Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in tshwane, south africa.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) first reported in Wuhan, China in December 2019 is a global pandemic that is threatening the health and wellbeing of people worldwide. To date there have been more than 274 million reported cases and 5.3 million deaths. The Omicron variant first documented in the City of Tshwane, Gauteng Province, South Africa on 9 November 2021 led to exponential increases in cases and a sharp rise in hospital admissions. The clinical profile of patients admitted at a large hospital in Tshwane is compared with previous waves. METHODS: 466 hospital COVID-19 admissions since 14 November 2021 were compared to 3962 admissions since 4 May 2020, prior to the Omicron outbreak. Ninety-eight patient records at peak bed occupancy during the outbreak were reviewed for primary indication for admission, clinical severity, oxygen supplementation level, vaccination and prior COVID-19 infection. Provincial and city-wide daily cases and reported deaths, hospital admissions and excess deaths data were sourced from the National Institute for Communicable Diseases, the National Department of Health and the South African Medical Research Council. RESULTS: For the Omicron and previous waves, deaths and ICU admissions were 4.5% vs 21.3% (p<0.00001), and 1% vs 4.3% (p<0.00001) respectively; length of stay was 4.0 days vs 8.8 days; and mean age was 39 years vs 49,8 years. Admissions in the Omicron wave peaked and declined rapidly with peak bed occupancy at 51% of the highest previous peak during the Delta wave. Sixty two (63%) patients in COVID-19 wards had incidental COVID-19 following a positive SARS-CoV-2 PCR test . Only one third (36) had COVID-19 pneumonia, of which 72% had mild to moderate disease. The remaining 28% required high care or ICU admission. Fewer than half (45%) of patients in COVID-19 wards required oxygen supplementation compared to 99.5% in the first wave. The death rate in the face of an exponential increase in cases during the Omicron wave at the city and provincial levels shows a decoupling of cases and deaths compared to previous waves, corroborating the clinical findings of decreased severity of disease seen in patients admitted to the Steve Biko Academic Hospital. CONCLUSION: There was decreased severity of COVID-19 disease in the Omicron-driven fourth wave in the City of Tshwane, its first global epicentre.

Premenopausal osteoporosis.

In premenopausal women, bone mineral density measurement by dual-energy X-ray absorptiometry should not be used as the sole guide for diagnosis or treatment of osteoporosis, universal screening with bone mineral density is not advised and the World Health Organization classification of bone status should not be applied. A diagnosis of premenopausal osteoporosis is reserved for those with evidence of fragility and may also be considered in women with low bone mass and an ongoing secondary cause of osteoporosis. Idiopathic osteoporosis in young women is rare. A thorough evaluation of secondary causes is indicated in all patients, with glucocorticoid treatment a common secondary cause of low bone mass and osteoporosis. Hypoestrogenism may be the primary cause of low bone mass and contribute to excessive bone loss in many conditions associated with premenopausal osteoporosis, and should be treated unless contra-indicated. The mainstay of treatment in premenopausal females with low bone mass includes risk factor reduction, advocating a healthy, active lifestyle and optimal treatment of secondary causes of bone loss. The safety of bone-specific therapy, especially long term and during pregnancy, remains uncertain. Bisphosphonates, teriparatide, denosumab and estrogen treatment increase bone density in premenopausal women with osteoporosis, but there are no study data confirming short-term fracture prevention with use of these agents.

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.

Osteoporosis management in hematologic stem cell transplant recipients: Executive summary.

BACKGROUND: Treatment advances have reduced the adverse events associated with hematopoietic stem cell transplant (HSCT) and led to an increased number of transplants performed. HSCT patients are living longer with concerns on long-term outcomes. Bone fragility and fracture are at the forefront for long-term morbidities post-HSCT. RESULTS: In HSCT recipients, evidence has accumulated to support recommendations for more extensive monitoring of bone fragility and more appropriate administration of osteoporosis pharmacotherapies for patients at high risk of bone loss and/or fracture. CONCLUSION: This executive summary reports and summarizes the main recommendations published previously, including bone assessment, dietary and lifestyle recommendations and osteoporosis medication.

Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis.

This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal. INTRODUCTION: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. METHODS: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). RESULTS: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). CONCLUSION: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.

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.

Revised global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies.

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.

A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates.

UNLABELLED: In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites. INTRODUCTION: This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis. METHODS: This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤-2.5 or ≤-1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo. RESULTS: Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442. CONCLUSION: Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.

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.

South African Menopause Society revised consensus position statement on menopausal hormone therapy, 2014.

The South African Menopause Society (SAMS) consensus position statement on menopausal hormone therapy (HT) 2014 is a revision of the SAMS Council consensus statement on menopausal HT published in the SAMJ in May 2007. Information presented in the previous statement has been re-evaluated and new evidence has been incorporated. While the recommendations pertaining to HT remain similar to those in the previous statement, the 2014 revision includes a wider range of clinical benefits for HT, the inclusion of non-hormonal alternatives such as selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors for the management of vasomotor symptoms, and an appraisal of bioidentical hormones and complementary medicines used for treatment of menopausal symptoms. New preparations that are likely to be more commonly used in the future are also mentioned. The revised statement emphasises that commencing HT during the 'therapeutic window of opportunity' maximises the benefit-to-risk profile of therapy in symptomatic menopausal women.

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.