Rosen, Clifford J.

Abstract Context Osteoanabolic therapy for osteoporosis should be followed by antiresorptive treatment (“consolidation”) to preserve bone mass. Although osteoanabolic therapy is increasingly endorsed for primary fracture prevention, real-world implementation of consolidation remains unknown. Objective To assess patterns and predictors of timely consolidation after osteoanabolic therapy for primary fracture prevention. Methods We conducted a retrospective cohort study using US commercial, Medicare Advantage, and traditional Medicare claims data. Adults aged ≥50 years who initiated romosozumab, teriparatide, or abaloparatide between 2011 and 2022 were included. The primary outcome was timely consolidation, defined as initiation of an antiresorptive medication within 3 months after osteoanabolic therapy. Secondary outcomes included delayed consolidation (initiation >3 months after completion), osteoanabolic restart following a treatment gap, and no consolidation therapy. We further distinguished participants who completed the full osteoanabolic course, defined as ≥12 months for romosozumab and ≥18 months for teriparatide or abaloparatide. Multivariable logistic regression models were used to identify predictors of consolidation patterns. Results Among 15 389 patients (mean age 70.6 years; 89% women; 85% White), 30% completed osteoanabolic therapy (median, 12.9 months for romosozumab; 23.4 months for teriparatide/abaloparatide). Overall, 25% had timely consolidation, 24% delayed consolidation, 12% restarted osteoanabolics, and 40% had no consolidation; only 12% completed therapy with timely consolidation. Timely consolidation was more likely with endocrinology (OR 1.31; 95% CI, 1.17-1.48) or rheumatology (OR 1.45; 1.30-1.62) vs primary care, and less likely among patients aged 50-64 years (OR 0.67; 0.58-0.77) vs 65-74, those enrolled in Medicare Advantage (OR 0.85; 0.74-0.98) vs traditional Medicare, or those recently hospitalized (OR 0.88; 0.80-0.97). Odds increased over time (OR 4.27; 3.63-5.05 for 2021 vs 2011 starts). Conclusion Only 1 in 4 patients received timely consolidation therapy after osteoanabolic treatment, and 1 in 8 completed the full sequence. Strategies to improve consolidation in primary fracture prevention are needed.

Abstract Context A national assessment of osteoporosis drug therapy (ODT) use can inform the extent of underdiagnosis and undertreatment of osteoporosis. Objective The aim was to describe trends in ODT use by age, sex, fragility fracture, and documented osteoporosis. Methods This was a retrospective analysis of patient-quarter observations for adults aged ≥50 years with commercial or Medicare Advantage health insurance in the OptumLabs Data Warehouse between 2011 and 2022. The primary outcome was the proportion of patient-quarter observations with ODT use stratified by age, sex, fragility fracture, and documented osteoporosis. Cuzick tests were performed to assess trends ODT use. Results Analysis of 166 673 420 patient-quarter observations revealed that over 70% of patients with fragility fractures did not have documented osteoporosis. Among women aged ≥65 years with documented osteoporosis, ODT fill rates increased between 2011 and 2022 from 36.3% to 50.1% for women without fragility fractures (P < .001) and from 30.8% to 43.7% for women with fragility fractures (P < .001). However, ODT fill rates declined (9.2% to 7.4% between 2011 and 2022) for women with fragility fractures and no documented osteoporosis (P = .015). Similar trends were observed among women aged 50-64 years and men. Conclusion ODT use for patients with documented osteoporosis has increased but remains low. Low rates of ODT use for patients with fragility fractures in the absence of documented osteoporosis suggests that underdiagnosis of osteoporosis contributes to underuse of ODTs.

Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. The effect of fasting on free cortisol levels is modified by sex. Further study is needed to determine the mechanisms driving the increases in cortisol.

Abstract Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. Significance: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

Abstract Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).©2019American Society for Bone andMineral Research.

Abstract Objective The objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the pharmacological management of osteoporosis in postmenopausal women using romosozumab. Conclusions We reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.

ABSTRACT Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.

Abstract Objective The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. Conclusions Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.

ABSTRACT Considerable data and media attention have highlighted a potential “crisis” in the treatment of osteoporosis. Specifically, despite the availability of several effective drugs to prevent fractures, many patients who need pharmacological therapy are either not being prescribed these medications or if prescribed a medication, are simply not taking it. Although there are many reasons for this “gap” in the treatment of osteoporosis, a major factor is physician and patient concerns over the risk of side effects, especially atypical femur fractures (AFFs) related to bisphosphonate (and perhaps other antiresorptive) drug therapy. In this perspective, we review the current state of undertreatment of patients at increased fracture risk and suggest possible short-, intermediate-, and long-term approaches to address patient concerns, specifically those related to AFF risk. We suggest improved patient and physician education on prodromal symptoms, extended femur scans using dual-energy X-ray absorptiometry (DXA) to monitor patients on antiresorptive treatment, better identification of high-risk patients perhaps using geometrical parameters from DXA and other risk factors, and more research on pharmacogenomics to identify risk markers. Although not the only impediment to appropriate treatment of osteoporosis, concern over AFFs remains a major issue and one that needs to be resolved for effective dissemination of existing treatments to reduce fracture risk. © 2016 American Society for Bone and Mineral Research.