Update on bone health: the International Menopause Society White Paper 2021.

Osteoporosis and associated fractures present a major challenge in improving global health outcomes. Key clinical aspects are the definition of osteoporosis and associated fractures, fracture risk prediction, stratification of risk of fracture, intervention thresholds and the most appropriate intervention based on integration of aforementioned. Correct understanding and application of these concepts are essential to stem the increasing tide of fragility fractures associated with an aging population. The role of muscle strength and function, sarcopenia, and the newly emerging concept of osteosarcopenia in maintaining bone health are discussed in detail.

Effects of ospemifene on bone in postmenopausal women.

Ospemifene is a selective estrogen-receptor modulator approved for treating menopause-related moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy (VVA), in the United States, and for treating menopause-related, symptomatic VVA in women not appropriate for local estrogen therapy in Europe. This review summarizes the effects of ospemifene on bone, including bone biomarker data from a phase 3 vaginal dryness study. Early-phase studies of postmenopausal women showed that ospemifene dose-dependently decreased bone turnover markers versus placebo, similar to raloxifene. A 12-week, phase 3 study of ospemifene 60 mg/day in postmenopausal women showed improvements in all VVA parameters and significantly greater decreases in seven of nine bone biomarkers versus placebo. Lower bone resorption markers with ospemifene were observed regardless of time since menopause (≤5 years or >5 years) or baseline bone mineral density (BMD) (normal [n = 18], osteopenia [n = 164], or osteoporosis [n = 21]). Biomarker studies (n = 565 who took ospemifene) therefore support a potential role for ospemifene in maintaining bone health (and possibly reducing fracture risk) in postmenopausal women taking it for VVA; however, caution is warranted because data are limited to biochemical markers, rather than fracture and BMD. Although studies show that bone turnover predicts BMD and fractures, any hypothesis about a bone-sparing effect of ospemifene needs testing in rigorous, long-term, phase 3 studies monitoring fractures and BMD.

Bone management in hematologic stem cell transplant recipients.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for patients with some malignant and non-malignant hematological diseases. Advances in transplantation techniques and supportive care measures have substantially increased the number of long-term HSCT survivors. This has led to an increasing patient population suffering from the late effects of HSCT, of which, bone loss and its consequent fragility fractures lead to substantial morbidity. Altered bone health, with consequent fragility fractures, and chronic graft-versus-host disease (GVHD) are factors affecting long-term quality of life after HSCT. Hypogonadism, HSCT preparative regimens, nutritional factors, and glucocorticoids all contribute to accelerated bone loss and increased fracture risk. Management strategies should include bone mineral density examination, evaluation of clinical risk factors, and general dietary and physical activity measures. Evidence has accumulated permitting recommendations for more attentiveness to evaluation and monitoring of bone health, with appropriate application of osteoporosis pharmacotherapies to patients at increased risk of bone loss and fracture.

Should women be screened for osteoporosis at midlife?

Osteoporosis and associated fractures are common in women after midlife and will increase as the population ages. Osteoporosis-related fractures cause a significant increase in morbidity and mortality. Osteoporosis decreases the quality of life and productivity of many older women, with an increasing burden on health-care resources. Future risk of fracture can be managed by evidence-based interventions. It is thus appropriate to estimate the future risk of fracture in all women at the age of 50 years or at menopause, whichever occurs first. This can be achieved in a non-invasive fashion by targeted clinical history-taking. The future risk of fracture can be quantified using computerized models that integrate all risk factors, with or without dual-energy X-ray absorptiometry (DXA). Individuals found to be at increased risk of fracture need also to be assessed by DXA and, in the absence of lateral vertebral assessment, also by conventional X-ray imaging. All women should be screened by DXA at the age of 65 years, if not done before that time. At the age of 50, all women should be informed about a bone-friendly lifestyle.

The quest for new drugs to prevent osteoporosis-related fractures.

There is a need for the development of new drugs to prevent osteoporosis-related fractures. Fractures are projected to increase and the present drugs have modest efficacy, significant side-effects and poor compliance. To illustrate the difficulties in the development of new drugs, the author reviews the fate of several drugs that have failed to gain regulatory approval. These drugs include arzoxifene, lasofoxifene, MK-5442, roncalceret and odanacatib. Romosozumab and abaloparatide are the only new drugs presently in phase-3 development. It is anticipated that ongoing studies of the mechanisms and signaling pathways involved in the regulation of bone remodeling will open up new opportunities for targeted pharmacological interventions to increase bone strength. However, the perfect drug is still a long way off and will face many obstacles before approval.

Cardiovascular risk assessment in women - an update.

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Although it is a disease of aging, vascular disease initiates much earlier in life. Thus, there is a need to be aware of the potential to prevent the development of the disease from an early age and continue this surveillance throughout life. The menopausal period and early menopause present an ideal opportunity to assess cardiovascular risk and plan accordingly. Generally in this period, women will be seen by primary health-care professionals and non-cardiovascular specialists. This review addresses female-specific risk factors that may contribute to the potential development of cardiovascular disease. It is important for all health-care professionals dealing with women in midlife and beyond to be cognisant of these risk factors and to initiate female-specific preventative measures or to refer to a cardiovascular specialist.

Effect of ospemifene on moderate or severe symptoms of vulvar and vaginal atrophy.

OBJECTIVES: To determine whether assessment of all moderate-to-severe symptoms at baseline gives a more accurate evaluation of the treatment effect of ospemifene in vulvovaginal atrophy (VVA) than the most bothersome symptom (MBS) approach. METHODS: Data were pooled from two pivotal phase-III clinical trials evaluating the efficacy and safety of oral ospemifene 60 mg/day for the treatment of symptoms of VVA (n = 1463 subjects). Symptoms of vaginal dryness, dyspareunia, and vaginal and/or vulvar irritation/itching reported as moderate or severe at baseline were evaluated. Clinically relevant differences between ospemifene and placebo were analyzed using a four-point severity scoring system and presented as improvement, substantial improvement, or relief. RESULTS: Subjects in these studies reported statistically significant improvement, substantial improvement, and relief for vaginal dryness (p < 0.00001), dyspareunia (p < 0.001) and statistically significant improvement and relief for vaginal and/or vulvar irritation/itching (p < 0.01) from baseline to week 12 with ospemifene compared with placebo. A similar trend was observed for women who reported substantial improvement of vaginal and/or vulvar irritation/itching. CONCLUSIONS: For drug registration purposes, the use of the MBS model is appealing because of its simplicity and ease of scientific validation. However, the MBS model may underestimate the total magnitude of the clinical benefit of ospemifene treatment for symptomatic women suffering from VVA.

The role of menopausal hormone therapy in the management of osteoporosis.

It is now 75 years since Fuller Albright published his observations on the causal relationship between menopausal estrogen deficiency and osteoporosis. He introduced the concept of menopausal hormone therapy (MHT) for the prevention of osteoporosis. Most of his remarkable observations have stood the test of time and scientific scrutiny. Unfortunately, the uptake of MHT for the prevention of osteoporosis and related fractures remains very low. This can be ascribed to several factors. The availability of new drugs, supported by randomized clinical trials, has increased therapeutic options and created the impression that all new drugs are better compared to MHT. Confusion exists as to the benefit/risk profile of menopausal hormone therapy, limitations on the age of initiation of treatment, limitations on the length of treatment, and the need for treatment in the young menopausal woman with low bone density.

The clinical relevance of the effect of ospemifene on symptoms of vulvar and vaginal atrophy.

OBJECTIVES: To explore clinically relevant differences in severity of vulvar and vaginal atrophy (VVA) in postmenopausal women treated with ospemifene compared with placebo. METHODS: Analysis of two multicenter, randomized, double-blind, 12-week phase-III studies in postmenopausal women (40-80 years, with VVA, treated with ospemifene 60 mg/day or placebo (Study 310 and Study 821)). Severity of vaginal dryness and dyspareunia were evaluated using a four-point scoring system and clinically relevant differences between ospemifene and placebo were analyzed and are presented as improvement (reduction in ≥ 1 unit on four-point scoring system), substantial improvement (reduction in 2-3 units on four-point scoring system) and relief (severity score of mild/none after 12 weeks). RESULTS: In Study 310, significantly more women with a most bothersome symptom of dyspareunia had improvement (68.3% vs. 54.1%; p = 0.0255) or relief (57.5% vs. 41.8%; p = 0.0205) in the severity of dyspareunia from baseline to week 12 with ospemifene compared with placebo. For those with a most bothersome symptom of vaginal dryness, significantly more experienced improvement (74.6% vs. 57.7%; p = 0.0101), substantial improvement (42.4% vs. 26.9%; p = 0.0172) and relief (66.1% vs. 49.0%; p = 0.0140) of vaginal dryness from baseline to week 12 with ospemifene compared with placebo. Proportions of women with improvement/substantial improvement/relief of symptoms of vaginal dryness or dyspareunia were similar in Study 821. Clinically relevant differences were noticeable by week 4. CONCLUSIONS: Treatment with ospemifene was consistently associated with greater improvement, substantial improvement or relief in the severity of the most bothersome symptoms of vaginal dryness or dyspareunia compared with placebo.

8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle?

Estrogen therapy was considered first-line therapy for the prevention and treatment of postmenopausal osteoporosis in 1984. Evidence from a large, randomized clinical trial in 2002 proved the efficacy of estrogen in the prevention of all types of osteoporosis-related fractures. Ironically, estrogen was relegated to second-line therapy, based on perceived safety concerns. The historical background to these decisions is presented. It is argued that this decision is not a reasonable reflection of the available evidence, especially in comparison to other available drugs.

Risks and benefits of hormone therapy: has medical dogma now been overturned?

BACKGROUND: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'. OBJECTIVES: To evaluate those claims. METHODS: Epidemiological criteria of causation were applied to the evidence. RESULTS: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor. CONCLUSIONS: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

Prevention of diseases after menopause.

Women may expect to spend more than a third of their lives after menopause. Beginning in the sixth decade, many chronic diseases will begin to emerge, which will affect both the quality and quantity of a woman's life. Thus, the onset of menopause heralds an opportunity for prevention strategies to improve the quality of life and enhance longevity. Obesity, metabolic syndrome and diabetes, cardiovascular disease, osteoporosis and osteoarthritis, cognitive decline, dementia and depression, and cancer are the major diseases of concern. Prevention strategies at menopause have to begin with screening and careful assessment for risk factors, which should also include molecular and genetic diagnostics, as these become available. Identification of certain risks will then allow directed therapy. Evidence-based prevention for the diseases noted above include lifestyle management, cessation of smoking, curtailing excessive alcohol consumption, a healthy diet and moderate exercise, as well as mentally stimulating activities. Although the most recent publications from the follow-up studies of the Women's Health Initiative do not recommend menopause hormonal therapy as a prevention strategy, these conclusions may not be fully valid for midlife women, on the basis of the existing data. For healthy women aged 50-59 years, estrogen therapy decreases coronary heart disease and all-cause mortality; this interpretation is entirely consistent with results from other randomized, controlled trials and observational studies. Thus. as part of a comprehensive strategy to prevent chronic disease after menopause, menopausal hormone therapy, particularly estrogen therapy may be considered as part of the armamentarium.

Cancer-associated bone disease.

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations.

Global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society.

Oncology in midlife and beyond.

The onset of the menopause is often a time when women's concerns can act as a powerful trigger to encourage healthy modifications in lifestyle which will maintain, or improve, their general health. This document aims to help women to understand their potential risks, to encourage them to find proactive preventive strategies by modifying some of their attitudes, and to use health resources (when available) to be screened. Cancer is an important cause of death but not the primary cause of mortality. Cardio/circulatory diseases represent 35-40% of causes of death in most developed countries and 20-25% of women will die from cancers in Western Europe, Australasia, high-income North America, high-income Asia Pacific, East Asia and Southern Latin America. Breast cancer, lung cancer and colorectal cancer are prevalent in most regions of the world. Cervical cancer remains a hallmark of low access to health care. Preventive strategies (decreasing smoking and alcohol consumption, losing weight, eating a healthy diet and undertaking physical activity) and implementation of screening could help to significantly decrease the incidence of and mortality from cancer. The mortality/incidence ratio is higher in developing countries compared to high-income regions as well as in subgroups of populations in developed countries with lower socioeconomic levels. Implementation of better diagnostic methods and management of cancer according to the local resources will help to decrease the mortality rate in developing countries, and effort has to be made to decrease social inequities and improve access to health care for low-income groups. In conclusion, cancer incidence is increasing as a consequence of longer life expectancy all over the world. National health programs are mandatory to implement screening and to improve individual management. Finally, educating women so that they are aware of ways to improve their general health, to minimize their own risk factors and to identify signs of change in their own health which may be markers of impending cancer will help to reduce the burden of disease and improve the prognosis for tumors detected at an earlier stage.

Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

SUMMARY: Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. INTRODUCTION: Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. METHODS: In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. RESULTS: The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. CONCLUSION: Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

The WHI: the effect of hormone replacement therapy on fracture prevention.

The Women's Health Initiative (WHI) randomized, controlled trial was the first study to prove that hormone replacement therapy (HRT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women, even those at low risk of fracture. The study authors concluded that the bone-friendly aspect of HRT was limited in clinical practice as possible adverse effects outweighed possible benefit. On the strength of these publications, regulatory authorities downgraded the use of HRT for the prevention of fracture to second-line therapy. This article examines the original and subsequent evidence presented by the WHI study and concludes that the restrictions placed on HRT as a bone-specific drug by regulatory bodies have not withstood the test of time and are not supported by the data of the WHI.

Randomized placebo- and active-controlled study of desvenlafaxine for menopausal vasomotor symptoms.

OBJECTIVE: To evaluate the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) vs. tibolone and placebo for menopausal vasomotor symptoms and the incidence of uterine bleeding. METHODS: This 12-week, double-blind, randomized, controlled trial was conducted at 35 sites in Europe, two sites in South Africa, and one site in Mexico. Postmenopausal women with ≥50 moderate or severe hot flushes per week (n = 485) were randomized to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, or placebo. Reduction in the average daily number of moderate and severe hot flushes at weeks 4 and 12 (primary endpoint) was evaluated using analysis of covariance. Safety assessments included incidence of uterine bleeding, adverse events, laboratory values, and vital signs. RESULTS: At week 12, no statistically significant difference was observed in reduction of the average daily number of moderate and severe hot flushes for desvenlafaxine (-5.78) vs. placebo (-5.82; p = 0.921), although time to 50% reduction was significantly less than placebo (13 vs. 26 days, p = 0.006). Hot flush reduction with tibolone (-8.21) was significantly greater than placebo (p < 0.001). Nausea was the most common adverse event with desvenlafaxine, was generally mild to moderate, and resolved within the first 2 weeks. Significantly more subjects experienced bleeding with tibolone (23%) vs. desvenlafaxine (12%; p < 0.024) or placebo (9%; p < 0.001). CONCLUSIONS: Desvenlafaxine did not separate from placebo in reducing the number of moderate to severe hot flushes at week 12, although it did allow women to achieve 50% reduction sooner than placebo. Tibolone did separate from placebo, but with smaller than expected effect. The placebo effect was high (57%). Adverse drug reactions were consistent with the known safety profile of desvenlafaxine, and significantly more women who received tibolone experienced episodes of bleeding compared with women who received desvenlafaxine or placebo.