**7.3. Pharmacotherapy**

The negative impact of several pharmaceutics on healing processes was reported, including chemotherapeutics, antimicrobial drugs, steroids, heparins and antiresorptive drugs.

**8. Final remarks**

of the risk non-union.

at all fractures after implants removal.

Healing of the bone fracture is a biological process that proceeds due to the cooperation of various cell lineages under the control of the molecular regulators. Since, it bases on mechanisms that were validated during skeletogenesis, everyone, who developed the skeleton properly, possess the mechanisms that enable him to heal the fracture. Thus, our role is just to

Fracture Repair: Its Pathomechanism and Disturbances http://dx.doi.org/10.5772/intechopen.76252 17

From the clinical point of view, an adequate supply of oxygen, nutrients, minerals, and vitamins under an appropriate biomechanical environment are the most important, as they enable those natural, biological mechanisms, to proceed uneventfully. Thus, fracture immobilizations or stabilizations, rational nourishment, improving circulation and local blood perfusion, withholding smoking, reducing alcohol intake, and rationalizing pharmaceutical medication are among the most effective activities that improve the healing. Factors that positively and negatively affect it were discussed above giving the clear suggestions for effective treatment. Unfortunately, several of them could not be corrected or just are above our limits. Nevertheless, in the vast majority of cases, one can introduce the treatment that could reduce

**Figure 10.** Comminuted, multiple-level fractures of the right femur in 41-years-old male (femoral neck, trochanteric, and the shaft) anatomically reduced and stabilized operatively. The final result (36 months) showing satisfactory bone union

provide optimal conditions for those natural mechanisms (**Figure 10**).

Chemotherapeutics are toxic to MSCs, reducing their number and activity and thus, depriving the fracture of osteoblastic progenitors. Their influence is aggravated by radiotherapy that is regularly used to treat neoplasms. Together with changed metabolism evoked by the tumor itself, those impair the healing.

Antibiotics were reported to affect the healing despite their beneficial capabilities to control infection. Tetracyclines were shown to impair ossification, thus arresting skeletal growth and fracture healing. Moreover, their negative impact prolongs for years, as bound with osteoid they impair bone remodeling decreasing its mechanical strength and thus, increase the risk of forthcoming fractures. Beta-lactams and cephalosporins, as well as ciprofloxacin, clindamycin, rifampicin, macrolides, and many others, and also evoke their negative impact. Their usage is justified as far as the positive antimicrobial effect is rationalized, that is weighed against negative influence on the reparative processes [58].

Corticosteroids, used in asthma, rheumatoid and dermatologic diseases, demineralize skeleton resulting in steroid-induced osteoporosis. In consequence, increased susceptibility to fractures, but also their impaired healing and remodeling, occur. Moreover, their chronic use threatens the bone viability bringing the risk of steroid-induced osteonecrosis [59]. Nevertheless, those unwanted side effects could easily be controlled modifying the route of administration and reducing their doses [60]. Analogically, nonsteroidal, anti-inflammatory drugs (NSAIDs), widely used analgesics, disturb reparative processes, usually expressing their negative influence, when chronically used at high doses [51]. Antihistamines were also reported to affect the healing [61].

Heparins, regularly used in trauma surgery for antithrombotic prophylaxis, are known to bind several growth factors including TGF-β and BMPs, FGF and EGF, decreasing their bioavailability for reparative processes [30]. Bisphosphonates, antiresorptive drugs dedicated for treatment of osteoporosis and prevention of fragility fractures, impair bone remodeling and healing, but also bring the risk of atypical fractures [62].

Other drugs were also shown to evoke negative impact on the bone union, including those used in the treatment of hypertension. Captopril, for instance, hinders angiogenesis and collagen deposition [63] and beta blockers affect wound healing through disturbed fibroblast proliferation [64].

### **7.4. Infection**

Pathogens, colonizing the fracture gap, compete with its cells for nutrients, oxygen, and growth regulators depriving them of substances that are necessary for reparative processes. Moreover, hypoxia turns progenitor's differentiation into chondroblastic cell lineage, and pathogen-associated molecular patterns activate immune response aggravating the risk of non-union [65].

Unfortunately, eradication of microbes from the fracture gap is very hard, at least due to limited blood perfusion and poor antibiotic penetration. Moreover, they produce biofilms that protect them from recognition and counteraction by the immune system and antibiotics [66].
