Many cases of atypical fractures of osteoporosis (low-violence fractures without violence) due to long-term diphosphonate administration have been reported.
Commonly used diphosphonate drugs: Fosamax, MIGUDA
How can these drugs, which are used to treat osteoporosis, cause osteoporotic fractures?
Analysis of the reasons: The mechanism of diphosphonates for osteoporosis is to treat osteoporosis by inhibiting osteoclastic bone resorption and reducing bone loss. Long-term use, inhibit osteoclastic bone resorption at the same time, can also inhibit bone metabolism inhibit osteogenesis. Bone metabolism is a dynamic balance between osteogenesis and osteolysis, and problems can occur when this balance is disturbed.
Although some pharmacological studies deny such side effects of diphosphonates and disagree with the clinical view (long-term use of diphosphonates leads to atypical fractures of osteoporosis),
At least, from a common sense analysis there is no one-size-fits-all drug, and it is not scientific to treat osteoporosis with one drug for a long time without interruption.
The clinical need for such medications should be regulated by a course of treatment, not exceeding 3 years, and beyond 5 years may increase the risk of atypical fractures.
Atypical femur fractures are very rare, occurring in only about 1% of high-grade femur fractures. The association between this type of fracture and long-term use of bisphosphonates should nevertheless be a cause for concern. Further studies will focus on the etiology and mechanism of action of bisphosphonates in atypical fractures in order to improve the diagnosis and monitoring of patients with atypical femur fractures.
The investigators also noted that bisphosphonates prevent common fractures, so patients should not stop taking these drugs for fear of an atypical femur fracture and should inform their physician as soon as possible if they develop thigh or groin pain. Although the risk of occurrence is very low, physicians should also be aware of atypical bone fractures and frequently ask patients using these drugs if they have thigh or groin pain, as well as consider whether the drug is appropriate for that patient before administering it.
Safety evaluation of diphosphonates
Diphosphonates (BP) are effective in antagonizing osteoclast-mediated bone resorption. Several large randomized controlled studies in menopausal women have shown that BP is effective in increasing bone mineral density (BMD) and reducing the risk of osteoporotic fractures of the spine, non-spine, and hip. In addition, both alendronate and risedronate have shown a reduced risk of spine fractures caused by glucocorticoid-induced osteoporosis.
There is also evidence that BP treatment improves patient morbidity and mortality and reduces health-related consumption. BP is undoubtedly the most commonly prescribed drug currently applied to patients at risk of fragility fracture, with millions of prescriptions containing BP written by physicians worldwide each year.
The first BP, alendronate, was marketed in 1995, when the drug’s instructions mentioned only one side effect, namely an upper gastrointestinal reaction. However, other safety aspects of this drug class have been widely discussed in recent years, and BP drug exposure has been associated with osteonecrosis of the jaw (ONJ), atrial fibrillation (AF), esophageal cancer, and atypical femur fracture (AFF).
Safety issues that have led to extensive discussion.
ONJ: When a patient is treated with BP for osteoporosis, is it necessary to assess the risk of ONJ?
(i) When BP is first used for osteoporosis, patients do not need to be evaluated by a dentist or receive additional treatment from a dentist.
(ii) Patients with suspected ONJ symptoms such as pain or swelling in the mouth, soft tissue ulcers, abnormal sensation, or loose teeth should be seen regularly by a dentist, maintain good oral hygiene, and follow the dentist’s orders.
(iii) Discontinuation of BP after initial BP treatment does not improve the prognosis of invasive stomatology treatment.
Is there a correlation between BP and AF:?
The evidence available does not yet support the claim that BP should not be used in patients at risk of developing AF. The absolute risk of developing AF is negligible compared to the benefit of reduced fracture risk associated with the use of the drug.
Esophageal cancer: does BP increase the risk of developing it?
The association between oral BP and esophageal cancer is not clear due to the inconsistent results of current studies. However, oral BP should be avoided in patients with symptoms of delayed esophageal emptying, and in patients with precancerous lesions, such as Barrett’s esophagus, the weighting between the benefit of receiving BP and the potential risk of post-dosing should be carefully assessed. (For such patients, intravenous administration may be more appropriate)
BP vs. AFF: What have the current studies found?
AFF was first reported by the medical community in 2005 and its main features include: fractures in the region below the lesser trochanteric tuberosity to above the distal epiphysis (the bone in this region should have the greatest resistance to tension); very mild trauma prior to fracture or lack of history of trauma; a transverse or slightly inclined (<30°) fracture line; non-comminuted fractures; complete fractures through the bilateral cortex, or incomplete fractures involving the lateral cortex.
The pathogenesis of the disease may be related to a long-term inhibition of bone renewal. Bone remodeling in healthy individuals contributes to the repair of skeletal microfractures and microdamage, and due to the inhibition of osteoclasts by BP, the aforementioned repair is impaired and the accumulation of skeletal microfractures eventually leads to atypical fractures. Animal studies found that BP-treated bones were more prone to microfractures, but there was no direct correlation between BP and microfracture formation, nor between microfracture formation and atypical fractures. In addition, atypical fractures also occur in patients who are not treated with BP.
Because the occurrence of AFF is rare, the current evidence for a correlation between BP and AFF is mainly derived from observational studies and case reports. The results of several current studies suggest a correlation between an increased risk of AFF and long-term BP application. There are also some contrary findings that found a similar incidence of AFF with BP compared to placebo for women.
Clinicians should pay more attention to the following patients treated with BP: patients with persistent groin area pain after treatment with BP; patients with stress fractures of the femur. If a patient has had a stress fracture of one femur, the contralateral femur should be examined radiologically because of the higher incidence of simultaneous bilateral fractures.
Is there a downtime in patients on long-term BP?
Three studies of long-term BP use have yielded the following results.
(i) BMD in the hip and spine decreased after interruption of BP treatment, but remained higher than the BMD values when treatment was first started 10 years ago.
(ii) There was no difference in the incidence of non-spinal fractures in those who continued alendronate for 10 years compared to those who discontinued it after 5 years of use.
(iii) Patients who continued to use BP had a decreased risk of spinal fractures.
(iv) Some other studies have found that the risk of hip fracture may be elevated in patients who discontinue BP therapy.
(v) Risedronate users are the first to experience bone loss after interruption of treatment. Therefore, the rest period may only apply to alendronate and zoledronic acid users.