Continued part 1, part 2 of ebook Pre-menopause, menopause and beyond (Volume 5: Frontiers in gynecological endocrinology) provide readers with content about: bone and cardiovascular impact; the effect of menopause and HRT on coronary heart disease; benign breast diseases, BRCA mutation and breast cancer; menopause symptoms - the therapies;... Please refer to the part 2 of ebook for details!
Part IV Bone and Cardiovascular Impact Healthy Bones After Menopause: What Has to Be Done? 14 Martin Birkhaeuser 14.1 Introduction Osteoporosis is one of the most frequent and most devastating diseases Fragility fractures (minimal trauma fractures) belong to the most important morbidity and mortality causes in the elderly Usually they occur as a result of a fall from standing height In women, the incidence of vertebral fractures starts to rise steeply in the first years after menopause, whereas the incidence of hip fractures rises sharply around the age of 70 Globally, during the year 2000, there were an estimated million new fragility fractures, of which 1.6 million were at the hip, 1.7 million at the wrist, 0.7 million at the humerus and 1.4 million symptomatic vertebral fractures [1] In the age group of 50–80 years corresponding to the life period after menopause, around 36% of classical fragility fractures occur in those below age 65 years [2, 3] In the UK, this amounts to more than 100,000 fractures per year in women aged 50–65 years, over 9000 of which are hip fractures ([2, 3]; www.uk2u.net) Nonetheless the importance of osteoporosis is still largely underestimated by lay people and by doctors Prevention of osteoporotic fractures should be one of the major goals of menopause specialists 14.1.1 Definition of Osteoporosis Osteoporosis leads to weakness of the skeleton and increased risk of fracture The World Health Organization (WHO) has defined osteoporosis as a systemic skeletal disease characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture M Birkhaeuser Professor emeritus for Gynaecological Endocrinology and Reproductive Medicine, University of Bern, Bern, Switzerland Postal correspondence/address: Gartenstrasse 67, CH-4052, Basel, Switzerland e-mail: martin.birkhaeuser@balcab.ch © International Society of Gynecological Endocrinology 2018 M Birkhaeuser, A.R Genazzani (eds.), Pre-Menopause, Menopause and Beyond, ISGE Series, https://doi.org/10.1007/978-3-319-63540-8_14 165 166 M Birkhaeuser 14.1.2 Epidemiology In developed countries, lifetime risk for a normal woman aged 50 years to suffer an osteoporotic fracture at any place is 52.3% [1, 4–8], and the likelihood of a fracture at any of the four major sites (spine, femoral neck, wrist, proximal humerus) is 40% or more Forty per cent is close to the probability of coronary heart disease In a woman at the menopause, the remaining lifetime probability after a major fracture is less favourable than the one after breast cancer 14.1.2.1 Vertebral Fractures Vertebral fractures remain most of the time ignored, even if they cause pain Less than 10% result in hospitalisation [9, 10] They may cause acute pain, loss of function and loss of quality of life but may also occur without serious symptoms They occur typically in the mid-thoracic or thoracolumbar regions of the spine [9] In Europe, the prevalence defined by radiological criteria increases with age and is 12% in females (range 6–21%) The age-standardised incidence of morphometric fracture is 10.7 per 1000 person-years in women [11], increasing markedly with age Vertebral fractures often recur New fractures are most likely in nearby vertebrae The consequent disability increases with the number of fractures 14.1.2.2 Distal Forearm (Wrist) Fractures In Europe, the annual incidences of distal forearm fractures in female were 7.3 per 1000 person-years in 2002 [12] Wrist fractures are most likely to occur in women over 65 years old There is an increase in age adjusted between 45 and 60 years of age Then the trend stabilises or slightly increases Functional recovery of distal radial fractures is usually good or excellent [12] 14.1.2.3 Humerus Fractures No reliable figures are available 14.1.2.4 Hip Fractures The worldwide annual incidence of hip fracture is approximately 1.7 million [13] They are more common in northern than in southern countries This might be due to a different duration, intensity and efficiency of sunlight in stimulating vitamin D production in the skin The sex ratio of hip fractures F/M is 4/5 90% of the hip fractures occur in people over 50 years old [14] Hip fracture is associated with serious disability and excess mortality Women who have sustained a hip fracture have a 10–20% higher mortality than would be expected for their age [15] Recovery is slow and rehabilitation is often incomplete, with many patients permanently institutionalised in nursing homes 14.2 General Prevention of Fragility Fractures General prevention of osteoporosis and fragility fractures is not restricted to women at risk It is of utmost importance that general preventive measures are undertaken even without diagnostic investigations to reduce the incidence of osteoporosis and of fragility fractures 14 Healthy Bones After Menopause: What Has to Be Done? 167 Primary prevention of osteoporosis includes all measures preventing the occurrence of osteoporosis Primary prevention starts in adolescence Its target is to obtain an optimal peak bone mass in adolescence and young adulthood, to slow down the physiological decrease of bone mineral density (BMD) after menopause up to the advanced age and to avoid a pathological loss of bone mass leading to osteoporosis Secondary prevention aims at the hindrance of fracture occurrence manifestation in already osteoporotic women In contrast to primary prevention, secondary prevention usually demands a complete investigation before preventive measures can be started Often a specific treatment has to be initiated being beyond the scope of the field of postmenopausal osteoporosis General prevention ensuring a normal bone metabolism includes [16–18]: 14.2.1 Supplementation with Vitamin D • 50–70% of adults living in developed countries are undersupplied with vitamin D [19] In elderly patients suffering from an acute hip fracture, more than 50% display a severe vitamin D deficiency (25-hydroxy-vitamin D = 25-OHD 1500 mg/day may lead to an increased cardiovascular risk, particularly in the presence of renal insufficiency [30–34] 14.2.3 Protein Intake A minimal protein intake of 1 g/kg body weight per day should be guaranteed for the maintenance of the musculoskeletal function Protein deficiency and underweight 168 M Birkhaeuser (body mass index 3 cm? –– Deformities of the spine and other signs for a vertebral compression fracture This often results in the curvature of the spine at the shoulders In older people, this is sometimes called a ‘widow’s hump’ or a ‘dowager’s hump’ –– Indications for other fractures –– Signs pointing to a secondary osteoporosis or a malignancy –– Signs pointing to an increased risk of falls, such as poor sight, muscle weakness, poor equilibrium and coordination and neurological affections 14 Healthy Bones After Menopause: What Has to Be Done? 169 Table 14.1 Clinical risk factors associated with an increased fracture risk in women [16] Women, age Vertebral fractures Oral glucocorticoids >5.0 mg/d Prednisolon equivalents >3 months Cushing syndrome Primary hyperparathyroidism (pHPT) Hypogonadismus (incl premature menopause) Therapy with glitazones Non-vertebral fracture(s) after the age of 50 Therapy with aromatase inhibitors Anti-androgen therapy Rheumatoid arthritis Proximal fracture of the hip in one parent Low body weight (BMI 2 units/day) Multiple falls (more than within the last 12 months) Immobility (cannot leave the house without help by someone else) Diabetes mellitus type TSH levels grade according to Kellgren), significant scoliosis and torsion scoliosis as well as atherosclerosis The results of DXA measurements are express as T-score (Table 14.2) The recommended reference range (IOF) is the NHANES III reference database [39–41] For diagnostic purposes, the Z-score is only used in premenopausal women The prevalence of low BMD and of osteoporosis rises with increasing age At the age of 80 years, 50% of all healthy women have a T-score of ≤2.5 and are therefore osteoporotic There is a significant correlation between age and T-score at the femoral neck and the absolute 10-year fracture risk But normal BMD or osteopenia not protect against hip fractures [8, 17, 35, 42, 43] (Table 14.3) Table 14.2 Densitometric classification at the spine or at the hip of osteoporosis by DXA measurement Status Normal Osteopenia Osteoporosis Severe (established) osteoporosis Hip BMD T-score of −1 or above T-score lower than −1 and greater than −2.5 T-score of −2.5 or lower T-score of −2.5 or lower, and the presence of at least one fragility fracture The World Health Organization has defined a number of threshold values (measurements) for osteoporosis The reference measurement is derived from bone density measurements in a population of healthy young adults (called a T-score) Osteoporosis is diagnosed when a person’s BMD is equal to or more than 2.5 standard deviations below this reference measurement [16, 17] Osteopenia is diagnosed when the measurement is between and 2.5 standard deviations below the young adult reference measurement Table 14.3 Relation between bone mineral density (BMD) and fracture risk BMD Normal Osteopenia Osteoporosis All women N (total) 204 322 142 668 10 years fracture incidence 7% 21% 37% 20% Data from: OFELY study [42] Number of women with fractures (%) 15 (11%) 67 (50%) 52 (39%) 134 (100%) 14 Healthy Bones After Menopause: What Has to Be Done? 171 Limitation to the Use of DXA Osteodensitometry by DXA is not a cost-effective screening method It should be used selectively in function of age and other relevant risk factors 14.3.2.3 Alternative Procedures to Evaluate Bone Density Quantitative ultrasound measurements and peripheral BMD can also provide information about the fracture risk [16, 17, 35] However, before starting osteoporosis treatment, a measurement of BMD by DXA cannot be replaced by ultrasound measurements 14.3.2.4 Scintigraphy In case of suspicion of a malignancy, scintigraphy of the skeleton is recommended (exception: the first step in a suspicion for multiple myeloma is a MRI) 14.3.3 Evaluation of Fracture Risk by FRAX© The individual 10-year risk of osteoporotic fractures can be evaluated by a computer- based algorithm, the Fracture Risk Assessment Tool (FRAX©, www.sheffield.ac.uk/FRAX/; 38, 44, 45) FRAX© is a scientifically validated risk assessment tool, endorsed by the World Health Organization It exists in specific versions for most countries, established by using local epidemiological data FRAX© is based on age and on individual risk factors It can be calculated with or without BMD value at the femoral neck Use of FRAX© without BMD is appropriate when BMD is not available or if individuals should be identified who may benefit from a BMD measurement [16, 17, 35, 38, 44, 45] Where DXA is available, BMD testing can be performed alongside the assessment of fracture probability using clinical risk factors Measurements other than BMD or T-score at the femoral neck by DXA are not recommended for use in FRAX© FRAX© with BMD predicts fracture risk better than clinical risk factors or BMD alone However, there are three important limitations to the use of FRAX®: FRAX® can only be used in women ≥40 years of age and without a treatment of osteoporosis; it is not appropriate to use FRAX© to monitor treatment response; fracture severity cannot be quantified in FRAX© (for additional clinically relevant limitations, see ref 38, 44, 46) The intervention level based on the 10-year fracture probability (%) calculated by FRAX is increasing from the age of 50 to the age of 85 [17, 38, 44, 45] Figure 14.1 shows the intervention threshold set at a fracture probability equivalent to a woman with a previous fragility fracture If DXA has not yet been done, BMD testing is recommended in individuals in whom fracture probabilities (assessed from clinical risk factors alone) are close to the intervention threshold (left-hand panel) This minimises the risk of misclassifying a high-risk patient as low risk and vice versa 172 M Birkhaeuser 10-year fracture probability (%) (Major fractures: spine, hip, humerus, wrist) 40 35 Drug therapy h YES 30 25 20 15 INTERVENTION THRESHOLD 10 No drug therapy 40 45 50 55 60 65 70 75 80 85 90 Age (years) 10-year fracture probability (FRAX®; % (Major fractures: spine, hip, humerus, wrist) Age 50 years 60 years 70 years ≥ 80 years ≥ 13% ≥ 17% 55 years 65 years ≥ 23% 75 years ≥ 28% ≥ 10% ≥ 20% ≥ 33% Fig 14.1 Intervention in women without fractures [16] 14.3.4 Other Diagnostic Steps Biochemical analysis should be done in the presence of fractures combined with indications from medical history and/or clinical examinations for particular fracture risks due for secondary osteoporosis In this review, the further diagnostic steps in secondary osteoporosis are not discussed (see [16, 17, 35]) Bone Turnover Markers Although bone turnover markers (BTMs) may predict fracture risk independently from BMD in postmenopausal women, they are not used 14 Healthy Bones After Menopause: What Has to Be Done? 173 for screening purposes [16, 17, 35] BTMs are used for monitoring treatment in the individual As adherence is an important issue of long-term therapy in chronic disease, some BTM (mainly s-CTX and s-PINP) may be used in clinical practice to assess the patient’s adherence to treatment [17, 47, 48] Clinical Diagnostic Tests The evaluation of muscle strength and coordination is important in elderly women prone to falls The risk of falls can be effectively evaluated by examinations such as the ‘timed up and go test’ or the ‘chair-rising test’ in combination with the ‘tandem stance test’ (for further information, see DVO (www dv-osteologie.org; [16, 17, 35])) 14.4 M enopausal Hormone Therapy (MHT) Including Tibolone for Fracture Prevention 14.4.1 Oestrogen and Oestrogen + Progestin 14.4.1.1 Efficacy Bone architecture and quality has to be maintained as early as in the peri- and early postmenopause Prescription of MHT for primary prevention of fragility fractures should be part of an overall preventive strategy including general preventive measures and lifestyle recommendations (see above) In peri- and postmenopausal women at risk of fracture and younger than 60 years or within 10 years of menopause (‘window of opportunity’), the International Menopause Society (IMS) recommendations on MHT and preventive strategies for midlife health, updated in 2016 [49], consider MHT as one of the first-line therapies for the prevention and treatment of osteoporosis-related fractures, because a first vertebral fracture should be avoided Although treatment of osteoporosis can reduce the increased risk for a subsequent fracture, it cannot eliminate the excess risk of a first fracture Oestrogen deficiency leads to a rapid loss of BMD. Already before 2002, some RCTs, many observational studies and several meta-analyses documented that MHT prevents menopausal bone loss when begun around or early after menopause [50–53] In contrast to all trials done with selective oestrogen receptor modulators (SERMs), bisphosphonates, denosumab or strontium ranelate, the WHI trial using MHT is the first RCT demonstrating that a therapeutic intervention reduces the risk of fractures in women without increased fracture risk at the hip, vertebrae and wrist and with mean T-scores in the normal to osteopenic range [49, 54–59] These data are consistent with the earlier observational data and meta-analyses mentioned above [50–53] In the CEE + MPA study, active therapy reduced (in the global analyses) all fractures significantly by 24% (RR, 0.76; 95% CI, 0.69–0.83) and hip fractures by 33% (95% CI, 0.47–0.96) In the CEE-alone study, CEE reduced all fractures by 29% (RR, 0.71; 95% CI, 0.45–0.94) and hip fractures by 29% (RR, 0.71; 95% CI, 0.64–0.80) (see Table 14.4; [54, 56]) Regarding the effect of therapy on all fractures, a beneficial effect was seen in all groups categorised by decade after menopause If the fracture data are analysed both by decade of age and by decade after menopause, the MHT effect on hip fractures (but not on vertebral fractures) ... Reports /20 10/Dietary-Reference-Intakes-for-Calcium -and- Vitamin-D/Report-Brief.aspx 20 10 30 Ross AC, Manson JE, Abrams SA et al (20 11) The 20 11 report on dietary reference intakes for calcium and vitamin D from the Institute... 49:1063–1069 27 Pilz S, Dobnig H, Nijpels G et al (20 09) Vitamin D and mortality in older men and women Clin Endocrinol 71:666–6 72 28 Giovannucci E, Liu Y, Hollis BW, Rimm EB (20 08) 25 -hydroxyvitamin D and. .. CH-40 52, Basel, Switzerland e-mail: martin.birkhaeuser@balcab.ch © International Society of Gynecological Endocrinology 20 18 M Birkhaeuser, A.R Genazzani (eds.), Pre -Menopause, Menopause and Beyond,