Recommendation
Question 5: What are the side effects associated with long-term bisphosphonate
• Administration of a bisphosphonate in the presence of a fracture can improve BMD in the short-term at the site of fracture [overall quality: moderate]
Question 5: What are the side effects
C H A P T E R 7 Osteoporosis and Metabolic Disorders
low.108,110 The ASBMR task force on ONJ recently reviewed
published and unpublished case reports of ONJ,108 and identified 57 cases of ONJ in patients treated with bisphos- phonates for osteoporosis, the majority of which were asso- ciated with alendronate. The review concluded that the risk for ONJ in this patient group was very low (between 1 in 10,000 and <1 in 100,000 patient-treatment years). The ASBMR task force on ONJ also developed a number of clinical management recommendations regarding ONJ for patients initiating or already receiving bisphosphonate therapy, which are outlined in Table 7.6. Woo et al.110 also conducted a systematic review of all potential cases of ONJ reported between 1966 and 2006 and came to a similar conclusion as the ASBMR task force on ONJ. Only 15 of 368 reported cases of ONJ were in patients using oral bisphos- phonates for osteoporosis.
In data from randomized clinical trials of the bisphos- phonates marketed in the US for the treatment of oste- oporosis, no cases of ONJ have been reported, out of over 17,000 patients exposed to alendronate, more than 44 000 patient-years of exposure to risedronate and over 12,000 patients exposed to ibandronate.109 However, none of these trials included the reporting of dental adverse events, nor was there an adjudication of suspicious dental findings.
These findings were documented in a recent review paper rate of serious or nonserious atrial fibrillation, regardless
of dose or duration of bisphosphonate therapy. Further, the FDA maintains that the current indications for bisphospho- nate use should remain unchanged.105
Osteonecrosis of the jaw Since 2003, there have been several case reports of osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates, primarily in patients with cancer,106,107 although a consensus on diagnostic criteria for ONJ is vague. The American Society for Bone and Mineral Research (ASBMR) task force on ONJ,108 a multidisciplinary expert group assembled to address key questions related to the disorder, developed the following definition of ONJ to help future investigations of the condition:
an area of exposed bone in the maxillofacial region that has not healed within 8 weeks after identification by a healthcare provider in a patient who is receiving or has been exposed to a bisphosphonate and has not had radiation therapy to the craniofacial region.
The clinical severity of ONJ has led to a number of inves- tigations examining the incidence and prevalence of ONJ among bisphosphonate users.109 Current evidence from case reports suggests that the risk for ONJ associated with oral bisphosphonate therapy for osteoporosis is very
Table 7.6 ASBMR Task Force on ONJ recommendations and precautions for patients with osteoporosis or other nonmalignant bone disease initiating or already receiving bisphosphonate therapy108
Patient Group Recommendations and precautions Inititating
bisphosphonate therapy
Patients should be informed that the risk of developing bisphosphonate-associated ONJ with routine oral therapy for osteoporosis or Paget’s disease seems to be low, ranging between 1/10,000 and 1/100,000
Patients who express concern about ONJ should be encouraged to seek additional information from a dentist or dental specialist Healthcare providers should encourage patients who are starting to take bisphosphonates to practice good oral hygiene and have regular dental visits
Because the risk of developing bisphosphonate-associated ONJ seems to be related to longer duration of bisphosphonate exposure and the risk is low, it is not necessary to recommend a dental examination before beginning oral bisphosphonate therapy or to otherwise alter routine dental management
Receiving bisphosphonate therapy
Healthcare providers should encourage patients to practice good oral hygiene and have regular dental visits
Patients with periodontal disease should receive appropriate nonsurgical therapy. If surgical treatment is necessary, it should be aimed primarily at reducing or eliminating periodontal disease. Modest bone recontouring may be considered when necessary Current information indicates that taking bisphosphonates for osteoporosis is not a contraindication for dental implant placement.
However, if dental implants are considered, appropriate informed consent is recommended and should be documented Endodontic treatment is preferable to extraction or periapical surgery when possible
If an invasive dental procedure is anticipated, some experts suggest stopping the bisphosphonate for a period before and after the procedure. There are no data to suggest stopping the bisphosphonate will improve dental outcomes, however, given the long retention of bisphosphonates in the skeleton, temporary discontinuation of bisphosphonate therapy is unlikely to have an adverse effect on the patient’s skeletal condition
Adapted from Khosla et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10)1479–89.
by Silverman et al.109 and were based on personal commu- nications between the authors and the corresponding drug companies. In a recently completed trial entitled the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial57—a major randomized clinical trial that evaluated yearly zoledronic acid 5 mg for the treatment of postmenopausal osteoporo- sis in 7,736 postmenopausal women—an adverse event review process was established to assess maxillofacial adverse events objectively and independently. This is the largest trial to date in which ONJ has been examined in a systematic fashion with adjudication of all potential cases.111 In the HORIZON Pivotal Fracture Trial there were no spon- taneous reports of ONJ; however, after a thorough review of all maxillofacial adverse events, two potential cases of ONJ were found to meet predefined adjudication criteria (exposed bone in the oral cavity present >6 weeks): one case in the treatment group and one in the placebo group, making incidence rates similar between groups. In both patients, the condition resolved after antibiotic therapy and debridement.
Atypical fractures Several case reports94,112–115 have docu- mented atypical fractures linked to long-term bisphospho- nate use. Atypical fractures are those occurring at sites that are uncommon (but not absolutely unlikely) for osteoporo- sis such as the midshaft femur, pelvis, and tibia, as well as those that have exhibited impaired healing. Recently, a multidisciplinary expert group (task force), similar to the one discussed previously for the issue of ONJ, was estab- lished by the ASBMR to address key questions related to these fractures. A report put out by this task force116 devel- oped a formal case definition for the condition, reviewed available published and unpublished data, and provided a set of recommendations for orthopedic and medical man- agement (Table 7.7). The report reviewed 310 cases of atypi- cal femoral fractures and found that 291 patients (94 %) with this condition had taken a bisphosphonate; however, a causal association was not established. The report con- cluded that the incidence of atypical femoral fractures asso- ciated with bisphosphonate therapy for osteoporosis is very low (∼3–10 per 10,000 patients), particularly in com- parison to the number of vertebral, hip and other fractures that are prevented by bisphosphonates. However, the find- ings suggested that the risk increases with increasing dura- tion of exposure, thus there was concern that a lack of awareness and under-reporting may currently mask the true incidence of the problem. Given the rarity of atypical femoral fractures, the task force recommended that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients will also be made aware of the possibility of
atypical femoral fractures through a change in labeling of bisphosphonates.
Recommendations
In patients aged 50 years or older who use long-term bisphosphonate therapy for osteoporosis, evidence sug- gests that:
• There is no clear association between bisphosphonate use and the rate of serious or nonserious atrial fibrillation, regardless of dose or duration of bisphosphonate therapy [overall quality: high]
• The risk of developing bisphosphonate-associated ONJ with routine oral therapy for osteoporosis is very low [overall quality: high]
• The benefits of bisphosphonates in preventing hip and other osteoporotic fractures outweigh the risk of develop- ing atypical femoral fractures. [overall quality: low]
Summary of recommendations
• Many patients who have sustained a hip or other fragil- ity fracture are not receiving appropriate evaluation and treatment for osteoporosis postfracture
• Significant progress has been made towards developing and implementing programs to address the osteoporosis care gap
• The FRAX tool can be used to calculate the 10-year prob- ability of a major osteoporotic fracture (clinical spine, hip, forearm or proximal humerus) and hip fracture
• Alternative methods are also available to determine absolute fracture risk
• Treatment decisions should be patient specific and guidelines developed by the appropriate country of origin should be considered
• Alendronate, risedronate, zoledronic acid, denosumab and HRT are all effective pharmacologic agents for reduc- ing the relative risk of hip fracture in patients with low BMD or prior fragility fractures
• Continuous administration of a bisphosphonate in the presence of a fracture may modestly delay hard callus remodeling in animals, but generally does not compromise the mechanical integrity of the fracture callus
• Single-dosing of bisphosphonates in the presence of a fracture can reduce delays in hard callus remodeling and improve bone strength in animals
• Administration of a bisphosphonate in the presence of a fracture can improve BMD in the short-term at the site of fracture
• There is no clear association between bisphosphonate use and the rate of serious or nonserious atrial fibrillation, regardless of dose or duration of bisphosphonate therapy
• The risk of developing bisphosphonate-associated ONJ with routine oral therapy for osteoporosis is very low
C H A P T E R 7 Osteoporosis and Metabolic Disorders
Table 7.7 ASBMR Task Force on Atypical Femoral Fractures recommendations for orthopedic and medical management of atypical femoral fractures116
Issue Recommendations
Surgical management History of thigh or groin pain in a patient on bisphosphonate therapy
Rule out femoral fracture. AP and lateral plain radiographs of the hip, including the full diaphysis of the femur should be performed. If the radiograph is negative and the level of clinical suspicion is high, a technetium bone scan or MRI of the femur should be performed to detect a periosteal stress reaction
Complete subtrochanteric/
diaphyseal femoral fracture
Orthopedic management includes stabilizing the fracture and addressing the medical management (below). Endochondral fracture repair is the preferred method of treatment since bisphosphonates inhibit osteoclast remodeling. Intramedullary reconstruction full-length nails accomplish this goal and protect the femur. Locking plates preclude endochondral repair, have a high failure rate, and are not recommended as the method of fixation. The medullary canal should be overreamed to compensate for the narrow intramedullary diameter, facilitate insertion of the reconstruction nail and prevent fracture of the remaining shaft. The proximal fragment may require additional reaming to permit passage of the nail and avoid malalignment. The contralateral femur must be evaluated radiographically whether or not symptoms are present Incomplete
subtrochanteric/
femoral shaft fractures
Prophylactic reconstruction nail fixation is recommended if pain is present. If there is minimal pain, a trial of conservative therapy in which weight bearing is limited through the use of crutches or a walker may be considered. However, if there is no symptomatic and radiographic improvement after 2– 3 months of conservative therapy, prophylactic nail fixation should be strongly considered because of the possibility of complete fracture. For patients with no pain, weight bearing may be continued but should be limited and vigorous activity avoided. Reduced activity should be continued until there is no bone edema on MRI
Medical management
Prevention Decisions to initiate pharmacologic treatment including bisphosphonates to manage patients with osteoporosis should be made based on an assessment of benefits and risks. Patients who are deemed to be a low risk of osteoporosis-related fractures should not be started on bisphosphonates. Physicians need to be wary of thigh or groin pain in patients on bisphosphonates. Complaints of thigh or groin pain in a patient on bisphosphonates require urgent radiographic evaluation of both femurs even if pain is unilateral
Treatment For patients with a stress reaction, stress fracture, or incomplete or complete subtrochanteric femoral shaft fracture, potent antiresorptive agents should be discontinued. Dietary calcium and vitamin D status should be assessed and adequate supplementation should be prescribed. Teriparatide should be considered in patients who suffer these fractures, particularly if there is little evidence of healing by 4 to 6 weeks after surgical intervention
Adapted from Shane et al. Atypical subtrochanteric and diaphyseal femoral fractures: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010; 25:2267–94.
• The benefits of bisphosphonates in preventing hip and other osteoporotic fractures outweigh the risk of develop- ing atypical femoral fractures
Conclusion
This chapter reviewed orthopedic issues relating to oste- oporosis including: (1) the identification of osteoporosis in patients with fractures, (2) treatment guidelines for patients with osteoporosis, (3) effective pharmacologic therapies for reducing fracture risk, (4) bisphosphonate therapy and fracture healing and (5) adverse effects associated with pharmacologic therapies for osteoporosis. Clinical evi- dence confirms that osteoporosis is an important ortho-
pedic concern and necessitates continued evaluation and attention.
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