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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:B196-B200 (2004)
© 2004 The Gerontological Society of America

Biomarkers of Bone Turnover Can Be Assayed From Human Saliva

John W. McGehee, Jr. and Roger B. Johnson

Department of Periodontics, School of Dentistry, University of Mississippi Medical Center, Jackson.

Address correspondence to Roger B. Johnson, DDS, PhD, Department of Periodontics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505. E-mail: rjohnson{at}sod.umsmed.edu


   Abstract
Top
 Abstract
Method
 Results
 Discussion
 References
 
The purpose of this study was to determine if biomarkers of bone turnover [deoxypyridinium (D-PYR) or osteocalcin (OC)] could be detected in human saliva. These biomarkers have been measured in ovariectomized sheep saliva, but not in human saliva. Saliva was collected from 37 women. The bone mineral density of the calcaneus was assessed by quantitative ultrasound and expressed as a T score. Salivary D-PYR and OC concentrations were determined by enzyme-linked immunosorbent assay. Data were analyzed by a Spearman's rho correlation test and factorial analysis of variance was followed by a post hoc Tukey's test. There were significant correlations between age, body mass index, D-PYR, or OC concentration and calcaneus T scores (p <.05), suggesting that saliva could be used as a fluid for assay of human biomarkers of bone turnover. Our data suggest a beneficial use of saliva in situations where a large number of patients are to be screened for metabolic bone diseases.

OSTEOPOROSIS is the most common bone disease and is a significant risk factor for bone fracture in the elderly population (1). The World Health Organization has created criteria to define whether a person has normal bone mass, osteopenia, or osteoporosis, according to measurements of bone mineral density (BMD). These criteria define normal BMD as within 1 standard deviation (SD) of the young adult mean (peak bone mass; T score > -1), osteopenia as a bone mass from 1–2.5 SD below the young adult mean (T score of -1 to -2.5), and osteoporosis as a bone mass > 2.5 SD below the young adult mean (T score < -2.5) (2). Osteoporosis features reduced bone mass in addition to reduced BMD, which often results in fractures of the hip, wrist, or vertebrae (3). Osteopenia is a disease that features less extensive loss of bone mass and BMD than osteoporosis.

More than 20 million people in the United States have osteoporosis, which results in approximately 2 million fractures each year (4). There are numerous risk factors for osteoporosis, including female gender, age, diet, and smoking. Ethnic status, early onset of menopause, alcoholism, and calcium deficiency are additional risk factors for this disease (2). Body mass index (BMI) is also a factor in the etiology of osteoporosis, and there is evidence that obesity may be protective for the disease (5,6).

Osteoporosis results from uncoupled bone remodeling due to either greater rates of resorption than deposition, or normal bone resorption with no associated deposition. Examples of uncoupled remodeling include: 1) achievement of low peak bone mass in young adulthood, which may result in a seriously low BMD later in life, 2) a rapid bone loss rate at or following menopause, resulting from estrogen deficiency, and 3) bone loss coincident to either various medications or to endocrine diseases. Recent data suggest that estrogen maintains a balance between osteoblast and osteoclast function, and at menopause, osteoclast longevity exceeds osteoblast longevity, resulting in a negative bone balance (7).

Bone fragility is determined by bone quality, which is often assessed by measurement of BMD (8) using several techniques. These techniques include single photon absorptiometry, dual energy X-ray absorption (DEXA) (9), quantitative computerized tomography, and quantitative ultrasound (10). The reproducibility of BMD by DEXA has limitations (11) that result in difficulties in early diagnosis of osteoporosis. As a result, many older adults may have osteoporosis without their knowledge. BMD is often expressed in relative terms (T and Z scores), which compare the BMD of the patient to the mean maximal BMD (T score) or the BMD to an age-matched control (Z score). Both scores can be determined by quantitative ultrasound (12).

DEXA is the most widely used noninvasive quantitative diagnostic method for measuring BMD, but it has several limitations for general screening and community-based studies. Quantitative ultrasound is an alternative method for measuring BMD that offers a high correlation with DEXA (13). However, ultrasound measurements of the calcaneus have a 26% false-positive rate, which limit their use for specific determination of BMD (14). However, the reliability of ultrasound could possibly be improved when results are taken together with biochemical methods for assessment of bone turnover.

Proper management of osteoporosis involves early diagnosis of the disease, which includes complementary tests for assessment of serum and urinary markers for bone turnover, to assess risk for bone fracture and to monitor response to therapy. Type I collagen is 90% of the organic matrix of bone (15). Pyridinium (PYR) and deoxypyridinium (D-PYR) are mature cross-links of collagen (16). Following bone resorption by osteoclasts, PYR and D-PYR are released into the systemic circulation. These cross-links prevent reuse of the degraded collagen molecules and are considered to be specific markers of bone resorption (17,18).

Osteocalcin (OC) is the most abundant noncollagenous protein of mineralized tissues and is incorporated into bone matrix during deposition (19). Serum OC is considered a valid marker for bone turnover, when resorption and formation are coupled (20,21). OC allows identification of women with high rates of bone turnover, who are at risk for osteoporosis, from women with low rates of bone turnover in menopause. However, there is evidence that D-PYR is a more reliable marker than OC for the diagnosis of postmenopausal osteoporosis (22).

There is increasing evidence of an association between estrogen status and periodontal disease (23–25) and loss of alveolar BMD (26,27). Studies have reported that mandibular bone mass is correlated with skeletal mass (28–30). Postmenopausal women without hormone replacement therapy (HRT) exhibit a strong negative correlation between the number of retained teeth and the time since the initiation of menopause (31). In addition, older women using HRT have better periodontal health than women without HRT (32,33). There is evidence that spinal fracture in older women is associated with fewer remaining teeth, suggesting that periodontitis may be more severe in patients with osteoporosis (34–37).

The association between osteoporosis and periodontal disease has been validated in animals in both a short-term (38) and long-term study (23) of ovariectomized sheep. In addition, alveolar BMD has been reported to be associated with both age and menopausal status in humans (26). These animal studies report that serum and salivary biomarkers accurately predict BMD of the alveolar process and radius and ulna (23). In addition, there are regional variations in loss of BMD following ovariectomy in sheep, with loss of BMD first evident in the alveolar process and later in the radius and ulna (23). This phenomenon has also been reported in perimenopausal and menopausal women (26). However, other studies have failed to demonstrate associations between periodontal diseases and changes in BMD coincident to estrogen deficiency (39,40).

Currently, serum and urinary biomarkers for bone turnover are measured in either serum or urinary samples from patients, which may be uncomfortable or inconvenient. There is little information concerning the presence of these biomarkers in human saliva. The objective of this study was to determine whether salivary concentrations of OC or D-PYR were statistically correlated with BMD. If a correlation could be established, the potential use of a salivary-based test for markers of bone turnover would be valid.


   METHOD
Top
 Abstract
 Method
Results
 Discussion
 References
 
Patient Population
Thirty-seven healthy women were recruited from an osteoporosis-screening event at the University of Mississippi Medical Pavilion. The patients were not edentulous and had a self-reported history of regular medical and dental treatment (including HRT, if appropriate). Patient age, height, and weight, and total number of teeth were recorded by a single investigator. The BMI was calculated for each individual from the height and weight data.

Saliva Collection
Stimulated whole saliva was collected as described by others (41). A piece of paraffin was weighed and then placed into the mouth of the patient, the patient was then instructed to initially swallow any accumulated saliva and then to chew the wax at a regular rate, expectorating into a preweighed plastic cup during a 5-minute collection period. The samples were weighed and the salivary volume recorded. Salivary flow rates were expressed as milliliters per minute.

Saliva Preparation
Saliva was centrifuged at 3000 g for 10 minutes to separate cells and large macromolecules. The supernatants were collected, frozen at -80°C, and used for analysis of the biomarkers.

Analysis of Serum and Salivary Biomarkers for Bone Turnover
Assays for concentrations of OC and D-PYR were performed in duplicate by enzyme-linked immunosorbent assay. OC (Novocalcin) and D-PYR (Pyrilinks-D) assay kits were used (Metra Biosystems, Inc.) for these assays. The absorbance of each well was determined using a microplate spectrophotometer at 490 nm; biomarker concentrations were calculated from a standard calibration curve and were expressed as either ng/ml for OC or nM/ml for D-PYR.

BMD Assessment
The BMD of the calcaneus was measured by ultrasound densitometry (QUS-2 Calcaneal Ultrasonometer; Hanson Medical Systems, Inc., Orlando, FL) and was expressed as a T score. T scores of < 1 were defined as "normal," T scores between -1 and -2.5 were defined as "osteopenia," and T scores < -2.5 were defined as "osteoporosis" (12).

Statistical Analysis
Power calculations.-- Our hypothesis was that an estrogen-deficient group would have a decrease in BMD by at least 15 ± 0.8%. We believe that we can appropriately assume equal variances in the human participants. Using these assumptions, we performed power calculations using an SAS 8.1 statistical software package (SAS Institute, Inc., Cary, NC). By using {alpha} =.01, we should have 87% power with sample sizes of 6 in each group.

Data Analysis
Outcome measures for the study, included age, race, salivary flow rate, HRT, number of teeth, BMI, sIgA concentrations (total and adjusted for salivary flow), and BMD (T scores). The data were analyzed using SAS 8.1 statistical software. Means were compared by factorial analysis of variance and a post hoc Tukey's HSD test. In addition, data were compared using Spearman's rho test to determine possible correlations between groups. P <.05 was used to reject the null hypothesis.


   RESULTS
Top
 Abstract
 Method
 Results
Discussion
 References
 
The mean age of our patients was 53.9 ± 12.4 years. These women had a mean BMI of 25.84 ± 4.36 and a mean salivary flow rate of 1.23 ± 0.59 ml/min. Groups 1 and Group 2 women were significantly younger than Group 3 women (p <.05), and Group 2 women had a significantly higher BMI than Group 3 women (p <.05) (Table 1). Group 1 women had a lower total and salivary flow-adjusted D-PYR compared with Group 2 and Group 3 (p <.001); Group 2 women also had lower concentrations of D-PYR than Group 3 women (total, p <.05; flow adjusted, p <.001) (Figures 1 and 2, Table 1). Group 1 women had a higher total and salivary flow-adjusted OC concentration than the Group 2 and Group 3 women (p <.001), and had a higher total salivary OC concentration than Group 3 women (p <.001) (Figures 1 and 2, Table 1).


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  		Table 1. Descriptive Statistics (Mean ± Standard Error) for the 3 Groups of Patients Studied.

 


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  		Figure 1. Salivary deoxypyridinium concentration in patients with T scores > -1 ("normal" [Group1]), T scores from -1 to -2.5 ("osteopenic" [Group 2]), and T scores < -2.5 ("osteoporotic" [Group 3]). Total salivary concentrations of deoxypyridinium (TD-PYR, ng/ml) and those adjusted for salivary flow (SFD-PYP, ng/ml/min) are illustrated

 


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  		Figure 2. Salivary osteocalcin concentration in patients with T scores > -1 ("normal" [Group1]), T scores from –1 to –2.5 ("osteopenic" [Group 2]), and T scores < –2.5 ("osteoporotic" [Group 3]). Total salivary concentrations of osteocalcin (T-Oc, ng/ml) and those adjusted for salivary flow (SF-Oc, ng/ml/min) are illustrated

 
Both total and flow-adjusted salivary concentrations of D-PYR and OC were significantly correlated with T scores (p <.01), and total D-PYR and OC concentrations were significantly correlated with flow-adjusted salivary concentrations (p <.01) (Table 2).


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  		Table 2. Spearman Rho Correlation Coefficients Between the T Scores and the Biomarker Concentrations in Saliva (Total and Flow Adjusted).

 

   DISCUSSION
Top
 Abstract
 Method
 Results
 Discussion
References
 
Our data suggested that salivary D-PYR and OC concentrations could be used to predict both osteopenia and osteoporosis in human participants, as they correlated with calcaneal T scores. While the data were obtained from a small population, the significant trends in the data suggest that further evaluation of salivary biomarkers for bone turnover would be useful. We also reported that both total and salivary flow-adjusted concentrations of these biomarkers were statistically correlated, suggesting that assessment of salivary flow rate was not necessary for the accurate analysis of either salivary OC or D-PYR. In addition, our data confirmed reports that D-PYR could predict BMD (22,42–45), and extended those studies to report specifically that salivary D-PYR could also predict calcaneal T scores in humans.

BMI scores of our Group 3 patients were significantly less than the Group 2 patients, but not significantly different from the Group 1 patients. These data do not support several other studies, which suggested that osteoporosis patients were thinner than normal participants (5,6). Our data represent general characteristics of our patient population, which reflect the high incidence of obesity in Mississippi relative to other states (46), which is a significant risk factor in the incidence of both osteoporosis and periodontal disease (6,47).

It is generally agreed that there is an increased bone turnover rate in patients with estradiol deficiency (48). Increased rates of bone turnover are strong predictors of fracture risk, independent of BMD (49). Estrogen deficiency is reported to be a significant risk factor for loss of both skeletal and alveolar (oral bone) BMD (50,51), which could result in accelerated rates of tooth loss in both osteoporotic and osteopenic individuals (5,52–54). Our data do not support an association between osteoporosis and accelerated tooth loss, as the number of teeth in our Group 3 participants was not different from the Group 1 participants. Recent evidence suggests that long-term HRT women have an average of 3.6 more teeth than those who do not receive HRT (52). All of the perimenopausal and menopausal women in our study were receiving HRT, which probably negated the adverse effects of estrogen deficiency on the skeleton and alveolar bone, which would enhance tooth retention. Patients in our study had high bone turnover rates coincident to HRT, suggesting that either their relatively young age could have affected our results or that they were noncompliant with their HRT treatment. The presence of these women at an osteoporosis screening clinic suggests that they were interested in reducing their risk factors for osteoporosis and probably were equally diligent in their dental care.

There is general agreement that the biomarkers for bone turnover utilized in this study are reliable predictors of metabolic bone disease. While we did not compare salivary, serum, and urinary concentrations of the biomarkers, previous studies of animals indicate a significant correlation between salivary and urinary/serum concentrations of the biomarkers, with a slightly lower absolute concentration of the biomarkers in saliva (23). Serum OC has been reported to be a reliable indicator of bone turnover (55), and urinary D-PYR has been reported to be a reliable indicator of bone-specific collagen breakdown and a potential indicator of bone resorption (56). OC has been reported to specifically identify women with high bone turnover who are at risk for osteoporosis from women with low bone turnover at menopause (48,57). Since the concentrations of these biomarkers are correlated between saliva, serum, and urine in animals, our study suggests that they could also be correlated in humans.

While our study reports significant differences in biomarker concentrations between groups of a small population of women, these data should be followed by a larger study of the significance of these correlations where diet, medications, and lifestyle variables could also be considered. In addition, these data should be compared to those from patients with low and high bone turnover diseases. Scientific evidence supports the hypothesis that medical conditions alter salivary secretion and composition. Thus, short-term changes in salivary biochemical markers for bone turnover could be valid predictors of long-term changes in BMD, and could also be used to monitor therapy with antiresorptive drugs such as alendronate (57,58).

In recent years, dental personnel have made significant contributions to the diagnosis and management of medical and craniofacial disorders. In future years, dental personnel will likely be included in management of various systemic diseases. Use of saliva to assess biomarkers of bone turnover could be a simpler and less-invasive method than assessment of serum or urine samples, and could easily be used in screening procedures for osteoporosis in the home, in a public health setting, or in a dental office. Since many patients visit a dental office more often than a medical office, routine salivary assays for biomarkers of bone disease in conjunction with routine dental care could provide an earlier diagnosis of metabolic bone diseases than is currently available.


   Acknowledgments
 
The authors thank Clarita V. Odvina, MD, for her assistance in recruitment of patients for this study.


   Footnotes
 
Decision Editor: James R. Smith, PhD

Received September 25, 2003

Accepted December 22, 2003


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 Results
 Discussion
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