Androgen deprivation therapy-related fracture risk in prostate cancer: an insurance claims database study in Japan.

INTRODUCTION: Androgen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan. MATERIALS AND METHODS: Data were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry. RESULTS: 30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52-1.75]). CONCLUSION: ADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

Real-world use of bone modifying agents in metastatic, castration-resistant prostate cancer.

BACKGROUND: Bone modifying agents (BMAs) prevent skeletal related events among patients with metastatic, castration-resistant prostate cancer (mCRPC) involving bone and prevent osteoporotic fractures among patients at high risk. BMA utilization for patients with mCRPC has not been well quantified. METHODS: We used linked SEER registry and Medicare claims data. We included men diagnosed with stage IV prostate adenocarcinoma during 2007-2015, aged > = 66 at diagnosis, with sufficient continuous enrollment in Medicare Parts A, B, and D, who received androgen deprivation therapy. We limited to those who subsequently received a CRPC-defining treatment (CDT). We identified patients with evidence of bone metastasis using claims. Our primary outcome was receipt of a BMA (zoledronic acid or denosumab) within 180 days of initiating CDT. RESULTS: Among 1292 included patients, 1034 (80%) had bone metastasis. BMA use within 180 days of initiating CDT was higher among patients with bone metastases than those without (705/1034 [68%] vs 56/258 [22%]). Among patients without bone metastasis, those with high osteoporotic fracture risk were more likely than those without to receive a BMA (OR = 2.48, 95% CI: 1.17, 5.29); however, only 26% of patients with high fracture risk received a BMA. Among patients who received BMAs, most (62%) first initiated them >90 days before initiating CDT. CONCLUSIONS: Two-thirds of patients with mCRPC and bone metastases received BMAs within 180 days after initiating CDT. A greater proportion of patients without bone metastasis may warrant BMA therapy for osteoporotic fracture prevention. Some patients with bone metastasis may be able to delay BMA initiation until CRPC.

Improving bone health in prostate cancer patients starting androgen deprivation therapy: does Fracture Risk Assessment Tool (FRAX®) enhance stratification and targeted management?

Androgen deprivation therapy for prostate cancer can lead to osteoporosis and increased fracture risk. The Fracture Risk Assessment Tool (FRAX®) questionnaire can be used for risk stratification, and our study has demonstrated that the majority of men (91%) in our cohort commencing ADT for prostate cancer were considered low risk for future osteoporotic fracture. PURPOSE/INTRODUCTION: Long-term use of androgen deprivation therapy (ADT) in prostate cancer patients results in increased bone turnover and decreased bone mineral density (BMD). Proper assessment of any existing osteoporotic fracture risk is crucial prior to starting treatment. However, this risk assessment is poorly performed in these patients in spite of available validated tools including the Fracture Risk Assessment Tool (FRAX®). The objective of this study was to assess the distribution of osteoporotic fracture risk in a cohort of men commencing ADT for prostate cancer using the FRAX® algorithm. METHODS: Between July 2020 and May 2022, 200 men filled in the FRAX® questionnaire just before ADT. They were stratified into the high-risk (> 20% probability of a MOF over the next 10 years), intermediate-, and low-risk categories for fragility fractures. We also measured their serum vitamin D and calcium levels. RESULTS: The average age was 73.5 years (54-89). It took less than 10 min to complete the assessment. Only six patients were at high-risk, were started on bisphosphonates immediately, and referred for a dual energy X-ray absorptiometry (DEXA) scan. Twelve patients in the intermediate-risk category were referred for DEXA scans for bone mineral density measurements. A total of 182 patients (91%), were in the low-risk category and given lifestyle advice only. All had normal calcium levels but 134 (67%) patients, mostly in the low-risk category, had reduced vitamin D levels (< 50 nmol/L). CONCLUSION: The FRAX® questionnaire is simple and immediately identifies patients who are at risk of fragility fractures. Our study has demonstrated that the majority of men (91%) in our cohort commencing ADT for prostate cancer were considered low risk for future osteoporotic fracture. We were surprised that more than half of our patients had low vitamin D levels.

Clinical Utility of Trabecular Bone Score (TBS) in Fracture Risk Assessment of Patients with Rheumatic Diseases Treated with Glucocorticoids.

Chronic glucocorticoid therapy is associated with osteoporosis and can cause fractures in up to 50% of patients. Increased risk of fractures in patients with glucocorticoid-induced osteoporosis does not result only from the decreased bone mineral density (BMD) but also bone microarchitecture deterioration. Trabecular bone score (TBS) is a method complementary to DXA, providing additional information about trabecular bone structure. The aim of this study was to assess the clinical utility of TBS in fracture risk assessment of patients treated with glucocorticoids. Patients with rheumatic diseases treated with glucocorticoids for at least 3 months were enrolled. All recruited patients underwent DXA with additional TBS assessment. We analyzed the frequency of osteoporosis and osteoporotic fractures and assessed factors that might be associated with the risk of osteoporotic fractures. A total of 64 patients were enrolled. TBS and TBS T-score values were significantly lower in patients with osteoporosis compared to patients without osteoporosis. Low energy fractures occurred in 19 patients. The disturbed bone microarchitecture was found in 30% of patients with fractures without osteoporosis diagnosis based on BMD. In the multivariate analysis, only TBS and age were significantly associated with the occurrence of osteoporotic fractures. TBS reflects the influence of glucocorticoid therapy on bone quality better than DXA measured BMD and provides an added value to DXA in identifying the group of patients particularly prone to fractures.

Status of fracture risk assessment and osteoporosis treatment in Japanese patients with rheumatoid arthritis.

OBJECTIVES: This study aimed to investigate the prevalence of patients with rheumatoid arthritis (RA) at a high risk of major osteoporosis (OP)-related fractures and the status of OP-related medical treatment for these patients. METHODS: We enrolled 120 patients aged ≥40 years (average, 69.1 years) with RA. The Fracture Risk Assessment Tool (FRAX®) was used to evaluate the fracture risk. Of the 120 patients, the femoral neck bone mineral density (BMD) was evaluated in 102 patients, and their FRAX® scores were calculated alongside the BMD values. Patients observed to be at a high risk of a major OP-related fracture (10-year probability >20% or hip fracture risk >3%), according to FRAX®, were identified as those requiring OP treatment; medication ratio for OP (percentage of patients actually receiving medication among patients requiring OP treatment) was assessed. RESULTS: OP treatment was indicated in 75 (63%) patients; the medication ratio for OP was 49%. The use of biological disease-modifying anti-rheumatic drugs and corticosteroids showed a positive effect; however, the use of methotrexate showed a negative effect on the medication ratio. CONCLUSION: The number of potential patients requiring OP treatment is underestimated. All patients with RA should be assessed to determine their eligibility for OP treatment.

Proton pump inhibitor use and risk of hip fracture in patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is associated with a high rate of comorbidity, including osteoporosis and peptic ulcers. Proton pump inhibitors (PPIs) are a group of acid-suppressing drugs commonly used for treating peptic ulcers. However, observational studies have reported an association between PPI therapy and osteoporotic fractures. This study investigated the association between PPI use and hip fracture (HFx) among patients with T2DM. We conducted this population-based propensity-matched retrospective cohort study using the National Health Insurance Research Database in Taiwan. Patients newly diagnosed with T2DM between 2000 and 2008 were identified. After excluding those who previously used PPIs or suffered HFx, 398,885 patients were recruited (44,341 PPI users; 354,544 non-users). HFx risk data from 2000 to 2013 were collected to calculate the cumulative rate of HFx in these two groups. Sensitivity analyses were conducted to evaluate the effects of PPI dose. After propensity score matching of 1:4, 44,431 and 177,364 patients were assigned to the PPI user and non-user groups, respectively. PPI user group showed an increased risk of HFx with an adjusted hazard ratio of 1.41 (95% CI 1.29-1.54) without dose-response relationship. Thus, there is an increased risk of HFx in patients with T2DM receiving long-term PPI treatment.

Impact of prescription drugs on second fragility fractures among US Medicare patients.

Drugs that increase the risk of fracture are commonly prescribed to survivors of a fragility fracture. This study shows that starting new high-risk medications after fracture increases the risk of a second, potentially preventable fracture. For most drug classes, however, it is safe to continue medications taken before the fracture. INTRODUCTION: Most patients who survive a fragility fracture are subsequently exposed to prescription drugs that have been linked to increased fracture risk. This study was designed to quantify the extent to which current prescribing practices result in potentially preventable second fractures. METHODS: We analyzed a cohort of 138,526 Medicare beneficiaries who returned to the community after a fragility fracture. Post-fracture drug use was defined using retail pharmacy fills. The risk of second fracture associated with individual drug classes was analyzed using Cox proportional hazard models. Data were further analyzed to determine whether there is a difference in risk between continuing previous therapy and initiating new therapy after fracture. RESULTS: Many drug classes previously identified as increasing fracture risk were not associated with increased fracture risk in this cohort. Discontinuing therapy at the time of fracture was only beneficial for patients taking selective serotonin reuptake inhibitors; however, initiating therapy in previous non-users increased second fracture risk for five classes of drugs (selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, proton pump inhibitors, and non-benzodiazepine hypnotics). CONCLUSION: Discontinuing high-risk drugs after fracture was not generally protective against subsequent fractures. Preventing the addition of new medications may result in greater improvements in post-fracture care.

Do FDA label changes work? Assessment of the 2010 class label change for proton pump inhibitors using the Sentinel System's analytic tools.

PURPOSE: To pilot use of the US Food and Drug Administration's (FDA's) Sentinel System data and analytic tools by a non-FDA stakeholder through the Innovation in Medical Evidence Development and Surveillance system of the Reagan Udall Foundation. We evaluated the US FDA 2010 proton pump inhibitor (PPI) class label change that warned of increased risk of bone fracture, to use PPIs for the lowest dose and shortest duration, and to manage bone status for those at risk for osteoporosis. METHODS: The cohort consisted of adults aged 18 years or older prescribed PPIs without fracture risk factors. We evaluated incident and prevalent uses of the 8 PPIs noted in the label change. Outcomes evaluated before and after label change were PPI dispensing patterns, incident fractures, and osteoporosis screening or interventions. Consistent with FDA use of descriptive tools, we did not include direct comparisons or statistical testing. RESULTS: There were 1 488 869 and 2 224 420 incident PPI users in the before [PRE] and after [POST] periods, respectively. Users with 1 year or more of exposure decreased (8.4% vs 7.5%), as did mean days supplied/user (130.4 to 113.7 d among all users and 830.8 to 645.4 d among users with 1 y or more of exposure). Osteoporosis screening and interventions did not appear to increase, but the proportion of patients with fractures decreased (4.4% vs 3.1%). Prevalent user results were similar. CONCLUSIONS: This analysis demonstrated the ability to use Sentinel tools to assess the effectiveness of a label change and accompanying communication at the population level and suggests an influence on subsequent dispensing behavior.

Assessment of bone mineral density in patients with cirrhosis treated with third-generation nucleos(t)ide analogues: comparison between tenofovir and entecavir.

BACKGROUND AND AIM: Tenofovir and entecavir are nowadays the first-line treatment in hepatitis B virus (HBV)-related cirrhosis. Both drugs were shown to be effective in HBV suppression and well tolerated. The effects of tenofovir on bone mineral density (BMD), however, were shown to worsen the rate of osteoporosis, which is already a common feature in cirrhosis. In contrast, entecavir seems to have no effect on mineral metabolism. The aim of our study was to compare the effects of nucleos(t)ide analogs on bone density in HBV-related cirrhosis. PATIENTS AND METHODS: Fourty-eight patients were treated with tenofovir and 22 patients were treated with entecavir, and were followed prospectively from 2008 to 2013. To evaluate BMD, laboratory examinations, dual-X-ray absorptiometry, and Fracture Risk Assessment Tool were assessed. RESULTS: During the study, no difference was found between the two groups in the plasmatic concentration of calcium, phosphate, vitamin D, parathyroid hormone, or creatinine. Dual-X-ray absorptiometry showed no difference in the T-score and Fracture Risk Assessment Tool showed no significant difference in the 10-year risk of osteoporotic fractures in the two groups. On univariate and multivariate analyses, the only predictors of osteoporosis development were the prognostic scores of liver disease and BMI. CONCLUSION: Both tenofovir and entecavir are effective in treating HBV in cirrhotic patients. The known effects of tenofovir on BMD do not worsen osteoporotic fractures risk compared with entecavir in these patients.

Treatment of postmenopausal osteoporosis: a literature-based algorithm for use in the public health care system.

Bisphosphonates are considered first-line agents in the treatment of postmenopausal osteoporosis based on extensive experience of use, safety, and proven efficacy in reducing vertebral, non-vertebral and femur fractures. However, post-marketing reports based on the treatment of millions of patients/year over lengthy periods of time have revealed the occurrence of initially unexpected adverse effects, such as osteonecrosis of the jaw and atypical femoral fracture, leading to the restriction of treatment duration with bisphosphonates by global regulatory agencies. However, despite the association between these effects and bisphosphonates, this risk should be analyzed in the context of osteoporosis treatment, alongside the benefit of preventing osteoporotic fractures and their clinical consequences. Therefore, we consider it plausible to discuss the restriction to the use of bisphosphonates, possible indications for prolonged treatment and alternative therapies following the suspension of this drug class for patients with persistent high risk of fracture after initial treatment, especially considering the problems of public health funding in Brazil and the shortage of drugs provided by the government. Thus, to standardize the treatment of osteoporosis in the public health care system, we aim to develop a proposal for a scientifically-based pharmacological treatment for postmenopausal osteoporosis, establishing criteria for indication and allowing the rational use of each pharmacological agent. We discuss the duration of the initial bisphosphonate treatment, the therapeutic options for refractory patients and potential indications of other classes of drugs as first-choice treatment in the sphere of public health, in which assessing risk and cost effectiveness is a priority.

Treatment of postmenopausal osteoporosis: a literature-based algorithm for use in the public health care system / Tratamento da osteoporose pós-menopáusica: um algoritmo baseado na literatura para uso no sistema público de saúde

ABSTRACT Bisphosphonates are considered first-line agents in the treatment of postmenopausal osteoporosis based on extensive experience of use, safety, and proven efficacy in reducing vertebral, non-vertebral and femur fractures. However, post-marketing reports based on the treatment of millions of patients/year over lengthy periods of time have revealed the occurrence of initially unexpected adverse effects, such as osteonecrosis of the jaw and atypical femoral fracture, leading to the restriction of treatment duration with bisphosphonates by global regulatory agencies. However, despite the association between these effects and bisphosphonates, this risk should be analyzed in the context of osteoporosis treatment, alongside the benefit of preventing osteoporotic fractures and their clinical consequences. Therefore, we consider it plausible to discuss the restriction to the use of bisphosphonates, possible indications for prolonged treatment and alternative therapies following the suspension of this drug class for patients with persistent high risk of fracture after initial treatment, especially considering the problems of public health funding in Brazil and the shortage of drugs provided by the government. Thus, to standardize the treatment of osteoporosis in the public health care system, we aim to develop a proposal for a scientifically-based pharmacological treatment for postmenopausal osteoporosis, establishing criteria for indication and allowing the rational use of each pharmacological agent. We discuss the duration of the initial bisphosphonate treatment, the therapeutic options for refractory patients and potential indications of other classes of drugs as first-choice treatment in the sphere of public health, in which assessing risk and cost effectiveness is a priority.

RESUMO Com base na vasta experiência de uso, segurança e eficácia comprovada na redução de fraturas vertebrais, não vertebrais e femorais, os bisfosfonatos são considerados agentes de primeira linha no tratamento da osteoporose pós-menopáusica. No entanto, os relatos pós-venda baseados no tratamento de milhões de pacientes/ano durante períodos prolongados de tempo revelaram a ocorrência de efeitos adversos inicialmente inesperados, como osteonecrose da mandíbula e fratura atípica do fêmur. Isso levou as agências reguladoras globais a restringirem a duração do tratamento com bisfosfonatos. No entanto, apesar da associação entre esses efeitos e os bisfosfonatos, esse risco deve ser analisado no contexto do tratamento da osteoporose, paralelamente ao benefício na prevenção de fraturas osteoporóticas e suas consequências clínicas. Portanto, considera-se plausível discutir a restrição ao uso dos bisfosfonatos, possíveis indicações para o tratamento prolongado e terapias opcionais após a suspensão dessa classe de fármaco para pacientes com alto risco persistente de fratura após o tratamento inicial, especialmente se considerarmos os problemas financeiros de saúde pública no Brasil e a escassez de fármacos fornecidos pelo governo. Assim, para padronizar o tratamento da osteoporose no sistema público de saúde pretende-se desenvolver uma proposta de tratamento farmacológico cientificamente fundamentada para a osteoporose pós-menopáusica, estabelecer critérios de indicação e permitir o uso racional de cada agente farmacológico. Discutem-se a duração do tratamento inicial com bisfosfonatos, as opções terapêuticas para pacientes refratários e potenciais indicações de outras classes de medicamentos como tratamento de primeira linha na esfera da saúde pública, em que a avaliação do risco e custo-efetividade é uma prioridade.

Importance of bone assessment and prevention of osteoporotic fracture in patients with prostate cancer in the gonadotropic hormone analogues use.

The antiandrogenic therapy (ADT) for prostate cancer represents an additional risk factor for the development of osteoporosis and fragility fractures. Still, bone health of patients on ADT is often not evaluated. After literature research we found that simple preventive measures can prevent bone loss in these patients, resulting in more cost-effective solutions to the public health system and family when compared to the treatment of fractures.

Risk of fractures in subjects with antihypertensive medications: A nationwide claim study.

BACKGROUND: The effect of antihypertensives on fracture has important clinical implications, since antihypertensives are frequently prescribed with lifelong exposure. This study aimed to compare risk of fracture between antihypertensive medication classes and non-users among adults. METHODS: Nationwide claim data from January 1, 2007 to December 31, 2011 were analyzed. Among 8,315,709 subjects with antihypertensive prescriptions in nationwide medical claim database in South Korea, 528,522 subjects, who initiated single-drug antihypertensives or non-users, were analyzed. Subjects were classified as non-user, alpha-blocker (AB), angiotensin-converting-enzyme-inhibitor (ACEI), angiotensin-receptor-blocker (ARB), beta-blocker (BB), calcium-channel-blocker (CCB), and diuretic users. Subjects with combination antihypertensive medications were excluded. RESULTS: A total of 16,805 fracture outcomes were observed during mean follow-up duration of 1.9 years. Fracture rate per 10,000 person-years varied significantly across type of antihypertensives, with ARB having the lowest rate (152.7, 95% confidence interval (CI) 145.4-160.4), and AB having the highest rate (323.7, 95% CI 237.4-441.4). Non-users had fracture rates (152.2, 95% CI 148.7-155.7) similar to ARB users. In models adjusting for age, gender, comorbidity score, diagnosis of diabetes, diagnosis of osteoporosis, osteoporosis treatment, and osteoporosis related diseases, AB users (adjusted hazard ratio (aHR)=2.26), ACEI users (aHR=1.68), diuretic users (aHR=1.45), CCB users (aHR=1.23), and BB users (aHR=1.15) showed significantly increased risk of fractures compared with non-users (P<0.05). Only the fracture risk of ARB users (aHR=1.00, 95% CI 0.95-1.05) was not significantly different from the non-users. CONCLUSIONS: The use of antihypertensives except for ARB is associated with increased risk of fracture, with ACEI and AB having higher risk among hypertensive adults.

Denosumab: a cost-effective alternative for older men with osteoporosis from a Swedish payer perspective.

OBJECTIVE: To assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥75years old from a payer perspective in Sweden. METHODS: A lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Background fracture risks, mortality rates, persistence rates, utilities, medical and drug costs were derived using published sources. Estimates of fracture efficacy were drawn from available studies in post-menopausal osteoporotic (PMO) women as BMD improvements have been shown to be similar across male osteoporosis (MOP) and PMO populations, and a recent clinical trial suggested that the fracture risk reduction from bisphosphonate therapy in men is similar to that seen in women in comparable studies. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, generic risedronate, ibandronate, zoledronate, strontium ranelate and teriparatide. On average, patients in the model were 78years old, with bone mineral density T-score at the femoral neck of -2.12. Prevalent vertebral fractures were present in 23% of patients. In the base-case, the model assumed that patients would experience treatment-related effects up to 2years after discontinuation. Costs and QALYs were discounted at 3% annually. Extensive sensitivity analyses were conducted. RESULTS: Total lifetime costs for denosumab, alendronate, strontium ranelate, zoledronate, risedronate, ibandronate and teriparatide were €31,004, €33,731, €34,788, €34,796, €34,826, €35,983 and €37,461, respectively. Total QALYs were 5.23, 5.15, 5.15, 5.17, 5.13, 5.12 and 5.22, respectively. Compared to other treatments, denosumab had the lowest costs and highest QALYs. In the one-way sensitivity analyses, when compared to alendronate (next least expensive strategy), the ICER for denosumab was most sensitive to the relative risk of hip fracture on denosumab. The probability of denosumab being cost-effective compared to the other treatments at a threshold of €66,000/QALY was 96.1%. CONCLUSION: Denosumab dominated all comparators, including generic bisphosphonates, in the treatment of osteoporosis in men who were ≥75years old in Sweden.

[Assessment of the treatment of glucocorticoid-induced osteoporosis].

Glucocorticoid-induced osteoporosis (GIOP) is known as a serious adverse side effect during long-term glucocorticoid treatment. Several clinical guidelines are available to whom and how we should start to treat GIOP. However, the assessment of the treatment of GIOP is still controversial. Accumulating evidences suggest us that both bone mineral density and bone turn over markers could reflect the effect of some pharmacological agents on bone metabolism. However, further studies would be required for precise assessment of the efficacy of drugs on fracture prevention in GIOP.