Pycnodysostosis (PYCD) is a rare autosomal recessive syndrome that belongs to the group of bone dysplasias. This disorder is caused by mutations in the CTSK gene located on chromosome 1q211,2 that encodes cathepsin K, a lysosomal cysteine protease present in osteoclasts which participates in the degradation of type I collagen (predominant protein in the bone matrix). Mutations in this gene lead to defective bone metabolism, more specifically deficient bone resorption.2–4

The prevalence of PYCD is 1 in 1.7 million and no sex predilection has been reported.1 Autosomal recessive inheritance is the pattern of transmission of mutations in the CTSK gene that encodes cathepsin K. Thus, parental consanguinity is an important etiological factor.3–5 PYCD is characterized by abnormal bone metabolism, reduced bone elasticity, endocrine and immunological dysfunction and altered extracellular matrix remodeling in organs such as the lung, thyroid and skin.1,3,5

Patients with PYCD commonly exhibit a short-stature phenotype, open bone sutures, short phalanges, bone dysplasia with altered density of the bone matrix, and pathological fractures as a result of reduced elasticity and poor bone healing. Oral manifestations include an obtuse mandibular angle, malocclusion, an ogival palate, and dental anomalies.1,6 The abnormal bone metabolism increases the susceptibility of patients to develop osteomyelitis. In gnathic bones, local factors related to the development of osteomyelitis include the bone characteristics of the maxilla and mandible, continuous traumas, alveolar surgical procedures, and conditions that affect the teeth such as periapical and periodontal disease.7–9 It should be emphasized that the treatment of osteomyelitis in gnathic bones is difficult and may require major surgical resections.5

Therefore, the hypothesis of this study is that manipulation of the jaws in patients with PYCD may favor the development of osteomyelitis. This systematic review was conducted to analyze the risk factors associated with the development of complications in the jaws (fractures and osteomyelitis), as well as their clinical-pathological characteristics and therapeutic approaches in patients with PYCD.

A systematic literature review on PYCD based on the 2009 PRISMA (Preferred reporting items for systematic reviews and meta-analyses) statement10 was conducted on 6 March 2019 to answer the following research question according to the PICO criterion (population, intervention, control, and outcome): “Is surgical manipulation of the jawbones the main risk factor for osteomyelitis in patients with PYCD?”. This systematic literature review was registered in PROSPERO (International prospective register of systematic reviews) under protocol number: CRD42020209580.

The databases selected for the systematic review were PubMed, Web of Science, SCOPUS, Cochrane, and LILACS. The following search terms were used: “Pycnodysostosis” OR “Pyknodysostosis” AND “Surgery, Oral” OR “Maxillofacial Surgery” OR “Oral Surgery” OR “Exodontics” OR “Dentistry, Operative” OR “Surgical Procedures, Oral” OR “Procedure, Oral Surgical” OR “Procedures, Oral Surgical” OR “Surgical Procedure, Oral” OR “Maxillofacial Procedures” OR “Maxillofacial Procedure” OR “Procedure, Maxillofacial” OR “Procedures, Maxillofacial” OR “Tooth extraction” AND “Osteomyelitis” OR “Osteomyelitides” OR “Diseases, Infectious Bone” OR “Bone Diseases, Infectious” OR “Diseases, Infectious Bone” OR “Infectious Bone Disease” OR “Infectious Bone Diseases” (Supplementary Table 1).

The criteria for inclusion were published studies specifically investigating osteomyelitis of the jaws in patients with PYCD. Only case reports and case series were included. Excluded were studies that did not address osteomyelitis as a complication in the jaws, studies addressing osteomyelitis in bones other than the jaws, articles that did not report the primary cause of osteomyelitis, studies based on animal models, in vitro studies, editorial letters, review articles, and studies whose full text was not available through inter-library loan.

The articles were selected independently by two of the authors. First, the authors selected articles by reading the title and abstract, according to the established inclusion and exclusion criteria. Articles not related to the topic were excluded. The full text of the remaining studies was downloaded, and the articles were selected based on the eligibility criteria. Articles whose full text was not available were excluded and the final sample of studies for qualitative synthesis was determined. Discrepancies were resolved by a third author.

The eligible studies were reviewed and the following data were extracted: (1) authors and year of publication; (2) number of patients; (3) sex and age (mean) of the patient; (4) cause; (5) clinical (family history, location, symptoms) and radiographic characteristics; (6) therapeutic intervention and outcome, (7) and patient follow-up. The reviewers did not disagree on the selection of the articles. The methodological quality of the articles was evaluated according to the CARE guidelines for case reports, a qualitative checklist for observational studies and case reports.

The osteoclasts of patients with PYCD are unable to degrade collagen I and other non-collagenous proteins that form the bone matrix, while these cells maintain their demineralizing activity, resulting in abnormal bone metabolism.24,25 The absence of cathepsin K also seems to stimulate cortical bone formation through the negative control of periostin secreted by osteoblasts and osteocytes, a fact that explains the apparent contradictory effect of the increased bone density in PYCD,26,27 demonstrated by the presence of osteosclerosis. The latter was observed in 11/26 patients.12,14,15,17,20–23,27–29

The bone quality in patients with PYCD is low (fragile and poorly organized matrix). Bone strength is reduced due to acidification, increasing the risk of fractures, particularly in the lower extremities1,27 (Fig. 3D). The present study demonstrated fractures in the long bones of 9/26 patients, corroborating the findings of enhanced mechanical sensitivity and an increased fracture risk in patients with PYCD. These can be explained by the fact that cathepsin K is important for bone resorption in bones with a high turnover rate (e.g., long bones). The present study demonstrated osteolytic lesions in 7/26 patients.11,13,14,16,19,22

The manifestation of osteomyelitis depends on the virulence factors of microorganisms, immune system and vascular factors of the patient. Increased susceptibility to osteomyelitis of the mandible is attributed to the increased bone density (osteosclerosis) favors the establishment of osteomyelitis, which has fewer medullary spaces and a single neurovascular bundle.17 Our results were consistent with the literature, with the mandible being the most affected site (n = 22).2,5,6,11–15,17–23,27–30

In the maxillary bones, osteomyelitis is commonly caused by the dissemination of an odontogenic infection (n = 7)5,11,12,16,17,29 or by surgical traumas (n = 16)2,5,6,13–15,18–23,27,28,30 Since the oral cavity harbors commensal microorganisms, diseases and manipulation of the teeth can create a route for microorganisms to enter the bone.8,31 Once it has reached the bone, the inflammatory response may culminate in the production of pus, increasing the intramedullary pressure and reducing blood flow into the bones. An increase in ischemic and necrotic bone contributes to the establishment of infection,8,32 demonstrated by the presence of bone sequestrum. The presence of pus can even compromise the integrity of cortical bone. The involvement of adjacent soft tissues is often observed, which is indicated by local edema (12/26)5,11,13,14,16,17,19,20,23,29 and by intra- or extraoral fistulas,8 as found in 5/26 of the reported cases.14,15,19,23 Purulent secretion was a finding in 9/26 cases.2,5,11,15,17,18,21 Pain (11/26)2,6,12,16,19,20,22,28,29 and trismus (1/26),20 characteristic of chronic osteomyelitis, the most common type observed in the present study, were also reported.

This study demonstrated that tooth extraction was the main risk factor of osteomyelitis. Such procedures are known to break down the bone barrier and to create a portal of entry for microorganisms that then populate the bone component. In addition, tooth extraction is a traumatic event that, in conjunction with the defective bone matrix in PYCD, favors the occurrence of bone fractures (Fig. 3E). Radiography revealed fractures in four cases.13,15,17,21

Osteomyelitis was reported in association with periodontitis in 4/26 cases.11,16,29 Periodontitis is a common oral inflammatory disease.33 There is evidence indicating that the inhibition of cathepsin K results in the suppression of immune system cells and in the reduction of osteoclast activity, reducing the malnutrition of alveolar bone in periodontitis34 (Fig. 3F). Periodontitis may occur in patients with PYCD and can be the primary cause of osteomyelitis, as highlighted in the present study.

Investigation of the role of cathepsin K in periapical diseases demonstrates that this protease is involved in bone resorption and immune system activation, as well as in events during establishment of the immune response related to the recognition of microorganisms by Toll-Like Receptors (TLR) on dendritic cells.33 In PYCD, patients therefore lack mechanisms related to the limitation of infection (an effective immune response), a fact favoring the invasion of medullary tissues and the development of osteomyelitis, which was reported in association with pulp events in 4/26 cases.5,12,16,17

Antimicrobial therapy and surgical debridement are the main treatment modalities for osteomyelitis.8,35 Despite advances in surgical procedures and chemotherapy, osteomyelitis remains difficult to treat and there is no universally accepted treatment protocol.8 In the cases of this systematic review, antibiotic therapy was the treatment of choice in patients with osteomyelitis associated with PYCD. This treatment was administered alone in three articles,2,12,27 or combined with some surgical procedure in 15 articles.5,6,11,12,14–16,18–23,29,30 The antibiotic and treatment regime used were specified in most cases.

Culture and antibiogram are laboratory support mechanisms used to reliably determine the causative agent of infection and the most efficient antibiotic therapy to combat it. This procedure was performed in three of the cases of this review.2,14,18 In most articles, the antibiotic regimen was combined with the use of two or more medications, including different administration routes (intramuscular, oral, intravenous and topical).16,18–21 Penicillin was the antibiotic of choice in most cases, although in one of the reported cases the antibiogram determined resistance to this antibiotic.2 In cultured cases, the antibiotic of choice was variable, including penicillin (carbenicillin and ampicillin), lincosamides (clindamycin), fluoroquinolones (moxifloxacin), cephalosporins (cefotaxime) and nitroimidazole (metronidazole) antibiotics.2,14,18

It is argued that radical treatments should be avoided in the management of osteomyelitis associated with PYCD because of the risk of trans- and postoperative complications. In four cases,2,5,16,17 the patients refused the surgical approach proposed and chose more conservative treatments. Four of the patients undergoing more invasive treatment developed subsequent complications.11,18,19,21 Patient-reported adherence, accessibility and tolerability of the adopted treatment should be considered, as done in four articles.2,6,12,22 The change of the adopted treatment in the case of unexpected side effects or recurrence, as reported in seven articles,2,11,12,18,19,21,22 is also important. Finally, the literature reports that pre- (antibiotic prophylaxis) and postoperative antibiotic therapy avoids postoperative complications of invasive dental procedures. In addition, these procedures favor tissue repair in the surgical region, subgingival scraping, and necropulpectomies.36,37

The findings of this review showed that patients with PYCD are more likely to develop osteomyelitis of the jaws, especially after tooth extraction and configure the main risk factor for its establishment. Whenever possible, pre- (antibiotic prophylaxis) and postoperative antibiotic therapy seems to be appropriate in patients with PYCD until complete tissue healing, even in the case of minor procedures, in order to avoid complications such as osteomyelitis and pathological fractures. In addition, more conservative osteomyelitis treatment should be chosen to prevent additional trauma to the jaws.

The work was supported by the Department of Dentistry, Oral Pathology Postgraduate Program, Brazil.

The authors declare no conflicts of interest.