Pei-Ran Ho

Discontinuation of denosumab and associated fracture incidence: Analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Trial

Osteoporosis is a chronic disease and requires long‐term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off‐treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off‐treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T‐scores. During treatment, more placebo‐treated subjects as compared with denosumab‐treated subjects sustained a fracture and had significant decreases in BMD. During the off‐treatment period (median 0.8 years per subject), 42% versus 28% of placebo‐ and denosumab‐treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject‐years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49–1.38), adjusted for age and total hip BMD T‐score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off‐treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off‐treatment period for up to 24 months.

Declining rates of osteoporosis management following fragility fractures in the U.S., 2000 through 2009.

BACKGROUND Clinical practice recommendations state that patients with fragility fractures should be evaluated for osteoporosis and treated for the disease if it is present. The purpose of this study was to assess osteoporosis evaluation and treatment patterns for patients with fragility fractures and assess whether anti-osteoporosis pharmacotherapy initiated immediately following a fragility fracture is associated with improved adherence to the treatment protocol. METHODS This retrospective cohort study involved data from a large commercially insured population seen in the period from 2001 through 2009. Patients were community-dwelling individuals aged fifty years or older who had a new low-energy fracture at the hip, vertebra, wrist, or humerus with no evidence of a fragility fracture, osteoporosis treatment, malignant disease, or Paget disease for twelve months preceding the fracture. Rates of diagnostic testing and pharmacotherapy for osteoporosis within twelve months post-fracture were evaluated. Patients treated with oral bisphosphonates were evaluated to determine whether twelve-month adherence to the treatment protocol differed between those who had initiated therapy sooner (at zero to ninety days) and those who initiated it later (at ninety-one to 365 days) following the fracture. RESULTS The 88,571 women and 41,984 men had an average age of 72.3 years and 70.5 years, respectively. Nineteen percent (16,464) of the women and 10% (4014) of the men initiated osteoporosis pharmacotherapy, and 30% (26,481) of the women and 15% (6427) of the men underwent diagnostic testing and/or pharmacotherapy following fracture. Treatment rates were highest following vertebral fracture and lowest following wrist or humeral fracture. Treatment rates significantly decreased over time (from 2001 through 2009). The average twelve-month adherence (medication possession ratio) was 56% and 61% among women and men, respectively. Adherence was similar between patients who had initiated treatment sooner after the fracture and those who had initiated it later after the fracture. CONCLUSIONS Clinical guidelines for evaluation and treatment following fragility fracture were met for less than one-third of women and less than one-sixth of men. While primary fracture prevention remains the ideal, secondary prevention is critical and there is a need to reverse the downward trend in adherence to post-fracture guidelines.

Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial.

BACKGROUND Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture. METHODS Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture. RESULTS Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009). CONCLUSIONS Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.

Treatment Satisfaction in Postmenopausal Women Suboptimally Adherent to Bisphosphonates Who Transitioned to Denosumab Compared With Risedronate or Ibandronate

CONTEXT For many patients, adhering to postmenopausal osteoporosis treatment is a challenge. Higher treatment satisfaction is associated with greater persistence with these therapies, which is associated with better outcomes. OBJECTIVE This study aimed to evaluate the change in treatment satisfaction in postmenopausal women who were suboptimally adherent to daily or weekly oral bisphosphonates and who transitioned to denosumab vs a monthly oral bisphosphonate. DESIGN AND SETTING Pooled data of outpatients from two international, multicenter, randomized, open-label studies were analyzed. PATIENTS Postmenopausal women (n = 1703) age 55 years or greater with low bone mineral density who were suboptimally adherent with prior oral bisphosphonate therapy, as assessed by the Osteoporosis-Specific Morisky Medication Adherence Scale, were included in the study. INTERVENTIONS Patients received denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand, 60 mg s.c. every 6 months vs the oral bisphosphonates ibandronate or risedronate, 150 mg once monthly for 12 months. MAIN OUTCOME MEASURES Change in treatment satisfaction scores from baseline to months 6 and 12 were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM is a validated tool that measures perception of four domains of treatment satisfaction: effectiveness, side effects, convenience, and global satisfaction. RESULTS Patients in both treatment groups showed improvement from baseline for all four TSQM domains at 6 and 12 months. However, the denosumab group had significantly (all P < .001) greater improvements among all four TSQM domains at 6 and 12 months compared with the oral bisphosphonate group. CONCLUSIONS Women with low adherence to oral bisphosphonates reported greater treatment satisfaction when transitioned to denosumab vs switching to a monthly oral bisphosphonate.

SAT0479 Early Findings from Prolia® Post-Marketing Safety Surveillance for Atypical Femoral Fracture, Osteonecrosis of the Jaw, Severe Symptomatic Hypocalcemia, and Anaphylaxis

Background Prolia has marketing authorization in the EU, US, Canada, Japan, and over 40 countries or administrative districts worldwide for the treatment of postmenopausal women with osteoporosis at high/increased risk for fracture. Since product registration, new data have provided further information about efficacy and safety. In the FREEDOM extension trial, 8 years of continued denosumab (Prolia) therapy was associated with continued increases in bone mineral density and maintenance of low fracture incidence. Rates of adverse events did not increase over time.1 In addition, a rigorous pharmacovigilance program has been established to complement safety data collection from clinical trials. Spontaneous adverse event reports, while often with insufficient information, are the cornerstone of safety surveillance programs and help detect rare and serious adverse drug reactions (ADR). Objectives We characterize post-marketing (PM) experience for 4 ADRs with Prolia: atypical femoral fracture (AFF), osteonecrosis of the jaw (ONJ), severe symptomatic hypocalcemia (SSH), and anaphylaxis. Methods The Amgen PM database undergoes continual assessment of adverse events reported from health care providers, patients, and other sources. AFF and ONJ cases were assessed and adjudicated by independent committees. SSH and anaphylaxis prompted further assessment by Amgen Global Safety because causality due to Prolia could not be excluded. Results As of September 2013, estimated exposure with Prolia was 1,252,566 patient-years. Four PM reports have been adjudicated as consistent with the ASBMR definition for AFF.2 All patients had prior bisphosphonate (BP) use. Two subjects had healing and two did not have follow-up information. For ONJ, 32 PM reports were adjudicated as consistent with the AAOMS definition.3 Risk factors included ≥1: glucocorticoids, chemotherapy, prior BP use, older age, and invasive dental procedures. One-third of reports indicated resolution, 1/3 were ongoing, and the remainder were unknown. Eight reports of SSH included symptoms of seizures and/or tetany; nearly all (7 of 8) had chronic kidney disease, a risk factor for hypocalcemia; most SSH events occurred within 30 days of Prolia administration and responded to IV/PO calcium/vitamin D. For anaphylaxis, 5 reports included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and/or urticaria. Most events occurred within 1 day of the first Prolia dose; emergency room treatments included antihistamines and IV/PO steroids with no fatal outcomes. Conclusions These PM events with Prolia have not shown any unexpected findings; the benefit/risk profile for Prolia remains favorable. Ongoing safety surveillance will continue in the clinical trial program and pharmacovigilance activities. References Papapoulos et al., JBMR 2013. Shane et al., JBMR 2010. Position Paper, AAOMS 2009. Disclosure of Interest M. Geller Shareholder of: Amgen Inc., Employee of: Amgen Inc., R. Wagman Shareholder of: Amgen Inc., Employee of: Amgen Inc., P. Ho Shareholder of: Amgen Inc., Employee of: Amgen Inc., S. Siddhanti Shareholder of: Amgen Inc., Employee of: Amgen Inc., C. Stehman-Breen Shareholder of: Amgen Inc., Employee of: Amgen Inc., N. Watts Shareholder of: OsteoDynamics, Grant/research support: Merck, NPS, Consultant for: AbbVie, Amarin, Amgen, Bristol-Meyers Squibb, Corcept, Endo, Imagepace, Janssen, Lilly, Merck, Novartis, Noven, Novo Nordisk, Pfizer/Wyeth, Quark, Radius, sanofi-aventis, S. Papapoulos Consultant for: Amgen, Axsome, Gador, GSK, Merck, Speakers bureau: Amgen, Eli Lilly, GSK, Merck, Novartis DOI 10.1136/annrheumdis-2014-eular.1170

OP0037 Denosumab discontinuation and associated fracture incidence: Analysis from the freedom trial

Background In the FREEDOM pivotal phase 3 fracture trial, denosumab 60 mg every 6 months decreased the risk of new vertebral, nonvertebral and hip fractures at 3 years versus placebo.1 As osteoporosis is a chronic disease, continued treatment is required to provide antifracture efficacy. Discontinuation of denosumab is associated with transient increases in bone remodelling and declines in bone mineral density (BMD),2,3 but the effect on fracture risk is not as well characterized. Objectives To understand fracture incidence in an osteoporotic population after cessation of denosumab treatment. Methods We evaluated subjects in FREEDOM who received 2–5 doses of investigational product (IP), either denosumab or placebo, and discontinued treatment while continuing study participation for ≥6 months since the last dose + 1-month study visit window (≥7 months). The off-treatment observation period began 7 months after last IP dose and lasted approximately 6–24 months (for subjects who received 5 to 2 doses, respectively). Results Among subjects eligible for this analysis, age, prevalent fracture, and lumbar spine and total hip BMD T-scores were similar at baseline in placebo (N=470) and denosumab groups (N=327). During the treatment period, more subjects treated with placebo than denosumab sustained a fracture (19% vs 11%) and had significant decreases in BMD (17% vs 1%). Alternative therapy after last IP dose was initiated by 42% of placebo-treated vs 28% of denosumab-treated subjects. After treatment cessation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate/100 subject-years of 13.5 and 9.7, respectively (Hazard Ratio 0.82; 95% Confidence Iinterval: 0.49, 1.38), adjusted for age and total hip BMD T-score at baseline. Fracture occurrence during the off-treatment period was not apparently different between the treatment groups. Conclusions This analysis indicated that there was no excess fracture risk after treatment cessation with denosumab when compared with placebo during the off-treatment period (≤24 months). References Cummings S et al., NEJM 2009. Miller PD et al., Bone 2008. Bone HG et al., JCEM 2011 Disclosure of Interest O. Törring Consultant for: Takeda Nycomed, Amgen, Speakers Bureau: Takeda Nycomed, Amgen, J. Brown Grant/Research support from: Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, sanofi-aventis, Servier and Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Novartis, sanofi-aventis, Warner Chilcott, Speakers Bureau: Amgen, Eli Lilly, Novartis, J.-E. B. Jensen Consultant for: Eli Lilly,Takeda Nycomed, Amgen, Novartis, MSD, Speakers Bureau: Eli Lilly,Takeda Nycomed, Amgen, Novartis, MSD, N. Gilchrist Grant/Research support from: Merck Sharpe & Dohme, Amgen, Consultant for: Eli Lilly, Merck Sharpe & Dohme, Amgen, Speakers Bureau: Eli Lilly, Merck Sharpe & Dohme, Amgen, C. Recknor Consultant for: Zelos, Takeda, Dramatic Health, Novartis, Eli Lilly, Paid Instructor for: Amgen, Novartis, Publicis Meetings, C. Roux Grant/Research support from: Amgen, Novartis, Consultant for: Amgen, Novartis, MSD, M. Austin Shareholder of: Amgen, Employee of: Amgen, A. Wang Shareholder of: Amgen, Employee of: Amgen, A. Grauer Shareholder of: Amgen, Employee of: Amgen, P.-R. Ho Shareholder of: Amgen, Employee of: Amgen, R. Wagman Shareholder of: Amgen, Employee of: Amgen