**5. Treatment**

The primary goal of the treatment is to minimize the occurrence of MRONJ. Even though cases of spontaneous formation of MRONJ do exist, the majority of cases develop after a surgery.

In the first place, it is necessary to carry out a preservation treatment and consequent prosthetic and surgical treatment lege artis. This includes restorations of carious teeth, repairing of overhanging fillings, or extracting devitalized or destroyed teeth with extensive periapical findings. ARM treatment should initiate or resume only after the extraction wound in the socket has healed thoroughly. Prevention is important in terms of maintaining the functionality of healthy teeth.

Examination of the affected mucosa is necessary in patients with prosthetic replacement, since decubiti, traumatic lesions or fissural granuloma may emerge in the area. For these reasons, temporary restoration is contraindicated in many cases. Dentoalveolar procedure must be carried out in the gentlest manner, preferably at a maxillofacial surgery facility. It is necessary to inform the patient about the possible risks. Chlorhexidine mouth washes are indicated both before and after the dentoalveolar procedure. The surgery is performed under the influence of antibiotics, which continue to be employed after the procedure.

MRONJ treatment is very demanding in terms of time; therefore, AAOMS recommends a conservative approach, in an attempt to delay the surgical resection treatment, which is indicated in the advanced stages of the disease. Palliative conservative treatment is usually applied, since only a small percentage of patients will experience complete healing ad integrum. The conservative approach consists of equalization of sharp bone edges, sequestrectomy, necrotic area teeth extractions, and incisions and drainages under total antibiotic and topical treatment.

Surgical treatment consists of complete removal of the necrotic foci, which serve as a fertile ground for infection, followed by wound closure with soft tissue that is finely vascularized, using layered suture. During the radical surgical resection, there are still concerns about the resulting wounds, difficulty in healing and progression of osteonecrotic foci.

Several studies point to the possibility of employing new treatment methods such as PRP, ozone or hyperbaric oxygen therapies. The benefit for cancer patients who are undergoing intravenous bisphosphonate treatment is bone pain relief and retreat of other bone complications. The basic rule is to preserve the quality of life for these patients, which includes a thorough oral health care, patient education, regular visits to the dentist, pain management and reports on health status, edemas, pain or bone exposure. It is also important to prevent the spread of new necrotic sockets by observing the proper prevention. Staging and management is described in **Table 1**.

Patients with aforementioned drugs in their medical history need to be treated as risk patients in view of invasive procedures in the oral cavity. Currently, the majority of osteonecrosis are of iatrogenic nature, caused by the incorrect choice of treatment for risk patients by the medical


**Table 1.** Staging and management.

The secondary prevention, in terms of ARM treatment interruption—the so-called drug holiday—is bit problematic. So far, there is no scientific evidence that the interruption of a therapy prior to surgery in the oral cavity reduced the risk of developing osteonecrosis of the jaw. According to AAOMS, suspending intravenous bisphosphonates has no significant short-term benefit in case the lesions are already present. Long-term treatment suspension, however, may stabilize the affected area, alleviate the clinical signs and also reduce the risk of new sites being affected. The priority still lies in the treatment of malignant diseases, and

The situation with monoclonal antibodies is different. Based on current knowledge about the effect of denosumab on bone remodeling, it is recommended to suspend the drug prior to any planned surgery in the oral cavity, in order to reduce the risk of developing osteonecrosis of the jaw. Suspending denosumab treatment seems to be appropriate, even in cases of an already developed osteonecrosis of the jaw, which can lead to heightened healing of the lesion. Some authors recommend suspending bevacizumab 6–8 weeks before surgery and resuming the medication 4 weeks after the procedure to prevent complications with

The primary goal of the treatment is to minimize the occurrence of MRONJ. Even though cases of spontaneous formation of MRONJ do exist, the majority of cases develop after a

In the first place, it is necessary to carry out a preservation treatment and consequent prosthetic and surgical treatment lege artis. This includes restorations of carious teeth, repairing of overhanging fillings, or extracting devitalized or destroyed teeth with extensive periapical findings. ARM treatment should initiate or resume only after the extraction wound in the socket has healed thoroughly. Prevention is important in terms of maintaining the functional-

Examination of the affected mucosa is necessary in patients with prosthetic replacement, since decubiti, traumatic lesions or fissural granuloma may emerge in the area. For these reasons, temporary restoration is contraindicated in many cases. Dentoalveolar procedure must be carried out in the gentlest manner, preferably at a maxillofacial surgery facility. It is necessary to inform the patient about the possible risks. Chlorhexidine mouth washes are indicated both before and after the dentoalveolar procedure. The surgery is performed under the influence of

MRONJ treatment is very demanding in terms of time; therefore, AAOMS recommends a conservative approach, in an attempt to delay the surgical resection treatment, which is indicated in the advanced stages of the disease. Palliative conservative treatment is usually applied, since only a small percentage of patients will experience complete healing ad integrum. The conservative approach consists of equalization of sharp bone edges, sequestrectomy, necrotic area teeth extractions, and incisions and drainages under total antibiotic and topical treatment.

antibiotics, which continue to be employed after the procedure.

therefore, the suspension of bisphosphonates has to be thoroughly assessed.

wound healing.

76 Newest Updates in Rheumatology

**5. Treatment**

ity of healthy teeth.

surgery.

staff. The cause of this unfavorable situation lies in the lack of communication between the specialist prescribing the high-risk drug and the treating dentist. The lack of awareness of the issue, both in patients and treating dentists, also plays its role. Medical specialist prescribing a high-risk drug is obligated to inform the patient about the risks and adverse effects of the planned treatment and to remind them to specifically inform their dentist about this fact. By disregarding this obligation on the part of the specialist (clinical oncologist, internist, rheumatologist, urologist, gynecologist, endocrinologist, orthopedist, etc.), the patient usually has no idea about the risk involved; however, the development of iatrogenic osteonecrosis may be prevented by the right approach by the treating dentist. They should not underestimate drug anamnesis prior to any invasive procedure in the oral cavity. Precise and targeted medical history can help identify at-risk patients and to choose the right treatment plan.

Large, randomized, placebo-controlled study called FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) studied the reduction of incidence of osteoporotic fractures. The authors monitored 7868 women aged 60–90, with an average BMD

Osteonecrosis of the Jaws

79

http://dx.doi.org/10.5772/intechopen.75878

After 3 years, the incidence of new vertebral fractures identified on X-rays in women treated with denosumab was 2.3%, while the incidence in the control group was 7.2%. The treatment reduced the relative risk of vertebral fractures by 68%. The cumulative incidence of hip fractures was 0.7% in the treatment group and 1.2% in the control group (40% reduction in the risk of fractures). There were no recorded significant differences in incidence of side effects such as cardiovascular complications, infections, fracture healing time and hypercalcemia

An important outcome of these studies was the discovery that denosumab significantly increases bone density, even in areas with prevalence of cortical bones. From these results, it can be concluded that alendronate has the longest half-life decay (10 years), while denosumab

Several studies refer to clinical cases of patients with antiresorptive drug-related osteonecrosis of the jaw that describe improvement in local findings and bone remodeling and an increase in patient's quality of life after switching bisphosphonates for hormonal therapy

Teriparatide was approved for the treatment of postmenopausal osteoporosis. Unlike the antiresorptive treatment, teriparatide has anabolic effect in bone which stimulates bone remodeling and bone tissue density. Intermittent administration (once a day) leads to a temporary increase of serum concentrations and preferential stimulation of the osteoblast activity, which leads to bone formation stimulation. The effect lies in the increase of bone mass and the num-

Some clinical trials document a positive effect of teriparatide and parathyroid hormone which reduces the risk of vertebral fractures while increasing the bone mineral density (BMD). The preparation is administered subcutaneously, one injection a day. Recommended treatment duration is 18 months. Side effects include cephalalgia, nausea and hypercalcemia. After its

According to the trial results, hormonal preparations used after stimulating the activity of osteoblast and osteoclasts could be employed in the treatment of non-oncological osteonecrosis. However, current trials are very small, and there is no sufficient evidence, which calls for more studies. Treatment is difficult, and it is therefore available only for some patients.

Teriparatide should not be used in cancer patients due to an increased risk of osteosarcomas, which were found in preclinical trials on rats. The teriparatide therapy should not be indicated in patients who inject their bisphosphonates, zoledronic acid or pamidronic acid because of the increased incidence of necrosis and associated severe complications, in contrast

T-score of −2.5, but not lower than −4.0.

between the treated and the control group [11].

has a reversible effect because it does not deposit into bone tissue.

**5.1. Combining antiresorptive drugs and hormonal therapy**

with recombinant parathyroid hormone teriparatide [12, 13].

ber of osteoblasts, and the consequent strength of bones.

to orally administered bisphosphonates.

administration, osteal healing in mouth cavity was documented.

The incidence of MRONJ can be divided into two groups: patients with non-oncological disease (osteoporosis, rheumatoid arthritis) and patients with cancer who take high doses of intravenous bisphosphonates.

In the second group, the incidence after 36 months of treatment ranges from 1 to 12%. The majority of cases described are connected with the use of zoledronate and pamidronate in treatment of multiple myeloma and bone metastases. So far, the results and recommendations on potential treatment for these conditions refer to the multicenter studies conducted in the last 15 years.

The study named DEFEND (Denosumab Evaluation for Preserving Bone Density) was a double-blind, multicenter, placebo-controlled, third phase study on 332 postmenopausal women with osteopenia and respective T-scores in the range of 1.5–2.5 SD. Denosumab was applied in 6-month intervals at a dose of 60 mg subcut, in contrast to placebo. Both groups of patients took a calcium supplement (100 mg a day) and vitamin D. The primary objective was to observe the lumbar spine bone mineral density after 24 months of treatment.

The results of the study showed that, compared with placebo, denosumab significantly increased the value of BMD in lumbar spine (by 6.5%). Denosumab also increased the density in the proximal part of femur (3.4%) and in the distal end of radius (by 1.4%). In the placebo group, the BMD decreased in these areas.

In another study, titled DECIDE (Determining Efficacy: Comparison of Initiating Denosumab vs. Alendronate), the effectiveness of denosumab with the same dosage as in the study DEFEND was compared to alendronic acid with a dosage of 70 mg, once a week, in order to reduce the risk of osteoporotic fractures. The yearlong study enrolled 1189 postmenopausal, relatively older women with more serious osteopenia than in the DEFEND, with half the women having a fracture in their medical history. Calcium and vitamin D supplementation has been the norm throughout the study. The primary measured indicator was the change in the density of proximal femur. Moreover, bone densities of lumbar spine, femoral neck, trochanter and distal radius were also monitored.

The results showed that denosumab improved bone density in all the monitored areas markedly better than alendronic acid, as early as at the end of the first month. At the same time, resorption markers significantly decreased in the group treated with denosumab, compared to the alendronic acid group.

Large, randomized, placebo-controlled study called FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) studied the reduction of incidence of osteoporotic fractures. The authors monitored 7868 women aged 60–90, with an average BMD T-score of −2.5, but not lower than −4.0.

After 3 years, the incidence of new vertebral fractures identified on X-rays in women treated with denosumab was 2.3%, while the incidence in the control group was 7.2%. The treatment reduced the relative risk of vertebral fractures by 68%. The cumulative incidence of hip fractures was 0.7% in the treatment group and 1.2% in the control group (40% reduction in the risk of fractures). There were no recorded significant differences in incidence of side effects such as cardiovascular complications, infections, fracture healing time and hypercalcemia between the treated and the control group [11].

An important outcome of these studies was the discovery that denosumab significantly increases bone density, even in areas with prevalence of cortical bones. From these results, it can be concluded that alendronate has the longest half-life decay (10 years), while denosumab has a reversible effect because it does not deposit into bone tissue.

#### **5.1. Combining antiresorptive drugs and hormonal therapy**

staff. The cause of this unfavorable situation lies in the lack of communication between the specialist prescribing the high-risk drug and the treating dentist. The lack of awareness of the issue, both in patients and treating dentists, also plays its role. Medical specialist prescribing a high-risk drug is obligated to inform the patient about the risks and adverse effects of the planned treatment and to remind them to specifically inform their dentist about this fact. By disregarding this obligation on the part of the specialist (clinical oncologist, internist, rheumatologist, urologist, gynecologist, endocrinologist, orthopedist, etc.), the patient usually has no idea about the risk involved; however, the development of iatrogenic osteonecrosis may be prevented by the right approach by the treating dentist. They should not underestimate drug anamnesis prior to any invasive procedure in the oral cavity. Precise and targeted medical

The incidence of MRONJ can be divided into two groups: patients with non-oncological disease (osteoporosis, rheumatoid arthritis) and patients with cancer who take high doses of

In the second group, the incidence after 36 months of treatment ranges from 1 to 12%. The majority of cases described are connected with the use of zoledronate and pamidronate in treatment of multiple myeloma and bone metastases. So far, the results and recommendations on potential treatment for these conditions refer to the multicenter studies conducted in the

The study named DEFEND (Denosumab Evaluation for Preserving Bone Density) was a double-blind, multicenter, placebo-controlled, third phase study on 332 postmenopausal women with osteopenia and respective T-scores in the range of 1.5–2.5 SD. Denosumab was applied in 6-month intervals at a dose of 60 mg subcut, in contrast to placebo. Both groups of patients took a calcium supplement (100 mg a day) and vitamin D. The primary objective was

The results of the study showed that, compared with placebo, denosumab significantly increased the value of BMD in lumbar spine (by 6.5%). Denosumab also increased the density in the proximal part of femur (3.4%) and in the distal end of radius (by 1.4%). In the placebo

In another study, titled DECIDE (Determining Efficacy: Comparison of Initiating Denosumab vs. Alendronate), the effectiveness of denosumab with the same dosage as in the study DEFEND was compared to alendronic acid with a dosage of 70 mg, once a week, in order to reduce the risk of osteoporotic fractures. The yearlong study enrolled 1189 postmenopausal, relatively older women with more serious osteopenia than in the DEFEND, with half the women having a fracture in their medical history. Calcium and vitamin D supplementation has been the norm throughout the study. The primary measured indicator was the change in the density of proximal femur. Moreover, bone densities of lumbar spine, femoral neck,

The results showed that denosumab improved bone density in all the monitored areas markedly better than alendronic acid, as early as at the end of the first month. At the same time, resorption markers significantly decreased in the group treated with denosumab, compared

history can help identify at-risk patients and to choose the right treatment plan.

to observe the lumbar spine bone mineral density after 24 months of treatment.

intravenous bisphosphonates.

78 Newest Updates in Rheumatology

group, the BMD decreased in these areas.

trochanter and distal radius were also monitored.

to the alendronic acid group.

last 15 years.

Several studies refer to clinical cases of patients with antiresorptive drug-related osteonecrosis of the jaw that describe improvement in local findings and bone remodeling and an increase in patient's quality of life after switching bisphosphonates for hormonal therapy with recombinant parathyroid hormone teriparatide [12, 13].

Teriparatide was approved for the treatment of postmenopausal osteoporosis. Unlike the antiresorptive treatment, teriparatide has anabolic effect in bone which stimulates bone remodeling and bone tissue density. Intermittent administration (once a day) leads to a temporary increase of serum concentrations and preferential stimulation of the osteoblast activity, which leads to bone formation stimulation. The effect lies in the increase of bone mass and the number of osteoblasts, and the consequent strength of bones.

Some clinical trials document a positive effect of teriparatide and parathyroid hormone which reduces the risk of vertebral fractures while increasing the bone mineral density (BMD). The preparation is administered subcutaneously, one injection a day. Recommended treatment duration is 18 months. Side effects include cephalalgia, nausea and hypercalcemia. After its administration, osteal healing in mouth cavity was documented.

According to the trial results, hormonal preparations used after stimulating the activity of osteoblast and osteoclasts could be employed in the treatment of non-oncological osteonecrosis. However, current trials are very small, and there is no sufficient evidence, which calls for more studies. Treatment is difficult, and it is therefore available only for some patients.

Teriparatide should not be used in cancer patients due to an increased risk of osteosarcomas, which were found in preclinical trials on rats. The teriparatide therapy should not be indicated in patients who inject their bisphosphonates, zoledronic acid or pamidronic acid because of the increased incidence of necrosis and associated severe complications, in contrast to orally administered bisphosphonates.
