**8. Our experience**

Nowadays, the published data on epidemiology of metabolic diseases in healthy volunteers and orthopedic patients without bone infection (except patients with osteoporosis and related diseases) are scarce. Therefore, these data cannot serve as statistical material for comparison with data in patients with bone infection.

Accordingly, our work is limited to patients with bone infection (chronic osteomyelitis and related diseases) already diagnosed. The dynamics of the parameters was studied with addition of metabolic disorders therapy and without it.

In 2019, we published a retrospective study; the aim was to evaluate dynamics and values of markers and parameters of bone metabolism [16], which included 112 patients with infected pseudarthroses of long bones (humerus, femur, tibia) developing as an exacerbation of chronic osteomyelitis. The study had three main purposes:


We formed two groups of 56 patients each using anatomical segment-stratified randomization. The main group received not only surgery and antibiotic therapy but also medication for correction of impaired bone metabolism. The control group received the same therapy except correction of bone metabolism.

The dynamics of parameters was evaluated only in the main study group. Data from the control group patients were used to evaluate the duration of bone consolidation and comparing them between groups.

To form a "picture" of a bone tissue metabolism, we evaluated the following parameters:


For therapy, we used calcium medicaments (Ca carbonate, ossein-hydroxyapatite complex) and active metabolite of D hormone (alfacalcidol). Dosage was set individually for each patient according to a patented way [41] on the basis of the following key parameters:


As an anti-resorptive drug, the ibandronate acid was administered (with the dosage of 3 mg (3 ml) one time in 3 months).

The described therapy was empirically proved to be effective not only against osteoporosis in patients that underwent arthroplasty but also in cases of osteoporosis connected with low intensity of ossification; that was the key reason why it was selected for treatment.

The numerical data of patients are described using descriptive statistics. To compare the changes in metabolic values after 3 months and before treatment, we used the Wilcoxon test. To compare the consolidation duration in main and control groups, we used Mann-Whitney U-test. The threshold p-value in all cases was set as p < 0.05. The software used was IBM SPSS Statistics 22. All values, including theoretically possible outliers, were considered in the statistics (**Table 1** and **Figure 5**).

Routine screening of the whole population described above exceeds the ranks of this study.

We found statistically significant changes after 3 months in osteocalcin level (decrease), PTH (decrease), and desoxypyridinoline/creatinine ratio (decrease) (respectively: p = 0.043, p = 0.043, p = 0.041). Changes in daily amounts of calcium and phosphate secreted with urine, as well as beta-cross-laps were not statistically significant but, in our opinion, the follow-up tie of 3 months can be insufficient. We suppose that the following mechanisms can take part in forming this "picture":

• Lowering of the resorption because of ibandronic acid use leads to decrease in desoxypyridinoline/creatinine ratio.

**147**

eliminated.

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis*

Са—0 months4 2.4 ± 0.1 2.1–2.71 mmol/l 0.172 0.05 A

Р—0 months 1.2 ± 0.2 0.7–1.6 mmol/l 0.180 B

Са2+—0 months 1.2 ± 0.2 0.96–2.2 mmol/l 0.807 C

373.0

148.0 B-cross-laps—0 months 0.7 ± 0.3 0.1–1.1 ng/ml 0.18 E

Osteocalcin—0 months 22.6 ± 11.1 2.0–46.0 ng/ml **0.043** F

PTH—0 months 12.5 ± 15.5 1.8–60.0 mol/l **0.043** G

25-ОН-D3—0 months 17.8 ± 10.2 6.6–40.0 ng/ml 0.715 I

mmol Cre

3.7 ± 1.5 1.00–6.34 mmol/day 0.180 K

42.5

11.6 ± 6.4 5.0–38.4 nmol/

**Range1 Units Test** 

**p-value2**

U/l 0.893 D

mmol/day 0.180 H

**0.041** J

**Threshold p-value**

**Plot3**

**, median ± SD**

123.5 ± 65.7 60.3–

113.7 ± 24.3 90.0–

24.0 ± 9.6 10.50–

9.9 ± 5.3 3.5–17.1

8.6 ± 3.3 3.5–17.5

2.5 ± 0.8 1.4–3.6

*Wilcoxon signed-rank test. Values are rounded to the third decimal place.*

*Data represent the study group (56 patients). Control group is quantitatively equal (56 patients).*

*Letters represent the particular plots at Figure 5A-K for the information to be easily to followed.*

*Comparative data of patients before and after 3-month therapy of metabolic bone disorders.*

• Decrease in osteocalcin level can be explained by lowering of the earlier increased (in a compensative way) osteoblast activity that at least partially normalized.

• Decrease of PTH level can be explained by administration of D hormone and elimination of D deficit, which also led to decrease in blood calcium. In other words, the immediate mechanism of secondary hyperparathyreosis was

*DOI: http://dx.doi.org/10.5772/intechopen.92052*

Са—3 months5 2.5 ± 0.6 2.38–2.63

Р—3 months 1.2 ± 0.147 1.0–1.39

Са2+—3 months 1.2 ± 0.1 1.11–1.33

B-cross-laps—3 months 0.7 ± 0.3 0.2–1.0

Osteocalcin—3 months 24.9 ± 11.5 11.5–39.0

PTH—3 months 2.6 ± 1.0 1.0–4.2

25-ОН-D3—3 months 19.0 ± 10.8 5.0–33.0

**Metabolic marker Value1**

Bone alkaline phosphatase—0 months

Bone alkaline phosphatase—3 months

Р (urine, day amount)—0 months

Р (urine, day amount)—3 months

Deoxypyridinoline/ creatinine—0 months

Deoxypyridinoline/ creatinine—3 months

Са (urine, day amount)—0 months

Са (urine, day amount)—3 months

*Rounded to first decimal place.*

*0 months—value before operative treatment.*

*3 months—value at 3 months after the operative treatment. Statistically significant values (p < 0.05) are labeled as bold.*

*1*

*2*

*3*

*4*

*5*

**Table 1.**


*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.92052*

*Data represent the study group (56 patients). Control group is quantitatively equal (56 patients). 1 Rounded to first decimal place.*

*2 Wilcoxon signed-rank test. Values are rounded to the third decimal place.*

*3 Letters represent the particular plots at Figure 5A-K for the information to be easily to followed.*

*4 0 months—value before operative treatment.*

*5 3 months—value at 3 months after the operative treatment.*

*Statistically significant values (p < 0.05) are labeled as bold.*

#### **Table 1.**

*Clinical Implementation of Bone Regeneration and Maintenance*

portation form of D hormone (25(OH)D3).

dation and comparing them between groups.

parameters:

ratio.

following key parameters:

• Densitometry results.

• Values of the parameters listed above.

dosage of 3 mg (3 ml) one time in 3 months).

desoxypyridinoline/creatinine ratio.

• Sex and age.

selected for treatment.

and **Figure 5**).

this "picture":

this study.

The dynamics of parameters was evaluated only in the main study group. Data from the control group patients were used to evaluate the duration of bone consoli-

To form a "picture" of a bone tissue metabolism, we evaluated the following

• Homeostasis of Ca and P-values: blood Ca, ionized Ca, blood P, PTH, trans-

• Ca and P (daily amount secreted with urine); deoxypyridinoline/creatinine

For therapy, we used calcium medicaments (Ca carbonate, ossein-hydroxyapatite complex) and active metabolite of D hormone (alfacalcidol). Dosage was set individually for each patient according to a patented way [41] on the basis of the

As an anti-resorptive drug, the ibandronate acid was administered (with the

The described therapy was empirically proved to be effective not only against osteoporosis in patients that underwent arthroplasty but also in cases of osteoporosis connected with low intensity of ossification; that was the key reason why it was

The numerical data of patients are described using descriptive statistics. To compare the changes in metabolic values after 3 months and before treatment, we used the Wilcoxon test. To compare the consolidation duration in main and control groups, we used Mann-Whitney U-test. The threshold p-value in all cases was set as p < 0.05. The software used was IBM SPSS Statistics 22. All values, including theoretically possible outliers, were considered in the statistics (**Table 1**

Routine screening of the whole population described above exceeds the ranks of

We found statistically significant changes after 3 months in osteocalcin level (decrease), PTH (decrease), and desoxypyridinoline/creatinine ratio (decrease) (respectively: p = 0.043, p = 0.043, p = 0.041). Changes in daily amounts of calcium and phosphate secreted with urine, as well as beta-cross-laps were not statistically significant but, in our opinion, the follow-up tie of 3 months can be insufficient. We suppose that the following mechanisms can take part in forming

• Lowering of the resorption because of ibandronic acid use leads to decrease in

• Ossification markers: bone alkaline phosphatase, osteocalcin.

• Resorption markers: beta-cross-laps (C-terminal telopeptide).

**146**

*Comparative data of patients before and after 3-month therapy of metabolic bone disorders.*


#### **Figure 5.**

*(A-K) "Box and whiskers" plots illustrating the data provided in Table 1. Blue box and whiskers (left at all figures) represent data of patients before therapy. Orange boxes and whiskers represent data of the same patients after 3 months of therapy. A: blood calcium. B: phosphate of the blood. C: ionized calcium, D: bone alkaline phosphatase levels, E: beta-cross-laps (C-terminal telopeptide), F: osteocalcin, G: PTH. H: phosphate (urine, day amount), I: 25 (OH) D3, J: deoxypyridinoline/creatinine, K: calcium (urine, daily amount). Units: see Table 1.*

**149**

*1*

*2*

*3*

**Table 2.**

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis*

• Decrease of Ca and phosphates in blood and their daily amounts secreted with urine is not statistically significant at 3-month follow-up (р = 0.172 for Ca, р = 0.18 for phosphates, р = 0.18 for both daily secreted amounts of Ca and phosphates in urine), but we can potentially explain these changes as an effect—even statistically insignificant—of PTH level decrease (partial

The rationale of metabolic bone tissue impairment correction is proved by clinical results (decrease of fracture consolidation type in the main group that received corresponding therapy). In each group (56 patients), the "anatomical distribution"

The software used was SPSS Statistics 22. All values, including theoretically possible outliers, were considered in the statistics. Statistically significant changes between groups were found in all studied segments (**Table 2** and

As shown, the additional therapy of metabolic disorders of bone tissue has a statistically significant effect on shortening the duration of bone consolidation in

In our opinion, the next step should be a comparative analysis of bone metabolism aspects in orthopedic patients with and without bone infection and a study of the dynamics of mentioned parameters during a long follow-up period (more than

**Range Test** 

243

321

399

559

351

427

**p-value2**

**Threshold р-value**

0.041 0.05 A

0.009 B

0.041 C

**Plot3**

**Consolidation duration1**

6 199.9 ± 31.6 147–

6 254.2 ± 45.1 196–

25 266.9 ± 52.7 190–

25 338.0 ± 107.1 197–

25 235.0 ± 49.3 154–

25 270.0 ± 61.1 189–

*Comparison of consolidation time in patients with (main group) or without (control group) bone tissue* 

**, days, mean ± SD**

*DOI: http://dx.doi.org/10.5772/intechopen.92052*

of patients according to a treated segment was as follows:

patients treated by external fixation apparatus.

**No. of patients**

*Both groups received "standard" surgery and antibiotic therapy.*

*Letters represent particular plots in Figure 6A–C.*

*Mann-Whitney U-test. Values are rounded to the third decimal place.*

normalization).

• Humerus—6 patients

• Femur—25 patients

• Tibia—25 patients

**Figure 6**).

3 months).

**Anatomical segment/study group**

Humerus, main group

Humerus, control group

Femur, main group

Femur, control group

Tibia, main group

Tibia, control group

*Rounded to first decimal place.*

*metabolism correction therapy.*

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.92052*

• Decrease of Ca and phosphates in blood and their daily amounts secreted with urine is not statistically significant at 3-month follow-up (р = 0.172 for Ca, р = 0.18 for phosphates, р = 0.18 for both daily secreted amounts of Ca and phosphates in urine), but we can potentially explain these changes as an effect—even statistically insignificant—of PTH level decrease (partial normalization).

The rationale of metabolic bone tissue impairment correction is proved by clinical results (decrease of fracture consolidation type in the main group that received corresponding therapy). In each group (56 patients), the "anatomical distribution" of patients according to a treated segment was as follows:

• Humerus—6 patients

*Clinical Implementation of Bone Regeneration and Maintenance*

**148**

**Figure 5.**

*see Table 1.*

*(A-K) "Box and whiskers" plots illustrating the data provided in Table 1. Blue box and whiskers (left at all figures) represent data of patients before therapy. Orange boxes and whiskers represent data of the same patients after 3 months of therapy. A: blood calcium. B: phosphate of the blood. C: ionized calcium, D: bone alkaline phosphatase levels, E: beta-cross-laps (C-terminal telopeptide), F: osteocalcin, G: PTH. H: phosphate (urine, day amount), I: 25 (OH) D3, J: deoxypyridinoline/creatinine, K: calcium (urine, daily amount). Units:* 


The software used was SPSS Statistics 22. All values, including theoretically possible outliers, were considered in the statistics. Statistically significant changes between groups were found in all studied segments (**Table 2** and **Figure 6**).

As shown, the additional therapy of metabolic disorders of bone tissue has a statistically significant effect on shortening the duration of bone consolidation in patients treated by external fixation apparatus.

In our opinion, the next step should be a comparative analysis of bone metabolism aspects in orthopedic patients with and without bone infection and a study of the dynamics of mentioned parameters during a long follow-up period (more than 3 months).


*Both groups received "standard" surgery and antibiotic therapy.*

*1 Rounded to first decimal place.*

*2 Mann-Whitney U-test. Values are rounded to the third decimal place.*

*3 Letters represent particular plots in Figure 6A–C.*

#### **Table 2.**

*Comparison of consolidation time in patients with (main group) or without (control group) bone tissue metabolism correction therapy.*

#### **Figure 6.**

*(a-c) "Box-and-whiskers" plots illustrating the duration (in days) of bone consolidation in patients that underwent treatment of the fractures of different segments exacerbated by orthopedic infection using the external fixation apparatus. Left (a): humerus; in the middle (b): femur; right (c): tibia. Blue box and whiskers (at the left at all figures) represent data for the main study group that received surgery, antibiotic and etiologic metabolism impairment therapy; red box and whiskers (at the right at all figures) represent the control group that received surgery and antibiotic therapy, but no treatment of bone metabolism impairment.*

#### **9. Conclusion**

In this chapter, we attempted to describe the basic pathophysiology of metabolic processes at the site of orthopedic infection. Knowledge of peculiarities of such processes is important for an orthopedic surgeon because the general success of treatment relies not only on surgery and antibiotic therapy but also etiologic therapy of bone metabolism impairment. This thesis is supported not only by pathophysiological rationale but also by the results of our study.

Metabolic disorders of bone tissue associated with orthopedic infection are complex and yet poorly understood. Research of this topic will improve not only the existing treatment strategy but also the philosophy of it and will greatly contribute to development of traumatology and orthopedics.

**151**

**Author details**

Russia

and Dmitry Gorbatyuk

Archil Tsiskarashvili\*, Nikolay Zagorodny, Svetlana Rodionova

\*Address all correspondence to: archil.tsiskarashvili@gmail.com

provided the original work is properly cited.

National Medical Research Center of Traumatology and Orthopedics, Moscow,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.92052*

*Metabolic Disorders in Patients with Chronic Osteomyelitis: Etiology and Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.92052*
