The purpose of this scientific literature review was to examine clinical recommendations for the duration of bisphosphonate therapy in patients with osteoporosis who have experienced osteoporotic fractures if they remain at high risk after 3–5 years of taking them. An electronic search of electronic databases was conducted, as well as a hand search of journals. A total of 94 publications were examined. 17 publications were included in the review. We concluded that patients who stopped taking bisphosphonates had a 20–40% higher risk of new clinical fractures and nearly twice the risk of vertebral fractures compared with the treatment period, indicating that a drug holiday is recommended not for all patients receiving therapy. However, long-term therapy with alendronate and zoledronic acid has been shown to reduce the risk of fractures in women with osteoporosis. The persistent increase in spinal bone mineral density with long-term bisphosphonate use may explain the lower incidence of vertebral fractures in patients on therapy long-term compared with patients who discontinued therapy after 3 years.

Bisphosphonates are the main medications in the treatment of osteoporosis, which are effective in reducing the risk of fractures in patients with osteoporosis. It is known that after treatment with bisphosphonates, bone mineral density remains quite stable for a certain time, as well as markers of bone metabolism remain reduced, which, along with the side effects of long-term bisphosphonate therapy, determines the possibility of “Drug holidays”. At the same time, during a break in bisphosphonate treatment, the risk of fractures begins to increase, which is a reason to resume therapy.

Currently, there is no uniform worldwide data of starting a “drug holidays” on bisphosphonates. The duration of the “drug holidays” also differs in clinical recommendations from different countries. When to conduct a risk assessment of fractures during a “drug holidays”? To answer these questions, we assessed existing clinical recommendations for treatment interruption/discontinuation of bisphosphonates. A literature search was conducted using the following resources: PubMed®, the Cochrane Library, websites of major international osteoporosis associations, and other targeted Internet searches. The main search terms were “Clinical Guideline of Osteoporosis”, “Bisphosphonates”, “Drug holidays in osteoporosis”, “Discontinuation of bisphosphonates”. Тhe search was carried out using articles in Russian and English published between January 1, 2016 and September 15, 2023. 17 clinical guidelines from different countries (Russian, American, European, Asian and Australian) were found and analyzed in which was information about the break in the treatment and withdrawal of bisphosphonates.

The majority of clinical recommendations have the same opinion on the issue of starting “drug holidays”: with a moderate risk of fractures, you can take a break from treatment with tableted bisphosphonates after 5 years, after zoledronic acid — after 3 years of therapy. At high and very high risk of fractures, the duration of treatment is 10 and 6 years, respectively. The duration of “drug holidays” vary in the recommendations, but in most cases the decision-making is based not on the duration, but on the assessment of the risk of fractures with their regular reassessment, which includes previous and new low-energy fractures, the emergence of new risk factors, a decrease in BMD, the dynamics of bone markers, re-evalua­tion of FRAX®.

Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis (OP) and reduce fragility fractures. The extended use of antiresorptive therapy has drawn attention to two extremely rare, although severe, adverse events. Аtypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ) are more common in patients with high cumulative doses and longer duration of therapy. The risk of AFF depends on the duration of treatment and is significantly increased among patients receiving BPs for more than 8 years. The risk may decrease and return to the initial level with discontinuation of BPs, it decreases by more than 50% during one year after the discontinuation. The risk of MRONJ is less dependent on the duration of therapy, it occurs more often in patients with cancer who are receiving higher cumulative doses of BPs. The combination of local trauma, microbial contamination and concomitant diseases induces this condition in patients with OP who are receiving BPs. BPs have demonstrated safety and effectiveness throughout the years and evidenced increased BMD and reduced fracture risks, and these benefits overweight the risks of rare adverse events.

A review of the literature which summarizes our knowledge on the use of surrogate markers of the osteoporosis treatment effectiveness when on bisphosphonate (BP) therapy. Bone mineral density (BMD) and markers of bone turnover, which have been shown to be associated with the clinical fracture end point, have been used as surrogate criteria for the effectiveness of treatment of osteoporosis in randomized controlled trials. When prescribing BP for the treatment of osteoporosis, BMD measurement every 12 months by dual-energy x-ray absorptiometry (DXA) is the well-described surrogate marker of BP efficacy. At the same time, stabilization of BMD is also a criterion for the treatment effectiveness since changes in BMD determined only 16% of the anti-fracture effectiveness of BP. Markers of bone remodeling can be used as surrogate markers after 3 (bone resorption) or 6 (bone formation) months from the start of BP therapy. A decrease of 30% or more is considered to be prognostically effective for both antifracture and BMD gain. There is a direct relationship between the degree of bone remodeling markers decrease and the antifracture effectiveness of BP therapy. The decrease in markers persists throughout the entire period of therapy and, accordingly, they can be used as surrogate markers of effectiveness and adherence to BP therapy throughout the entire treatment period. However, the presence of pathological fractures is a key clinical manifestation of osteoporosis and should be considered first in every decision making compared to any surrogate marker.

Thus, when prescribing BP treatment, surrogate markers of changes in BMD and/or markers of bone remodeling can be used to monitor the effectiveness of treatment throughout the entire period of treatment and patients’ monitoring.

The term deprescribing (de-prescribe) means the abolition of appointments. In the modern researches, deprescribing is presented as a planned and controlled process of dose reduction or drug cessation, which can potentially harm the patient and/or does not benefit the patient. The target population for deprescribing is the older people, as old age and limited life expectancy are themselves reasons to try to reduce and optimize the drug load. Frailty syndrome or dementia, decreased kidney function and comorbidity are expected to coexist with polypragmasy and inconsistent appointments of different specialists. In foreign and domestic scientific studies there are manuals and recommendations on deprescribing of various groups of drugs for the elderly and seniors: proton pump inhibitors, sugary drugs, psychotropic drugs and others. However, with regard to osteoporosis drug therapy, the concept of deprescribing is debated rather sparingly, despite the possible serious side effects of osteoporosis treatment in the older age group.

The review presents data from small clinical studies and systematic reviews describing deprescribing antiosteoporotic drugs from the bisphosphonate group, the reasons for their withdrawal and its consequences for the elderly and seniors with osteoporosis, as well as the analysis of tools for optimizing pharmacotherapy in elderly and seniors with respect to deprescribing of bisphosphonates.