The Effects of Long-term Use of Nitrogen-containing Bisphosphonates on Fracture Healing

Abstract

Nitrogen-containing bisphosphonates (N-BPs) are pharmaceutical agents that have been used for many years to treat osteoporosis, multiple myeloma, Paget's disease, metastatic bone disease, and a variety of other diseases in which bone mineral density is reduced. Given that N-BPs inhibit bone resorption, an important stage in the fracture healing process, they have been extensively studied in preclinical models for their activity. In animal models, treatment with N-BPs is associated with a larger callus formation in fracture area and delay in remodeling from primary woven bone to lamellar bone, but there is no delay in formation of the fracture callus. In humans, all existing evidence suggest that initiating treatment with N-BPs, after upper and lower limb fractures, does not appear to have a significant effect on fracture healing. Rarely, patients with long-term use of N-BPs may develop “atypical fractures” and delay in their healing. Therefore, this clinical condition is not fully understood and many questions remain unanswered. Similarly, there are few studies about the benefits of stopping a long-term treatment with them, if a fracture occurs. Although most studies support that chronic N-BP therapy may lead to fracture healing delay, this is not fully documented. On the other hand, there are studies that are in complete disagreement with them. All of the above suggest that there is a need for more detailed future research into larger patient populations and different types of fractures, with sufficient data on the type, dosage, route and duration of administration of N-BPs, and the control methods of fracture healing, in order to have a safe final conclusion on the effect of their long-term administration in this highly complex process.

Bisphosphonates do not affect healing of a critical-size defect in estrogen-deficient mice

“…The effect of BP on fracture healing remains controversial, with clinical studies showing minor or no influence on bone repair in humans ( Begkas et al, 2019 ; Kates and Ackert-Bicknell, 2016 ; Gao et al, 2021 ; Xue et al, 2014 ). The outcome in rodent models varied from delayed healing to improved mechanical stability of bone defects, depending on the agent, dosage, and treatment protocol ( Hadjiargyrou, 2022 ).…”

Current vision on mechanism of action of bisphosphonates. The effect of long-term administration of bisphosphonates on bone tissue (preclinical studies)

“…Использовались несколько животных моделей, включая модели на мышах, крысах, кроликах, собаках и овцах. По данным исследований, использование БФ, в том числе при длительном применении, приводило к увеличению размера костной мозоли, что совпадало с задержкой ее ремоделирования -от первичной незрелой кости до зрелой ламеллярной (пластинчатой) кости, но не влияло на время заживление перелома и не снижало или даже повышало механические свойства образовавшейся мозоли [26][27][28][29].…”

“…Поскольку однократное применение азотсодержащего БФ приводит к образованию более прочной первичной костной мозоли со способностью к дальнейшему ремоделированию, Begkas D. с соавт. высказали мнение о целесообразности уменьшения частоты введения терапевтических доз, чтобы свести к минимуму их влияние на ремоделирование твердой мозоли [29]. Для разработки оптимальных дозировок и внедрения этой концепции в клиническую практику потребуются дальнейшие исследования.…”