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Summary: Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptives. Among female patients treated for osteoporosis, ONJ risk was threefold higher after 2–3 years of treatment and eightfold after 10 years compared with past use. Absolute risks remained low (~ 0.05% after 5 years) and diminished after discontinuation. Purpose: Osteonecrosis of the jaw (ONJ) is a rare adverse effect of antiresorptive drug use; however, the magnitude of risk in osteoporosis patients has not been clearly described. Methods: We conducted a cohort study among cancer-free female patients aged 40–89 with, or at risk for, osteoporosis in United Kingdom Clinical Practice Research Datalink (CPRD) Aurum. We followed patients from first osteoporosis treatment until first of osteonecrosis diagnosis, age 90, record end, or other prespecified censoring event, and accumulated person-time by osteoporosis treatment. ONJ cases were selected from CPRD Aurum and linked Hospital Episode Statistics data using an algorithm and manual review. We estimated incidence rates (IR) of ONJ by current treatment type and post discontinuation. We conducted a nested case–control analysis to further describe risk by cumulative dose and duration of antiresorptive therapies. Results: Among 467,654 eligible patients, there were 208 ONJ cases. IR among patients currently treated with antiresorptives (primarily alendronate) was 1.2 (95% confidence interval [CI] 1.0–1.4) per 10,000 person-years. Compared with past use of antiresorptives, odds ratios of ONJ were 3.0 (95% CI 1.5–5.7) after 2–3 years of treatment and 8.1 (95% CI 4.4–15) after 10 years. However, absolute risks remained low (~ 0.05% after 5 years and ~ 0.18% after 10 years) and elevated risks diminished to near zero within 6 to 9 months of discontinuation. Conclusion: Risk of ONJ increased after 2–3 years of treatment with antiresorptives; however, the absolute risk was low and returned to baseline shortly after treatment discontinuation. [ABSTRACT FROM AUTHOR]

Summary: To determine denosumab's effectiveness for fracture prevention among postmenopausal women with osteoporosis in East Asia, the risk of fracture was compared between patients continuing denosumab therapy versus patients discontinuing denosumab after one dose. The real-world effectiveness was observed to be consistent with the efficacy demonstrated in the phase III trial. Introduction: After therapeutic efficacy is demonstrated for subjects in global clinical trials, real-world evidence may provide complementary knowledge of therapeutic effectiveness in a heterogeneous mix of patients seen in clinical practice. This retrospective cohort study was conducted to compare the fracture risk in real-world clinical care received in Taiwan and Hong Kong between a treatment cohort (patients receiving denosumab 60 mg subcutaneously every 6 months) versus an off-treatment cohort (patients discontinuing after 1 dose of denosumab, which has no known clinical benefit) among real-world postmenopausal women. Methods: This study included 38,906 and 2,835 postmenopausal women receiving denosumab in Taiwan and Hong Kong, respectively. The primary endpoint was hip fracture, and secondary endpoints were clinical vertebral and nonvertebral fractures. Propensity-score-matched analysis, adjusting for known covariates, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The robustness of findings was evaluated with a series of sensitivity and quantitative bias analyses. Results: In this study, 554 hip fractures were included in the primary Taiwan population analysis. The crude incidence rate was 0.9 per 100 person-years in the treatment cohort (n = 25,059) and 1.7 per 100 person-years in the off-treatment cohort (n = 13,847). After adjusting for prognostic differences between cohorts, denosumab reduced the risk of hip fractures by 38% (HR = 0.62, CI:0.52–0.75). Risk reductions of similar magnitude were observed for the secondary endpoints and for the analysis of the smaller Hong Kong population. Conclusion: The effectiveness of denosumab for fracture reduction among real-world postmenopausal women with osteoporosis was consistent with the efficacy demonstrated in a global clinical trial. Registration: EnCePP registration number: EUPAS26372; registration date: 12/11/2018. [ABSTRACT FROM AUTHOR]

Summary: In patients discontinuing ALN after a median of 7.0 years (range 5.0–20.0 years), BMD decreased, and bone turnover markers increased within the premenopausal reference range over 2 years. Increased p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD is dependent on continued suppression of bone turnover. Introduction: It is unknown how to monitor patients discontinuing alendronate (ALN) after more than 5 years. We investigated if BTM measured before or during treatment discontinuation with ALN predict bone loss after 1 or 2 years. Methods: PROSA was a cohort study conducted at Aarhus University Hospital including postmenopausal women and men above 50 years treated with ALN ≥ 5 years who had osteopenia at the hip and BMD T-score at the lumbar spine > − 4. ALN was discontinued and BTMs were measured at baseline, months (M) 1, 3, 6, and 12, and DXA was performed at baseline, M6, and M12. We extended the study and measured BTMs and performed DXA at M24. The primary endpoint was if changes in p-CTX at M3 or M6 predict changes in THBMD after 1 year (Clinicaltrials.gov: NCT03051620). Results: We enrolled 136 participants discontinuing ALN after a median of 7.0 years (range 5.0–20.0 years) in PROSA and 124 participants in PROSA Extension. There was a significant decrease in LSBMD − 0.74% ± 0.27, THBMD − 2.65% ± 0.39, FNBMD − 2.35% ± 0.33, and trabecular bone score − 0.97% ± 0.35 and an increase in p-CTX by 61.1% ± 4.7 (p < 0.05 for all) after 24 months. Increase in p-CTX at M3 was associated with bone loss at the hip sites at M12 and M24. Conclusion: In patients discontinuing ALN, BMD decreased significantly and BTMs increased within the reference range over 2 years. An increase in p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD during treatment discontinuation is dependent on continued suppression of bone turnover. [ABSTRACT FROM AUTHOR]

Summary: Teriparatide is an anabolic therapy used to treat patients with osteoporosis and is only approved for 2 years of treatment. This is the first study to look at two common osteoporosis drugs in maintaining its beneficial effects: denosumab and zoledronic acid. Denosumab treatment was associated with the greatest increase in bone mineral density (BMD) at the femoral neck and lumbar spine, an amount that was statistically greater than no treatment and zoledronic acid treatment.Introduction: Teriparatide, a hallmark treatment for osteoporosis, has been shown to increase BMD and bone turnover. This can be measured using BMD scans, N-terminal propeptide of type-1 collagen (P1NP) for bone formation and C-terminal telopeptide (CTX) for bone resorption. This study examines the effects of the two most common antiresorptive drugs prescribed following 2 years of teriparatide treatment: zoledronic acid and denosumab. The purpose of this study is to quantify the beneficial effects of teriparatide and compare the ability of each antiresorptive drug to maintain the effects.Methods: Ninety-four patients with prior fragility fractures were identified from a bone health clinic associated with a level I trauma center. All of the study participants completed 2 years of treatment with teriparatide between 2008 and 2013 followed by 2 years of treatment with zoledronic acid, denosumab, or no treatment. After excluding patients with insufficient laboratory data, 64 patients remained for analysis in this retrospective cohort study. Bone mineral density was measured in the lumbar spine and femoral neck.Results: Following completion of teriparatide, patients who were started on denosumab showed the largest increase in bone mineral density after 2 years of treatment: lumbar spine 4.94% ± 8.2%, femoral neck 5.68% ± 6.7%.Conclusions: Patients who elected to discontinue osteoporosis treatment experienced a significant decline in the change in BMD compared to the change on teriparatide putting them at higher risk for recurrence of fragility fractures. Patients on denosumab following teriparatide had the largest increase in BMD. [ABSTRACT FROM AUTHOR]

Summary: In a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures. Introduction: The purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis. Methods: This was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months. Results: The 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group ( p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17-0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip ( t test: p < 0.0001). No new adverse events or osteonecrosis of the jaw were observed in this study. Conclusions: Once-yearly administration of ZOL 5 mg to Japanese patients with primary osteoporosis reduced the risk of new morphometric vertebral fractures and was found to be safe. [ABSTRACT FROM AUTHOR]

Summary: Apparent modulus and failure stress of trabecular bone structure from 45 women with osteoporosis treated with bisphosphonates for varying durations were studied using finite element analyses and statistical modeling. Following adjustments for patient age and bone volume, increasing bisphosphonate treatment duration for up to 7.3 years was associated with treatment-time-dependent increases in bone apparent modulus and failure stress. Treatment durations exceeding 7.3 years were associated with time-dependent decreases in apparent modulus and failure stress from the peak values observed. Introduction: The purpose of this study was to clarify the relationship between bisphosphonate (BP) treatment duration and human bone quality. This study quantified changes in the apparent modulus and failure stress of trabecular bone biopsied from patients with osteoporosis who were treated with BPs for widely varying durations. Methods: Forty-five iliac crest bone samples were obtained from women with osteoporosis who were continuously treated with oral BPs for varying periods of up to 16 years. Micro-CT imaging was used to develop three-dimensional virtual models of the trabecular bone from these samples. Apparent modulus and failure stress of these virtual models were determined using finite element analyses (FEA). Polynomial regression and cubic splines, adjusted for relevant (age and BV/TV) covariates, were used to statistically model the data and quantify the relationships between BP treatment duration and apparent modulus or failure stress. Results: Second-order polynomial models were needed to relate apparent modulus or failure stress to BP treatment duration. These models showed that these bone quality parameters (a) increased with increasing BP treatment duration up to approximately 7.3 years, (b) reached a maximum at this (~7.3 years) time, and then (c) declined with BP treatment durations exceeding ~7.3 years. A similar result was obtained by modeling with cubic splines. Conclusions: Changes in FEA-derived apparent stiffness and failure stress are attributable to changes in trabecular bone structure, which in turn are related to the duration of BP treatment. These relationships are evident even after adjustments are made in the statistical models for changes in age and BV/TV. According to these models, increases in trabecular bone apparent stiffness and failure stress linked to BPs cease and appear to reverse after approximately 7.3 years of treatment. Conclusions regarding optimal BP therapy duration await study of additional bone quality parameters. [ABSTRACT FROM AUTHOR]

Summary: In postmenopausal women with low bone mass and hormone-receptor-positive breast cancer on an aromatase inhibitor, risedronate maintained skeletal health assessed by bone density and turnover markers. Women with the greatest decreases in bone turnover markers at 12 months had the greatest increases in bone density at 24 months. Introduction: Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if (1) oral bisphosphonate therapy can prevent bone loss in women on an AI and (2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD). Methods: We conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) for hormone-receptor-positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo, and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)], and safety. Results: Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 ± 0.7 percentage points at the spine and 3.2 ± 0.5 percentage points at the hip (both p < 0.05). The adjusted difference between the active treatment and placebo groups were 0.09 ± 0.04 nmol/LBCE for CTX and 23.3 ± 4.8 μg/mL for P1NP (both p < 0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD ( p < 0.05). The oral therapy was safe and well tolerated. Conclusion: In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health. [ABSTRACT FROM AUTHOR]

Summary: The addition of Limited Use criteria (less restrictive access) for zoledronic acid resulted in an immediate and significant increase in uptake and resulted in differences in patient/physician characteristics. In comparison, the uptake of denosumab (only listed with Limited Use) was rapid. Thus, formulary access restrictions have significant implications for prescribing. Introduction: We sought to describe the use of zoledronic acid and denosumab by physicians and patients over time and examine the impact of a 2012 provincial formulary modification that removed the administrative burden on physicians when prescribing zoledronic acid. Methods: We identified users of zoledronic acid and denosumab using Ontario pharmacy claims data. The number of new patients and physicians was plotted and examined over time. Interrupted time series analysis examined the impact of a formulary modification to zoledronic acid use and prescribing. Descriptive characteristics of patients and prescribers were summarized pre- and post-formulary modification for zoledronic acid and overall for denosumab. Results: We identified 1463 zoledronic acid patients treated by 627 physicians and 16,736 denosumab patients treated by 2904 physicians. In the first 2 months on the market, we identified a rapid uptake of denosumab (>450 physicians and >1200 patients) in contrast to zoledronic acid (<10 physicians and <10 patients). Zoledronic acid use increased significantly in the 2-month post-formulary change, yet no change in denosumab was observed. Prior to the formulary modification, more zoledronic acid patients had a history of osteoporosis therapy (41 vs. 26 %) or bone density testing (30 vs. 10 %). Compared to zoledronic patients (post-formulary modification), more denosumab patients had prior osteoporosis therapy (55 vs. 26 %), yet fewer had a gastrointestinal diagnosis (6 vs. 11 %). Conclusion: We identified a rapid uptake of denosumab in only 15 months of observation. A provincial formulary modification to zoledronic acid resulted in an increase in utilization and impacted patient characteristics. [ABSTRACT FROM AUTHOR]

The World Health Organization defines osteoporosis as a systemic disease characterized by decreased bone tissue mass and microarchitectural deterioration, resulting in increased fracture risk. Since this statement, a significant amount of data has been generated showing that these two factors do not cover all risks for fracture. Other independent clinical factors, such as age, as well as aspects related to qualitative changes in bone tissue, are believed to play an important role. The term “bone quality” encompasses a variety of parameters, including the extent of mineralization, the number and distribution of microfractures, the extent of osteocyte apoptosis, and changes in collagen properties. The major mechanism controlling these qualitative factors is bone remodeling, which is tightly regulated by the osteoclast/osteoblast activity. We focus on the relationship between bone remodeling and changes in collagen properties, especially the extent of one posttranslational modification. In vivo, measurements of the ratio between native and isomerized C-telopeptides of type I collagen provides an index of bone matrix age. Current preclinical and clinical studies suggests that this urinary ratio provides information about bone strength and fracture risk independent of bone mineral density and that it responds differently according to the type of therapy regulating bone turnover. [ABSTRACT FROM AUTHOR]

Intercurrent illness and episodes of hospitalization and surgery are common in an aging population, who, at the same time, are experiencing age-related bone loss. The objective was to test the hypotheses (1) that intercurrent illness severe enough to require hospitalization produces clinically important bone loss, and (2) that antiresorptive therapy will reduce that loss. The study was a retrospective analysis of bone mineral density (BMD) change at hip and spine in subjects of the risedronate postmenopausal osteoporosis phase III trials experiencing serious adverse events (SAEs). Subjects were 243 hospitalized for non-skin cancers, pneumonia, myocardial infarction, cerebrovascular accident, gallbladder disease, and pancreatitis, on whom BMD data were available both before and after the SAE; and 286 non-hospitalized control subjects matched to those with SAEs by age, height, weight, prevalent fracture, and visit interval. In hospitalized, placebo-treated participants, the annualized percent change in BMD (mean ± SEM) across the period of hospitalization was −0.65±0.39 at lumbar spine, −1.13±0.55 at femoral neck, and −2.66±0.58 at femoral trochanter; the corresponding values for the non-hospitalized, placebo controls were +0.46±0.28, −0.77±0.34, and −0.67±0.34. These values were more negative at all three sites for the hospitalized subjects, and significantly so at lumbar spine and femoral trochanter ( P =0.019 and 0.002, respectively). By contrast, in the risedronate-treated participants, all sites exhibited bone gain and there was no significant difference between hospitalized and non-hospitalized participants. Intercurrent illness resulting in hospitalization produced a rapid bone loss across the period of illness comparable in magnitude to documented age-related loss. Risedronate in a dose of 5 mg/day effectively abolished this loss. [ABSTRACT FROM AUTHOR]