignment and reduced strength. This suggests that transient suppression of OCN might enhance mineral accumulation but must be followed by restoration of OCN function for proper ossification and bone quality.
There is growing interest in botanical or natural approaches to modulate bone remodeling in a gentler, more physiological manner. Epidemiological evidence links tea consumption (rich in polyphenols) with reduced age-related bone loss, and many traditional medicinal herbs (especially in Chinese medicine “kidney tonics”) have shown both anabolic (osteoblast-stimulating) and anti-catabolic (osteoclast-inhibiting) effects on bone. For example, a herbal formula (Epimedium, Ligustrum, Psoralea – ELP) demonstrated increased osteoblast activity and reduced bone resorption in vitro, protected bone mineral density (BMD) in ovariectomized rats, and even showed a trend of BMD preservation in postmenopausal women. Such findings highlight the potential of multi-component botanical therapies to positively influence bone metabolism. Compared to hormone replacement therapy (HRT) or bisphosphonates, which can cause adverse effects (HRT raises cancer/thrombosis risks, and bisphosphonates can lead to overly suppressed remodeling and atypical fractures), bioactive plant compounds might achieve a balance of promoting bone formation while maintaining bone quality.
In this context, we propose a framework for botanical modulation of skeletal mineralization and ossification using two exemplar formulations: Osteva Red and Osteva Green. These formulations are conceptual and derived from evidence-based selection of three botanicals:
Daemonorops draco (Dragon’s Blood resin),
Humulus lupulus (common hops), and
Camellia sinensis (green tea).
Daemonorops draco resin (referred to as Sanguis Draconis in ethnomedicine) is a deep red resin traditionally used for wound healing, fracture mending, and as an anti-osteoporotic remedy. Modern studies confirm its bone-healing reputation: ethanol extracts of Dragon’s Blood stimulate osteoblast proliferation, increase alkaline phosphatase (ALP) activity and calcium mineralization in bone cell cultures, and upregulate bone morphogenetic protein-2 (BMP-2) along with key osteogenic genes like Runx2, collagen-I, osteopontin and osteocalcin. Notably, Dragon’s Blood is also rich in flavonoids and phenolic compounds (e.g. dracorhodin, loureirin, pinocembrin) that have been shown to inhibit osteoclast formation. By both promoting osteoblast differentiation and curbing osteoclastogenesis, Daemonorops draco provides a dual action on bone remodeling. Of particular interest is its influence on OCN: by boosting BMP-2/Runx2 signaling, it drives osteoblast maturation (which raises OCN production in late-stage osteoblasts), yet the overall outcome in vivo might be a functional “suppression” of excessive OCN effects if timed correctly (i.e. allowing mineral deposition to outpace OCN-mediated mineral organization). This conceptual nuance underlies Osteva Red’s design, as described below.
Humulus lupulus (hops) is included for its well-documented phytoestrogenic and bone-preserving properties. Hops cones contain prenylflavonoids such as 8-prenylnaringenin (8-PN), one of the most potent plant estrogens known. 8-PN binds estrogen receptors with higher affinity and specificity than other phytoestrogens (exceeding even soy isoflavones). Estrogen is a key hormone for skeletal maintenance: it promotes osteoblast activity and suppresses osteoclastogenesis via increasing osteoprotegerin (OPG) and reducing RANKL. In estrogen-deficient states like menopause, bone resorption accelerates and formation lags, leading to net loss. Hops extract, through 8-PN, can counteract this imbalance. In vitro, 8-PN stimulates osteoblast differentiation and mineralization while potently inhibiting osteoclast differentiation. In vivo, oral hops or 8-PN supplementation prevents bone loss in ovariectomized (OVX) rodent models. Remarkably, a 12-week study found that a dose of 8-PN as low as ~68 mg/kg in OVX rats achieved similar improvement in bone strength as standard estrogen therapy. Clinical data are now emerging: a recent 1-year placebo-controlled trial in osteopenic postmenopausal women showed that a hop extract standardized to 8-PN (in addition to calcium and vitamin D) increased total body BMD by ~1–2% and improved physical function scores. Thus, hops provide an estrogenic stimulus that can be harnessed to enhance bone formation and reduce resorption. However, timing and dose are critical. During puberty, estrogen surges promote growth plate maturation and eventual closure, ending longitudinal bone growth. Excessive estrogenic activity too early can prematurely ossify growth plates (a known side effect when high-dose estrogen is used clinically to limit growth). Therefore, our framework envisions using a lower dose of hops (minimal estrogenic effect) in the initial Osteva Red phase to avoid premature ossification, and a higher dose in the later Osteva Green phase to capitalize on estrogen’s bone-consolidating effects once the desired bone length or preliminary matrix is achieved.
Camellia sinensis (green tea) is incorporated primarily for its antioxidant and osteogenic polyphenols. Green tea catechins, especially epigallocatechin-3-gallate (EGCG), have demonstrated multiple bone-beneficial actions. Laboratory studies indicate EGCG and related catechins can directly stimulate osteoblastogenesis: in mesenchymal stem cells, EGCG increases ALP activity and upregulates Runx2 and other osteoblast markers, promoting differentiation into bone-forming cells. EGCG has also been reported to enhance mineralized nodule formation in osteoblast cultures (though extremely high concentrations or prolonged exposure might down-tune late-stage differentiation to avoid over-mineralization) – highlighting a dose-sensitive profile. Concurrently, green tea compounds inhibit osteoclastogenesis and bone resorption, partly by suppressing inflammatory mediators. For instance, EGCG can block the expression of MMP-9 and other factors that facilitate osteoclast activity. Animal models reinforce these findings: OVX rats given green tea polyphenols show higher serum OCN and bone formation rates, lower bone resorption (TRAP) markers, and ultimately greater BMD than controls. The antioxidant capacity of green tea likely contributes by reducing oxidative stress in bone microenvironment, which otherwise impairs osteoblast function and accelerates osteoclastogenesis. In a short-term human study, 6 months of green tea extract supplementation in postmenopausal women was shown to be safe and yielded favorable trends in bone turnover markers (increased formation, reduced resorption), although changes in BMD required longer to manifest. These pleiotropic effects of green tea make it an ideal supporting component to enhance bone formation incrementally and protect the bone matrix from oxidative damage during the remodeling process.
In summary, each chosen botanical targets bone biology from a distinct angle: D. draco resin drives osteoblast differentiation and initial mineral deposition (while modulating OCN’s role), hops’ phytoestrogens provide hormonal-like regulation of bone turnover (with timing crucial to avoid untimely ossification), and green tea ensures an antioxidative, pro-osteogenic milieu that supports sustained bone formation. By combining these, the Osteva framework aims to modulate when and how mineralization vs. ossification occurs in a healing or developing bone. The following sections detail the proposed methodology (conceptual), the specific compositions of Osteva Red and Green, the mechanistic rationale for their use, and a discussion of their potential applications and limitations. Importantly, we clarify that this is a framework.
Framework and Methodological Basis
The Osteva Red/Green framework is conceived as a two-phase treatment paradigm to influence bone regeneration or growth in a temporal manner. It is predicated on the ability to decouple early mineral deposition from later ossification to some extent, thereby optimizing each phase. In practical terms, this means initially promoting the accumulation of mineral content in bone (to increase density and mass) without prematurely inducing the final maturation signals that lock the bone architecture in place. Then, in a subsequent phase, encouraging the maturation/ossification processes to solidify bone structure and quality once sufficient matrix and mineral are in place. This temporal modulation could be useful in scenarios such as: enhancing fracture healing (first build callus mass, then remodel to strong bone), treating osteoporosis (first rapidly refill bone mass deficit, then improve bone micro-architecture), or even extending growth plate activity in young adults (delay epiphyseal closure to allow continued growth, then later ensure proper ossification).
Methodologically, the framework would involve administering Osteva Red during Phase 1 (the Mineralization Phase), followed by Osteva Green during Phase 2 (the Ossification Phase). The transition timing would depend on the specific clinical goal. For instance, in fracture repair one might use Red in the early post-fracture weeks to foster callus formation, then switch to Green as the callus begins to consolidate. In an osteopenic patient, Red might be given for an initial few months to boost bone mass, then Green to maintain long-term quality. In growth extension use, Red could be used while epiphyseal plates are open to maximize growth without triggering closure, and Green introduced once the desired stature or bone lengthening is achieved to ensure the new bone ossifies strongly.
From a research standpoint, validating this framework would require multilevel monitoring of bone markers and outcomes over time. Key readouts would include: biochemical markers (e.g. serum ALP, OCN levels, collagen crosslinks) to gauge bone formation vs resorption activity; imaging (DXA for BMD, and ideally QCT or MRI for quality and structure); histomorphometry or bone biopsies to directly observe changes in osteoid thickness, mineral apposition rate, and osteocyte density during each phase. The framework’s success hinges on demonstrating that Osteva Red can indeed transiently enhance matrix and mineral deposition without causing chaotic ossification, and that Osteva Green can then improve organization and strength of that bone.
Emulsion-Based Ethanol Extract Delivery
A core methodological choice is the use of an ethanol extract emulsion as the delivery vehicle for both Osteva formulations. All three botanicals in Osteva (resin, hops, tea) contain hydrophobic bioactive compounds (terpenoids, flavonoids, catechins) that are not readily soluble in water. Ethanol extraction concentrates these compounds: for example, ethanol extracts of Dragon’s Blood yield substantially higher total phenolic content and flavonoid yield than aqueous extracts. However, purely ethanolic tinctures can have low bioavailability when taken orally, due to poor dispersion in the aqueous gastrointestinal environment. By formulating the extract into an emulsion, we improve the delivery in two ways: (1) the ethanol-extracted actives are embedded in tiny lipid droplets that facilitate solubility and transport across the gut wall, and (2) the small droplet size of a nano or micro-emulsion increases the surface area for digestive enzymes, enhancing release and absorption of the phytochemicals. Emulsion-based systems are known to increase the bioaccessibility and bioavailability of lipophilic nutrients and drugs, in part by enabling lymphatic uptake and protecting compounds from premature degradation.
Each Osteva formulation would thus be prepared by first creating a concentrated ethanol extract of the botanical ingredients (e.g. by maceration or ultrasound-assisted extraction), then blending this extract into a biocompatible oil (such as medium-chain triglycerides) and with appropriate emulsifiers and cosolvents to form a stable emulsion. The goal is a palatable, ingestible emulsion (for example, a shake or tonic) that can be taken daily. An emulsified ethanol extract also allows dose standardization – important because the dose-response of these botanicals is not linear. For instance, hops’ effects on osteogenesis vs. adipogenesis in marrow are dose-dependent; low doses preferentially stimulate bone markers, whereas excessive doses might saturate estrogen receptors or even exert negative feedback on endogenous hormone production. Fine-tuning the dose in an emulsion form (versus raw herb form) is much easier, as one can measure the extract’s active compound concentration and administer precise milliliter amounts.
Safety and Monitoring Considerations
Because this is a novel approach, safety monitoring is paramount in any investigative trial. Ethanol-extracted botanicals in an emulsion will deliver a complex mixture of actives. While each ingredient is individually consumed by humans (Dragon’s Blood in traditional medicine, hops in beer or supplements, green tea as a beverage), their concentrated combination could have unforeseen interactions. We would monitor liver and kidney function (as these extracts are metabolized there) – noting that green tea extracts in high doses have occasionally been associated with liver stress in sensitive individuals, and that hops can have sedative effects due to bitter acids. Hormonal profiles should also be tracked: hops may have estrogenic effects (e.g. changes in estradiol or follicle-stimulating hormone levels), and Dragon’s Blood’s endocrine effects are largely uncharted (though one study in male rats suggested no adverse effect on testosterone). Additionally, bone turnover markers (P1NP, CTX) would be periodically measured to ensure we are achieving the intended phase effects (e.g. higher formation marker during Red phase, then a balanced formation/resorption during Green phase).
In summary, the methodological basis of our framework is a phasic treatment strategy delivered via a high-bioavailability botanical emulsion, guided by real-time biomarkers to adjust timing. Next, we detail the specific composition of the Osteva Red and Green formulations and the roles of their components.
Botanical Matrix Composition
Osteva Red and Osteva Green are each comprised of the same three botanical extracts but in different proportions to create distinct pharmacological profiles. Both are formulated as ethanol-extract emulsions as discussed.
Osteva Red: Daemonorops draco resin 20 g, Humulus lupulus (hops) 1 g, Camellia sinensis (green tea) 1 g (extract weights referring to dry starting material equivalents), combined and extracted in ~70% ethanol, then emulsified for delivery. The extract ratio is heavily weighted towards Dragon’s Blood (≈91% of total botanical content by mass). This “red” formula (named for the deep red color imparted by Dragon’s Blood resin) is designed to deliver a concentrated dose of Dragon’s Blood phytochemicals with only minor contributions from hops and green tea. The rationale is to maximize the osteogenic signals from D. draco – i.e. high ALP, collagen synthesis, and initial mineralization – while minimizing estrogenic or anti-resorptive influences in this phase. In practical terms, 20 g of Dragon’s Blood resin might yield a rich array of flavonoids like loureirin A/B, dracoresinotannols, and the distinctive red pigment dracorhodin. These compounds collectively give Osteva Red a strong osteoblast-activating activity (as evidenced by increased osteoblast ALP and matrix production in prior studies) and a moderate inhibitory effect on osteoclasts (Dragon’s Blood’s anti-osteoclast IC_50 values in the tens of micromolar range for isolated compounds). The small 1 g of hops in Osteva Red provides only a minimal amount of 8-PN – deliberately kept low to avoid significant estrogen receptor activation at this stage. Similarly, 1 g of green tea contributes a modest level of catechins – enough to provide some antioxidant support and baseline osteoblast stimulation, but not enough to overshadow Dragon’s Blood’s effects. We can consider Osteva Red as matrix-centric: rich in ingredients that lay down bone matrix and seed mineral, but low in those that would finalize or harden the structure.
Osteva Green: Daemonorops draco 10 g, Humulus lupulus 10 g, Camellia sinensis 10 g, extracted in ethanol and emulsified. This “green” formulation is evenly balanced (1:1:1 by mass of the three botanicals). Halving the Dragon’s Blood content relative to Red and dramatically increasing hops (10× higher than in Red) shifts the activity profile. Osteva Green delivers robust phytoestrogenic and antioxidant signals alongside moderate osteogenic support. The 10 g of hops is a substantial dose – hops extracts given at ~1 g/kg in animal models raised serum estrogen levels and improved bone microarchitecture comparably to low-dose estradiol. In our human-scaled framework, 10 g dried hops (depending on 8-PN content of the cultivar) could yield on the order of tens of milligrams of 8-PN per dose, which is in the range used in clinical trials for menopausal symptom relief (e.g. 100 µg to 250 µg 8-PN per day achieves measurable estrogenic effects in women; our dose is higher but we assume partial extraction and first-pass metabolism reduce the effective yield). This phytoestrogenic load in Osteva Green is intentional – by Phase 2, we want to engage estrogen receptors to promote osteoblastic maturation, closure of growth plates (if applicable), and suppression of any excessive bone turnover. The 10 g of green tea ensures a high intake of catechins (possibly 300–500 mg of EGCG plus other catechins per dose, if using typical green tea content), which aids bone by mitigating oxidative stress from the increased remodeling and by directly stimulating new bone formation on a cellular level. Meanwhile, Dragon’s Blood at 10 g still contributes significant osteogenic compounds, but at half the concentration of the Red formula, its influence on OCN and mineralization is now more modulated. Osteva Green can be viewed as balance-centric: it provides hormonal balance (via phytoestrogen) and antioxidant protection to consolidate and improve the quality of the bone formed, while still maintaining an osteoblast-stimulating background.
To illustrate the contrast: if Osteva Red is akin to pouring a strong foundation (lots of concrete, minimal finishing), Osteva Green is the finishing crew that comes in to scaffold, polish, and strengthen that foundation into a resilient structure. The color designation also reflects a practical difference: Osteva Red’s solution would appear reddish due to Dragon’s Blood concentration, whereas Osteva Green, with much more green tea and hops, would be brownish-green in hue.
Formulation Notes: Both formulations are prepared in ethanol because many active constituents (e.g. xanthohumol from hops, epicatechins from tea, dracorhodin from resin) are more effectively extracted in alcohol than in water. However, direct consumption of an ethanol tincture at these doses would be unpalatable and suboptimal. By creating an emulsion, we also dilute the ethanol to safe levels and mask the bitter flavors (especially from hops). The emulsified product could be flavored or integrated into a smoothie or shake for easier ingestion. Each batch of Osteva Red/Green would be standardized for key marker compounds – for example, standardize Red to contain a certain % of dracorhodin or total phenolics, and Green to contain a specific 8-PN and EGCG content – to ensure batch-to-batch consistency.
In the next section, we delve deeper into the mechanistic rationale behind how these formulations exert their effects at the molecular and cellular levels, focusing on the key regulators: osteocalcin, BMP-2, Runx2, ALP, and hormonal signals.
Mechanistic Rationale
The mechanistic action of Osteva Red and Green can be understood by examining how each formulation influences critical bone formation regulators and pathways:
Osteocalcin (OCN): Osteva Red is hypothesized to transiently suppress or delay OCN’s influence on the bone formation timeline. OCN is a late-stage osteoblast product that, once carboxylated and incorporated into bone, helps regulate mineralization and also acts as a hormone. High OCN levels correlate with active bone turnover; paradoxically, complete absence of OCN can increase bone mass (as seen in knockout mice) but at the cost of bone quality. Dragon’s Blood resin in Osteva Red elevates osteoblast differentiation markers including OCN in vitro, but within our phased approach, we interpret that it may uncouple mineral deposition from OCN’s organizing role. By driving early osteoblast activity (ALP, collagen) and perhaps oversaturating the system with early matrix, Red might create a scenario similar to OCN deficiency in effect: rapid mineral accrual and higher bone mass, but potentially less organized mineral. This is acceptable (even desired) in Phase 1, because Phase 2 (Green) will reintroduce the signals needed for organization. In other words, Osteva Red “suppresses” OCN function in context – not necessarily by lowering OCN expression outright (it might actually increase OCN gene expression as part of osteoblast maturation), but by overwhelming early mineralization relative to OCN’s activity. It’s a controlled imbalance: more mineral laid down than OCN can immediately bind and organize, effectively delaying the ossification (maturation) while bone mass increases. Osteva Green, conversely, aims to enhance OCN’s role at the right time. Hops phytoestrogens and green tea in Green can raise OCN levels in circulation modestly and improve OCN’s carboxylation indirectly via improved nutritional status (green tea polyphenols might spare vitamin K by reducing oxidative load). Also, estrogen signaling from hops is known to reduce uncarboxylated OCN and bone turnover in OVX models, indicating a normalization of OCN function. Thus, mechanistically, Red-phase pulls back OCN’s reins (for mass gain), Green-phase restores OCN’s reins (for quality gain).
Bone Morphogenetic Protein-2 (BMP-2): BMP-2 is a potent growth factor driving osteoblast differentiation. Dragon’s Blood resin strongly upregulates BMP-2 expression in osteoblasts. This is a central reason for including Dragon’s Blood in both Red and Green. In Osteva Red, abundant BMP-2 creates an osteogenic microenvironment: more mesenchymal stem cells commit to osteoblast lineage and existing osteoblasts enter a maturation pathway. Elevated BMP-2 would increase Runx2 (the master osteoblast transcription factor) and downstream markers, fueling bone matrix production. In Osteva Green, BMP-2 is still present (from Dragon’s Blood 10 g), but now hops and green tea also contribute to osteoblast support, so BMP-2 works in concert with those. Notably, hops extract in a separate study increased BMP-2 protein in osteoblast cultures at optimal doses, so hops might also promote BMP signaling. The mechanistic upshot is that both formulations promote BMP-2 pathways, but Red does so more aggressively (to kickstart osteogenesis), whereas Green maintains a supportive BMP-2 level to continue differentiation and aid remodeling of the newly deposited matrix.
Runx2 (Runt-related transcription factor 2): Runx2 is often called the “master switch” of osteoblast differentiation; without Runx2, osteoblasts cannot mature. Our botanicals modulate Runx2 extensively. Dragon’s Blood extract was shown to elevate Runx2 expression in osteoblastic cells, consistent with its promotion of differentiation. Hops phytoestrogen 8-PN also increases Runx2: treatment of bone marrow stem cells with hops led to higher Runx2 gene expression and a bias toward osteoblastic over adipogenic differentiation. Green tea catechins, like ECG, have been reported to activate Runx2 by facilitating nuclear cofactors (TAZ). Therefore, both Osteva Red and Green elevate Runx2 activity, but their timing differs. In Red, Runx2 surge initiates robust differentiation of pre-osteoblasts and deposition of osteoid (early ossification). This sets the stage with plenty of immature osteoblasts and osteoid tissue. In Green, continued Runx2 support ensures those osteoblasts progress to fully functional cells (which produce OCN and orchestrate mineralization properly). We might think of Runx2-driven ossification vs. mineralization in phases: initial Runx2 (with Red) drives ossification (matrix formation), later Runx2 (with Green) under estrogenic environment drives mineralization completion (because estrogen/Runx2 interplay yields more mature osteoblasts that mineralize). Mechanistically, estrogen via hops also stabilizes Runx2 by mitigating excessive PPARγ (adipogenic factor) – indeed, 8-PN reduced marrow fat and promoted osteoblasts in vivo.
Alkaline Phosphatase (ALP): ALP is an enzyme critical for mineralization; it hydrolyzes pyrophosphate, an inhibitor of mineralization, thus allowing calcium phosphate crystals to form. It is a classic marker of early osteoblast differentiation and the onset of mineral deposition. Osteva Red is formulated to strongly induce ALP activity, reflecting its emphasis on mineralization. Dragon’s Blood extract significantly increased ALP activity and mineralized nodule formation in osteoblast cultures (with staining confirming abundant ALP on the matrix). Green tea catechins can also enhance ALP in osteoblasts (studies show EGCG and ECG raise ALP gene expression at certain doses). Hops extract had an interesting dose effect: in one experiment, a moderate dose (20 µg/mL) of hops extract promoted osteoblast proliferation and markers like BMP-2, while a higher dose (100 µg/mL) was needed to maximize ALP activity and matrix mineralization. This suggests dose-sensitive ALP induction by hops. In Osteva Red, ALP induction comes mainly from Dragon’s Blood (plus a bit from tea), and we expect high ALP in Phase 1, signifying active mineral deposition. In Osteva Green, ALP stimulation is still present (hops at high dose can directly increase osteoblastic ALP), but systemic ALP might actually decrease relative to Red phase because the frantic mineral deposition slows as bone matures. Indeed, in OVX mice, hops treatment reduced elevated ALP levels back toward normal, since OVX induces high bone turnover ALP and hops normalized it by curbing excessive turnover. Mechanistically, this means Osteva Green likely ensures that mineralization is completed and then tempered to avoid pathological over-mineralization. The transition from a high-ALP state (Red) to a moderated-ALP state (Green) would be a sign that initial mineralization is successful and that bone formation is proceeding to completion with proper regulation.
Hormonal (Estrogenic) Balance: A major mechanistic role of Osteva Green is to restore or mimic the hormonal milieu that optimizes bone remodeling. Estrogen’s role in bone is to maintain a balance: it limits osteoclast lifespan and activity while keeping osteoblasts functional. Osteva Red intentionally minimizes estrogenic activity (with only 1 g hops) to avoid interfering with growth or early mass accumulation. However, prolonged lack of estrogenic signaling is detrimental (mimicking menopause or OVX conditions where high bone turnover leads to poor quality bone). Thus, Osteva Green, with 10 g hops, floods the system with phytoestrogens sufficient to bind estrogen receptors in bone tissue. 8-PN from hops acts as an agonist on estrogen receptor-alpha in osteoblasts and osteoclasts, leading to increased OPG (osteoclast inhibitor) and decreased RANKL (osteoclast stimulator) production by osteoblasts. The net effect is fewer new osteoclasts and reduced bone resorption. Indeed, in bone cell co-culture studies, hops extract lowered the RANKL/OPG ratio significantly. Additionally, estrogen signaling promotes the apoptosis of mature osteoclasts and extends osteoblast lifespan by reducing oxidative stress-induced apoptosis. We expect Osteva Green to reproduce these effects: a transient rise in estrogenic activity that brings down bone resorption to normal levels after the Red phase (where bone formation might have outpaced resorption). This balancing act is important – any bone gained in Red phase should not be lost to overactive osteoclasts, and Green ensures that by both direct osteoclast inhibition and by completing the maturation of bone (mature bone is less prone to rapid turnover). An interesting hormonal aspect is that hops phytoestrogens have selective action: they strongly target bone and do not significantly stimulate uterine tissue at moderate doses, suggesting they might confer bone benefits with fewer side effects than estradiol. Green tea may also contribute modestly to hormonal balance; some studies indicate green tea polyphenols can increase sex hormone-binding globulin or mildly influence estrogen metabolism, but these effects are subtle. More prominently, green tea’s reduction of inflammation can lower inflammatory cytokines (like IL-1, IL-6, TNFα) that are elevated in estrogen deficiency and drive osteoclast activity. Thus, the combined action of hops and green tea in Osteva Green re-establishes a eubalance in bone remodeling: formation and resorption come to equilibrium, and any remaining excess osteoid from Red phase can be properly mineralized and remodeled.
To synthesize mechanistic actions in each phase:
During Osteva Red phase: High BMP-2/Runx2 activity leads to exuberant osteoblast differentiation and osteoid production. ALP is high, indicating active mineral deposition. OCN is present but its organizing effect is lagging behind the pace of mineral influx, functionally creating a scenario of rapid bone mass gain. Osteoclast activity is somewhat inhibited by Dragon’s Blood (and a bit by green tea), so resorption is kept low. This results in a net positive bone balance – a lot of bone is being laid down quickly. The bone at this stage may be hypermineralized but immature (resembling woven bone or a calcified cartilage scaffold, depending on context).
During Osteva Green phase: Estrogenic signals from hops kick in, reducing any excessive formation (ALP might normalize) and significantly inhibiting resorption to preserve the new bone. Osteoblasts, under continued Runx2 and now optimal OCN function, start organizing the mineral into better architecture (transition from woven to lamellar bone, in a fracture analogy). OCN gets carboxylated and integrated, improving crystal-collagen alignment. Any newly added mineral is now more orderly. Meanwhile, antioxidant polyphenols from green tea ensure that osteoblasts can function at their best (since oxidative stress is known to impair osteoblast and induce osteocyte apoptosis; green tea prevents that). The bone formed in Red phase undergoes maturation and strengthening. Markers like OCN and collagen cross-links would increase in this phase, reflecting improved bone quality, even if BMD gains plateau. In essence, Green phase solidifies the gains of Red phase, turning a high quantity of bone into high quality bone.
This two-step mechanistic approach draws inspiration from natural bone healing: during fracture repair, an initial unorganized callus forms (lots of matrix and minerals quickly, but weakly organized), followed by a remodeling phase where that callus is replaced with strong, oriented bone. Here, Osteva Red creates an “extra callus” (or extra bone mass) in the whole skeleton or target sites, and Osteva Green helps remodel and refine it. The novelty is doing this pharmacologically with botanicals rather than relying solely on the body’s intrinsic cues.
It is important to acknowledge that this mechanistic model, grounded in current biological understanding and preclinical data, is a complex and great framework for pharmaceutical use. Complex feedback loops (for instance, OCN’s hormone effect on pancreas and testosterone, or systemic endocrine responses to phytoestrogens) may modulate outcomes. We have strived to keep the mechanistic rationale biologically plausible and conservative – for example, we do not assume phytoestrogens will completely substitute for estrogen, only that they provide enough signaling to benefit bone. We also do not exaggerate hormonal effects; hops extract is not equivalent to HRT, but it does show measurable bone-protective estrogenic effects in animals and humans. By maintaining such scientific precision, we aim for a framework that could be realistically translated into hypotheses for animal studies or clinical trials.
Having outlined the mechanistic basis, we now discuss the broader implications of the Osteva Red/Green approach, potential use cases, and limitations in the discussion section.
Discussion
The Osteva Red and Green framework represents an approach to bone health that integrates insights from bone biology, phytochemistry, and traditional medicine. In this discussion, we explore the potential applications of this framework, compare it to existing therapies, and address its limitations and the challenges ahead.
Potential Applications and Advantages
One envisioned application of Osteva Red/Green is in the management of osteoporosis or low bone mass. Conventional osteoporosis treatments often either focus solely on anti-resorption (e.g. bisphosphonates, denosumab) or solely on anabolic stimulation (teriparatide, PTH analogs), but rarely both in a coordinated sequence. Our framework offers a sequential anabolic-then-consolidation strategy using natural agents. Osteva Red’s initial bone-building phase could be particularly useful for patients with very low BMD or osteoporotic fractures, to quickly accrue bone where it’s needed. By temporarily tilting the balance heavily toward formation (and modestly inhibiting resorption via Dragon’s Blood’s anti-osteoclast effects), one might achieve in a few months what current anabolics do in a year – a hypothesis that would need testing. Osteva Green would then serve as a “lock-in” phase, similar to how one might follow teriparatide (an anabolic drug) with an anti-resorptive to maintain gains. The difference is that here both phases are mediated by multi-component botanicals rather than high-cost single agents, potentially reducing side effects. For instance, the hops and green tea in Osteva Green not only preserve bone mass but could also improve metabolic profiles (green tea aids weight management and reduces inflammation, hops may improve menopause symptoms). Thus, patients might gain ancillary health benefits beyond bone.
Another application is in fracture healing and orthopedic recovery. In difficult-to-heal fractures or in cases like spinal fusion surgery where bone growth is desired, Osteva Red could be used post-injury to enhance callus formation. Dragon’s Blood has been noted in ethnomedicine to “knit bones” (heal fractures), and modern studies corroborate its fracture-healing potential. By boosting local osteogenesis and mineralization, it might accelerate the union of fracture ends. Once a substantial callus is formed, switching to Osteva Green would encourage the maturation of the callus into solid bone and prevent excessive callus resorption. Notably, Dragon’s Blood resin has shown anti-inflammatory and angiogenic properties as well, which could further aid fracture repair by improving blood supply and reducing inflammatory impediments to healing. The presence of green tea in both phases adds an antioxidant shield, which could mitigate oxidative stress known to impair fracture healing in the elderly or diabetics.
A more speculative application is in peak bone mass augmentation in young adults or extension of growth in late adolescence. There is a narrow window (teens to early 20s) when interventions can increase peak bone mass, which is a strong determinant of lifetime fracture risk. Osteva Red, by delaying ossification signaling (through minimal estrogenic activity) and maximizing bone formation, could hypothetically extend that window or amplify bone accretion during it. For instance, an 18-year-old with osteopenia (perhaps due to suboptimal diet or genetic factors) might benefit from a course of Osteva Red to pack on extra bone mineral content. Similarly, some orthodontic or orthopedic scenarios seek to modulate growth plate activity (e.g. enhancing mandibular growth in a retrognathic jaw). There are anecdotal reports – even on forums (as our search turned up) – of individuals using Dragon’s Blood resin in an attempt to delay growth plate closure and lengthen bone growth duration. While currently such use is not scientifically validated, our framework provides a rationale: by reducing OCN and estrogenic signals (via Red formulation), one could slow the endochondral ossification that leads to growth plate fusion, potentially yielding more longitudinal growth time. Then, proper ossification (via Green) would be needed to strengthen the newly grown bone. This concept intersects with the idea of modulating endochondral ossification – essentially using Red to keep the cartilage-to-bone conversion in a slower state, then Green to finalize it. Any such application would require extreme caution and ethical oversight, as altering growth plate timing can have unpredictable outcomes and must avoid disrupting normal development.
Comparison with Conventional Therapies
It is illuminating to compare Osteva Red/Green with classical treatments:
Versus Bisphosphonates/Denosumab: These agents solely cut down osteoclast activity, thereby reducing bone loss but also reducing bone formation (since bone formation and resorption are coupled). They increase BMD but can lead to “frozen” bone remodeling. Osteva Green has some overlap here – hops phytoestrogen does reduce osteoclastogenesis (in OVX mice hops lowered TRAP and cathepsin K expression significantly, similar to an anti-resorptive) – but importantly, Green also still supports some formation (through Runx2, BMP-2, etc.). And Osteva Red is outright anabolic. So together they more closely mimic normal bone turnover cycling rather than complete suppression. Another advantage is that bisphosphonates can cause overly mineralized, brittle bone with long-term use (e.g. atypical femur fractures), partly because microdamage accumulates when remodeling is too low. Our Red/Green aims to avoid that by actually stimulating remodeling in a controlled way (Red builds, Green remodels; bone is never static). Of course, this is contingent on fine control – too long on Red without Green could in theory cause a similar “over-mineralized” problem, which is why monitoring is key.
Versus PTH Analogues (Teriparatide): Teriparatide is an anabolic that increases osteoblast number and activity, somewhat analogous to what Dragon’s Blood + green tea catechins do in Osteva Red. Teriparatide’s downsides include high cost, daily injections, and a limited 2-year usage window (due to osteosarcoma risk in animal studies). A botanical approach, if effective, could be an oral alternative without those restrictions. However, teriparatide has a well-characterized mechanism (PTH pathway activation), while our botanicals hit multiple targets. This polypharmacy approach can be a double-edged sword: potentially synergistic (as we intend) but also harder to predict. One advantage of Osteva framework is the inclusion of a “consolidation” phase (Green) – something teriparatide therapy relies on doctors to implement by following up with anti-resorptives. Here it’s built-in to the protocol with natural agents.
Versus Hormone Replacement (Estrogen/SERMs): Estrogen replacement is highly effective at preventing bone loss but isn’t typically anabolic (it prevents resorption more than it builds new bone). SERMs (Selective Estrogen Receptor Modulators) like raloxifene give estrogen-like benefits in bone without stimulating breast tissue, but their magnitude of effect is modest and they don’t increase bone mass dramatically. Osteva Green essentially functions like a mild SERM – hops 8-PN is selective (more bone and vasculature effects, minimal uterine effect at typical doses). The difference is that Green is paired with the anabolic Red phase to add bone, which pure estrogen or SERM therapy cannot do. In that sense, our framework could accomplish both an increase in bone mass and an improvement in bone microarchitecture/hormonal milieu, using phytoestrogens in place of synthetic SERMs. An interesting note is that 8-PN’s potency as a phytoestrogen is higher than genistein (soy) or resveratrol, and animal studies showed it can match estradiol in preventing bone loss, so we are leveraging one of the strongest natural estrogen mimics known. By combining it with Dragon’s Blood (which has no known estrogenic action, thus complementary), we cover both non-hormonal and hormonal pathways.
Limitations and Considerations
Despite its promise, the Osteva framework has several important limitations and unknowns:
Lack of Clinical Validation: While each individual ingredient has encouraging data (e.g. Dragon’s Blood in cell and animal models, hops in animal and early clinical studies, green tea in epidemiological and animal studies), the safety and efficacy of using them together is not established. Botanical mixtures can have synergistic effects but also antagonistic ones. For example, could some polyphenols from green tea interfere with the absorption of hop prenylflavonoids? It’s possible; tea tannins might bind some compounds. Or might the sedative effects of hops (from its bitter acids) be enhanced by ethanol in the extract, causing drowsiness or cognitive slowing in some patients? These practical aspects need assessment. Additionally, we assume the phytoestrogen 8-PN will primarily act on bone and not strongly stimulate breast or uterine tissue, but at high doses that needs confirmation – 8-PN is potent enough that its systemic endocrine effects must be carefully observed (in the referenced trial, 100 µg/day of 8-PN improved bone density trend with no serious adverse effects, but in our framework the dose could be higher in phase 2).
Measurement of Outcomes: How to clearly measure “ossification vs mineralization” separately in a clinical setting? Standard DXA gives BMD which conflates both aspects. We would likely rely on proxies: serum OCN (especially the ratio of carboxylated to uncarboxylated OCN) could indicate how fully mineralized the bone matrix is – e.g. a sudden spike in OCN might mean a lot of new osteoid is being mineralized (or, conversely, if unOCN is high, maybe mineralization is lagging). Likewise, ALP (bone-specific ALP) can indicate mineral apposition rate. New imaging like trabecular bone score (TBS) or high-resolution peripheral QCT could show changes in microarchitecture that differentiate quality from quantity. In initial trials of Osteva, one would incorporate such endpoints to validate that Red phase truly increases mass and Green phase improves micro-architecture. Animal histology would directly show if Red induces more woven bone and Green transitions it to lamellar.
Regulatory and Reproducibility Issues: Botanicals suffer from variability – different resin batches, hop varieties, or tea preparations can differ in active content. To be scientific, we would have to standardize extracts stringently (e.g. ensure Dragon’s Blood extract contains X% dracorhodin and Y% total flavonoids, hops contains Z% 8-PN etc.). The good news is that many of these can be quantified by HPLC and modern methods, as referenced by various phytochemical studies (for instance, standardizing hop extract to 8-PN is already done in research). Another regulatory consideration: combining these into a “drug-like” regimen might draw scrutiny – in many jurisdictions, high-dose phytoestrogen supplements are regulated. Clinical trials would need ethics approval, especially if targeting young individuals for growth modulation.
Broader Implications for Botanical Therapeutics
If the Osteva concept proved successful, it would exemplify a broader principle: that phased botanical therapies can be designed to mimic complex physiological sequences. In conventional pharmacotherapy, we usually use one agent at a time or concurrently use several. The idea of time-sequenced combination therapy is somewhat rare (one example in oncology is using drugs in a specific sequence to exploit cell cycle, but in chronic disease it’s less common). Botanicals, with their multi-target actions, could be especially well-suited for such strategies. They can provide the “push” and the “brake” in the same toolkit, depending on how we formulate them. This might encourage research into other systems – could we have a “liver regeneration Red/Green” or a “cartilage repair Red/Green” using different herbs? It invites a new way of thinking about herbal medicine: moving from empirical mixtures to rationally designed, dynamic regimens.
Future Research Directions
To move this framework into the pharmaceutical industry, several research steps are needed:
Preclinical Trials: Test Osteva Red and Green in animal models. Start with ovariectomized rodents to simulate postmenopausal bone loss: compare groups receiving placebo, Red-alone, Green-alone, and Red→Green sequentially. Measure BMD, bone strength, and histology. A successful outcome would show the sequential treatment yielding higher bone mass than placebo or Green-alone, but better bone quality (microarchitecture, strength) than Red-alone. Fracture healing models could also be explored (e.g. create a standardized bone defect in rats and treat with Osteva vs control).
Mechanistic Studies: Delve into the cellular effects of combined extracts. For example, treat osteoblast cultures with Dragon’s Blood vs hops vs both to see if their effects are additive or one dominates. Evaluate osteoclast precursors similarly. Examine if Dragon’s Blood indeed lowers OCN production or secretion in any context (or if the “suppression” effect is only functional as hypothesized). Using gene expression profiling could reveal pathways activated by Red and Green extracts (are they activating Wnt signaling? Are they downregulating NF-κB in osteoclasts? etc.).
Safety Pharmacology: Assess toxicity margins in animals. Identify any organ toxicity or hormonal imbalance at doses multiples of the intended human dose. This would build confidence for human trials.
Clinical Trials: If preclinical data are promising, initial small clinical trials (Phase I/II) could be done in a controlled setting. Possibly start with an osteopenic but otherwise healthy adult population. Monitor bone turnover markers and BMD over, say, 6–12 months of Red→Green vs placebo or vs standard supplement (calcium/Vit D). Also monitor safety endpoints (liver enzymes, thyroid function – note green tea extract in high doses can affect thyroid in rare cases, etc.). If aiming at fracture healing, a trial could randomize patients with a certain fracture to receive Osteva vs placebo and compare healing time and outcomes.
Refinements: It may turn out that only two of the three ingredients are really necessary, or that an additional herb could improve it. For instance, one might consider adding a vitamin K source (like Polygonum cuspidatum which has resveratrol that stimulates OCN carboxylation, or simply add vitamin K2 supplement) in the Green phase to maximize osteocalcin’s mineral-binding capacity. We kept our formulation to three for simplicity, but future refinements could tweak the formula ratios or components for even better results.
Ethical and Public Understanding
As we maintain a publicly understandable tone, it’s worth clarifying: Osteva Red and Green are not “magic potions” or proven cures – they are conceptual formulations grounded in current scientific evidence from plants and bone biology. While we discuss them in a scientific manner, any suggestion of use in humans is purely hypothetical until more research is done. We also caution that using high-dose phytoestrogens or other extracts unsupervised could be harmful. For example, someone reading about hops might think “more is better” and take large amounts of hop supplements; however, studies show an optimal window (too low does nothing, too high might not increase benefit and could have side effects). Similarly, green tea extract in excess can stress the liver in rare individuals – moderation and proper formulation (as an emulsion, in our case) is important.
One interesting point for public takeaway is that nature’s pharmacopeia offers multi-pronged tools. Dragon’s Blood resin, a substance used for centuries (its usage dates back to ancient Greek and Chinese medicine), contains within it the ability to both spur bone formation and limit bone breakdown. It’s fascinating that a single traditional remedy aligns with modern molecular targets (BMP-2, Runx2 for bone formation; NFATc1 pathway for osteoclasts as indicated by dracorhodin’s effect). Hops, known mostly for beer brewing, turns out to harbor a molecule (8-PN) that is essentially a plant estrogen that can strengthen bones as effectively as pharmaceutical SERMs in animal tests. And green tea, a daily beverage, quietly supports bone health through its antioxidant and anti-resorptive effects. By harnessing these in a thoughtful way, we might open a new chapter of integrative bone health therapy.
Conclusion of Discussion
In conclusion, the Osteva Red and Green framework is a novel model that proposes to modulate skeletal mineralization and ossification through staged botanical therapy. Its success would depend on precise calibration of dosage and timing, and its validation is contingent on future rigorous studies. While the idea is compelling – essentially using “nature’s toolkit” to bioengineer bone formation in phases – we remain cautious. Biological systems are complex, and translating in vitro or animal effects to human outcomes is notoriously challenging. The discussion here serves to highlight what could be possible and to encourage further research bridging ethnopharmacology and modern endocrinology. Even if the exact Osteva formulations do not become therapeutics, the insights gained on how botanicals affect bone markers like OCN, ALP, Runx2, BMP-2, and hormones will be valuable in their own right.
Conclusion
We have outlined "Osteva Red and Green" as a comprehensive framework for botanical modulation of bone formation, wherein two sequential phytochemical formulations are used to first promote bone mineral accumulation and then enhance bone ossification and quality. Osteva Red, rich in Daemonorops draco (Dragon’s Blood) resin with supporting green tea and minimal hops, is designed to jump-start osteoblast activity, raise ALP and BMP-2 levels, and generate a surge of bone matrix and mineral deposition while functionally tempering osteocalcin’s organizing influence. Osteva Green, with balanced proportions of Dragon’s Blood, hops, and green tea, is intended to subsequently foster proper ossification: it provides phytoestrogenic signaling to refine and strengthen the bone (through Runx2/OCN alignment and osteoclast restraint) and antioxidant protection to ensure sustainable bone cell function.
The benefits of this two-phase approach include an ability to attain significant bone mass gain without sacrificing bone microstructural integrity – essentially addressing the quantity-vs-quality conundrum in osteoporosis therapy by tackling each sequentially. Furthermore, the use of an ethanol-extract emulsion as the delivery method enhances the bioavailability of the botanicals’ active compounds, leveraging modern pharmaceutics to potentiate traditional remedies. This highlights an appealing aspect of our framework: it marries traditional knowledge (Dragon’s Blood for fractures, hops for menopausal relief, green tea for health) with contemporary scientific understanding to yield a novel intervention concept.
We have grounded this paper it in peer-reviewed evidence – citing sources ranging from cell culture studies and animal experiments to clinical trials – but the combination and timing strategy proposed have not been clinically tested. The safety of high-dose Dragon’s Blood resin ingestion, the efficacy of sequential phytoestrogen therapy, and the validity of intentionally modulating osteocalcin activity are all key questions that need to be answered through research. There are encouraging signs (e.g. Dragon’s Blood improving osteoblast markers, hops improving BMD in osteopenic women), but also cautionary flags (e.g. potential liver strain from concentrated tea catechins, or unknown long-term effects of continuous phytoestrogen use).
In implementing this framework experimentally, careful monitoring of bone turnover markers, density, and biomechanical properties is essential to ensure that Phase 1 (Red) does not inadvertently produce weak bone and that Phase 2 (Green) successfully rectifies any deficiencies. The outcome of interest is not merely a higher BMD, but a resilient skeleton resistant to fractures – thus both phases must work in concert to achieve that.
In a broader context, this work serves as a proof-of-concept for how a mechanistic understanding of both bone biology and botanical pharmacology can lead to creative therapeutic hypotheses. It underscores the idea that botanical medicines can be more than adjuncts – with the right formulation and strategy, they might be orchestrated to drive complex physiological outcomes. As research progresses, we anticipate new data will either support, refine, or refute aspects of the Osteva framework. We are fully transparent that Osteva Red and Green are conceptual examples, not ready-to-use treatments. They are introduced to stimulate scientific discussion and further investigation into botanical modulation of bone remodeling.
Ultimately, our hope is that this framework opens avenues toward safe, effective, and holistic therapies for bone health. If successful, patients in the future might take a sequence of plant-based emulsions to rebuild their bones, reducing reliance on harsher medications. Even if partially successful, elements of Osteva (like the use of Dragon’s Blood compounds or hops extract in osteoporosis) could be incorporated into integrative treatment plans. And if it fails, it will yield valuable lessons – perhaps showing the limits of decoupling mineralization from ossification, or teaching us more about OCN’s role – which will still advance the field.
In conclusion, Osteva Red and Green provides a scientifically grounded yet imaginative framework for modulating skeletal biology. By focusing on temporal control and multi-target modulation, it invites a new perspective on treating bone disorders. We encourage rigorous testing of this framework and welcome collaboration across disciplines (from ethnobotany to orthopedics) to fully explore its potential. The road to therapy is long, but every journey begins with an idea – and here we present ours, at the intersection of traditional wisdom and modern science, for the betterment of bone health.
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