Bilateral Atypical Femoral Fractures after Bisphosphonate Treatment for Osteoporosis: A Literature Review.

INTRODUCTION: This literature review aimed to investigate the incidence, anatomical concerns, etiology, symptoms, diagnostic tools, management, and prognosis of bisphosphonate (BP)-associated bilateral atypical femoral fractures (AFFs). METHODS: The PubMed, Cochrane Library, Web of Sciences, and CINAHL databases were searched up to 20 March 2022. All cases of bilateral AFFs were included, excluding those without any bisphosphonate treatment information and those in which the femoral fracture did not precisely fit into the diagnostic criteria for AFF. RESULTS: We identified 43 patients with bilateral AFFs associated with BP use and conducted a comprehensive analysis. Among 43 patients, 29 (67%) had prodromal symptoms. Regarding the simultaneity of fracture, 21 cases (49%) occurred simultaneously, and 22 cases (51%) occurred sequentially. Alendronate was the most commonly used BP treatment (59%). Regardless of the medication type, BP intake duration was more than 5 years in 77%. The initial diagnosis was performed using X-rays in all cases. A total of 53% of patients had complete fractures, and all patients underwent surgical treatment. Among the remaining patients with incomplete fractures, 18% and 29% received surgical and medical treatments, respectively. After BP discontinuation, teriparatide was most commonly used (63%). CONCLUSIONS: The careful evaluation of relevant imaging findings in patients with thigh/groin pain allows the identification of early incomplete fractures and timely management. Since the rate of contralateral side fractures is also high, imaging studies should be performed on the asymptomatic contralateral side.

Anti-osteoporosis medication dispensing by clinical commissioning groups in England - an ecological study of variability in practice and of the effect of the Covid-19 pandemic.

PURPOSE: To investigate whether the rate of Anti-Osteoporosis Medication (AOM) dispensing was related to prevalence of risk factors and hip fracture incidence in the local population. METHODS: The Open Prescribing database was used to analyse dispensed AOM at the level of Clinical Commissioning Groups (CCGs) in England. Male Healthy Life Expectancy (MHLE), Female Healthy Life Expectancy (FHLE), the prevalence of smoking and active adults, the incidence of hip fracture and of alcohol related hospital admissions, and local dispensing of a comparator drug (atorvastatin) were considered as predictor variables. Linear and multilinear regression were performed. Using atorvastatin as a comparator, AOM dispensing was compared after the start of the Covid-19 pandemic with the same quarter the previous year. RESULTS: Rates of AOM per 1000 people aged over 65 years in a CCG area varied between 379.2 and 1129.1, with a mean of 670.3. Population risk factors were individually related to the amount of AOM dispensed in an area. Collectively, local activity levels in adults (p = 0.042) and local hip fracture incidence (p = 0.003) were significantly negatively correlated with rates of AOM dispensed. Rates of alendronate dispensing fell significantly at the start of the Covid-19 pandemic (p < 0.001), whilst atorvastatin dispensing rates significantly increased (p < 0.001). CONCLUSION: Lower rates of AOM dispensing were seen in areas with a higher proportion of active adults and higher incidence of hip fracture. Multidisciplinary services should be developed to address this care gap with consideration given to local population risk factors. Community pharmacists are ideally placed to play a vital role in osteoporosis management.

Pros and Cons of Skeletal Medications in the COVID-19 Era.

Purpose of Review: This review provides an overview regarding osteoporosis therapies during the COVID-19 pandemic. Recent Findings: The COVID-19 pandemic has disrupted treatments for osteoporosis and resulted in decreased adherence particularly for parenteral regimens. Osteoporosis medications are safe and effective during the pandemic and should be continued whenever possible. Bisphosphonates have long-lasting effects on bone turnover such that delays in their administration are unlikely to be harmful to skeletal health. In contrast, interruption of denosumab treatment is strongly discouraged because of rapid loss of bone mass and an associated increased risk for rebound vertebral fractures. When osteoanabolic treatments cannot be continued during the pandemic, change to an oral bisphosphonate is advised. Preclinical data suggest possible beneficial effects of some therapies against COVID-19, but require validation in clinical studies. Vitamin D deficiency is associated with a more severe COVID-19 clinical course but data supporting improvements in outcomes with vitamin D supplementation are lacking. Summary: The impact of the COVID-19 pandemic on long-term bone health remains unknown but focused interventions to ensure osteoporosis treatment initiation/maintenance should be implemented. Future studies are needed to determine whether osteoporosis medications have an impact on SARS-CoV-2 pathophysiology and COVID-19 clinical outcomes.

Optimisation of denosumab prescription in osteoporosis patients

Background and importanceBisphosphonates should be the first choice for osteoporosis treatment, with lower cost and no less benefit than denosumab.Aim and objectivesTo evaluate the indication for treatment with denosumab and to develop proposals for optimising osteoporosis treatment.Material and methodsCross-sectional study in a primary care area (8 centres). Data from the ECAP digital medical record of denosumab-treated patients during January 2020 were reviewed by the Pharmacy Service. Variables: demographic (age and sex), diagnosis, bone mineral density (BMD) and previous fractures, indication, previous treatment and adherence.ResultsA total of 394 denosumab-treated patients, aged 74.9 ± 9.6 years, 92.6% women, were included. BMD T-score was ≤–2.5 (indicative of osteoporosis) in 48.3% of men and 64.1% of women, while it was >–2.5 in 6.9% of men and 14.8% of women. There was no densitometric test in the remaining patients. The most prevalent previous fracture in men was hip fracture (31%), while previous fracture was not present in most women (49.6%). Other fractures in men: 27.6% none, 24.1% vertebral, 17.3% ≥2 vertebral. In women: 16.7% ≥2 vertebral, 13.7% vertebral, 13.4% hip, 6.6% peripheral. Therefore, 80.8% of patients actually suffered from osteoporosis, while 19.2% had no true diagnosis. Osteoporosis patients receiving denosumab without a clear indication were 47.1%. Some 63% received prior treatment and 72.6% were adherent. Regarding those with an indication, 54.9% were due to ≥2 previous vertebral or hip fractures, 21.3% to adverse effects or poor adherence to bisphosphonates, 7.9% to chronic corticosteroid therapy, 7.4% to incident hip fracture or increased risk of fracture with age between 65 and 70 years, 5% to digestive alteration that contraindicates the use of therapeutic alternatives, and finally 3.5% to glomerular filtration <35 mL/min/m2. Denosumab should be withdrawn in 22% of patients and it should be changed to bisphosphonate in 25.1%, thus leading to a theoretical €75 100 annual saving.Conclusion and relevanceDenosumab should be withdrawn or replaced in 47.1% of patients. The proposals of the clinical pharmacist contribute to safe drug use and health system efficiency. It would be necessary to know the final implementation of the proposals by rheumatologists, which were pending due to the COVID-19 pandemic.References and/or acknowledgementsConflict of interestNo conflict of interest

Immobilization-Induced Hypercalcemia in COVID-19 With a Prolonged Intensive Care Unit Stay.

Immobilization is an uncommon etiology of hypercalcemia. It is usually seen in conditions associated with limited movements such as spinal cord injuries, vascular events, or following prolonged hospitalization. Hereby, we present a case of a young patient who had prolonged hospitalization following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During her prolonged and complicated hospital stay, she developed severe hypercalcemia secondary to immobilization, which was resistant to treatment with hydration, calcitonin, and denosumab. One dose of zoledronic acid was used, although the patient was on hemodialysis, with adequate response in calcium levels. This case illustrates that patients with COVID-19-related hospitalization are at increased risk of immobilization-induced hypercalcemia, likely due to prolonged hospital stay due to critical illness and lack of early physical therapy during hospitalization.

Is a Patient with Paget's Disease of Bone Suitable for Living Kidney Donation?-Decision-Making in Lack of Clinical Evidence.

Living donor kidney transplantation is a widely performed medical procedure. Living kidney donation requires an in-depth health assessment of candidates. The potential living kidney donor must remain healthy after kidney removal. A consequence of donation can be a decrease in glomerular filtration rate (GFR), and donors can become at risk of developing chronic kidney disease (CKD). We present a rationale for potential living kidney donor withdrawal due to Paget's disease of bone (PDB) based on a literature review. The treatment for PDB includes the use of, for example, non-steroidal anti-inflammatory drugs (NSAIDs), which can lead to acute kidney injury (AKI) as well as CKD, or bisphosphonates, which are not recommended for patients with decreased GFR.

Consensus evidence-based clinical practice guidelines for the diagnosis and treat-to-target management of osteoporosis in Africa: an initiative by the African Society of Bone Health and Metabolic Bone Diseases.

The objective of this consensus statement is to inform the clinical practice communities, research centres and policymakers across Africa of the results of the recommendations for osteoporosis prevention, diagnosis and management. The developed guideline provides state-of-the-art information and presents the conclusions and recommendations of the consensus panel regarding these issues. PURPOSE: To reach an African expert consensus on a treat-to-target strategy, based on current evidence for best practice, for the management of osteoporosis and prevention of fractures. METHOD: A 3-round Delphi process was conducted with 17 osteoporosis experts from different African countries. All rounds were conducted online. In round 1, experts reviewed a list of 21 key clinical questions. In rounds 2 and 3, they rated the statements stratified under each domain for its fit (on a scale of 1-9). After each round, statements were retired, modified or added in view of the experts' suggestions and the percent agreement was calculated. Statements receiving rates of 7-9 by more than 75% of experts' votes were considered as achieving consensus. RESULTS: The developed guidelines adopted a fracture risk-centric approach. Results of round 1 revealed that of the 21 proposed domains, 10 were accepted whereas 11 were amended. In round 2, 32 statements were presented: 2 statements were retired for similarity, 9 statements reached consensus, whereas modifications were suggested for 21 statements. After the 3rd round of rating, the experts came to consensus on the 32 statements. Frequency of high-rate recommendation ranged from 83.33 to 100%. The response rate of the experts was 100%. An algorithm for the osteoporosis management osteoporosis was suggested. CONCLUSION: This study is an important step in setting up a standardised osteoporosis service across the continent. Building a single model that can be applied in standard practice across Africa will enable the clinicians to face the key challenges of managing osteoporosis; furthermore, it highlights the unmet needs for the policymakers responsible for providing bone health care together with and positive outcomes of patients' care.

The Use of Oral Amino-Bisphosphonates and Coronavirus Disease 2019 (COVID-19) Outcomes.

The determinants of the susceptibility to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and severe coronavirus disease 2019 (COVID-19) manifestations are yet not fully understood. Amino-bisphosphonates (N-BPs) have anti-inflammatory properties and have been shown to reduce the incidence of lower respiratory infections, cardiovascular events, and cancer. We conducted a population-based retrospective observational cohort study with the primary objective of determining if oral N-BPs treatment can play a role in the susceptibility to development of severe COVID-19. Administrative International Classification of Diseases, Ninth Revision, Clinical ModificationI (ICD-9-CM) and anatomical-therapeutic chemical (ATC) code data, representative of Italian population (9% sample of the overall population), were analyzed. Oral N-BPs (mainly alendronate and risedronate) were included in the analysis, zoledronic acid was excluded because of the low number of patients at risk. Incidence of COVID-19 hospitalization was 12.32 (95% confidence interval [CI], 9.61-15.04) and 11.55 (95% CI, 8.91-14.20), of intensive care unit (ICU) utilization because of COVID-19 was 1.25 (95% CI, 0.38-2.11) and 1.42 (95% CI, 0.49-2.36), and of all-cause death was 4.06 (95% CI, 2.50-5.61) and 3.96 (95% CI, 2.41-5.51) for oral N-BPs users and nonusers, respectively. Sensitivity analyses that excluded patients with prevalent vertebral or hip fragility fractures and without concomitant glucocorticoid treatment yielded similar results. In conclusion, we found that the incidence of COVID-19 hospitalization, intensive care unit (ICU) utilization, and COVID-19 potentially related mortality were similar in N-BPs-treated and nontreated subjects. Similar results were found in N-BPs versus other anti-osteoporotic drugs. We provide real-life data on the safety of oral N-BPs in terms of severe COVID-19 risk on a population-based cohort. Our results do not support the hypothesis that oral N-BPs can prevent COVID-19 infection and/or severe COVID-19; however, they do not seem to increase the risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

No association of anti-osteoporosis drugs with COVID-19-related outcomes in women: a nationwide cohort study.

This study was performed to evaluate whether the use of drugs in the treatment of osteoporosis in women is associated with COVID-19 outcomes. The results showed that the risk of hospitalization, intensive care unit admission, and mortality was not altered in individuals taking anti-osteoporosis drugs, suggesting no safety issues during a COVID-19 infection. INTRODUCTION: Whether patients with COVID-19 receiving anti-osteoporosis drugs have lower risk of worse outcomes has not been reported yet. The aim of this study was to evaluate the association of anti-osteoporosis drug use with COVID-19 outcomes in women. METHODS: Data obtained from a nationwide, multicenter, retrospective cohort of patients diagnosed with COVID-19 from March 11th to May 30th, 2020 was retrieved from the Turkish Ministry of Health Database. Women 50 years or older with confirmed COVID-19 who were receiving anti-osteoporosis drugs were compared with a 1:1 propensity score-matched COVID-19 positive women who were not receiving these drugs. The primary outcomes were hospitalization, ICU (intensive care unit) admission, and mortality. RESULTS: A total of 1997 women on anti-osteoporosis drugs and 1997 control patients were analyzed. In the treatment group, 1787 (89.5%) women were receiving bisphosphonates, 197 (9.9%) denosumab, and 17 (0.9%) teriparatide for the last 12 months. Hospitalization and mortality rates were similar between the treatment and control groups. ICU admission rate was lower in the treatment group (23.0% vs 27.0%, p = 0.013). However, multivariate analysis showed that anti-osteoporosis drug use was not an independent associate of any outcome. Hospitalization, ICU admission, and mortality rates were similar among bisphosphonate, denosumab, or teriparatide users. CONCLUSION: Results of this nationwide study showed that preexisting use of anti-osteoporosis drugs in women did not alter the COVID-19-related risk of hospitalization, ICU admission, and mortality. These results do not suggest discontinuation of these drugs during a COVID-19 infection.

Management of bone metastasis and cancer treatment-induced bone loss during the COVID-19 pandemic: An international perspective and recommendations.

Optimum management of patients with cancer during the COVID-19 pandemic has proved extremely challenging. Patients, clinicians and hospital authorities have had to balance the risks to patients of attending hospital, many of whom are especially vulnerable, with the risks of delaying or modifying cancer treatment. Those whose care has been significantly impacted include patients suffering from the effects of cancer on bone, where delivering the usual standard of care for bone support has often not been possible and clinicians have been forced to seek alternative options for adequate management. At a virtual meeting of the Cancer and Bone Society in July 2020, an expert group shared experiences and solutions to this challenge, following which a questionnaire was sent internationally to the symposium's participants, to explore the issues faced and solutions offered. 70 respondents, from 9 countries (majority USA, 39%, followed by UK, 19%) included 50 clinicians, spread across a diverse range of specialties (but with a high proportion, 64%, of medical oncologists) and 20 who classified themselves as non-clinical (solely lab-based). Spread of clinician specialty across tumour types was breast (65%), prostate (27%), followed by renal, myeloma and melanoma. Analysis showed that management of metastatic bone disease in all solid tumour types and myeloma, adjuvant bisphosphonate breast cancer therapy and cancer treatment induced bone loss, was substantially impacted. Respondents reported delays to routine CT scans (58%), standard bone scans (48%) and MRI scans (46%), though emergency scans were less affected. Delays in palliative radiotherapy for bone pain were reported by 31% of respondents with treatments often involving only a single dose without fractionation. Delays to, or cancellation of, prophylactic surgery for bone pain were reported by 35% of respondents. Access to treatments with intravenous bisphosphonates and subcutaneous denosumab was a major problem, mitigated by provision of drug administration at home or in a local clinic, reduced frequency of administration or switching to oral bisphosphonates taken at home. The questionnaire also revealed damaging delays or complete stopping of both clinical and laboratory research. In addition to an analysis of the questionnaire, this paper presents a rationale and recommendations for adaptation of the normal guidelines for protection of bone health during the pandemic.

Vaccination for Coronavirus Disease 2019 (COVID-19) and Relationship to Osteoporosis Care: Current Evidence and Suggested Approaches.

The development of coronavirus disease 2019 (COVID-19) vaccines has proceeded at an unprecedented pace, with numerous trials conducted simultaneously across the world as a result of massive technological and financial resource expenditures. With multiple vaccines having now received regulatory approval, public health efforts to promote widespread vaccine dissemination are currently underway. There has been particular emphasis placed on vaccination of older populations, the age group in which COVID-19 infection has been most lethal. However, such widespread vaccination approaches have necessarily raised important questions related to potential interactions with underlying diseases and concomitant treatments among persons to be vaccinated. Osteoporosis is a chronic condition marked by reduced bone strength and an associated increased risk for fracture that generally requires sustained medical intervention(s). Osteoporosis is neither associated with a higher risk of COVID-19 infection nor by more pronounced disease severity following infection, such that individuals with osteoporosis need not be more highly prioritized for COVID-19 vaccination. Osteoporosis therapies do not interfere with the efficacy or side effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Depending on the specific drug profile within an anti-osteoporosis medication category, minor adjustments to the timing of drug administration may be considered with respect to the patient's COVID-19 vaccination schedule. Herein we provide practical recommendations for the care of patients requiring treatment for osteoporosis in the setting of COVID-19 vaccination. © 2021 American Society for Bone and Mineral Research (ASBMR).

Controversies in the use of new bone-modifying therapies in multiple myeloma.

Bone-modifying therapies are essential in the treatment of patients with multiple myeloma. Zoledronic acid is preferred over other bisphosphonates due to its superiority in reducing the incidence of skeletal-related events and improving survival. The anti-receptor activator of nuclear factor-κΒ ligand (RANKL)-targeted agent denosumab has shown its non-inferiority compared to bisphosphonates in preventing skeletal-related events among newly diagnosed patients with myeloma bone disease. Denosumab may confer a survival benefit in patients eligible for autologous transplantation. Denosumab may present a safer profile for patients with renal impairment. Discontinuation of bone-directed therapies can be considered for patients with deep responses and after an adequate time period on treatment; however, a rebound effect may become evident especially in the case of denosumab. Three-monthly infusions of zoledronic acid or at-home denosumab administration should be considered during the coronavirus disease 2019 (COVID-19) pandemic. Measures to prevent hypocalcaemia, renal toxicity and osteonecrosis of the jaw are important for all bone-modifying agents.

Overview: Systemic Inflammatory Response Derived From Lung Injury Caused by SARS-CoV-2 Infection Explains Severe Outcomes in COVID-19.

Most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF, and IL-1ß increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine storm syndrome (CSS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is herein called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge.

Boning up: amino-bisphophonates as immunostimulants and endosomal disruptors of dendritic cell in SARS-CoV-2 infection.

Amino-bisphosphonates such as zoledronic acid (ZA) can possibly ameliorate or prevent severe COVID-19 disease by at least three distinct mechanisms: (1) as immunostimulants which could boost γδ T cell expansion, important in the acute response in the lung; (2) as DC modulators, limiting their ability to only partially activate T cells; and (3) as prenylation inhibitors of small GTPases in the endosomal pathway of the DC to prevent expulsion of lysosomes containing SARS-CoV-2 virions. Use of ZA or other amino-bisphosphonates as modulators of COVID-19 disease should be considered.