Osteocalcin
Introduction
Section titled “Introduction”Osteocalcin, also known as bone gamma-carboxyglutamate (Gla) protein (BGLAP), is a small protein hormone predominantly produced by osteoblasts, the cells responsible for bone formation. It is the most abundant non-collagenous protein in bone, where it plays a crucial role in bone mineralization and the regulation of calcium homeostasis. The biological activity of osteocalcin is highly dependent on vitamin K, which is essential for the post-translational modification process known as carboxylation. During carboxylation, specific glutamic acid residues within the osteocalcin molecule are converted to gamma-carboxyglutamic acid (Gla), enabling the protein to bind to calcium ions and hydroxyapatite, a key mineral component of bone.[1]When vitamin K is insufficient, osteocalcin remains undercarboxylated (ucOC), impairing its ability to properly integrate into the bone matrix. Levels of osteocalcin, particularly its undercarboxylated form, can be measured in serum and plasma, serving as a biomarker for bone turnover and vitamin K status.[2]
Clinical Relevance
Section titled “Clinical Relevance”Due to its direct involvement in bone metabolism and its dependence on vitamin K, osteocalcin is a significant biomarker in clinical practice. Elevated levels of undercarboxylated osteocalcin are associated with poor bone health, including reduced bone mineral density and an increased risk of fractures, particularly hip fractures in elderly women.[3]Consequently, monitoring osteocalcin levels, especially the percentage of undercarboxylated osteocalcin, can provide insights into an individual’s vitamin K status and overall bone health. Research has explored the role of vitamin K supplementation in preventing fractures, highlighting the importance of adequate vitamin K for optimal osteocalcin function and bone integrity.[4]Genome-wide association studies (GWAS) have investigated osteocalcin as a select biomarker trait, identifying genetic regions that may influence its circulating levels.[5]For instance, the percentage of undercarboxylated osteocalcin has been identified as a trait of interest in genetic analyses, with specific associations noted on Chromosome 7.[5]
Social Importance
Section titled “Social Importance”The understanding of osteocalcin’s role carries substantial social importance, particularly in the context of public health strategies aimed at preventing and managing bone diseases like osteoporosis, which disproportionately affects aging populations. By identifying individuals with suboptimal vitamin K status through osteocalcin measurements, interventions such as dietary modifications or supplementation can be implemented to support bone health. This is crucial for reducing the burden of fractures, improving quality of life, and decreasing healthcare costs associated with bone-related conditions. Furthermore, genetic studies exploring the heritability and genetic determinants of osteocalcin levels contribute to a deeper understanding of individual predispositions to bone health issues, potentially paving the way for personalized prevention and treatment approaches.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Initial genome-wide association studies (GWAS) often rely on moderate cohort sizes, which can inherently limit the statistical power required to detect genetic effects of modest size.[5]This limitation increases the susceptibility to false negative findings, meaning that genuine genetic associations with osteocalcin levels might be overlooked, particularly when accounting for the extensive multiple testing inherent in GWAS.[5] Conversely, some observed associations, even those with moderate statistical support, may represent false positives, especially if they are not subsequently replicated in independent cohorts.[5]The accuracy of reported genetic variance explained by single nucleotide polymorphisms (SNPs) is also dependent on the underlying assumptions about the precision of estimated phenotypic variance and heritability.[6] Replication in independent cohorts is a critical step for validating genetic findings, and the lack of such replication remains a significant challenge.[5] Non-replication of previously reported phenotype-genotype associations can arise from several factors, including initial false positive discoveries, substantial differences in key characteristics between study cohorts that modify genetic effects, or insufficient statistical power in replication attempts.[5]Furthermore, specific study design choices, such as conducting only sex-pooled analyses to mitigate the multiple testing burden, may inadvertently obscure sex-specific genetic associations that could influence osteocalcin levels, leading to undetected findings.[7] Discrepancies in study power and design between different investigations can also contribute to the non-replication of associations.[8]
Generalizability and Phenotype Measurement Challenges
Section titled “Generalizability and Phenotype Measurement Challenges”A primary limitation of many genetic studies is the restricted generalizability of their findings, as cohorts are frequently drawn from specific demographics, such as middle-aged to elderly individuals of European descent.[5] This demographic homogeneity makes it challenging to confidently extrapolate results to younger populations or individuals from diverse ethnic and racial backgrounds.[5] Studies involving specialized populations, such as twins or volunteers, may introduce selection or participation biases that limit the applicability of findings to the broader general population.[6] Additionally, the timing of DNA collection, if performed at later examinations, could introduce a survival bias, further narrowing the representativeness of the study cohort.[5]Measurement of biomarkers like osteocalcin presents intrinsic challenges, including inherent variability within laboratory assays; for instance, coefficients of variation for undercarboxylated osteocalcin concentrations have been reported to range from 7.8% to 22.3%.[5] Environmental factors and specific collection protocols can also influence biomarker levels, with variations in blood collection time or menopausal status potentially confounding observed genetic associations if not rigorously controlled for.[6]Moreover, the use of genotyping platforms with incomplete coverage of the entire spectrum of genetic variation, such as the Affymetrix 100K gene chip, means that a significant number of genetic variants may be missed. This incomplete coverage limits the ability to comprehensively study candidate genes or fully capture all relevant genetic influences on osteocalcin.[5]
Gene-Environment Interactions and Unaccounted Heritability
Section titled “Gene-Environment Interactions and Unaccounted Heritability”Genetic variants are known to exert their influence on phenotypes in a context-specific manner, often being significantly modulated by environmental factors.[9]The frequent absence of detailed investigations into gene-environment interactions represents a substantial knowledge gap, as such interactions can profoundly alter the expression of genetic predispositions related to osteocalcin levels.[5]This oversight means that a portion of the heritability of traits like osteocalcin may remain unexplained, due to the incomplete characterization of the complex interplay between genetic and environmental factors. Furthermore, standard GWAS approaches, typically focused on common SNPs, may not fully account for rarer variants or more complex genetic architectures that contribute to the “missing heritability” of a trait.[7] For instance, the associations of ACE and AGTR2 with LV mass were reported to vary according to dietary salt intake in one investigation, illustrating the critical role of environmental context.[9] Even when genetic associations are successfully identified, pinpointing the precise causal variants and understanding their underlying biological mechanisms remains a considerable challenge. Different SNPs associated with a particular trait across various studies might each be in strong linkage disequilibrium with an unknown causal variant, or they could represent multiple distinct causal variants within the same gene, complicating the definitive identification of the true genetic drivers.[8]Current research methodologies may also be insufficient for a comprehensive study of candidate genes, leaving gaps in our understanding of their full genetic contribution to osteocalcin levels.[7] Additionally, an exclusive focus on multivariable models, while statistically robust, might lead to overlooking important bivariate associations between individual SNPs and the phenotype, thereby limiting the breadth of potential discoveries.[10]
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing a wide array of biological processes, including bone metabolism and the regulation of osteocalcin, a key hormone involved in bone formation and energy metabolism. Among these, variants in genes likeVKORC1 and APOE have particularly notable implications. The VKORC1gene, or Vitamin K Epoxide Reductase Complex Subunit 1, is essential for recycling vitamin K, a fat-soluble vitamin critical for the carboxylation of osteocalcin.[1] The rs2359612 variant within VKORC1may influence the efficiency of vitamin K recycling, thereby affecting the proper activation of osteocalcin, which is crucial for its role in bone mineralization and as a hormone regulating glucose and fat metabolism. Inadequate carboxylation of osteocalcin due to insufficient vitamin K status has been linked to increased risk of hip fractures.[3] The APOEgene, or Apolipoprotein E, is a central component of lipid metabolism, responsible for transporting fats and cholesterol in the blood. Thers7412 variant, a component of the well-known APOE ε4 allele, is associated with differences in lipid levels and an increased risk for cardiovascular diseases and neurodegenerative disorders.[11]Given osteocalcin’s emerging role as an endocrine hormone influencing glucose metabolism and fat deposition, variations inAPOEcould indirectly impact bone health and osteocalcin signaling through their broader effects on metabolic homeostasis and systemic inflammation, as well as directly through its role in apolipoprotein E processing.[12]Variants in genes involved in immune regulation and inflammatory responses can also impact bone health and osteocalcin.CFH (Complement Factor H) plays a vital role in regulating the complement system, a part of the innate immune response, with variants like rs2019727 and rs2300429 potentially affecting its function. Dysregulation of the complement system can lead to chronic inflammation, which is known to negatively influence bone remodeling and density, thereby indirectly affecting osteocalcin levels and activity.[5] Similarly, NLRP12 (NLR Family Pyrin Domain Containing 12) is a component of the inflammasome, a multiprotein complex that initiates inflammatory responses. The rs62143194 variant may alter NLRP12function, contributing to chronic low-grade inflammation, which can disrupt the delicate balance between bone formation and resorption, and influence osteocalcin’s hormonal signaling. TheBTNL2 gene (Butyrophilin-like 2), with the associated rs3117116 variant, also plays a role in immune modulation and is often linked to autoimmune conditions, where systemic inflammation can significantly impair bone health and impact osteocalcin’s endocrine functions.[13] Its antisense partner, TSBP1-AS1, may regulate BTNL2 expression.
Further genetic influences on bone biology and osteocalcin include developmental transcription factors, lipid synthesis enzymes, and non-coding RNAs.PRRX1 (Paired Related Homeobox 1), a transcription factor, is crucial for craniofacial and limb development, and its rs35363078 variant could affect bone formation processes directly, thereby influencing the production and function of osteocalcin. TheSPTLC3gene (Serine Palmitoyltransferase Long Chain Base Subunit 3), with variants such asrs1367742 , rs142870288 , and rs34899016 , is involved in the biosynthesis of sphingolipids, which are critical signaling molecules impacting cell growth, differentiation, and apoptosis in various cell types, including osteoblasts and osteoclasts, thus indirectly affecting osteocalcin levels. Long intergenic non-coding RNAs (lincRNAs), such as those associated withLINC02341 (rs58973023 ) and LINC01723 (rs1321940 , rs168622 , rs2327451 ), are regulatory molecules that do not code for proteins but influence gene expression. Variants in these lincRNAs could alter regulatory networks that govern bone metabolism, cell differentiation, or nutrient sensing, thereby impacting osteocalcin’s synthesis or activity.[10] Finally, COLEC10 (Collectin Subfamily Member 10), with variant rs13264172 , encodes a collagen-binding protein. Given that collagen is a primary component of the bone matrix, variations inCOLEC10could influence bone structure and integrity, potentially affecting the availability or release of osteocalcin from the bone matrix.[14]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs58973023 | LINC02341 | heel bone mineral density osteoarthritis, knee alkaline phosphatase measurement osteocalcin measurement collagen alpha-1(I) chain measurement |
| rs13264172 | COLEC10 | femoral neck bone mineral density spine bone mineral density psoriasis osteocalcin measurement |
| rs2359612 | VKORC1 | osteocalcin measurement |
| rs1321940 rs168622 rs2327451 | LINC01723 | level of phosphatidylcholine sphingomyelin measurement osteocalcin measurement genotoxic compound exposure measurement Sphingomyelin (d18:1/21:0, d17:1/22:0, d16:1/23:0) measurement |
| rs1367742 rs142870288 rs34899016 | SPTLC3 | level of phosphatidylcholine sphingomyelin measurement osteocalcin measurement genotoxic compound exposure measurement |
| rs7412 | APOE | low density lipoprotein cholesterol measurement clinical and behavioural ideal cardiovascular health total cholesterol measurement reticulocyte count lipid measurement |
| rs3117116 | TSBP1-AS1, BTNL2 | osteocalcin measurement lactobacillus phage virus seropositivity forced expiratory volume |
| rs2019727 rs2300429 | CFH | complement factor H-related protein 1 measurement osteocalcin measurement amount of leukocyte immunoglobulin-like receptor subfamily A member 5 (human) in blood level of leukocyte immunoglobulin-like receptor subfamily A member 5 in blood serum |
| rs62143194 | NLRP12 | interleukin 1 receptor antagonist measurement double-stranded RNA-binding protein Staufen homolog 1 measurement tumor necrosis factor receptor superfamily member 16 measurement inosine-5’-monophosphate dehydrogenase 1 measurement very long-chain acyl-CoA synthetase measurement |
| rs35363078 | PRRX1 | heel bone mineral density osteocalcin measurement bone tissue density |
Definition and Biological Context
Section titled “Definition and Biological Context”Osteocalcin is a well-characterized biological entity, for which methods of isolation, characterization, and detection have been established.[1]Its significance is largely understood in the context of bone health and vitamin K status.[2]A key characteristic of osteocalcin is its carboxylation state, which is dependent on vitamin K. The undercarboxylated form of osteocalcin is particularly relevant for assessing an individual’s vitamin K status and its implications for bone metabolism.[2]
Clinical Significance and Biomarker Classification
Section titled “Clinical Significance and Biomarker Classification”Undercarboxylated osteocalcin is classified as a biomarker, particularly for assessing bone health and fracture risk.[3]Studies have demonstrated that serum undercarboxylated osteocalcin levels can serve as an indicator for the risk of hip fracture, especially in elderly women.[3]In broader research, such as genome-wide association studies, “Vitamin K percentage of undercarboxylated osteocalcin” is considered a quantitative trait and is analyzed alongside other biomarkers within a specific biological domain, often grouped with other vitamin-related or inflammatory markers.[5]
Measurement and Operational Definitions
Section titled “Measurement and Operational Definitions”The operational definition of osteocalcin in research typically involves the measurement of its undercarboxylated form. The “percentage of undercarboxylated osteocalcin” is precisely determined through specific laboratory methods, such as radioimmunoassay.[5] For statistical analyses in large-scale studies, this trait is frequently natural log-transformed to address skewed distributions and is subjected to multivariable adjustment to account for potential confounding factors.[5]The reliability of osteocalcin as a biomarker is supported by its reported good reproducibility, ensuring consistent results in both clinical and research applications.[5]
Biochemical Assessment of Osteocalcin Status
Section titled “Biochemical Assessment of Osteocalcin Status”Osteocalcin is a key biochemical marker utilized in the diagnosis and monitoring of bone metabolism. Specifically, the percentage of undercarboxylated osteocalcin serves as an important indicator, reflecting vitamin K status and its impact on bone health . This biomarker is crucial for understanding the dynamic processes of bone formation and turnover.
Laboratory testing for undercarboxylated osteocalcin typically involves biochemical assays, such as radioimmunoassay, performed on plasma or serum samples.[5]This method allows for the quantification of different osteocalcin forms, providing insights into bone formation and the efficacy of vitamin K-dependent carboxylation, which is crucial for osteocalcin’s function in bone mineralization. The reproducibility of these biomarker measurements, which are part of broader bone health assessments, is generally considered good, contributing to the reliability of these diagnostic tests.[5]
Clinical Utility in Bone Health and Fracture Risk
Section titled “Clinical Utility in Bone Health and Fracture Risk”The clinical utility of osteocalcin, particularly its undercarboxylated form, extends to assessing an individual’s risk for bone-related pathologies. Elevated levels of serum undercarboxylated osteocalcin have been identified as a marker associated with an increased risk of hip fracture in elderly women.[3]This provides a valuable diagnostic criterion for identifying individuals at higher risk, allowing for targeted preventative strategies or interventions aimed at improving bone health.
Beyond fracture risk, osteocalcin levels contribute to the broader clinical evaluation of bone metabolism, often considered alongside other nutrient markers like vitamin K phylloquinone and vitamin D, which are integral to maintaining bone health.[5]While direct clinical assessment criteria for osteocalcin itself are typically based on biomarker levels rather than physical examination findings, its measurement aids in comprehensively evaluating a patient’s overall bone health status.
Genetic Associations and Molecular Markers
Section titled “Genetic Associations and Molecular Markers”Recent genome-wide association studies (GWAS) have begun to uncover genetic variants influencing osteocalcin levels, positioning genetic testing as an emerging diagnostic approach in understanding individual variability in bone metabolism. For instance, a specific locus on chromosome 7 has been identified as potentially influencing Vitamin K % undercarboxylated osteocalcin levels.[5]These findings highlight the genetic underpinnings of osteocalcin regulation.
These genetic insights suggest that molecular markers could eventually help predict an individual’s predisposition to altered osteocalcin metabolism or related bone health issues. While still largely in the research phase, combining genetic information with biochemical assays could offer a more personalized approach to diagnosing and managing conditions influenced by osteocalcin. This approach integrates understanding of genetic predispositions with observable biomarker traits for a comprehensive diagnostic profile.
Osteocalcin: A Key Bone Matrix Protein and its Biochemical Nature
Section titled “Osteocalcin: A Key Bone Matrix Protein and its Biochemical Nature”Osteocalcin is a prominent non-collagenous protein predominantly found in the bone matrix, serving as a crucial biochemical indicator of bone metabolism. Its fundamental role reflects the dynamic processes of bone formation and resorption, making it a key component in assessing overall skeletal health.[15]The isolation, characterization, and detection methods for osteocalcin have been well-established, providing foundational knowledge for understanding its biological importance and utility in research and clinical settings.[1]
Vitamin K-Dependent Regulation and Molecular Function
Section titled “Vitamin K-Dependent Regulation and Molecular Function”The biological activity of osteocalcin is intricately linked to vitamin K through a vital post-translational modification known as gamma-carboxylation. This process enables osteocalcin to bind calcium ions, a critical step for its proper integration into the bone mineral, hydroxyapatite . The extent of this carboxylation directly reflects an individual’s vitamin K status, with undercarboxylated osteocalcin representing a less functional form that indicates insufficient vitamin K . The measurement of undercarboxylated osteocalcin, often performed via radioimmunoassay, is therefore a significant tool for evaluating both vitamin K status and bone health.[5]This molecular detail highlights a key regulatory network where nutrient availability directly impacts the functional capacity of a crucial bone protein, influencing overall skeletal homeostasis.
Genetic Influences and Systemic Interactions
Section titled “Genetic Influences and Systemic Interactions”The levels of osteocalcin and its modified forms are not solely dictated by vitamin K intake but are also subject to genetic influences and broader systemic interactions. Research has explored the genetic contribution to overall bone metabolism, as well as the regulation of essential bone-related hormones like vitamin D and parathyroid hormone.[16]These genetic factors can indirectly impact osteocalcin’s synthesis or processing, thereby affecting its circulating concentrations and activity.
Furthermore, genome-wide association studies have investigated the genetic underpinnings of various biomarker traits, including vitamin K phylloquinone and the percentage of undercarboxylated osteocalcin.[5]Such research aims to identify specific genetic variants that contribute to inter-individual variability in these crucial bone health indicators, revealing complex regulatory networks at play that extend beyond simple nutritional intake.
Clinical Relevance and Pathophysiological Implications
Section titled “Clinical Relevance and Pathophysiological Implications”The clinical significance of osteocalcin, particularly its undercarboxylated form, lies in its strong association with bone health outcomes and disease states. Elevated levels of undercarboxylated osteocalcin have been identified as a reliable marker for an increased risk of hip fractures, especially in elderly women.[3]This highlights a critical pathophysiological mechanism where inadequate vitamin K status leads to dysfunctional osteocalcin, contributing to bone fragility.
Monitoring osteocalcin levels, alongside vitamin K and vitamin D status, provides valuable insights into the homeostatic balance of bone remodeling and potential disruptions that can lead to conditions like osteoporosis . Understanding these interconnections is vital for developing diagnostic strategies and targeted interventions to maintain skeletal integrity throughout life and mitigate the risk of debilitating bone diseases.
Osteocalcin Biosynthesis
Section titled “Osteocalcin Biosynthesis”Osteocalcin is a protein primarily synthesized by osteoblasts, the cells responsible for bone formation, as a precursor molecule. This initial production involves the fundamental cellular machinery for protein synthesis, marking its entry into the metabolic pathways governing bone matrix components. Following its synthesis, the nascent polypeptide chain undergoes further processing within the cell before being secreted into the bone matrix. This continuous biosynthetic process is essential for providing the necessary supply of osteocalcin to fulfill its critical functions in skeletal tissue.[1], [15]
Vitamin K-Dependent Post-Translational Regulation
Section titled “Vitamin K-Dependent Post-Translational Regulation”A crucial regulatory mechanism for osteocalcin’s biological activity involves its post-translational modification through gamma-carboxylation of specific glutamic acid residues. This carboxylation process is strictly dependent on vitamin K as an essential cofactor. The availability of vitamin K, therefore, acts as a critical control point, modulating the proportion of fully carboxylated, biologically active osteocalcin versus its undercarboxylated, less functional forms. This modification is vital for osteocalcin’s ability to effectively bind calcium ions and integrate properly into the developing bone matrix..[1]
Role in Bone Metabolism
Section titled “Role in Bone Metabolism”Osteocalcin is a significant non-collagenous protein found abundantly in the bone matrix, where it is secreted by osteoblasts. It plays an integral role in the metabolic pathways associated with bone formation, mineralization, and the broader processes of bone remodeling. The specific carboxylation status of osteocalcin influences its interaction with bone mineral, thereby impacting the structural integrity and dynamic balance of bone tissue. Its presence and activity highlight its contribution to the complex metabolic network that underpins skeletal health.[2], [15]
Clinical Relevance and Disease Mechanisms
Section titled “Clinical Relevance and Disease Mechanisms”Dysregulation in the vitamin K-dependent carboxylation pathway of osteocalcin represents a significant disease-relevant mechanism, directly affecting bone health. Elevated levels of serum undercarboxylated osteocalcin are strongly associated with an increased risk of hip fractures in elderly women, indicating compromised bone quality. This pathway dysregulation suggests that inadequate vitamin K status or impaired carboxylation leads to a less functional osteocalcin, contributing to bone fragility. Consequently, undercarboxylated osteocalcin serves as a crucial biomarker for assessing both vitamin K status and an individual’s susceptibility to bone fractures, offering potential therapeutic targets for intervention.[2], [3], [4], [5]
Role in Bone Health and Fracture Risk
Section titled “Role in Bone Health and Fracture Risk”Osteocalcin, a protein synthesized by osteoblasts, serves as a significant biomarker reflecting bone formation and turnover, offering insights into bone health. Its clinical utility is particularly pronounced when considering its carboxylation status, which is modulated by vitamin K. Undercarboxylated osteocalcin (ucOC) levels are particularly informative, as elevated concentrations are often associated with suboptimal bone mineralization. Research has established that serum ucOC acts as a marker for assessing the risk of hip fractures, especially in elderly women, thereby aiding in the identification of high-risk individuals who may benefit from preventative strategies.[3]This prognostic capability allows for better patient stratification and guides tailored interventions to mitigate the long-term consequences of bone fragility.
Vitamin K Status and Therapeutic Monitoring
Section titled “Vitamin K Status and Therapeutic Monitoring”The post-translational carboxylation of osteocalcin is a process critically dependent on vitamin K, making the proportion of undercarboxylated osteocalcin a direct indicator of an individual’s functional vitamin K status . Consequently, monitoring the percentage of undercarboxylated osteocalcin can be a valuable diagnostic tool for detecting vitamin K deficiency, which is known to influence both bone health and blood coagulation pathways. This biomarker also holds promise for evaluating the efficacy of therapeutic interventions aimed at improving bone mineral density or preventing fractures, such as vitamin K supplementation. A comprehensive systematic review and meta-analysis of randomized controlled trials support the role of vitamin K in preventing fractures, suggesting that osteocalcin levels could be leveraged to guide and monitor such preventive and treatment strategies.[4]
Genetic Influences and Personalized Approaches
Section titled “Genetic Influences and Personalized Approaches”Genetic factors contribute to the individual variability observed in various biomarker traits, including vitamin K percentage of undercarboxylated osteocalcin. Genome-wide association studies have identified specific genetic loci, such as those on Chromosome 7, that are potentially associated with vitamin K % undercarboxylated osteocalcin levels.[5]While these findings necessitate further validation and functional characterization in diverse cohorts, they suggest a pathway toward incorporating genetic information into risk stratification models. Identifying individuals with genetic predispositions affecting osteocalcin levels or vitamin K metabolism could facilitate the development of personalized medicine approaches, enabling earlier identification of those at high risk for bone-related conditions and the implementation of tailored prevention strategies.
References
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[12] Reiner AP et al. “Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.”Am J Hum Genet, 2008, 82:115-125.
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[15] Christenson, R. H. “Biochemical markers of bone metabolism: An overview.”Clinical Biochemistry, vol. 30, 1997, pp. 573–593.
[16] Hunter, D., et al. “Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation.”Journal of Bone and Mineral Research, vol. 16, no. 2, 2001, pp. 371-378.