Osteoporosis-related fractures result in increased mortality, morbidity, and huge social costs worldwide. After the age of 50, one in three older women and one in five older men will experience a fragility fracture, mainly of the spine, hip, and forearm (1-3).

The landscape of anti-osteoporotic therapies, for the last two decades, have been dominated by bisphosphonates (BPs). The results of randomized placebo-controlled trials of at least 3-4 years duration supported the efficacy of nitrogen-containing BPs in decreasing the risk of vertebral fractures (by 40-70%), hip fractures (by 20-50%) and non-vertebral fractures (by 15-39%), depending on the drug used, skeletal site, and individual risk profile. BPs have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of postmenopausal, glucocorticoid-induced, and male osteoporosis (1).

Within the last several years, however, reports on serious complications, potentially related to the long-term therapy with BPs, have been published. The most alarming of them are osteonecrosis of the jaw (ONJ), first reported by dentists and oral surgeons in 2003, and atypical femoral fractures (AFFs), first described in 2007. Many subsequent publications, including 3 major reports of American Society for Bone and Mineral Research (ASBMR) Task Forces paid attention to the possible correlations between long-term BP therapy and morbidities mediated by decreased bone turnover due to reduced osteoclast function (1, 4-6). It has been noticed, however, that AFFs could occur in patients not receiving any antiresorptive therapy (1, 7-9). Growing number of incidents of AFFs in patients on long-term treatment with BPs induced FDA in 2010 to review available data and release “Warnings and Precautions”, suggesting that information on the risk of AFFs should be added to the labels of all BP products approved for the prevention and/or treatment of osteoporosis (6, 10). In 2011 FDA re-reviewed long-term safety and efficacy of BPs and recommended physicians to verify indications for continuation of long-term therapy with BPs beyond the period of 3-5 years (1, 11).

The concept of “drug holiday” has been suggested to minimize side effects and maximize benefits of long-term treatments of chronic diseases (1, 12). Two clinical trials provided data on benefits and risks of long-term use of BPs in patients with osteoporosis. Fracture Intervention Trial Long-Term Extension (FLEX) revealed that postmenopausal women treated with alendronate for as long as 10 years experienced fewer clinical vertebral fractures than patients switched to placebo after 5 years of active therapy. In the HORIZON extension trial, women given 6 annual infusions of zoledronic acid had less morphometric vertebral fractures compared with those switched to placebo after 3^rd dose of the drug. Beneficial response to continued therapy was observed, however, only in women with low bone mineral density (BMD): T-score at femoral neck between -2 and -2.5 in FLEX trial and below -2.5 in HORIZON extension study. Considering these results the ASBMR Task Force have suggested to reassess risk-benefit ratio after 5 years of oral or 3 years of intravenous therapy with BPs. Continuation of oral treatment for up to 10 years or intravenous therapy up to 6 years, with its periodic evaluation, should be considered in patients at high risk for fracture, with low BMD, previous major osteoporotic fracture, or in women who experienced fracture on therapy. In other patients 3-5 years of treatment with BPs should be followed by a period of “drug holiday” lasting 2-3 years. Suggested approach could be applicable, with some adaptations, to men and patients with glucocorticoid-induced osteoporosis (1).

The American Association of Clinical Endocrinologists (AACE) guidelines have suggested a “drug holiday” after 4-5 years of BP treatment in patients at moderate risk of fractures, and after 10 years of active therapy for high-risk patients, but terms “high” and “moderate” risks have not been defined (1, 13).

Osteonecrosis of the jaw (ONJ) as a possible complication of bisphosphonate therapy was first reported in 2003, in patients with metastatic cancer treated with high doses of intravenous BPs. The incidence of ONJ in patients with osteoporosis was estimated to be between 1/10,000 and 1/100,000, only slightly higher than the incidence of the disease in general population (1, 14).

Osteonecrosis of the jaw is characterized by:

– an exposed necrotic bone in the maxillofacial region persisting for at least 8 weeks in spite of appropriate therapy,

– exposure to potent anti-resorptive or anti-angiogenic agents,

– no history of radiation therapy on the jaw (15).

The clinical course of the disease was originally grouped into three stages: the presence of exposed bone without pain or signs of infection (stage 1), with pain and signs of infection (stage 2) and with the appearance of fistulas, fractures and osteolysis (stage 3). Recently stage 0 characterized by certain symptoms and radiological changes in the absence of exposed bone has been additionally proposed. The majority of cases of ONJ in patients with osteoporosis are at stages 0-1, whilst in cancer patients at stages 2-3.

The pathogenesis of ONJ remains unclear, but several potential mechanisms have been proposed. These include long-term suppression of bone remodeling, reduced blood supply due to inhibition of angiogenesis, recurrent microtraumas, infection/inflammation and immune dysfunction. Higher incidence of ONJ in Asian populations suggests genetic predisposition to the disease (16). The cases of ONJ in cancer patients treated with high doses of potent BPs or denosumab (DSB) strongly suggest that profound and prolonged inhibition of bone remodeling may be the primary cause. Significant suppression of the bone turnover with BPs in the jaw bones, observed in animal studies, may explain predisposition of this region to ONJ compared with other parts of the skeleton (16-18).

Inhibition of angiogenesis can be another important mechanism as ONJ is a form of avascular necrosis. It was found that zoledronic acid in vitro inhibited angiogenesis and in cancer patients decreased serum vascular endothelial growth factor (VEGF) concentration. The results of clinical studies has combined ONJ and treatment with antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors. On the other hand it was found that treatment with DSB did not result in inhibition of angiogenesis (19-21).

The main localization of ONJ is mandible and only one-third of cases occur in the maxillary bone. It suggests that frequent, recurrent microdamages inflicted upon the lower jaw bones with mastication might play role in pathogenesis of the disease (18, 21). Other potential risk factors of ONJ in patients treated with antiresorptive drugs include poor oral hygiene, cigarette smoking, diabetes mellitus, concomitant glucocorticoid- and/or chemotherapy, and invasive dental procedures, such as dental extractions or implants, especially in patients with preexisting periodontal or periapical disease. Complex biofilms have been found on the bone/tooth and mucosal surfaces around BP-related ONJ, composed of Actinomyces and other organisms including fungi and viruses. It is still unknown whether BP-related ONJ is the result of direct drug toxicity to the bone and/or soft tissues that become secondarily infected or a primary infection is subsequently exacerbated by the treatment with antiresorptive agents (17-24).