The National Osteoporosis Foundation (NOF) focuses on patient and professional education, advocacy, and research in the United States. Their recommendations target both healthcare providers and individuals with osteoporosis and are based on FDA recommendations to regularly monitor patients and individualize treatment plans. NOF’s clinical guide to prevention and treatment of osteoporosis was updated in 2013 [34] and includes useful tools for clinicians on how to assess risk and when treatment should be indicated.

Osteoporosis Canada promotes osteoporosis risk reduction and treatment, providing medically accurate information to patients, healthcare professionals, and the public. The organization published guidelines in 2010, reviewing when osteoporosis pharmacotherapies including alendronate, risedronate, and zoledronic acid should be discontinued to prevent high-risk fracture in patients with osteoporosis [43]. According to Osteoporosis Canada, adverse events caused by bisphosphonates are considered to be rare, including ONJ and atypical fractures of the femur. The absolute risk of bisphosphonate-related ONJ is approximately 1 case per 100,000 person-years when bisphosphonates are administered for osteoporosis treatment [44]. The development of ONJ increases when individuals have poor oral hygiene and if oncology patients are receiving high-dose antiresorptive treatment. According to Osteoporosis Canada, little is known about features associated with atypical fractures of the femur. The absolute risk of bisphosphonate-associated atypical subtrochanteric diaphyseal femur fracture is between 2 and 78 cases per 100,000 persons [44]. However, while long-term clinical trial data has not shown an increase in atypical fracture of the femur risk, some studies have indicated that these trials are too small in nature to detect uncommon events [13, 44–46]. The most common bisphosphonate-associated with atypical femoral fractures is alendronate, likely due to its earlier availability relative to other currently used bisphosphonates.

Individuals at high risk for fracture are recommended to continue osteoporosis therapy without a drug holiday (Grade D evidence) as their anti-fracture benefits considerably outweigh potential for harm. This decision was based on rates of clinical vertebral fractures being reduced by 55 % for those who remained on alendronate therapy , compared to those who discontinued after 5 years in the FLEX trial [47]. High risk was identified as those over the age of 50 who had a prior fragility fracture of the hip or vertebrae, or those that suffered more than one fragility fracture , being offered a pharmacological therapy (Grade B evidence) or as greater than 20 % fracture probability, a major fracture probability over 10 years, using either FRAX or CAROC (Grade D evidence). Adverse effects were evidenced using Cochrane meta-analysis systematic reviews, as well as highlighting post-marketing surveillance [43].

A subsequent position statement on the duration of bisphosphonate use and drug holidays recommended that drug holidays should be considered for patients at low risk of fracture after 3–5 years of therapy with bisphosphonates [48]. For those at high risk of fracture with a history of fragility fracture or osteoporotic BMD, bisphosphonates should be continued without a drug holiday. A radiograph of the full length of the femur or a bone scan has been recommended for those with a history of thigh pain to assess for possible atypical subtrochanteric fractures [43]. Osteoporosis Canada findings and recommendations are in agreement with the ASBMR, FDA, and AHRQ.

Health Canada is the nation’s federal regulator of therapeutic drugs and provides public information on human pharmaceutical and biological drugs, veterinary drugs, and disinfectant products approved for use in Canada. The organization is in agreement with Osteoporosis Canada and has encouraged practicing clinicians to recognize that while the risk of adverse events is higher with bisphosphonate use, it remains minor and osteoporosis-related fracture prevention benefits outweigh ONJ and atypical femoral fracture risks [43, 44].

The European Medicines Agency (EMA) conducts scientific evaluations and European public assessment reports (EPARs) of pharmaceuticals developed for use. Authorization assessments are conducted based on scientific criteria related to quality, safety, efficacy, and risk–benefit standards, and EPARs establish the scientific criteria based on which a pharmaceutical was granted authorization, as well as a detailed summary of product characteristics, labeling/packaging, and assessment and authorization procedural steps [49].

An increased risk of atypical fracture of the femur with little or no trauma was noted by the CHMP’s Pharmacovigilance Working Group in association with alendronic acid use in 2008, resulting in a warning addition to the product information of related medicines. The Working Group also decided to review this risk in other bisphosphonates (as a class effect) and identified published literature and post-marketing reports suggestive of atypical stress femoral fractures as a class effect by April 2010, leading to a further review by the CHMP to determine the need for regulatory action on bisphosphonate-containing medicines [50, 51].

The CHMP has examined all case reports, epidemiological studies, and other relevant data from published literature and industries relevant to bisphosphonate-related stress fractures. The optimal duration of bisphosphonate treatments has not been established by the EMA; the treatments have been recommended on a continual basis, with reevaluation of benefits and potential risks on an individual patient basis, particularly following 5 or more years of use [50, 51].

Authorized by the EU since April 15, 2005, zoledronic acid has been recommended as a single intravenous 5 mg infusion for osteoporosis in men at increased risk of fracture or with a recent low-trauma hip fracture, postmenopausal women, patients with long-term systemic glucocorticoid therapy, Paget’s disease of the bone patients, and low-trauma hip fracture patients (initiated 2 or more weeks following fracture repair) [52]. Zoledronic acid has been contraindicated in patients with creatinine clearance of <35 ml/min (severe renal impairment), hypersensitivity to bisphosphonates or the drug’s active substance, hypocalcaemia, and pregnant and breast-feeding women [52]. The HORIZON Pivotal Fracture Trial (n = 7736 postmenopausal women with osteoporosis) identified one case of ONJ in both intervention and placebo-controlled groups. Compared to placebo, zoledronic acid was found to significantly reduce the days of limited activity (p < 0.01) and the days of bed rest due to fractures (p < 0.01) [26]. Overall, adverse reactions have been reported by 44.7 %, 16.7 %, and 10.2 % of patients following first, second, and third infusions, respectively. Fever (17.1 %), myalgia (7.8 %), flu-like symptoms (6.7 %), arthralgia (4.8 %), and headaches (5.1 %) were commonly reported mild or moderate adverse effects, particularly within the first three days following administration [26, 52, 53]. An increased incidence of serious atrial fibrillation adverse events was also reported (51/3862 vs. 22/3852 placebo patients). Other common adverse events associated with zoledronic acid use include ocular hyperemia, dizziness, nausea, vomiting, diarrhea, bone pain, back pain, extremity pain, chills, fatigue, asthenia, general pain, malaise, infusion site reactions, and C-reactive protein increases [26, 52, 53].