The overall safety profile of osteoporosis treatments for the prevention of fractures is favourable, with the benefit far outweighing the risk. The most common side effects for each drug have been described in each of their respective sections. However, two rare side effects with more severe outcomes, namely atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ), are described below.
Atypical femoral fractures (AFF)
An ESCEO and IOF publication describes the different aspects, outlined below, of AFF Rizzoli, R., et al., Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int, 2011. 22(2): p. 373-90.
Long-term bisphosphonate (BP) and denosumab treatment may be associated with atypical fractures, at the subtrochanteric and femoral shaft regions of the femur.
AFF is defined based on the following observations:
- This fracture type arises with minimal or no trauma
- The fracture line is transverse or short oblique
- Prodromal pain is present before the diagnosis of the fracture
- There is an appearance of localized periosteal or cortical thickening of the cortex (“beaking”)
The ASBMR Task Force reports a similar definition Shane, E., 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(11): p. 2267-94.
The pathophysiology of AFF is not known, however potential mechanisms are that BPs may:
- Negatively affect collagen, impacting bone mechanical properties
- Affect bone mineralization density distribution
- Delay or prevent healing of stressed fractures
The incidence of AFF is extremely low initially but increases with the duration of AR treatment:
- Incidence is estimated at 1 per 100’000 patients treated for less than three years, up to 1 per 1’000 patients treated for 10 years Dell, R.M., et al., Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res, 2012. 27(12): p. 2544-50.
- For each AFF, more than 1200, including 135 hip fractures are prevented in the first three years of BPs therapy Black, D.M., et al., Atypical Femur Fractures: Review of Epidemiology, Relationship to Bisphosphonates, Prevention, and Clinical Management. Endocr Rev, 2019. 40(2): p. 333-368.
, but rates of fractures prevented / AFF decline thereafter
Due to the low incidence of AFF, there is limited evidence of risk factors, however the following may be associated to an increased risk of AFF Black, D.M., et al., Atypical Femur Fractures: Review of Epidemiology, Relationship to Bisphosphonates, Prevention, and Clinical Management. Endocr Rev, 2019. 40(2): p. 333-368.
- Asian race (in North America and Europe)
- Femoral bowing
- Glucocorticoid use
- The fracture line is transverse or short oblique
- There is a cortical thickening and periosteal reaction
- Physicians should advise patients of any potential side effects or risks
- Patients with pain in the hips, thighs or femurs should be radiologically assessed
- When a stress fracture is evident, AR should be discontinued until the fracture is healed. Isolated reports mention the potential benefits of teriparatide in this context. Resuming AR therapy thereafter will depend on the reassessment of the individual benefits/risk profile
- Radiographic changes should be monitored
Osteonecrosis of the jaw (ONJ)
IOF as part of the International Task Force on Osteonecrosis of the Jaw, published an international consensus for the diagnosis and management of osteonecrosis of the jaw (ONJ) Khan, A.A., et al., Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res, 2015. 30(1): p. 3-23.
. Below is a summary of the main points.
The definition of ONJ relies on the following criteria:
- Exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider
- Exposure to an anti-resorptive agent
- No history of radiation therapy to the craniofacial region
The pathophysiology of ONJ is not well understood, however the following point have been raised:
- Infection: it is not clear whether infection precedes or follows the necrosis
- Bone turnover: suppression of bone turnover may play a role in the development of ONJ
- Vascularity: bisphosphonates have angiogenic properties and it has been postulated that these may contribute to the development of ONJ
- Genetic predisposition: pharmacogenomics may influence the risk of ONJ development
Incidence of ONJ in osteoporosis with:
- Oral bisphosphonates range from 1.04 to 69 per 100,000 patient‐years
- I.V. bisphosphonates ranges from 0 to 90 per 100,000 patient‐years
- Denosumab ranges from 0 to 30.2 per 100,000 patient‐years
The following risk factors for ONJ in osteoporosis have been identified:
- Use of bisphosphonates and denosumab
- Dental extraction(s)
Radiographic features of ONJ remain relatively nonspecific. Imaging modalities may include plain radiographs, CT, magnetic resonance imaging (MRI), and functional imaging with bone scintigraphy and positron emission tomography (PET).
Recommendations for imaging are:
- Patients with low dose of anti-resorptive treatment without signs of ONJ do not require any additional imaging over routine dental evaluation
- Patients on high‐dose antiresorptive treatment without ONJ are at significant risk of developing ONJ and early identification of dental disease is important
- Patients in whom ONJ is a clinical consideration on low‐dose or high‐dose antiresorptive therapy presenting with oral symptoms, CBCT or CT imaging may aid in evaluating early changes in the cortical and trabecular architecture of the maxilla and mandible
- Patients with clinical ONJ under conservative management, the nature and extent of osseous changes around the area of clinical bone exposure can be evaluated with CT or small‐FOV high‐resolution CBCT imaging
- Patients with clinical ONJ where surgical intervention is considered, CBCT or CT may be complemented with MRI, bone scan, or PET for a more thorough evaluation of involved bone and soft tissues
These have not been shown to be useful in managing patients with or at risk of ONJ.
- Completion of necessary oral surgery prior to initiation of antiresorptive therapy
- Use of antibiotics before and/or after the procedure
- Use of antimicrobial mouth rinsing
- Ensuring appropriate closure of the wound following tooth extraction
- Ensuring maintenance of good oral hygiene
A defined treatment algorithm for ONJ has not yet been established, however the generally accepted approach includes:
- Palliation of symptoms
- Control of associated infection
- Treatment decision may depend on age, sex, disease status, ONJ stage, size of the lesion, medication exposure, among other factors, however the two treatment options are:
- Conservative nonsurgical therapy: optimal oral hygiene, elimination of active dental and periodontal disease, topical antibiotic mouth rinses, systemic antibiotic therapy
- Surgical management
- Attitude regarding osteoporosis therapy in case of ONJ depends on the physician’s decision, to either stop definitively, or transiently or continue. Although common practice is to interrupt antiresorptive therapy at least as long as the ONJ has not healed, clear benefit has not been demonstrated and the risk of osteoporosis fracture will increase.