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Journal of Bone and Mineral Research :... May 2024Romosozumab treatment in women with postmenopausal osteoporosis increases bone formation while decreasing bone resorption, resulting in large BMD gains to reduce... (Randomized Controlled Trial)
Randomized Controlled Trial
Romosozumab treatment in women with postmenopausal osteoporosis increases bone formation while decreasing bone resorption, resulting in large BMD gains to reduce fracture risk within 1 yr. DXA-based 3D modeling of the hip was used to assess estimated changes in cortical and trabecular bone parameters and map the distribution of 3D changes in bone parameters over time in patients from 2 randomized controlled clinical trials: FRAME (romosozumab vs placebo followed by denosumab) and ARCH (romosozumab vs alendronate followed by alendronate). For each study, data from a subset of ~200 women per treatment group who had TH DXA scans at baseline and months 12 and 24 and had provided consent for future research were analyzed post hoc. 3D-SHAPER software v2.11 (3D-SHAPER Medical) was used to generate patient-specific 3D models from TH DXA scans. Percentage changes from baseline to months 12 and 24 in areal BMD (aBMD), integral volumetric BMD (vBMD), cortical thickness, cortical vBMD, cortical surface BMD (sBMD), and trabecular vBMD were evaluated. Data from 377 women from FRAME (placebo, 190; romosozumab, 187) and 368 women from ARCH (alendronate, 185; romosozumab, 183) with evaluable 3D assessments at baseline and months 12 and 24 were analyzed. At month 12, treatment with romosozumab vs placebo in FRAME and romosozumab vs alendronate in ARCH resulted in greater increases in aBMD, integral vBMD, cortical thickness, cortical vBMD, cortical sBMD, and trabecular vBMD (P < .05 for all). At month 24, cumulative gains in all parameters were greater in the romosozumab-to-denosumab vs placebo-to-denosumab sequence and romosozumab-to-alendronate vs alendronate-to-alendronate sequence (P < .05 for all). 3D-SHAPER analysis provides a novel technique for estimating changes in cortical and trabecular parameters from standard hip DXA images. These data add to the accumulating evidence that romosozumab improves hip bone density and structure, thereby contributing to the antifracture efficacy of the drug.
Topics: Humans; Alendronate; Female; Denosumab; Absorptiometry, Photon; Bone Density; Aged; Antibodies, Monoclonal; Imaging, Three-Dimensional; Middle Aged; Hip
PubMed: 38477808
DOI: 10.1093/jbmr/zjae028 -
Journal of Bone and Mineral Research :... May 2024Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who...
Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n = 20) and without (n = 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17 yr. Despite the matched range of treatment duration (4-17 yr), AFF patients received alendronate for significantly longer time (10.7 yr) than non-AFF patients (8.0 yr) (P = .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6 mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.
Topics: Humans; Female; Femoral Fractures; Aged; Postmenopause; Middle Aged; Diphosphonates; Alendronate; White
PubMed: 38477744
DOI: 10.1093/jbmr/zjae018 -
European Journal of Medicinal Chemistry Apr 2024The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their...
The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates in these tissues. We describe in this article the synthesis of light-responsive prodrugs of HMBP alendronate. These prodrugs include lipophilic photo-removable nitroveratryl groups which partially mask the highly polar alendronate HMBP scaffold. Photo-responsive prodrugs of alendronate are stable in physiological conditions and display reduced toxicity compared to alendronate against MDA-MB-231 cancer cells. However, the antiproliferative effect of these prodrugs is efficiently restored after cleavage of their nitroveratryl groups upon exposure to UV light. In addition, substitution of alendronate with such photo-responsive substituents drastically reduces its bone-binding properties, thereby potentially improving its biodistribution in soft tissues after i.v. administration. The development of such lipophilic photo-responsive prodrugs is a promising approach to fully exploit the anticancer effect of HMBPs on non-skeletal tumors.
Topics: Humans; Alendronate; Prodrugs; Tissue Distribution; Diphosphonates; Neoplasms
PubMed: 38460269
DOI: 10.1016/j.ejmech.2024.116307 -
BMC Pediatrics Mar 2024Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male...
BACKGROUND
Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male patient of 2 years 7 months old, with failure to thrive, hepatomegaly, metabolic acidosis, hypophosphatemia, hypokalemia, hyperlactatemia.
RESULTS
Exome sequencing identified the homozygous pathogenic variant NM_000340.2(SLC2A2):c.1093 C > T (p.Arg365Ter), related with Fanconi-Bickel syndrome. He received treatment with bicarbonate, amlodipine, sodium citrate and citric acid solution, enalapril, alendronate and zolendronate, and nutritional management with uncooked cornstarch, resulting in an improvement of one standard deviation in weight and height.
CONCLUSIONS
The importance of knowing the etiology in rare genetic disease is essential, not only to determine individual and familial recurrence risk, but also to establish the treatment and prognosis; in this sense, access to a new genomic technology in low- and middle-income countries is essential to shorten the diagnostic odyssey.
Topics: Humans; Male; Fanconi Syndrome; High-Throughput Nucleotide Sequencing; Homozygote; Prognosis; Child, Preschool
PubMed: 38454379
DOI: 10.1186/s12887-024-04641-1 -
Radiology Case Reports May 2024Paget's disease of bone is a disorder of osteoclasts which hampers the physiological process of bone remodeling. It is the most common metabolic orthopedic disease in...
Paget's disease of bone is a disorder of osteoclasts which hampers the physiological process of bone remodeling. It is the most common metabolic orthopedic disease in the Caucasian populace; we report the diagnosis of Paget's disease of bone in a South-Asian male in his early 50s with a history of gastrointestinal symptoms, weight loss and back pain. An alkaline phosphatase level of 1104 IU/L was noted. A 3-phase bone scan showed noncontiguous heterogenous nuclear uptake. After exhaustive evaluation, the patient was diagnosed with Paget's disease of bone. Despite the disease activity being mitigated by alendronate and monitored by ALP levels within normal range per protocol, the patient had compression fractures of the vertebrae requiring early reinitiation of oral bisphosphonates. This raised doubts about the efficacy of metabolic marker-based management in Paget's disease of bone.
PubMed: 38434784
DOI: 10.1016/j.radcr.2024.01.037 -
Journal of Feline Medicine and Surgery Feb 2024Cats with ionized hypercalcemia that were fed diets with either more than 200 mg calcium per 100 kilocalories (kcal), a calcium:phosphorus (Ca:P) ratio greater than...
CASE SERIES SUMMARY
Cats with ionized hypercalcemia that were fed diets with either more than 200 mg calcium per 100 kilocalories (kcal), a calcium:phosphorus (Ca:P) ratio greater than 1.4:1 or both, based on diet history, were included in this case series. Ionized hypercalcemia was documented at least twice in all cats before enrollment. Cats were referred for evaluation of ionized hypercalcemia (n = 5) or were incidentally found to have ionized hypercalcemia (n = 5). After medical workups, cats were diagnosed with either idiopathic hypercalcemia (IHC; n = 7) or chronic kidney disease (n = 3). Cats receiving medications to treat IHC (eg, alendronate, corticosteroids) were excluded. Nutritional recommendations were made to transition the cats to diets with less thn 200 mg calcium per 100 kcal and a Ca:P ratio less than 1.4:1. Ionized calcium (iCa) concentrations were rechecked in all cats, with a median recheck time of 9 weeks (range 3-20). Of the 10 cats, nine (90%) had a decrease in iCa. Of the 10 cats, six (60%) became normocalcemic after the diet change, three (30%) had a partial response and one (10%) did not respond. Of the four cats that did not achieve normocalcemia with a change in diet, two (50%) received chia seeds (1-2 g per day), and at the next recheck, both cats' iCa concentrations had normalized. Three cats had a long-term follow-up. Ionized normocalcemia was maintained for at least two consecutive follow-up visits over a median follow-up period of 33 weeks (range 12-34).
RELEVANCE AND NOVEL INFORMATION
Dietary calcium concentrations and the dietary Ca:P ratio appear to be important variables in considering nutritional approaches for hypercalcemic cats.
Topics: Cats; Animals; Hypercalcemia; Calcium; Renal Insufficiency, Chronic; Alendronate; Cat Diseases
PubMed: 38415620
DOI: 10.1177/1098612X241229811 -
Family Practice Apr 2024Medication-related ear canal osteonecrosis (MRECO) is a growing concern linked to prolonged anti-resorptive medication use. Despite primary care providers being key...
INTRODUCTION
Medication-related ear canal osteonecrosis (MRECO) is a growing concern linked to prolonged anti-resorptive medication use. Despite primary care providers being key prescribers of these medications, there is limited information about MRECO in primary care literature. This article presents a case of bisphosphonate-induced osteonecrosis of the external auditory canal (EAC), emphasizing the vital role of primary care providers in identifying this rare yet significant side effect of anti-resorptive medication.
MAIN SYMPTOMS AND CLINICAL FINDINGS
A 65-year-old female, on long-term alendronic acid for osteoporosis, presented to primary care with a 2-year history of left-sided ear blockage and itchiness. Despite prolonged topical treatment for ear wax, symptoms persisted, leading to an Otolaryngology referral. Microsuction revealed exposed bone in the left EAC.
DIAGNOSES, INTERVENTIONS, AND OUTCOMES
A computed tomography scan confirmed bony erosion of the left EAC, and in the absence of other osteonecrosis risk factors, bisphosphonate-induced osteonecrosis was diagnosed. Management involved bisphosphonate discontinuation, regular aural toilet, and topical treatment, achieving complete ear canal epithelialisation within 6 months.
CONCLUSION
MRECO, a rare complication of anti-resorptive therapy, is anticipated to rise with increasing antiresorptive medication use in the ageing population. Unexplained ear symptoms in those with a history of current or prior anti-resorptive therapy should raise clinical concern, prompting evaluation for exposed bone in the EAC. Raising awareness of MRECO among primary care providers is crucial for early diagnosis and timely management.
Topics: Female; Humans; Aged; Bisphosphonate-Associated Osteonecrosis of the Jaw; Diphosphonates; Bone Density Conservation Agents; Alendronate; Primary Health Care
PubMed: 38413046
DOI: 10.1093/fampra/cmae012 -
Orthopedic Research and Reviews 2024While osteoporosis increases the risk of fragility fractures, bisphosphonate has been proven to increase bone strength and reduce the risk of vertebral and non-vertebral...
BACKGROUND
While osteoporosis increases the risk of fragility fractures, bisphosphonate has been proven to increase bone strength and reduce the risk of vertebral and non-vertebral fractures. In addition to its efficacy, substituting the brand with generic medication is a strategy to optimize healthcare expenditures. This study aimed to evaluate the efficacy of generic alendronate treatment and assess potential adverse events in patients with osteoporosis.
MATERIALS AND METHODS
A retrospective review was conducted on 120 patients who met the indications for osteoporosis treatment, received weekly generic alendronate (70 mg) for >1 year, and underwent evaluation through standard axial dual-energy X-ray absorptiometry (DXA). The outcomes of this study were the percent change in bone mineral density (BMD) at the lumbar spine, femoral neck, and total hip after one year of treatment. The major adverse events occurring during medication that led to the discontinuation of drug administration were documented.
RESULTS
Most patients were female (96.7%) with an average age of 69.0 ± 9.3 years. The percent change in BMD increased at all sites after one year of generic alendronate treatment (lumbar spine: 5.6 ± 13.7, -value <0.001; femoral neck: 2.3 ± 8.3, -value = 0.023; total hip: 2.1 ± 6.2, -value = 0.003), with over 85% of patients experiencing increased or stable BMD. Three patients discontinued the medication due to adverse effects: two had dyspepsia, and one had persistent myalgia.
CONCLUSION
Generic alendronate may be considered an effective antiresorptive agent for osteoporosis treatment with a low incidence of adverse effects.
PubMed: 38410814
DOI: 10.2147/ORR.S445202 -
Biomolecules Feb 2024Bone is a site of distant metastases, which are a common cause of morbidity and mortality with a high socio-economic impact, for many malignant tumours. In order to...
Bone is a site of distant metastases, which are a common cause of morbidity and mortality with a high socio-economic impact, for many malignant tumours. In order to engineer pharmacological therapies that are suitable for this debilitating disease, this experimental work presents injectable lipid nanoemulsions, which are endowed with a long history of safe clinical usage in parenteral nutrition, their loading with vincristine and their grafting with alendronate, with a dual purpose: merging the anticancer activity of bisphosphonates and vincristine, and enhancing bone-targeted delivery. In cell studies, alendronate synergised with the anti-migration activity of vincristine, which is important as migration plays a key role in the metastatisation process. In preliminary animal studies, carried out thanks to IVIS technology, alendronate conjugation enhanced the bone targeting of fluorescently labelled nanoemulsions. These encouraging results will drive further studies on suitable animal models of the disease.
Topics: Animals; Alendronate; Vincristine; Diphosphonates; Bone and Bones; Models, Animal
PubMed: 38397475
DOI: 10.3390/biom14020238 -
Bone May 2024Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian...
BACKGROUND
Antiresorptive treatment is currently used in millions of patients with osteoporosis and cancer worldwide. Early studies of denosumab suggested a small signal in ovarian cancer incidence and emerging data suggest that denosumab stimulates germ cell proliferation in the gonads. This study aims to determine the association between the use of denosumab and the risk of reproductive cancers compared with the use of alendronate.
RESEARCH DESIGN AND METHODS
Using a cohort study design, we used the Danish nationwide registries to identify a population of subjects ≥50 years of age during 2010-2017 who started denosumab after being on alendronate treatment for at least six months. The cohort was matched 1:2 with patients who had been treated with alendronate alone for at least six months. The risk of reproductive cancers and the risk difference between groups were estimated using the Longitudinal Targeted Maximum Likelihood Estimation (L-TMLE) method.
RESULTS
We identified 6054 Danish individuals who underwent treatment with denosumab. These individuals were matched with 12,108 receiving alendronate. The absolute risk of reproductive cancer was 1.05 % (95 % CI 0.75-1.34) after three years for denosumab users and was not different 0.03 % (-0.34-0.39) than for alendronate users. In supplemental analyses, there was no increased risk of non-reproductive cancers associated with the use of denosumab (risk difference of 0.54 % (-0.41-1.19). Analysis comparing denosumab users with the general population gave similar results.
CONCLUSION
There was no difference in the risk of cancer following treatment with denosumab compared to treatment with alendronate assessed after a short follow-up of 3 years.
Topics: Humans; Female; Alendronate; Denosumab; Bone Density Conservation Agents; Cohort Studies; Neoplasms; Osteoporosis, Postmenopausal
PubMed: 38395247
DOI: 10.1016/j.bone.2024.117053