Shoring Up Osteoporosis Management: A Fresh Start?

Anabolic bone agents, such as parathyroid hormone receptor agonists (teriparatide and abaloparatide) and sclerostin-inhibiting monoclonal antibody (romosozumab), are superior at preventing clinically significant fractures and/or vertebral fractures in women with and without severe osteoporosis compared with bisphosphonates.

Bisphosphonate-Related Osteonecrosis of the Jaw and Oral Microbiome: Clinical Risk Factors, Pathophysiology and Treatment Options.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a serious health condition, impacting the lives of many patients worldwide. The condition challenges clinical care due to its complex etiology and limited therapeutic options. A thorough understanding of the pathophysiological and patient-related factors that promote disease development is essential. Recently, the oral microbiome has been implicated as a potential driver and modulating factor of BRONJ by several studies. Modern genomic sequencing methods have provided a wealth of data on the microbial composition of BRONJ lesions; however, the role of individual species in the process of disease development remains elusive. A comprehensive PubMed search was conducted to identify relevant studies on the microbiome of BRONJ patients using the terms "microbiome", "osteonecrosis of the jaws", and "bisphosphonates". Studies focusing on symptoms, epidemiology, pathophysiology, risk factors, and treatment options were included. The principal risk factors for BRONJ are tooth extraction, surgical procedures, and the administration of high doses of bisphosphonates. Importantly, the oral microbiome plays a significant role in the progression of the disease. Several studies have identified alterations of microbial composition in BRONJ lesions. However, there is no consensus regarding bacterial species that are associated with BRONJ across studies. The bacterial genera typically found include Actinomyces, Fusobacterium, and Streptococcus. It is postulated that these microbes contribute to the pathogenesis of BRONJ by promoting inflammation and disrupting normal bone remodeling processes. Current therapeutic approaches are disease-stage-specific and the necessity for more effective treatment strategies remains. This review examines the potential causes of and therapeutic approaches to BRONJ, highlighting the link between microbial colonization and BRONJ development. Future research should seek to more thoroughly investigate the interactions between bisphosphonates, the oral microbiome, and the immune system in order to develop targeted therapies.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. METHODS: Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. RESULTS: Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. CONCLUSIONS: Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Efficacy and safety of minodronate in the treatment of postmenopausal osteoporosis with low back pain: a single-centre, randomized and open-label controlled trial.

BACKGROUND: Low back pain is one of the most common symptoms of osteoporosis. The pain can seriously affect patients' mood and quality of life; it can also further aggravate bone loss, causing a serious social burden. Minodronate is an oral bisphosphonate that needs to be administered daily. It significantly reduces levels of bone turnover markers (BTMs) and rapidly improves symptoms of low back pain in patients with osteoporosis. Osteoporosis requires long-term treatment, and daily dosing reduces patient compliance. Minodronate has a better safety profile than other bisphosphonates. The objective of the trial is to explore the efficacy and safety of minodronate in the treatment of low back pain in postmenopausal osteoporosis patients. METHODS: This is a single-centre, randomized, open-label controlled trial with a 24-week duration. Seventy-two eligible patients will be randomly divided into 4 groups. Subjects will be randomized at a 1:1 ratio to receive either minodronate (1 mg/day) or alendronate (10 mg/day) every day; senior women (≥ 75 years old) and older women (< 75 years old) will be at a ratio of 1:2. The primary outcome is the time required for the visual analogue scale (VAS) score to decline by ≥ 10 from baseline. The secondary outcome is the changes in VAS scores from baseline, the frequency and dosage of rescue medication, BTMs, bone mineral density (BMD), and variations in upper gastrointestinal (GI) symptom scores from baseline (including heartburn, pain, and bloating). DISCUSSION: This study will provide objective evidence for the efficiency and safety of minodronate. Furthermore, it will be helpful to evaluate the quantitative relationship between BTMs and BMD in patients with osteoporosis under different ages. TRIAL REGISTRATION: This study protocol has been registered with ClinicalTrials.gov ID NCT05645289 ( https://clinicaltrials.gov/search?term=NCT05645289 ) on December 8, 2022. The registry name is Peking University Third Hospital. This study protocol was reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2022465, 2022.08.09, V2.0). The results will be published in scientific peer-reviewed journals. TRIAL STATUS: The protocol was registered at ClinicalTrials.gov (registration number: NCT05645289). Recruitment has started in January 2023 and is still ongoing.

Bone Augmentation With Alloplastic Graft Material in a Patient Under Bisphosphonate Therapy: A Case Report and Literature Review.

Cases of relatively safe dental implant treatment in patients with low-volume bisphosphonate (BP) have been gradually reported. Although bone augmentation is commonly used when the bone volume is insufficient for implant placement, the studies and case reports regarding the safety of bone augmentation in patients treated with BP remain insufficient. Herein, we report a case wherein bone augmentation was performed after BP treatment with bone healing realized according to imaging, and we review the literature regarding BP and bone augmentation. A 67-year-old Japanese woman requested implant treatment for a hopeless lower right second molar. She had been taking minodronic acid hydrate (50 mg/4 wk) for 18 months to treat steroid-induced osteoporosis. After obtaining informed consent, tooth extraction and bone augmentation within the extraction socket were performed. The tooth was extracted atraumatically to preserve the surrounding alveolar bone, and the extraction socket was intensely curetted. Subsequently, the socket was filled with carbonate apatite granules and covered with a biodegradable membrane, and the wound was sutured without tension. Although protracted wound healing without any symptoms of infection was observed, the wound healed completely. No clinical symptoms were observed, the color of the mucosa at the site was healthy, and imaging findings at 6 months postoperation indicated that osteogenesis had progressed uneventfully.

Root resorption of primary molars and dental development of premolars in children with Osteogenesis Imperfecta medicated with bisphosphonates, grouped according to age and gender.

BACKGROUND: Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and skeletal alterations. The administration of bisphosphonates (BPs) to patients with OI reduces pain, thereby improving their quality of life. The main mechanism of action of BPs is the inhibition of osteoclast action. In the oral cavity of children with OI during growth and development, physiological processes that require the function of osteoclasts occur. The aim of this investigation was to study the dental development of premolars and the root resorption of primary molars in children with OI medicated with BPs according to age and sex. METHODS: An observational and analytical study was designed. The study sample consisted of 26 6- to 12-year-old children with a confirmed diagnosis of OI treated with BPs with available panoramic radiographs. The control group consisted of 395 children with available panoramic radiographs. Both groups were divided into subgroups according to sex and age. The third quadrant was studied, focusing on the first left temporary molar (7.4), the second left temporary molar (7.5), the first left permanent premolar (3.4) and the second left permanent premolar (3.5). The Demirjian method was used to study the dental development of 3.4 and 3.5, and the Haavikko method was used to study the root resorption of 7.4 and 7.5. The Mann‒Whitney U test was used for comparisons, and p < 0.05 indicated statistical significance. RESULTS: The mean chronological age of the 421 patients was 9.21 years (95% CI 9.05-9.37). The sample was reasonably balanced by sex, with 52.5% (221 patients) boys versus 47.5% (200 patients) girls. Delayed exfoliation and tooth development were described in children with OI (p = 0.05). According to sex, the root resorption of primary molars and tooth development were significantly lower in boys in both groups and in girls in the OI group, but the differences between the age groups were not significant. CONCLUSIONS: Children with OI treated with BPs exhibit delayed dental development of the premolars and delayed root resorption of the primary molars. Boys exhibited delays in both variables, but the differences by age subgroup were not significant. These clinical findings support the importance of clinically and radiographically monitoring the dental development and root resorption of primary teeth in children with OI treated with BPs to avoid alterations of the eruptive process.

Utility of a bone health clinic in bridging the osteoporosis care gap: Prescribing habit review at an academic institution.

OBJECTIVE: To analyze osteoporosis medication prescribing trends across specialties in the context of a Bone Health Clinic. INTRODUCTION: Osteoporosis affects over 10 million adults in the US, taking a significant toll on patients and the healthcare system. Although screening methods and treatments are improving, the disease remains underdiagnosed and undertreated. This study aims to evaluate the prescribing trends of osteoporosis medication among department specialties to delineate the benefits of a bone health clinic. METHODS: Retrospective data collection identified and analyzed patients within the Penn State Health system prescribed one of the following osteoporosis medications: Bisphosphonate, denosumab, romosozumab, teriparatide, abaloparatide, or raloxifene. Date range: 4/18/2016 to 4/14/2021. Data collection identified the specialty origin of prescriptions for osteoporosis medications across various medical specialties (e.g., orthopaedics, family medicine, and internal medicine). RESULTS: 10,736 prescription orders were issued to patients with an average age of 68 years. Non-Hispanic Caucasian patients received 88.6% of prescriptions, followed by Asian (3.4%) and African American (2.2%). Female patients accounted for 87.8% of all prescriptions. The Bone Health Clinic under two orthopaedic providers wrote 3,619 prescriptions, averaging 361.9 prescriptions per provider per year-marking the highest rate among specialties. The clinic prescriptions constituted 33.7% of all prescriptions across specialties. Orthopaedic surgery prescribed the most denosumab, romosozumab, teriparatide, and abaloparatide prescriptions, and had the highest number of male osteoporosis patients compared to other specialties (15.6%), consequently prescribing the most male prescriptions (578). CONCLUSION: Establishing a bone health clinic dedicated to osteoporosis management leads to significantly higher prescription rates per provider, increased utilization of anabolic therapies compared to other specialties, and more male patients being treated-an often-neglected population in osteoporosis.

Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis.

BACKGROUND: Bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women. OBJECTIVES: To assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs). SEARCH METHODS: We identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials. SELECTION CRITERIA: We included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings. MAIN RESULTS: Forty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options). Bone mineral density We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty). Quality of life No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined. Overall fracture rate We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty). Overall survival We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty). Osteonecrosis of the jaw We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty). Renal impairment We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). AUTHORS' CONCLUSIONS: When considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.

Bone-active drugs in premenopausal women with breast cancer under hormone-deprivation therapies.

BACKGROUND: Bone health management in premenopausal women with breast cancer (BC) under hormone-deprivation therapies (HDTs) is often challenging, and the effectiveness of bone-active drugs is still unknown. METHODS: This retrospective multicenter study included 306 premenopausal women with early BC undergoing HDTs. Bone mineral density (BMD) and morphometric vertebral fractures (VFs) were assessed 12 months after HDT initiation and then after at least 24 months. RESULTS: After initial assessment, bone-active drugs were prescribed in 77.5% of women (151 denosumab 60 mg/6 months, 86 bisphosphonates). After 47.0 ± 20.1 months, new VFs were found in 16 women (5.2%). Vertebral fracture risk was significantly associated with obesity (odds ratio [OR] 3.87, P = .028), family history of hip fractures or VFs (OR 3.21, P = .040], chemotherapy-induced menopause (OR 6.48, P < .001), preexisting VFs (OR 25.36, P < .001), baseline T-score less than or equal to -2.5 standard deviation (SD) at any skeletal site (OR 4.14, P = .036), and changes at lumbar and total hip BMD (OR 0.94, P = .038 and OR 0.88, P < .001, respectively). New VFs occurred more frequently in women untreated compared to those treated with bone-active drugs (14/69, 20.8% vs 2/237, 0.8%; P < .001) and the anti-fracture effectiveness remained significant after correction for BMI (OR 0.03; P < .001), family history of fractures (OR 0.03; P < .001), chemotherapy-induced menopause (OR 0.04; P < .001), and preexisting VFs (OR 0.01; P < .001). CONCLUSIONS: Premenopausal women under HDTs are at high risk of VFs in relationship with high BMI, densitometric diagnosis of osteoporosis, preexisting VFs, and family history of osteoporotic fractures. Vertebral fractures in this setting might be effectively prevented by bisphosphonates or denosumab.

MASCC/ISOO Clinical Practice Statement: Adjuvant bone-modifying agents in primary breast cancer patients - prevention of medication-related osteonecrosis of the jaw.

PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS raises awareness to the prevention of medication-related osteonecrosis of the jaw (MRONJ) in patients with breast cancer treated with adjuvant bone-modifying agents (BMA). METHODS: This CPS was developed based on a critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care. RESULTS: In patients treated with adjuvant BMA, dento-alveolar surgery poses a moderate risk for MRONJ that ranges between the high risk for MRONJ in patients with metastatic breast cancer and the low risk for MRONJ in patients with osteoporosis. Existing MRONJ guidelines serve as a starting point for adjuvant BMA use. Urgent procedures should be delivered without delay using the accepted precautions to prevent MRONJ. If elective surgery is considered, the individual risk for MRONJ following surgery should be assessed according to common risk factors. CONCLUSION: Prevention of MRONJ in primary breast cancer patients treated with adjuvant BMA requires risk-benefit assessment; collaboration between the medical team, dental professional, and patient; and patient-specific tailored dental treatment planning. The patient should be informed about this risk. Additional research is needed to define optimal MRONJ care for this population.

Pamidronate Response in a Novel Biallelic CREB3L1 Gene Mutation-Associated Osteogenesis Imperfecta: A Case Report.

CASE: We report a 15-year-old adolescent boy being followed up for 6 years with osteogenesis imperfecta (OI). Genetic testing of this child revealed a novel missense variant c.925C>T p.Arg309Cys in the CREB3L1 gene. Treatment with regular pamidronate therapy showed increased bone mineral density and a reduced fracture rate. His lower limb rush rodding improved his mobility. His withdrawal from bisphosphonate therapy worsened his mobility status but started improving after he restarted treatment, suggesting a response to pamidronate therapy. CONCLUSION: We report a novel biallelic missense variant c.925C>T, p.Arg309Cys, in the CREB3L1 gene causing OI, which responded to bisphosphonate therapy and corrective surgery.

Effects of daily teriparatide, weekly high-dose teriparatide, or bisphosphonate on cortical and trabecular bone of vertebra and proximal femur in postmenopausal women with fragility fracture: Sub-analysis by quantitative computed tomography from the TERABIT study.

PURPOSE: The effects of daily teriparatide (D-PTH, 20 µg/day), weekly high-dose teriparatide (W-PTH, 56.5 µg/week), or bisphosphonate (BP) on the vertebra and proximal femur were investigated using quantitative computed tomography (QCT). METHODS: A total of 131 postmenopausal women with a history of fragility fractures were randomized to receive D-PTH, W-PTH, or bisphosphonate (oral alendronate or risedronate). QCT were evaluated at baseline and after 18 months of treatment. RESULTS: A total of 86 participants were evaluated by QCT (Spine: D-PTH: 25, W-PTH: 21, BP: 29. Hip: PTH: 22, W-PTH: 21, BP: 32. Dropout rate: 30.5 %). QCT of the vertebra showed that D-PTH, W-PTH, and BP increased total vBMD (+34.8 %, +18.2 %, +11.1 %), trabecular vBMD (+50.8 %, +20.8 %, +12.2 %), and marginal vBMD (+20.0 %, +14.0 %, +11.5 %). The increase in trabecular vBMD was greater in the D-PTH group than in the W-PTH and BP groups. QCT of the proximal femur showed that D-PTH, W-PTH, and BP increased total vBMD (+2.8 %, +3.6 %, +3.2 %) and trabecular vBMD (+7.7 %, +5.1 %, +3.4 %), while only W-PTH and BP significantly increased cortical vBMD (-0.1 %, +1.5 %, +1.6 %). Although there was no significant increase in cortical vBMD in the D-PTH group, cortical bone volume (BV) increased in all three treatment groups (+2.1 %, +3.6 %, +3.1 %). CONCLUSIONS: D-PTH had a strong effect on trabecular bone of vertebra. Although D-PTH did not increase cortical BMD of proximal femur, it increased cortical BV. W-PTH had a moderate effect on trabecular bone of vertebra, while it increased both cortical BMD and BV of proximal femur. Although BP had a limited effect on trabecular bone of vertebra compared to teriparatide, it increased both cortical BMD and BV of proximal femur.

Bisphosphonates show no association with preventing, slowing, or delaying radiographic changes and pain in hip osteoarthritis: A 4-year study in female adults using data from the Osteoarthritis Initiative Study.

OBJECTIVE: This study aimed to investigate the association of bisphosphonates with outcomes related to radiographic changes and pain in hip osteoarthritis (OA) over 4 years. METHODS: This study examined data from the Osteoarthritis Initiative (OAI), which included 4088 hips from 2057 participants. Bisphosphonate users were identified as those who reported usage at least three times, including at baseline and during the subsequent 1, 2, 3, and 4-year follow-up visits. Non-users were participants who did not use bisphosphonates in the 5 years preceding the baseline and at subsequent follow-up visits. Generalized estimating equations were performed to assess the association between bisphosphonate use and outcomes related to radiographic changes and pain in hip OA over a 4-year follow-up. RESULTS: The analysis revealed no statistically significant difference between bisphosphonate users and non-users concerning outcomes related to radiographic changes and pain in hip OA over 4 years. Specifically, the odds ratios for the incidence and transition of radiographic hip OA were 0.55 (95% Confidence Interval [CI]: 0.26 to 1.17) and 0.78 (95% CI: 0.47 to 1.28), respectively. Furthermore, the odds ratios for the development and resolution of frequent hip pain were 1.04 (95% CI: 0.76 to 1.42) and 0.99 (95% CI: 0.72 to 1.36), respectively. CONCLUSION: The findings from this longitudinal study do not suggest an association between bisphosphonate use and the prevention, slowing, or delay of development and transition of radiographic changes or pain in hip OA over a 4-year follow-up.

The efficacy of bisphosphonates for osteoporosis in young Cushing's disease patients with biochemical remission: a retrospective cohort study.

Background: Patients with Cushing's disease (CD) often experience slow recovery of bone mineral density (BMD), and the effectiveness of anti-osteoporosis drugs in young CD patients who have achieved biochemical remission after surgery is not well understood. Therefore, we aimed to explore whether bisphosphonates could help accelerate the recovery of osteoporosis in young CD patients with remission. Methods: We retrospectively enrolled 34 young patients with CD who achieved postoperative biochemical remission. All patients suffered from osteoporosis before surgery and were divided into postoperative bisphosphonate treatment group (16 cases) and without bisphosphonate treatment group (18 cases). Clinical data, BMD (Z Value), and bone turnover markers were collected at the time of diagnosis and one year after successful tumor resection. Results: The Z values in the lumbar spine showed slight improvement in both groups at follow-up compared to baseline, but this improvement was not statistically significant. There was no significant difference observed between the two groups at follow-up. One year after operation, bone formation markers (OC and P1NP) were significantly higher than those at baseline in both groups. However, OC and P1NP in the bisphosphonate treatment group were lower than those in control group at one year follow-up. In without bisphosphonate treatment group, ß-CTX from follow-up visit was higher than that at baseline, while no significant difference was observed in the bisphosphonate treatment group before and after surgery. Conclusion: Young patients with Cushing's disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission.

THE IMPACT OF SYSTEMIC DRUGS ON DENTAL IMPLANT OSSEOINTEGRATION: A REVIEW.

The process of osteointegration of dental implants is a biological process. Systemic therapy can interfere with this process, affecting the growth and breakdown processes of the bone and ultimately leading to implant failure. This literature review focuses on specific groups of systemic drugs that directly impact osteointegration. The research in electronic literature was conducted using the National Library of Medicine's PubMed/MEDLINE database from March 2000 to February 2024. The following MeSH (Medical Subject Headings) terms were used: "implant osseointegration," "bisphosphonates," "non-steroidal anti-inflammatory drugs," "glucocorticoids," "proton pump inhibitors," and "selective serotonin reuptake inhibitors (SSRIs)." This search yielded 1,258 articles on implant osseointegration. Among these, 30 articles met our criteria for implant osseointegration and bisphosphonates, 2 articles for non-steroidal anti-inflammatory drugs (NSAIDs), 7 articles for glucocorticoids, 14 articles for proton pump inhibitors (PPIs), and 14 articles for selective serotonin reuptake inhibitors (SSRIs). Clinicians considering implant therapy should be mindful of potential medication-related implant failures. The present systematic review has identified an association between proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), glucocorticoids, and bisphosphonates with an increased implant failure rate.

[Expert consensus on safety management of bone-modifying agents (2024 edition)].

Bone-modifying agents are a class of drugs that alleviate a series of bone-related events such as pain, pathologic fracture, spinal cord compression, and hypercalcemia caused by bone metastases, and currently include bisphosphonates and RANKL inhibitors. Due to the widespread use of bone-modifying agents, the adverse effects of them are gradually increasing and affecting patients' quality of life. The Breast Cancer Group, Chinese Medical Doctor Association, and the International Medical Society, Chinese Anti-Cancer Association have organized relevant experts to focus on the treatment of bone metastases of advanced malignant tumors based on evidence-based medicine, discuss the management of adverse reactions to bone-modifying agents and form the consensus. Based on the first Expert Consensus on Safety Management of Bone-modifying Agents in China, this consensus added the definition of osteonecrosis of the jaw related to bone-modifying agents, the occurrence of adverse reactions of bone-modifying drugs reported in the literature, and summarized the clinical experience of clinicians in the management of adverse reactions in practice in recent years, and ultimately, the expert group members discussed and proposed reasonable suggestions to guide clinicians in the safety management of bone-modifying agents.

Jaw osteoporosis: Challenges to oral health and emerging perspectives of treatment.

Osteoporosis is a prevalent bone metabolic disease that poses a significant challenge to global human health. Jaw osteoporosis, characterized by microstructural damage of the jaw resulting from various factors, is one of the common manifestations of this condition. Recent studies have demonstrated that jaw osteoporosis has multifaceted effects on oral health and can negatively impact conditions such as periodontitis, oral implantation, orthodontic treatment, and wound healing. However, there are still some limitations in the conventional treatment of osteoporosis. For instance, while bisphosphonates can enhance bone quality, they may also lead to osteonecrosis of the jaw, which poses a potential safety hazard in oral diagnosis and treatment. In recent years, considerable attention has been focused on improving the pathological condition of jaw osteoporosis. Treatment strategies such as gut microbial regulation, extracellular vesicles, molecular targeted therapy, herbal medicine, mechanical stimulation are expected to enhance efficacy and minimize adverse reactions. Therefore, understanding these effects and exploring novel treatments for jaw osteoporosis may provide new insights for oral health maintenance and disease treatment. This article reviews the impact of jaw osteoporosis on oral health and describes the limitations associated with current methods. It also discusses emerging perspectives on treatment, offering a comprehensive overview of the challenges and future directions in managing jaw osteoporosis.

Denosumab, for osteoporosis, reduces the incidence of type 2 diabetes, risk of foot ulceration and all-cause mortality in adults, compared with bisphosphonates: An analysis of real-world, cohort data, with a systematic review and meta-analysis.

AIM: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long-term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all-cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta-analysis. METHODS: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long-term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random-effects meta-analysis. Risk of bias and evidence quality were assessed using Cochrane-endorsed tools. RESULTS: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78-0.88]). Secondary analysis showed significant risk reduction in all-cause mortality (0.79 [0.72-0.87]) and foot ulceration (0.67 [0.53-0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta-analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79-0.87]) (I2 = 10.76%). CONCLUSIONS: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all-cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D.

Bisphosphonate effectiveness in patients with cirrhosis: An emulated clinical trial.

BACKGROUND: Falls and fractures are common and morbid for patients with cirrhosis. Bisphosphonates are recommended for the prevention of fractures for people with osteoporosis cirrhosis; however, data supporting effectiveness in cirrhosis are lacking. AIM: We sought to emulate a clinical trial of bisphosphonates in cirrhosis. METHODS: We used national Medicare data (2008-2020) to examine the 5-year risk of fractures in patients who did or did not receive bisphosphonates with a new-user design among people diagnosed with cirrhosis and osteoporosis. We balanced treated and untreated with inverse probability of treatment weighting, evaluated intention-to-treat and as-treated effects, and examined both control exposures (statin use) and outcomes (decompensation) to test causal relationships. RESULTS: There were 253 and 20,888 new users and non-users of bisphosphonates, respectively. The median age was 74 years. The most common bisphosphonate used was alendronate (73.6%). Bisphosphonates significantly reduced fractures overall (27.5% vs. 33.0%, p = 0.0004) in the intention-to-treat analysis, particularly for people <65 years (sHR 0.56) old, men (sHR 0.64) and those with non-alcohol related liver disease (sHR 0.85). Though there were fewer arm (20.7% vs. 26.4%, p < 0.0001) and femur (28.9% vs. 31.2%, p = 0.005), there were more spinal (25.8% vs. 19.0%), rib (40.0% vs. 32.2%) and skull (10.1% vs. 8.7%) fractures. In the as-treated analysis, cumulative bisphosphonate exposure significantly reduced fractures, sHR 0.95 95% CI (0.91, 0.98). Treatment was inconsistent; bisphosphonate users spent 29.9% person-years of follow-up on the drug. CONCLUSION: In a nationally representative cohort of elderly patients with cirrhosis, bisphosphonates reduced fractures overall. Efforts to increase uptake and drug continuation are needed.