Bilateral Pathological Femoral Fractures Secondary to Long-Term Tenofovir Disoproxil Fumarate-Induced Osteomalacia in a Woman Living with HIV: A Case Report.

Introduction

People living with HIV (PLWH) experience a heightened risk of bone mineral density (BMD) loss and fragility fractures compared to the general population. 1 The prevalence rates of osteoporosis are estimated at 15–20% in this group. 2–4 This increased susceptibility arises from a multifactorial interplay, including chronic HIV-related inflammation, immune activation, traditional risk factors such as age, low body mass index, smoking, and corticosteroid use, as well as the direct effects of antiretroviral therapy (ART). 5 Emerging evidence from the field of osteoimmunology indicates that HIV infection and ART act on a shared immune-skeletal interface, whereby HIV-driven B- and T-lymphocyte dysfunction disrupts the RANKL/osteoprotegerin (OPG) axis, favouring osteoclast activation and accelerated bone resorption independently of, and in addition to, the direct nephrotoxic effects of individual antiretroviral agents. 6 In resource-limited settings like sub-Saharan Africa, where over 25 million PLWH reside, additional contributors such as malnutrition, vitamin D deficiency, and co-infections (eg, tuberculosis) exacerbate bone health challenges, particularly among postmenopausal women and those on long-term ART. 7 , 8 Early recognition of these risks is crucial, as fragility fractures can lead to significant morbidity, including chronic pain, immobility, and secondary complications like pressure ulcers and rectal prolapse, ultimately impacting quality of life and healthcare costs. 9 , 10

Among ART agents, tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor widely used in first-line regimens (eg, TDF/lamivudine/dolutegravir or TLD), has been implicated in accelerated BMD decline and bone toxicity. 11 TDF’s mechanism involves proximal renal tubular dysfunction, often manifesting as Fanconi syndrome with phosphate wasting, hypophosphatemia, and secondary hyperparathyroidism, which disrupts bone remodeling and leads to osteomalacia or osteoporosis. 11 , 12 Clinical trials and observational studies demonstrate that TDF-containing regimens cause an additional 1–3% BMD loss at the hip and spine compared to non-TDF alternatives, 13 with the most pronounced effects in the first 48 weeks of therapy and persisting with prolonged exposure. 14 , 15 In aging PLWH, particularly postmenopausal women, this translates to a 10–20% increased fracture risk, compounded by perimenopausal hormonal changes. 16

Evidence from cohort studies further links cumulative TDF exposure to fragility fractures. For instance, a large Japanese cohort of 3251 HIV-infected patients found that ≥5 years of TDF use was associated with a cumulative fracture probability exceeding 1.5%, including hip fractures at a rate of 7.2 per 10,000 person-years, even in younger men. 17 Similarly, US Veterans Health Administration data revealed a 12% elevated risk of fragility fractures with TDF, modifiable by concomitant antiretrovirals. 18 Case reports highlight rare but severe presentations, such as multifocal fractures, osteonecrosis, and hypophosphatemic osteomalacia resolving after TDF discontinuation and mineral supplementation. 19–21 However, bilateral pathological femoral fractures, combining intertrochanteric and subcapital types, remain underreported, especially in African women with >10 years of TDF exposure and complications from immobility.

This case report, therefore, describes a bilateral pathological femoral fracture attributed to long-term TDF-induced osteomalacia in a 43-year-old postmenopausal African woman with HIV, complicated by advanced pressure ulcers and rectal prolapse. It indicates the reversible nature of TDF toxicity upon regimen switch, with emphasis on the need for routine BMD monitoring, hypophosphatemia screening, and preferential use of safer alternatives like tenofovir alafenamide (TAF) or abacavir in high-risk groups. 22 By presenting this case, we aim to raise awareness of skeletal risks associated with TDF in low-resource settings and advocate for individualized ART strategies to mitigate preventable fractures.

Case

A 43-year-old African woman with a history of HIV infection diagnosed more than 15 years previously presented to the Infectious Disease Ward at Mulago National Referral Hospital, Kampala, Uganda. She was postmenopausal and had no known endocrine disorders, significant tobacco use, or long-term corticosteroid exposure.

The patient reported progressive generalized bone pain over several months, predominantly affecting the thighs, hips, and lower back, which had worsened to the point of inability to bear weight or ambulate independently. This culminated in acute worsening after a minor stumble (low-energy trauma), leading to severe bilateral thigh pain and complete immobility. She had experienced a single brief generalized tonic-clonic seizure one month prior to admission, but no focal neurological deficits or ongoing seizures occurred.

The patient had been on tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART) for 12 years as part of her HIV management. One year before presentation, due to emerging diffuse bone pain, her regimen was switched to abacavir/lamivudine/dolutegravir (ABC/3TC/DTG). Her HIV was well-controlled, with a recent CD4 count of 409 cells/µL. She had no family history of metabolic bone disease, osteoporosis, or genetic disorders relevant to phosphate metabolism. Psychosocial history was unremarkable for substance abuse or significant stressors beyond chronic illness; she lived in an urban setting with family support but became largely bedridden during this episode.

Prior to the current presentation, the only notable intervention was the ART switch from TDF-based to ABC/3TC/DTG one year earlier, prompted by progressive bone symptoms. No prior orthopaedic procedures, bisphosphonate use, or specific bone health interventions had been undertaken. No other relevant past medical interventions (eg, for renal issues or vitamin D deficiency) were documented, and she had no history of fractures before this event.

Timeline

This is summarized in Table 1 .

Clinical Findings

On admission to the Infectious Disease Ward at Mulago National Referral Hospital, the patient was bedridden and in severe pain. Her vital signs were stable: blood pressure within normal limits, pulse rate normal, respiratory rate normal, temperature afebrile, and oxygen saturation normal on room air. Her body mass index was 24 kg/m 2 (weight 60 kg, height 158 cm), with mild pallor of the conjunctivae and oral mucosa.

General and Neurological Examination

The patient was fully alert, oriented to time, place, and person, with no focal neurological deficits. Cranial nerves were intact, and there were no signs of meningism or residual effects from the single generalized tonic-clonic seizure one month prior. Power in the upper limbs was normal (5/5 bilaterally), but lower limb examination was limited by pain.

Musculoskeletal and Hip Examination

Both hips were exquisitely tender to palpation and passive movement. Any attempt at active or passive range of motion in the hips or knees elicited severe pain, rendering the patient unable to flex, extend, abduct, adduct, or rotate either lower limb. She could not bear weight, perform straight leg raise, or log-roll without intense pain. There was no obvious deformity, swelling, or ecchymosis around the hips, but diffuse tenderness over the thighs and lower back was noted. Proximal muscle strength in the lower limbs could not be fully assessed due to pain, but appeared reduced based on antigravity testing where possible. No joint effusions, synovial thickening, or signs of active synovitis were present elsewhere.

Skin and Pressure Areas

Prolonged immobility had resulted in significant pressure injuries: A deep stage-4 sacral pressure ulcer on the left gluteal region, characterized by full-thickness tissue loss, exposed bone at the base, adherent yellow-tan slough interspersed with red granulation tissue and necrotic areas, irregular margins with surrounding erythema, mild maceration, and undermining along the superior edge ( Figure 1 ).

A right ischial pressure ulcer with adherent yellow slough, moderate exudate, and surrounding erythema ( Figure 2 ).

Perineal and Rectal Examination

Rectal prolapse was evident on inspection, with redundant rectal mucosa protruding, likely secondary to chronic straining from immobility-associated constipation. No active bleeding or ulceration was noted in the prolapsed tissue.

Other Systems

Cardiovascular, respiratory, and abdominal examinations were unremarkable. No lymphadenopathy, organomegaly, or signs of active infection were present. The patient reported no urinary symptoms suggestive.

Investigations

Laboratory Testing

Complete blood count: Normocytic anemia (Hb 10.5 g/dL), other cell lines normal.

Bone and mineral panel: Severe hypophosphatemia (initially 0.33 mmol/L, reference 0.8–1.5 mmol/L), elevated alkaline phosphatase (ALP 320 U/L), low-normal 25-hydroxy-vitamin D (20 ng/mL), upper-normal parathyroid hormone (PTH).

Renal profile: Normal creatinine and estimated glomerular filtration rate; urinalysis showed no glycosuria or significant proteinuria (no overt Fanconi syndrome at the time of testing).

Serial monitoring: Phosphate and calcium levels trended toward normalization post-TDF discontinuation and supplementation (eg, phosphate improved to 0.88 mmol/L, calcium from 1.70 to 2.04 mmol/L by mid-follow-up).

Infectious work-up: Negative serum cryptococcal antigen, negative blood cultures, negative TB sputum GeneXpert and AFB smear.

Other: Normal serum protein electrophoresis (no monoclonal band), normal tumor markers (CEA, CA-125), CD4 count 409 cells/µL. These are summarized in Table 2 .

Imaging

Pelvic radiographs: Confirmed bilateral pathological femoral fractures, right intertrochanteric and left subcapital (neck) types, consistent with fragility fractures on a background of metabolic bone disease ( Figure 3 ).

CT brain (contrast-enhanced): Moderate cerebral atrophy, no acute hemorrhage, mass lesion, or meningeal enhancement (performed for prior seizure; Figure 4 ).

CT chest/abdomen/pelvis: No evidence of malignancy, granulomatous disease, lytic or blastic bone lesions.

DEXA scan: Not performed due to acute fracture management priorities and resource constraints.

Other: Ulcer swabs (sacral and ischial) sent for culture and sensitivity to guide antimicrobial therapy. No bone biopsy was performed, as the clinical, biochemical, and radiographic picture was consistent with drug-induced osteomalacia.

Diagnosis

The primary diagnosis was bilateral pathological femoral fractures secondary to tenofovir disoproxil fumarate (TDF)-induced hypophosphatemic osteomalacia in the setting of long-term ART for HIV. This was supported by the long duration of TDF exposure (12 years), characteristic biochemical profile (severe hypophosphatemia, elevated ALP, low-normal vitamin D, upper-normal PTH), exclusion of alternative etiologies (normal renal function excluding overt Fanconi at testing, no hyperparathyroidism), improvement in phosphate levels and symptoms after TDF discontinuation and supplementation, and radiographic evidence of fragility-type fractures without high-energy trauma.

Differential Diagnoses Included

Opportunistic infection-related osteomyelitis (negative TB/infectious work-up),

Malignancy/metastatic disease (negative CT and tumor markers),

Primary hyperparathyroidism or multiple myeloma (normal PTH range, no monoclonal protein),

Nutritional vitamin D deficiency alone (low-normal but not profoundly deficient 25-OH vitamin D; poor response expected without phosphate wasting),

HIV-associated osteoporosis without TDF contribution (less likely given biochemical pattern and reversibility post-discontinuation).

Therapeutic Intervention

The therapeutic approach was multidisciplinary and targeted the acute bilateral pathological femoral fractures, the underlying tenofovir disoproxil fumarate (TDF)-induced hypophosphatemic osteomalacia, the secondary complications from prolonged immobility, including advanced pressure ulcers and rectal prolapse, and the ongoing management of HIV infection. Interventions encompassed pharmacologic adjustments, surgical fixation, intensive wound care, supportive measures, and rehabilitation efforts.

The cornerstone pharmacologic intervention involved the permanent discontinuation of TDF as part of the ART regimen. Approximately one year prior to admission, the patient’s regimen had already been switched from a TDF-based combination to abacavir 600 mg plus lamivudine 300 mg plus dolutegravir 50 mg once daily due to emerging bone pain, and this non-TDF regimen was maintained indefinitely after the fractures were attributed to chronic TDF toxicity. Mineral and vitamin supplementation was initiated promptly on admission to correct the severe hypophosphatemia and support bone remineralization. This included oral phosphate supplementation (typically starting at 500mg elemental phosphorus three times daily), calcium carbonate providing 500mg elemental calcium two times daily, and cholecalciferol at 4000 IU daily loading doses. Supplementation continued for several months and was tapered once phosphate and alkaline phosphatase levels normalized and remained stable Multimodal analgesia was administered throughout the hospital stay, incorporating paracetamol, weak opioids such as tramadol, and nonsteroidal anti-inflammatory drugs, with doses titrated to achieve adequate pain control while monitoring for tolerability. Stool softener, lactulose (15–30 mL daily), was prescribed along with dietary fiber to facilitate conservative handling of the rectal prolapse.

Surgical intervention consisted of operative fixation of the bilateral femoral fractures, performed within days of admission after the patient was medically optimized. The orthopaedic team proceeded with pelvic replacement surgery.

Supportive and preventive measures included intensive wound care for the stage-4 sacral and ischial pressure ulcers. This involved twice-daily cleansing initially followed by once daily cleansing, surgical debridement of necrotic tissue and slough as required, application of hydrocolloid foam, matched to exudate levels and infection risk, two-hourly turning schedules, and protective devices for heels and elbows. The rectal prolapse was managed conservatively with manual reduction when necessary, avoidance of straining, and the aforementioned bowel regimen, as surgical repair was considered too high-risk given the patient’s immobility and overall condition. Thromboprophylaxis with subcutaneous low-molecular-weight heparin, enoxaparin 40 mg daily, was provided during the period of prolonged immobilization to reduce the risk of venous thromboembolism. Nutritional support was maintained to preserve body mass index and promote healing.

All interventions were guided by ongoing multidisciplinary input from infectious disease specialists, orthopaedic surgeons, wound care nurses, physiotherapists, and nutritionists, with serial clinical assessments and laboratory monitoring ensuring timely modifications. No experimental or off-label therapies were employed.

Follow-Up and Outcomes

The patient was hospitalized for five weeks following admission, during which time multidisciplinary follow-up focused on fracture healing, metabolic correction, wound healing, mobility rehabilitation, and prevention of further complications. After discharge, she continued outpatient monitoring through the Infectious Disease Clinic at Mulago National Referral Hospital, with periodic reviews over the ensuing months.

Clinician-assessed outcomes showed substantial improvement in the metabolic derangements attributable to TDF toxicity. Serum phosphate levels rose progressively from the severe hypophosphatemia of 0.33 mmol/L on admission to 0.88 mmol/L within weeks and remained within the normal reference range (0.8–1.5 mmol/L) thereafter. Serum calcium improved from an initial hypocalcemia of 1.70 mmol/L to 2.04 mmol/L, approaching the lower reference limit of 2.2 mmol/L, while alkaline phosphatase declined from the elevated 320 U/L toward normal. Bone pain resolved completely, and no new fractures or skeletal events occurred during follow-up. The pressure ulcers demonstrated gradual healing with reduced slough, decreased exudate, and progressive granulation tissue formation, although full epithelialization was incomplete at the last documented review due to the initial depth and exposed bone. The rectal prolapse stabilized with conservative measures and did not recur acutely. Orthopaedic follow-up indicated stable fracture fixation without hardware failure or non-union, though weight-bearing progression was slow because of generalized deconditioning and muscle atrophy from prolonged immobility.

The patient remained largely non-ambulatory at the time of the most recent follow-up, requiring assistance for transfers and limited to short distances with a walker or support when pain permitted. She reported persistent fatigue and reduced functional independence, but she expressed subjective relief from the severe generalized bone pain that had dominated her presentation. No formal patient-reported outcome measures were documented, but her ability to engage in conversations, tolerate oral intake, and participate in basic physiotherapy exercises reflected a meaningful improvement in quality of life compared to the acute admission phase.

Important follow-up diagnostic results included serial biochemistry demonstrating sustained normalization of phosphate, calcium, and alkaline phosphatase levels, confirming reversal of the hypophosphatemic osteomalacia after TDF discontinuation. Viral load monitoring remained suppressed, and the CD4 count stayed stable above 400 cells/µL on the abacavir/lamivudine/dolutegravir regimen.

Adherence to the prescribed interventions was excellent and was assessed through direct observation during hospitalization and pharmacy refill records for ART and supplements during outpatient visits, and patient self-reporting at each clinic encounter. The non-TDF ART regimen was well tolerated with no reported side effects. Mineral and vitamin supplementation was generally well accepted. Analgesia was tolerated without significant opioid-related adverse effects. Wound care and pressure off-loading were adhered to as part of the nursing care plan, with the patient and family educated on turning schedules and off-loading techniques post-discharge.

Adverse and unanticipated events were limited to the expected complications of prolonged immobility. The sacral and ischial pressure ulcers progressed to stage-4 severity before aggressive wound management reversed the trend, and the rectal prolapse represented an unanticipated but mechanistically related consequence of chronic straining and constipation during bed rest. No new infections, deep vein thrombosis, pulmonary embolism, or worsening renal function occurred. There were no medication-related adverse events requiring discontinuation or major dose adjustment beyond routine titration of supplements. The overall course was complicated primarily by the functional limitations from immobility rather than new pathological processes.

In summary, the outcomes confirmed the reversible nature of TDF-induced osteomalacia following drug withdrawal and supportive therapy, with biochemical and symptomatic recovery, although full functional restoration remained limited by secondary immobility-related sequelae.

Discussion

This case illustrates severe tenofovir disoproxil fumarate (TDF)-related bone toxicity manifesting as bilateral pathological femoral fractures, one intertrochanteric on the right and one subcapital on the left, in a 43-year-old postmenopausal African woman with long-standing HIV infection after 12 years of TDF exposure. While chronic HIV infection and associated inflammation contribute to accelerated bone loss and increased fracture risk compared to HIV-negative populations, 23 Antiretroviral agents remain major modifiable factors in this context. TDF, a widely used nucleotide reverse transcriptase inhibitor in first-line regimens, is well-established to cause proximal renal tubular dysfunction, leading to phosphate wasting, hypophosphatemia, and hypophosphatemic osteomalacia. 24 The patient’s chronic hypophosphatemia, elevated alkaline phosphatase, low-normal vitamin D, upper-normal PTH, preceding diffuse bone pain, and fragility-type fractures on minimal trauma align closely with this mechanism, especially given the absence of overt Fanconi syndrome features, which can be subtle or intermittent in chronic cases.

Alternative etiologies for pathological fractures were rigorously excluded through comprehensive evaluation. Malignancy (including metastatic disease or lymphoma) and infection (eg, TB osteomyelitis, cryptococcosis, or bacterial osteomyelitis) were ruled out by negative tumor markers, CT chest/abdomen/pelvis showing no lytic/blastic lesions or granulomas, negative blood cultures, cryptococcal antigen, and TB studies. Primary hyperparathyroidism was unlikely with PTH only upper-normal and no profound hypercalcemia, while multiple myeloma was excluded by normal serum protein electrophoresis. Nutritional vitamin D deficiency alone or primary rickets was inconsistent with the biochemical pattern and history of long-term TDF use. The temporal association, progressive bone pain prompting TDF switch one year prior, yet fractures occurring later, with biochemical and symptomatic stabilization post-permanent discontinuation, strongly supports drug causality.

The literature consistently documents TDF’s adverse skeletal effects. Clinical studies show an additional 1–3% BMD decline with TDF compared to non-TDF regimens. 25 This is predominantly in the first year but persisting with prolonged exposure, mediated by increased bone resorption and impaired mineralization. 26 Mechanistic insights reveal TDF’s mitochondrial toxicity in proximal tubular cells, leading to phosphate wasting and secondary hyperparathyroidism. 27 Cohort data indicate elevated fracture risk (up to 12% increased annual risk in some analyses), while case reports frequently describe fragility fractures (often femoral neck, subtrochanteric, or multifocal) in long-term TDF users, 28 , 29 with resolution after discontinuation, phosphate/calcium/vitamin D repletion, and regimen switch. 29 Bilateral femoral involvement, as in this patient (intertrochanteric and subcapital), is rarer but reported in recent cases of TDF-induced Fanconi syndrome or osteomalacia, 30 , 31 including sequential or simultaneous neck/stress fractures in HIV patients on prolonged therapy. Complications from immobility, such as stage-4 pressure ulcers and rectal prolapse from chronic constipation/straining, highlight underrecognized secondary morbidity in non-ambulatory patients with fragility fractures. 32

Strengths and Limitations of the Report

Strengths of our approach included systematic exclusion of differentials through multimodal diagnostics (biochemistry, imaging, cultures), prompt TDF discontinuation upon suspicion, multidisciplinary management (orthopaedics, infectious diseases, wound care), and supplementation tailored to serial labs, resulting in biochemical normalization, pain resolution, and no new fractures. Limitations include the lack of DEXA scanning (resource-constrained setting) to quantify baseline/pre-existing bone loss, the absence of bone biopsy (though not essential given the clinical-biochemical-radiographic concordance), and limited long-term functional follow-up data due to ongoing immobility challenges. Additionally, the exact onset of subtle tubular dysfunction may have been missed earlier, as monitoring for hypophosphatemia is not routine in all TDF-treated patients.

Conclusion

In conclusion, this case emphasizes that unexplained bone pain or pathological fractures in PLWH on long-term TDF should prompt early consideration of drug-induced osteomalacia, particularly in postmenopausal women or those with prolonged exposure. Key lessons include the importance of vigilant monitoring of mineral metabolism (eg, periodic phosphate, ALP, and renal parameters), prompt TDF substitution with safer alternatives (eg, abacavir- or TAF-based regimens) upon suspicion of toxicity, aggressive correction of hypophosphatemia and vitamin D deficits, and proactive prevention of immobility complications through early mobilization and wound care. Such measures can reverse metabolic abnormalities, prevent recurrent fractures, and improve quality of life in vulnerable patients.

Acknowledgments

The authors express their sincere gratitude to the multidisciplinary team at Mulago National Referral Hospital, including the orthopaedic, infectious diseases, wound care, physiotherapy, and nursing staff, for their dedicated management of the patient. We also thank the patient and her family for their cooperation and consent to share this clinical experience for educational purposes.

Funding Statement

This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Artificial Intelligence (AI) Use

The authors declare that Artificial Intelligence tools were used in the preparation of this manuscript in accordance with the Taylor & Francis AI Policy. Grammarly (Free version, Chrome extension v14.1314.0; Grammarly Inc., San Francisco, CA, USA) was used for grammar checking, spelling correction, sentence clarity, and language polishing throughout the manuscript. The authors confirm that Grammarly’s Terms of Service and Privacy Policy in effect during the manuscript preparation period in 2026 were reviewed, that its use was consistent with those terms, and that the tool was assessed by the authors as suitable for this non-generative, language-editing use in preparing the manuscript for publication. All suggestions generated by Grammarly were carefully reviewed, critically evaluated, and edited by the authors. The final content, clinical interpretations, diagnostic reasoning, scientific conclusions, and intellectual responsibility remain entirely with the authors.

Data Sharing Statement

All relevant de-identified data supporting the findings of this case report, including laboratory results, imaging descriptions, and clinical notes, are available from the corresponding author (Morrish Obol Okello) upon reasonable request, subject to institutional approval and compliance with data protection regulations.

Ethics Approval and Consent to Participate

This case report was prepared in accordance with ethical principles for medical case reporting. No separate formal ethical approval was required for publication of a single anonymized case report at our institutions, as it does not constitute human subjects research involving systematic investigation or generalizable knowledge. However, written informed consent for publication was obtained as described above, in line with institutional guidelines and international standards, ICMJE recommendations, and CARE guidelines. Patient confidentiality was maintained throughout, and all data were handled in compliance with data protection principles.

Consent for Publication

Written informed consent was obtained from the patient’s sister-in-law (primary caregiver and legal representative) for publication of this case report and any accompanying images. This was done with the patient’s explicit verbal consent and agreement, as the patient was physically immobilized and in significant pain at the time of consent acquisition. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Dr David Meya reports research funding from UK Medical Research Council, US National Institutes of Health, during the conduct of the study; grants or contracts from Elion Therapeutics; Data safety/advisory board participation for UK Meningitis Research Foundation, US National Institute for Allergy and Infectious Diseases; leadership or fiduciary roles for Advanced HIV Technical working group, Ministry of Health, Uganda, MARA Rural Health Consortium, Uganda, Meningitis Foundation, Minnesota; receipt of equipment/materials/services from Elion Therapeutics, outside the submitted work. The authors declare that they have no other competing interests, financial or otherwise, related to this case report.

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Associated Data

Data Availability Statement

All relevant de-identified data supporting the findings of this case report, including laboratory results, imaging descriptions, and clinical notes, are available from the corresponding author (Morrish Obol Okello) upon reasonable request, subject to institutional approval and compliance with data protection regulations.