{"id":53080,"date":"2023-12-31T11:16:32","date_gmt":"2023-12-31T11:16:32","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=53080"},"modified":"2024-01-05T06:24:54","modified_gmt":"2024-01-05T06:24:54","slug":"estimation-of-serum-parathyroid-hormone-related-protein-in-the-assessment-of-pubertal-growth-spurt-in-skeletal-class-ii-malocclusion-subjects","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no4\/estimation-of-serum-parathyroid-hormone-related-protein-in-the-assessment-of-pubertal-growth-spurt-in-skeletal-class-ii-malocclusion-subjects\/","title":{"rendered":"Estimation of Serum Parathyroid Hormone Related Protein in the Assessment of Pubertal Growth Spurt in Skeletal Class II Malocclusion Subjects"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Modification\nof skeletal jaw discrepancies is best attempted during the adolescent growth spurt.\nDuring adolescence, the timing of the pubertal growth spurt occurs two years\nearlier in girls in comparison to boys.1<\/sup> It\nhas also been reiterated that treatment timing in mandibular deficiencies is\ndirectly dependent on mandibular growth spurt in sync with pubertal onset.2<\/sup>\nBiological skeletal\nmaturity indicators helps identify this pubertal growth spurt. The radiologic\nbiomarkers like hand-wrist radiograph3<\/sup>, MP3 stages on periapical x-ray\nfilms4<\/sup> and cervical vertebral maturation assessment on lateral\ncephalograms5-10 <\/sup>have been reported to be used extensively for\nskeletal maturity assessment and for noting peak attainment in mandibular\ngrowth. <\/p>\n\n\n\n

Cervical\nvertebral changes served as reliable skeletal maturity indicators without the\nneed for an additional radiograph11 <\/sup>and in Class II jaw\ndiscrepancies, their assessment was found sufficient for functional appliance\ntherapy.12<\/sup> Several authors have also eschewed the reliability and\nvalidity of this method.13<\/sup><\/sup><\/p>\n\n\n\n

However, radiographic methods have their inherent disadvantages like inter and intra-observer variability and failure to accurately determine the growth potential and end of growth spurt. The final stage of development as depicted in the radiographs also does not necessarily determine whether complete growth has been attained. Non radiologic biomarkers in contrast to radiologic biomarkers have been reported to be not only accurate in determining skeletal maturity but also in predicting the amount of growth left. Many non-radiologic biomarkers like insulin-like growth factor-1(IGF-1), insulin-like growth factor binding protien-3(IGFBP3) and osteocalcin have been used to assess the skeletal maturity of an individual.14, 15<\/sup><\/p>\n\n\n\n

Parathyroid Hormone related Protein (PTHrP), a poly hormone comprising of a family of distinct peptide hormones is secreted sometimes by cancer cells but primarily by the mesenchymal cells. Besides its parathyroid hormone like function, it also engages itself in epithelial cell growth, relaxation of smooth muscle, development of fetus, placental calcium transfer as also in skeletal morphogenesis.16<\/sup> PTHrP is synthesized at the periarticular ends of bone. Chondrocytes distant from the influence of PTHrP differentiate and secrete Indian hedgehog protein (Ihh) which further triggers release of PTHrP. Early maturation of chondrocytes thus induces osteogenesis.17<\/sup> During longitudinal growth, chondrocyte proliferation and differentiation is tightly controlled by the interplay between PTHrP & Ihh signaling in the growth plate facilitated also invariably by the PTHrP target gene (Zfp521).18<\/sup> Chondrocyte differentiation is affected by PTHrP and in mice with PTHrP null mutancy, intramembranous & endochondral ossification abnormalities leading to deformities in the mandible have also been observed, reiterating its role in the control of muscle development too.19<\/sup> Analysis of PTHrP null mutant mice revealed the formation of ectopic cartilage of a small proportion in the coronoid process of the mandible with increased multinucleated osteoclasts & abnormal bone marrow expansion. These immunohistochemical findings reiterated the role PTHrP played in bone modeling and chondrocyte differentiation.20<\/sup> It has also been reported that mechanical loading on the condyle brought about by a bite-jumping device in Sprague Dawley rats caused condylar cartilage growth due to the expression of SOX9 and PTHrP.21<\/sup><\/p>\n\n\n\n

The\nobjective of our study was thus to assess the serum levels of the PTHrP biomarker\nand correlate the same with the cervical vertebral stages to identify the\npubertal growth spurt to facilitate timely correction of the skeletal class II\nmalocclusion.<\/p>\n\n\n\n

Materials and Methods<\/strong><\/p>\n\n\n\n

Eighty subjects, males (n= 38), females (n=42), in\nthe age range of 11\u201318 years, were selected from the outpatient department of\nOrthodontics & Dentofacial Orthopedics, Sree Balaji Dental College &\nHospital, Chennai. All the subjects were screened for Class II skeletal\nmalocclusion by extraoral and intraoral clinical examination.Subjects with chronic systemic illness,\nendocrinological disorders, bleeding disorders, growth abnormalities, congenital\nsyndromes and history of facial trauma\/injury were excluded. Written informed\nconsent was obtained from the participant and their parent\/guardian\nrespectively before recruitment. The proposed study design & protocol was\nreviewed and approved by the Human Institutional Ethics Committee. The study design was a cross sectional\nstudy. Sample size of 80 was calculated with \u03b1 level of 0.05 and \u03b2 power of 0.8\nfor this study based on our previous study on non radiologic biomarkers in\nskeletal Class II malocclusion subjects. The samples were selected using\nsystematic sampling method.<\/p>\n\n\n\n

Complete case history of each patient was\nrecorded alongwith information regarding the pubertal status of the subjects\nfrom the parents concerned. Lateral cephalometric radiograph of the subjects was taken\nin the natural head position and lateral cephalometric analysis was carried out\nto confirm skeletal Class II pattern. Morphological evaluation of the 2nd<\/sup>, 3rd<\/sup> & 4th<\/sup>\ncervical vertebrae (CV) was carried out by visual inspection of the lateral cephalograms\nby 2 investigators independently as per the method advocated.22 <\/sup>Based on the cervical stages ranging from CS2\nto CS6, the 38 male & 42 female subjects were classified as has been\ndepicted in (Table 1). <\/p>\n\n\n\n

Two mL of blood was collected from the study\nsubjects. The collected sample was centrifuged at 1000x g at 2-80 <\/sup>C\nfor a duration of 20 minutes. Serum was then separated & stored at -20\u00b0C\nuntil the ELISA test was performed. Human PTHrP in the serum was quantitatively\nassessed by ELISA-Sandwich principle using Elabscience, ELISA kit (E-EL-H1478,\nElabscience\u00ae<\/sup>, USA). The absorbance (OD) was read at 450 nm using a microplate reader\n(TECAN, InfiniteM200PRO, Switzerland) within 10 minutes of addition of Stop\nSolution. <\/strong><\/p>\n\n\n\n

The average of the duplicate OD values for each standard & patient\u2019s sample was first calculated & the average zero standard OD was then subtracted from it. A standard curve was plotted with x-axis denoting standard concentration & y-axis the OD values. Using the average absorbance values of each sample, PTHrP concentration in each sample was calculated. <\/p>\n\n\n\n

Table 1: Study subjects classified based on cervical stages<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Cervical Stages<\/strong><\/p>\n<\/td>\n

\n

Male (n = 38)<\/strong><\/p>\n<\/td>\n

\n

Female (n = 42)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

n<\/strong><\/p>\n<\/td>\n

\n

Age (years)<\/strong><\/p>\n<\/td>\n

\n

n<\/strong><\/p>\n<\/td>\n

\n

Age (Years)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Mean<\/strong><\/p>\n<\/td>\n

\n

SD<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

Mean<\/strong><\/p>\n<\/td>\n

\n

SD<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

CS 2<\/p>\n<\/td>\n

\n

8<\/p>\n<\/td>\n

\n

11.5<\/p>\n<\/td>\n

\n

.8<\/p>\n<\/td>\n

\n

11.0<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

12.3<\/p>\n<\/td>\n

\n

1.0<\/p>\n<\/td>\n

\n

12.5<\/p>\n<\/td>\n<\/tr>\n

\n

CS 3<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

13.4<\/p>\n<\/td>\n

\n

1.3<\/p>\n<\/td>\n

\n

13.0<\/p>\n<\/td>\n

\n

3<\/p>\n<\/td>\n

\n

12.7<\/p>\n<\/td>\n

\n

1.2<\/p>\n<\/td>\n

\n

12.0<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

13.9<\/p>\n<\/td>\n

\n

1.4<\/p>\n<\/td>\n

\n

14.0<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

13.4<\/p>\n<\/td>\n

\n

1.0<\/p>\n<\/td>\n

\n

13.5<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5<\/p>\n<\/td>\n

\n

4<\/p>\n<\/td>\n

\n

16.8<\/p>\n<\/td>\n

\n

1.0<\/p>\n<\/td>\n

\n

16.5<\/p>\n<\/td>\n

\n

19<\/p>\n<\/td>\n

\n

15.8<\/p>\n<\/td>\n

\n

1.8<\/p>\n<\/td>\n

\n

16.0<\/p>\n<\/td>\n<\/tr>\n

\n

CS 6<\/p>\n<\/td>\n

\n

7<\/p>\n<\/td>\n

\n

16.7<\/p>\n<\/td>\n

\n

1.0<\/p>\n<\/td>\n

\n

17.0<\/p>\n<\/td>\n

\n

6<\/p>\n<\/td>\n

\n

16.0<\/p>\n<\/td>\n

\n

1.7<\/p>\n<\/td>\n

\n

17.0<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Statistical Analysis<\/strong><\/p>\n\n\n\n

CVM staging\nwas assessed by two orthodontists blinded regarding patient\u2019s details like age,\nsex & PTHrP serum levels. Kappa statistics was used to measure intra-observer\nand inter-observer reliability and it was found to be 0.98 and 0.96 respectively\nwith an almost perfect agreement. The data based on PTHrP serum levels was subjected to normality tests.\nSince the P<\/em> value of Shapiro-Wilk\ntest was less than 0.05, the hypothesis that PTHrP data was normally\ndistributed was rejected. Hence, non-parametric tests were carried out.\nStatistical analysis for gender wise comparison of PTHrP serum levels at each\ncervical stage and in the four intervals of the cervical stages was carried out\nusing Kruskal-Wallis test and for intergroup comparisons, Mann-Whitney U test\nwith Bonferroni\u201ds correction was done. (P <\/em><0.05 was considered\nstatistically significant). Analysis of the data was carried out utilizing SPSS\n(Version 24.0).<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Gender wise comparison of serum PTHrP levels at each cervical stage (CS) is depicted in (Table 2). In males, the highest mean PTHrP levels was 26.02 \u00b1 37.57 pg\/mL in CS3 with a decline subsequently from CS4 to CS6 with the lowest mean PTHrP levels in CS5 (12.29 \u00b1  1.69 pg\/mL) but it was statistically not significant (P<\/em> = 0.988). In females, the highest mean PTHrP levels was 22.64 \u00b1 9.73 pg\/mL in CS2 with an appreciable increase in CS5 (16.90 \u00b1 11.57 pg\/mL) and the lowest mean PTHrP levels was in CS3 (11.32 \u00b1 0.65 pg\/mL). However, it was not significant statistically (P<\/em> = 0.268) (Table 2A & 2B), (Figure 1).<\/p>\n\n\n\n

Table 2. Gender wise distribution of PTHrP (pg\/mL) serum levels at each cervical stage. <\/p>\n\n\n\n

Table 2A: PTHrP (pg\/mL) serum levels in males at each cervical stage.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

Cervical Stages<\/strong><\/p>\n<\/td>\n

\n

Mean PTHrP (pg\/mL) \u00b1 SD<\/strong><\/p>\n<\/td>\n

\n

SEM<\/strong><\/p>\n<\/td>\n

\n

95.0%  Confidence interval for Mean<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

PTHrP (pg\/mL)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

LL<\/strong><\/p>\n<\/td>\n

\n

UL<\/strong><\/p>\n<\/td>\n

\n

Min.<\/strong><\/p>\n<\/td>\n

\n

Max.<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

CS 2<\/p>\n<\/td>\n

\n

13.77 \u00b1 4.70<\/p>\n<\/td>\n

\n

1.66<\/p>\n<\/td>\n

\n

9.84<\/p>\n<\/td>\n

\n

17.70<\/p>\n<\/td>\n

\n

12.09<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

24<\/p>\n<\/td>\n<\/tr>\n

\n

CS 3<\/p>\n<\/td>\n

\n

26.02 \u00b1 37.57<\/p>\n<\/td>\n

\n

11.88<\/p>\n<\/td>\n

\n

-.85<\/p>\n<\/td>\n

\n

52.90<\/p>\n<\/td>\n

\n

11.83<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

132<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4<\/p>\n<\/td>\n

\n

15.04 \u00b1 8.53<\/p>\n<\/td>\n

\n

2.84<\/p>\n<\/td>\n

\n

8.48<\/p>\n<\/td>\n

\n

21.60<\/p>\n<\/td>\n

\n

11.89<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

36<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5<\/p>\n<\/td>\n

\n

12.29 \u00b1 1.69<\/p>\n<\/td>\n

\n

.85<\/p>\n<\/td>\n

\n

9.60<\/p>\n<\/td>\n

\n

14.98<\/p>\n<\/td>\n

\n

12.40<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

14<\/p>\n<\/td>\n<\/tr>\n

\n

CS 6<\/p>\n<\/td>\n

\n

13.56 \u00b1 3.03<\/p>\n<\/td>\n

\n

1.15<\/p>\n<\/td>\n

\n

10.75<\/p>\n<\/td>\n

\n

16.36<\/p>\n<\/td>\n

\n

13.74<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

19<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 Kruskal-Wallis test: P<\/em> = 0.988 (NS)<\/p>\n\n\n

Table 2B: PTHrP (pg\/mL) serum levels in females at each cervical stage.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

Cervical Stages<\/strong><\/p>\n<\/td>\n

\n

Mean PTHrP (pg\/mL)<\/strong><\/p>\n

SD<\/strong><\/p>\n<\/td>\n

\n

SEM<\/strong><\/p>\n<\/td>\n

\n

95.0%  Confidence interval for Mean<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

PTHrP (pg\/mL)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

LL<\/strong><\/p>\n<\/td>\n

\n

UL<\/strong><\/p>\n<\/td>\n

\n

Min.<\/strong><\/p>\n<\/td>\n

\n

Max.<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

CS 2<\/p>\n<\/td>\n

\n

22.64 \u00b1 9.73<\/p>\n<\/td>\n

\n

4.87<\/p>\n<\/td>\n

\n

7.16<\/p>\n<\/td>\n

\n

38.13<\/p>\n<\/td>\n

\n

20.75<\/p>\n<\/td>\n

\n

14<\/p>\n<\/td>\n

\n

35<\/p>\n<\/td>\n<\/tr>\n

\n

CS 3<\/p>\n<\/td>\n

\n

11.32 \u00b1 0.65<\/p>\n<\/td>\n

\n

.38<\/p>\n<\/td>\n

\n

9.70<\/p>\n<\/td>\n

\n

12.94<\/p>\n<\/td>\n

\n

11.06<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

12<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4<\/p>\n<\/td>\n

\n

15.59 \u00b1 5.75<\/p>\n<\/td>\n

\n

1.82<\/p>\n<\/td>\n

\n

11.47<\/p>\n<\/td>\n

\n

19.70<\/p>\n<\/td>\n

\n

13.18<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

26<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5<\/p>\n<\/td>\n

\n

16.90 \u00b1 11.57<\/p>\n<\/td>\n

\n

2.65<\/p>\n<\/td>\n

\n

11.32<\/p>\n<\/td>\n

\n

22.47<\/p>\n<\/td>\n

\n

12.26<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

45<\/p>\n<\/td>\n<\/tr>\n

\n

CS 6<\/p>\n<\/td>\n

\n

13.16 \u00b1 2.32<\/p>\n<\/td>\n

\n

.95<\/p>\n<\/td>\n

\n

10.73<\/p>\n<\/td>\n

\n

15.59<\/p>\n<\/td>\n

\n

13.34<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

16<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Kruskal-Wallis test: P<\/em> = 0.268 (NS)<\/p>\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Mean PTHrP serum levels at each cervical stage.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

To evaluate intergroup comparisons of PTHrP serum levels with different cervical vertebral stages, Mann-Whitney U test with Bonferroni\u2019s correction was carried out (Table 3). The results showed none of the variables were statistically significant (Table 3A, Table 3B).  <\/p>\n\n\n\n

Table 3: Intergroup comparison of PTHrP (pg\/mL) serum levels with different cervical stages in both males and females. <\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

A. Intergroup comparison of serum PTHrP levels with different CS in male subjects<\/strong><\/p>\n<\/td>\n

\n

B. Intergroup comparison of  serum PTHrP levels with different CS in female subjects<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Cervical Stage<\/strong><\/p>\n<\/td>\n

\n

Compared Stage<\/strong><\/p>\n<\/td>\n

\n

P <\/em>Value<\/strong><\/p>\n<\/td>\n

\n

Cervical Stage<\/strong><\/p>\n<\/td>\n

\n

Compared Stage<\/strong><\/p>\n<\/td>\n

\n

P <\/em>Value<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

CS 2<\/p>\n<\/td>\n

\n

CS 3<\/p>\n<\/td>\n

\n

0.829 (NS)<\/p>\n<\/td>\n

\n

CS 2<\/p>\n<\/td>\n

\n

CS 3<\/p>\n<\/td>\n

\n

0.057 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4<\/p>\n<\/td>\n

\n

0.963 (NS)<\/p>\n<\/td>\n

\n

CS 4<\/p>\n<\/td>\n

\n

0.142 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5<\/p>\n<\/td>\n

\n

0.933 (NS)<\/p>\n<\/td>\n

\n

CS 5<\/p>\n<\/td>\n

\n

0.081 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.867 (NS)<\/p>\n<\/td>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.067 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 3<\/p>\n<\/td>\n

\n

CS 4<\/p>\n<\/td>\n

\n

0.780 (NS)<\/p>\n<\/td>\n

\n

CS 3<\/p>\n<\/td>\n

\n

CS 4<\/p>\n<\/td>\n

\n

0.573 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5<\/p>\n<\/td>\n

\n

0.839 (NS)<\/p>\n<\/td>\n

\n

CS 5<\/p>\n<\/td>\n

\n

0.408 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.740 (NS)<\/p>\n<\/td>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.381 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4<\/p>\n<\/td>\n

\n

CS 5<\/p>\n<\/td>\n

\n

0.825(NS)<\/p>\n<\/td>\n

\n

CS 4<\/p>\n<\/td>\n

\n

CS 5<\/p>\n<\/td>\n

\n

0.804 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.758 (NS)<\/p>\n<\/td>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.792 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5<\/p>\n<\/td>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.527 (NS)<\/p>\n<\/td>\n

\n

CS 5<\/p>\n<\/td>\n

\n

CS 6<\/p>\n<\/td>\n

\n

0.926 (NS)<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Mann-Whitney U test with Bonferroni\u2019s correction for 10 comparisons, alpha value set at 0.05\/10=0.005; (P<\/em> < 0.005); Sig.: Significant; NS – Not Significant<\/p>\n\n\n

Gender wise comparison of serum PTHrP levels at each interval of cervical stage is depicted in (Table 4).  In males, PTHrP levels was highest in CS2-CS3 & in CS3-CS4 (20.82 \u00b1 27.75 pg\/mL) with a gradual decline in CS4-CS5, to being lowest in CS5-CS6 (13.09 \u00b1 2.60 pg\/mL) but statistically was not significant (P<\/em> = 0.984). <\/strong>In females, the highest mean PTHrP levels was 17.79 \u00b1 9.17 pg\/mL in CS2-CS3 stage with a slight decline in CS3-CS4, CS4-CS5 & CS5-CS6, to being lowest in CS3-CS4 (14.60 \u00b1 5.33 pg\/mL). It too was statistically not significant (P<\/em> = 0.819) (Table 4A & 4B), (Figure 2).<\/p>\n\n\n\n

Table 4. Gender wise distribution of PTHrP (pg\/mL) serum levels at each interval of cervical stage. <\/p>\n\n\n\n

Table 4A: PTHrP (pg\/mL) serum levels of male subjects at each interval of cervical stage<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n
\n

Cervical Stages<\/strong><\/p>\n<\/td>\n

\n

Mean PTHrP (pg\/mL) \u00b1<\/strong><\/p>\n

SD<\/strong><\/p>\n<\/td>\n

\n

SEM<\/strong><\/p>\n<\/td>\n

\n

95.0% Confidence interval  for Mean<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

PTHrP (pg\/mL)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

LL<\/strong><\/p>\n<\/td>\n

\n

UL<\/strong><\/p>\n<\/td>\n

\n

Min.<\/strong><\/p>\n<\/td>\n

\n

Max.<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C2 – C3<\/p>\n<\/td>\n

\n

20.58 \u00b1 28.21<\/p>\n<\/td>\n

\n

6.65<\/p>\n<\/td>\n

\n

6.55<\/p>\n<\/td>\n

\n

34.60<\/p>\n<\/td>\n

\n

12.09<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

132<\/p>\n<\/td>\n<\/tr>\n

\n

C3 – C4<\/p>\n<\/td>\n

\n

20.82 \u00b1 27.75<\/p>\n<\/td>\n

\n

6.37<\/p>\n<\/td>\n

\n

7.45<\/p>\n<\/td>\n

\n

34.19<\/p>\n<\/td>\n

\n

11.89<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

132<\/p>\n<\/td>\n<\/tr>\n

\n

C4 – C5<\/p>\n<\/td>\n

\n

14.20 \u00b1 7.14<\/p>\n<\/td>\n

\n

1.98<\/p>\n<\/td>\n

\n

9.88<\/p>\n<\/td>\n

\n

18.51<\/p>\n<\/td>\n

\n

12.06<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

36<\/p>\n<\/td>\n<\/tr>\n

\n

C5 – C6<\/p>\n<\/td>\n

\n

13.09 \u00b1 2.60<\/p>\n<\/td>\n

\n

.79<\/p>\n<\/td>\n

\n

11.34<\/p>\n<\/td>\n

\n

14.84<\/p>\n<\/td>\n

\n

12.74<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

19<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

  Kruskal-Wallis test: P<\/em> = 0.984 (NS)<\/p>\n\n\n

Table 4B: PTHrP (pg\/mL) serum levels of female subjects at each interval of cervical stage<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n
\n

Cervical Stages<\/strong><\/p>\n<\/td>\n

\n

Mean PTHrP (pg\/mL) \u00b1<\/strong><\/p>\n

SD<\/strong><\/p>\n<\/td>\n

\n

SEM<\/strong><\/p>\n<\/td>\n

\n

95.0% Confidence interval  for Mean<\/strong><\/p>\n<\/td>\n

\n

Median<\/strong><\/p>\n<\/td>\n

\n

PTHrP (pg\/mL)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

LL<\/strong><\/p>\n<\/td>\n

\n

UL<\/strong><\/p>\n<\/td>\n

\n

Min.<\/strong><\/p>\n<\/td>\n

\n

Max.<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C2 – C3<\/p>\n<\/td>\n

\n

17.79 \u00b1 9.17<\/p>\n<\/td>\n

\n

3.47<\/p>\n<\/td>\n

\n

9.31<\/p>\n<\/td>\n

\n

26.27<\/p>\n<\/td>\n

\n

14.04<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

35<\/p>\n<\/td>\n<\/tr>\n

\n

C3 – C4<\/p>\n<\/td>\n

\n

14.60  \u00b1 5.33<\/p>\n<\/td>\n

\n

1.48<\/p>\n<\/td>\n

\n

11.38<\/p>\n<\/td>\n

\n

17.82<\/p>\n<\/td>\n

\n

12.06<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

26<\/p>\n<\/td>\n<\/tr>\n

\n

C4 – C5<\/p>\n<\/td>\n

\n

16.45 \u00b1 9.85<\/p>\n<\/td>\n

\n

1.83<\/p>\n<\/td>\n

\n

12.70<\/p>\n<\/td>\n

\n

20.19<\/p>\n<\/td>\n

\n

12.26<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

45<\/p>\n<\/td>\n<\/tr>\n

\n

C5 – C6<\/p>\n<\/td>\n

\n

16.00 \u00b1 10.21<\/p>\n<\/td>\n

\n

2.04<\/p>\n<\/td>\n

\n

11.79<\/p>\n<\/td>\n

\n

20.21<\/p>\n<\/td>\n

\n

12.31<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

45<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Kruskal-Wallis test: P<\/em> = 0.819 (NS)<\/p>\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Mean PTHrP serum levels in the four intervals of cervical stages.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

To evaluate intergroup comparisons of serum PTHrP levels with different cervical stage intervals, Mann-Whitney U test with Bonferroni\u2019s correction was carried out (Table 5). The results showed none of the variables were statistically significant (Table 5A, Table 5B). <\/p>\n\n\n\n

Table 5. Intergroup comparison of PTHrP (pg\/mL) serum levels with different cervical stage intervals in both males and females. <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

A. Intergroup comparison of serum PTHrP levels with different cervical stage intervals in males<\/strong><\/p>\n<\/td>\n

\n

B. Intergroup comparison of serum PTHrP levels with different cervical stage intervals in females<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Cervical Stage<\/strong><\/p>\n<\/td>\n

\n

Compared Stage<\/strong><\/p>\n<\/td>\n

\n

P<\/em> Value<\/strong><\/p>\n<\/td>\n

\n

Cervical Stage<\/strong><\/p>\n<\/td>\n

\n

Compared Stage<\/strong><\/p>\n<\/td>\n

\n

P<\/em> Value<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

CS 2 –  CS 3<\/p>\n<\/td>\n

\n

CS 3 \u2013 CS 4<\/p>\n<\/td>\n

\n

0.964 (NS)<\/p>\n<\/td>\n

\n

CS 2 –  CS 3<\/p>\n<\/td>\n

\n

CS 3 \u2013 CS 4<\/p>\n<\/td>\n

\n

0.311 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4 \u2013 CS 5<\/p>\n<\/td>\n

\n

0.767 (NS)<\/p>\n<\/td>\n

\n

CS 4 \u2013 CS 5<\/p>\n<\/td>\n

\n

0.456 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5 \u2013 CS 6<\/p>\n<\/td>\n

\n

0.842 (NS)<\/p>\n<\/td>\n

\n

CS 5 \u2013 CS 6<\/p>\n<\/td>\n

\n

0.420 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 3 \u2013 CS 4<\/p>\n<\/td>\n

\n

CS 4 \u2013 CS 5<\/p>\n<\/td>\n

\n

0.880 (NS)<\/p>\n<\/td>\n

\n

CS 3 \u2013 CS 4<\/p>\n<\/td>\n

\n

CS 4 \u2013 CS 5<\/p>\n<\/td>\n

\n

0.851  (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 5 \u2013 CS 6<\/p>\n<\/td>\n

\n

1.000 (NS)<\/p>\n<\/td>\n

\n

CS 5 \u2013 CS 6<\/p>\n<\/td>\n

\n

0.903 (NS)<\/p>\n<\/td>\n<\/tr>\n

\n

CS 4 \u2013 CS 5<\/p>\n<\/td>\n

\n

CS 5 \u2013 CS 6<\/p>\n<\/td>\n

\n

0.608 (NS)<\/p>\n<\/td>\n

\n

CS 4 \u2013 CS 5<\/p>\n<\/td>\n

\n

CS 5 \u2013 CS 6<\/p>\n<\/td>\n

\n

—<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Mann-Whitney U test with Bonferroni\u2019s correction for 10 comparisons, alpha value set at 0.05\/6=0.008; (P<\/em> < 0.008); Sig.: Significant; NS – Not Significant<\/p>\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

Radiologic\nbiomarkers like hand wrist radiograph, CVMI and MP3 used to assess skeletal\nmaturity are highly subjective techniques with questionable validity and\nreliability. They lack the ability to determine the intensity & end of growth\nspurt as also fail to identify the peak in mandibular growth. CVM assessment is\nbased on the morphological changes of the 2nd, 3rd & fourth cervical\nvertebrae that occurs simultaneously with growth reflecting the initiation and\ncompletion of the pubertal growth spurt. However, biological and technical reasons could preclude\nreproducibility in CV staging. The timing of the growth spurt would also be difficult to\nassess as one is not aware of what point in time of the CS the lateral\ncephalometric radiograph was obtained. <\/p>\n\n\n\n

These limitations highlighted the need to identify various other\nnon-radiologic biomarkers that could accurately determine the skeletal maturity\nof an individual and detect the peak in pubertal growth spurt with less ambiguity.\nThough IGF-1, IGFBP-3 and osteocalcin have been used as potential biomarkers, PTHrP\nwas chosen as available literature on PTHrP in assessing the adolescent growth\nspurt more particularly in skeletal Class II malocclusion subjects was scarce\nand non- existent. The comparison of these non-radiologic biomarkers was done\nwith the CVM method as these cervical vertebrae could be readily analyzed in a\nlateral cephalometric radiograph that is routinely taken for orthodontic\ndiagnosis and treatment planning. <\/p>\n\n\n\n

Literature has been evidence of the fact that PTHrP plays a very\nimportant role in the eruption of teeth by promoting osteoclast formation above\nthe dental crypt. 23,24<\/sup> Some authors observed that\nthe chondroblasts differentiated in increased numbers with increase in volume\nof the cartilage when the mandible was advanced with functional appliances in\n35 days old Sprague-Dawley rats and that with increased PTHrP expression levels\nthere was a slowing of chondrocyte hypertrophy and resultant increased growth.25<\/sup>\nPTHrP that is synthesized by the chondrocytes & perichondrial cells present\nat the end of cartilage mold in early fetal life, irrevocably controls endochondral\nossification and development of bone. Chondrocytes also synthesize Indian\nhedgehog (Ihh) required for PTHrP synthesis and differentiation of\nchondrocytes. Animal experiments in knock-in mouse also confirmed the\nmechanical regulatory action of PTHrP on subjacent bone cell populations at\ninsertion sites of ligament\/tendon & periosteum of endochondral bones.26 <\/sup>The role of\nPTHrP in the regulation of endochondral bone formation in fetal life and bone\nremodeling in post natal life has been widely reported.27<\/sup><\/p>\n\n\n\n

Our\ndata revealed that in males the mean PTHrP levels peaked in CS3 with a decline\nin the levels till CS6 and in females it peaked at CS2 with another less\nintense peak in CS5.  In males, this\nincrease was found in the interval CS2-3 leading upto CS3-CS4 whereas in\nfemales this increase was observed in the interval CS2-CS3. Our findings were\nin tune with the findings of another study where the levels of PTHrP expression\n& Ihh in hypertrophic chondrocytes was found to be increased in early rather\nthan in the later stages of puberty leading to the speculation that PTHrP and\nIhh could both serve as regulators of pubertal growth in humans.28 <\/sup>However, our findings\ndid not correlate with the findings of another study where the human serum\nPTHrP levels was found to be increased in late rather than in the early stages\nof puberty.29<\/sup> The role played by PTHrP in cartilage and bone development\nhas been reiterated time and again in literature.30<\/sup> Most of the\nPTHrP functions are either autocrine or paracrine with its classical endocrinal\nrole exhibited only in lactation and in placental maternal\u2012fetal calcium\ntransport, and in Humoral Hypercalcemia Malignancy syndrome. Mutations in the PTHrP<\/em> gene\nis reported to be associated with chondrodysplasia and brachydactyly type E.31\n<\/sup>PTHrP signaling has also been documented to regulate a network of\ndownstream events that alter chondrocyte proliferation and differentiation\nduring development.32,33<\/sup><\/p>\n\n\n\n

However, the reportage of PTHrP as a skeletal maturity indicator\nto determine peak pubertal growth was observed to be scant in orthodontic\nliterature. In adolescence, though we can predict the sequential\nchanges in puberty fairly well, the timing of puberty is however variable.\nGenetic and environmental factors affect variations in pubertal timing in\ndifferent ethnic populations.34 <\/sup>Our data revealed that in both the genders,\npeak PTHrP levels was expressed more so in the pubertal stage of cervical\nvertebral development.<\/p>\n\n\n\n

Several authors35<\/sup> have reiterated the fact that\ncondylar growth was greatly influenced by PTHrP, Ihh, and SOX 9 transcription\nfactor and that the latter was upregulated by PTHrP. This chain of events\nseemed to bring about delayed maturation of replicating chondrocytes and promotion\nof chondroblast differentiation in the condylar cartilage. Animal experiments too\nhave indicated a five-fold PTHrP increase after the advancement of the mandible\nwith functional appliance therapy. Extrapolating these findings to humans it\nmay be construed that commencement of functional appliance therapy in early\npubertal stages could enhance condylar cartilage growth in Class II skeletal\npattern with retrognathic mandible. It has been reported that in healthy\nsubjects the detected circulating PTHrP with immunoradiometric assay was 2.6\npmol per liter.36<\/sup> We had used ELISA in our study for its reported analytical\nspecificity and sensitivity and hence our values were also different from that\nreported in literature. The low values of PTHrP that was observed in our data could be\nattributed to the hook-effect. Hook effect normally contributes to false-low\nresults primarily due to the presence of excess amount of analyte in single\nstep heterogenous assays particularly Sandwich-ELISA. Nevertheless, this could\nbe negated by serial dilution of the patient\u2019s samples. Owing to the escalating\ncost that could incur, serial sample dilutions were not performed. This could\nbe a limitation of our study.<\/p>\n\n\n\n

CVM, a commonly used skeletal\nmaturity indicator as seen in a lateral cephalogram is also not a perfect\nrating system. At best it is an imprecise science, ordinal in nature in\ncontrast to the continuous nature of growth process and is also plagued with\nintra and inter-examiner reliability and high staging subjectivity. However, 3-D Cone Beam Computerized Tomography would\nyield a much more precise evaluation of the cervical vertebrae in comparison to\na 2-D evaluation on a lateral cephalogram.<\/p>\n\n\n\n

Longitudinal\nstudies are recommended to highlight the use of this biomarker to precisely\nestimate the intensity & timing of the pubertal growth spurt. Reference ranges\nof PTHrP serum levels at different CVM stages pertaining to South Indian\npopulation to assess peak pubertal growth could also be considered for future\nresearch.  <\/p>\n\n\n\n

Conclusions<\/strong><\/p>\n\n\n\n

Mean PTHrP serum levels in males witnessed an increase in CS3-4 interval & in females, first CS2 & then CS5 witnessed a spike, exhibiting a pre-pubertal trend in females and a pubertal trend in males.<\/p>\n\n\n\n

Comparison of mean PTHrP serum levels in the four intervals of cervical staging showed it being expressed more so in CS2 through to CS4 in males and in CS2-CS3 in females, showing an increase of this biomarker in the pre and pubertal stages in both the sexes.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There is no conflict of interest<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

There are no funding sources<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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