Abstract
Menopause has an overall adverse impact on musculoskeletal health. It is associated with osteoporosis, osteoarthritis and sarcopenia [1]. Osteoporosis and related fractures, together with the consequent pain and locomotor disability, affect the quality of life and life expectancy of postmenopausal women. Poor musculoskeletal health may progress to frailty and higher incidence of falls and fractures, which further increase the associated morbidity and mortality [1]. This leads to high economic costs worldwide [1, 2].
Menopause has an overall adverse impact on musculoskeletal health. It is associated with osteoporosis, osteoarthritis and sarcopenia [1]. Osteoporosis and related fractures, together with the consequent pain and locomotor disability, affect the quality of life and life expectancy of postmenopausal women. Poor musculoskeletal health may progress to frailty and higher incidence of falls and fractures, which further increase the associated morbidity and mortality [1]. This leads to high economic costs worldwide [1, 2].
The fact that female sex hormones play an important role in the aetiology and pathophysiology of a variety of musculoskeletal degenerative diseases and osteoporosis, is supported by the increased prevalence of these conditions in postmenopausal women [3]. For example, low back pain is commoner in postmenopausal women than age-matched men, and this is associated with the physiological changes caused by the relatively lower level of sex hormones after menopause in women [3, 4].
The pathophysiology of osteoporosis, which is characterized by progressive loss of bone tissue, is multifactorial and complex. Various cytokines, mediators and signalling pathways in combination with genetic, hormonal and environmental influences regulating the bone remodelling process are involved. The presence of osteoporosis especially in the mother and the existence of previous fractures are significant risk factors for the occurrence of osteoporosis [5]. The development and differentiation of osteoblasts and osteoclasts is tightly controlled by growth factors and cytokines synthesized in the bone marrow microenvironment in order to maintain a dynamic equilibrium between their formation, survival and function. Women with low BMD have higher levels of adipokines, and lower levels of markers of bone turnover such as PINP, PINP/CTX ratio in their circulation as compared to those with normal BMD [6]. The increase in osteoclastogenesis and impaired osteoblastogenesis, rather than the alteration in the activity of these cells, are responsible for postmenopausal osteoporosis [7].
The Role of Estrogen in Bone Turnover
Estradiol levels are significantly lower in women with low BMD of the hip and spine [6]. Estrogen regulates the secretion of cytokines involved in bone homeostasis exerting a role in bone remodelling. It inhibits the formation of locally produced pro-inflammatory cytokines and suppresses new osteoclast formation.
When there is oophorectomy, this leads to a significant increase in bone resorption. This occurs because a decline in circulating estrogen results in an increase in osteoclastogenesis and prolongation of osteoclasts’ lifespan by decreasing apoptosis. However, the unlimited rise in osteoclasts number and lifespan is restrained by a compensatory increase in bone formation at each remodelling unit. Estrogen deficiency causes expansion of the pool of early mesenchymal progenitors as well as an increase in committed pluripotent precursors to the osteoblastic lineage, both enhancing the number of osteoblasts. However, lack of estrogen limits osteoblastogenesis by accelerating osteoblast apoptosis and enhancing the formation of inflammatory cytokines such as IL-7 and TNF, which inhibit the functional activity of mature osteoblasts. Thus, the overall increase in osteoblastogenesis is insufficient to compensate for osteoclastic bone resorption [8].
Decreased levels of bioavailable estradiol inhibit the activity of osteoblasts and stromal cells. This results in decreased osteoprogenitor secretion permitting more binding of RANKL to receptor activator of nuclear factor kappa-B (RANK) hence increasing osteoclastogenesis and bone resorption. In postmenopausal osteoporosis, the increase in bone resorption is brought about by a rise in paracrine production of bone resorbing cytokines. Decreased estradiol levels also increase the expression and secretion of IL-6, IL-11 and RANKL, which in turn directly activate more osteoclasts formation and activity. The secretion of these cytokines is significantly higher in bone marrow cells isolated from postmenopausal women [8, 9].
Menopausal hormone therapy (MHT) involves the administration of physiologic levels of estrogen and progestogen to replace and artificially boost the hormones which decline during menopause. MHT maintains a steady rate of bone loss in osteoporotic patients. It elevates calcium absorption and as a result of a decline in the bone resorption rate, bone balance is either maintained or becomes slightly positive. This positive bone balance is mainly pronounced in trabecular bone while bone mass is maintained in areas of the skeleton rich in cortical bone.
Estrogen is known to inhibit osteoclasts’ activity. It causes a decline in erosion depth and osteoclast activation frequency by inducing apoptosis which is mediated by TGF-β and suppressing osteoclastogenesis. The decline in bone resorption is also mediated by a reduction in the formation and sensitivity of bone cells to IL-6, IL-1 and TNF-α and increase in the formation of IL-4. This causes a decrease in the differentiation of precursor cells to osteoclasts. Additionally, administering MHT to postmenopausal women causes a decline in proportion of bone marrow cell to express RANKL in lymphocytes but its concentration per cell is not altered. Hence, a decline in the osteoclasts’ formation, differentiation and survival is observed. Moreover, estrogen reduces the lytic enzyme activity of osteoclasts, alters the concentration of growth factors and interferons and affects bone collagen metabolism [9].
As estrogen receptors are present on osteoblasts, estrogen supplied through MHT acts directly on such receptors to prevent bone loss. Long-term treatment with MHT administered at high doses not only decreases bone resorption but also activates bone formation by enhancing proliferation of osteoblasts resulting in a net anabolic action. This is known to result from the non-genotropic effect of estrogen on osteoblast apoptosis [9].
The indirect action of estrogen involves decreasing the responsiveness of bone to parathyroid hormone (PTH) and altering its secretion. It also elevates intestinal absorption and reduces the renal excretion of calcium.
Epidemiological studies have shown that a short-term treatment with MHT decreases the occurrence of osteoporotic fractures. It has been determined that undergoing estrogen therapy for 5 years reduces vertebral fractures by 60 per cent whilst hip fractures may decline by 50 per cent. Generally, by using estrogen treatment, bone turnover is reduced by half, decreasing postmenopausal bone loss and lowering the incidence of an osteoporotic fracture. However, once treatment with MHT is terminated, estrogen level declines and protection against osteoporosis is lost again. Most studies suggest that bone loss will progress at the same rate prior to treatment with MHT. Thus the accelerated bone loss during menopause is postponed by the duration of MHT treatment. To date, trabecular bone score, an indirect evaluation of skeletal microarchitecture, is calculated from dual-energy X-ray absorptiometry (DEXA) [10]. Several biomarkers have been studied as potential predictors of osteoporosis. One promising marker is urinary N-telopeptide U-NTX can be used early in the menopause transition to determine if a woman is about to experience significant bone loss, especially in the lumbar spine, before there is been substantial skeletal deterioration [11].
MHT has been shown to be highly effective in preventing postmenopausal osteoporosis during the first 5–10 years following the onset of menopause and treatment should be continuous and lifelong. This is because the rate of bone loss is the highest during the first 2 years of menopause. However, studies suggest that when estrogen therapy is initiated beyond the age of 60 years, BMD is either maintained or increased after 2 years of use. The increase in bone mass in such patients is a result of a decline in bone resorption more than bone formation. Women who initiate HRT at an older age, gain 5–10 per cent of bone density during the initial 2 years of therapy and then lose 0.5 per cent of bone density each year. Studies suggest that estrogen therapy initiated in the early sixties is as advantageous as continuous treatment that began immediately after menopause. When MHT is discontinued, 2 per cent of bone density is lost each year for 5 years and 1 per cent each year thereafter [7].
Progestogens (either natural progesterone, or a progestin, which is a synthetic analogue) decrease the rate of bone resorption as they reduce urinary calcium excretion. Administration of progestogen in combination with estrogen not only decreases the rate of bone loss but it has been proven to promote bone formation by enhancing osteoblasts’ activity via suppression of glucocorticoid action. A number of studies have shown the positive effect of progesterone on bone proliferation and inhibition of bone resorption. Administration of estrogen and progestogen alone may have distinct yet complementary roles in the maintenance of bone architecture.
Intervertebral Discs
Each intervertebral disc is composed of high collagen content and glycosaminoglycans. Intervertebral discs are responsible for 20 per cent of the spinal column height and allow flexion and extension of the back, and also act as ‘shock absorbers’ of the spinal column. This may have an important role on osteoporotic compression fractures. With the ageing process, there is a change in collagen type, with a more profound difference with increasing years since menopause. The collagen types I, III and VI predominate at the expense of collagen types II, IV and IX. There is also a significant decrease in glycosaminoglycans and elastin in the aged intervertebral disc.
The lumbar intervertebral disc height as measured by DEXA bone densitometry has been shown to be significantly higher in the premenopausal group and hormone-treated group, compared to the untreated postmenopausal women. The premenopausal women and hormone-treated women had disc heights of 2.01 ± 0.09 cm and 2.15 ± 0.08 cm, respectively, the latter results being significantly higher than the untreated postmenopausal group (height of three lumbar discs 1.82 ± 0.06 cm) and the osteoporotic fracture group (1.58 ± 0.1 cm) (p < 0.0001) [12]. This association between menopause and disc degeneration in the lumbar spine has further been confirmed using a magnetic resonance imaging-based eight-level grading system, and has been shown to occur in the first 15 years after the menopause [13, 14].
This does strongly suggest that estrogen deficiency might be a risk factor of disc degeneration of the lumbar spine. This may lead to loss of the shock-absorbing properties of the intervertebral discs and an altered discoid shape, influencing the occurrence of osteoporotic vertebral body fractures. Hormone-treated and premenopausal women have thicker intervertebral discs than untreated postmenopausal women. Alterations in the extracellular matrix in the intervertebral discs appear to be intimately related to the menopausal process. Loss of disc height may predate osteoporotic fracture [12].
Postmenopausal women show accelerated disc degeneration due to relative estrogen deficiency, resulting in narrower intervertebral disc space in women than age-matched men, increased prevalence of spondylolisthesis, and increased prevalence of facet joint osteoarthritis [4]. Postmenopausal women also show higher osteoporosis-related spine fracture rate, particularly at the thoracic-lumbar junction site [4].
In rat models ovariectomy induces oxidative stress, autophagy and intervertebral disc degeneration. The level of autophagy of the intervertebral disc, which is negatively correlated with oxidative stress, can be reduced by estrogen replacement therapy through modulating the redox balance and downregulating the autophagy level [15].
Similarly, menopause has also been associated with cartilage degeneration of the knee joint. After menopause, cartilage showed progressive severe degeneration that occurred in the first 25 years after the menopause, suggesting estrogen deficiency might be a risk factor of cartilage degeneration of the knee joint. Further studies are needed to investigate whether age or menopause plays a more important role in the progression of cartilage degeneration in the knee joint [16].
Considering MHT’s consistent efficacy reported with menopause-associated osteoarthritis and osteoporosis, an in-depth understanding of the role of the gonadal hormones in low back pain modulation warrants further study. MHT initiated at early postmenopausal phase may be protective for recurring low back pain. If this is the case, further cost–benefit analysis should be performed for optimal MHT regimen in cases of women with high risk of recurring severe low back pain [4].
Muscle
Sarcopenia includes age-related muscle wasting as well as loss of muscle function. It is a relatively newly recognized condition and is known to be accelerated by estrogen deficiency [1]. In menopause, there is a decline in muscle mass and strength when serum estrogen declines. Estrogen improves muscle strength. The underlying mechanism involves estrogen receptors to improve muscle quality rather than quantity. MHT attenuates exercise-induced skeletal muscle damage in postmenopausal women. Postmenopausal women not using hormonal therapy experience greater muscle damage. MHT modifies skeletal muscle composition and function. It gives better mobility, greater muscle power, prevents muscle weakness and thus prevents mobility limitation [17].
Many elderly postmenopausal women experience physical disabilities and loss of independence related to sarcopenia, which reduces life quality and is associated with substantial financial costs. There is inverse correlation between dominant hand grip strength (measured with a digital dynamometer) and age, and earlier age at menopause was associated with an increased dynapenia risk [18].
Thus, in order to maintain the integrity of the musculoskeletal system, the main recommendations are to do regular physical exercise, maintain protein intake and in the postmenopause, consider estrogen replacement. Resistance training and dietary optimization can counteract or at least decelerate the degenerative ageing process, but lack of estrogen in postmenopausal women may reduce their sensitivity to these anabolic stimuli and accelerate muscle loss.
Tendons and ligaments are also affected by sex hormones, but the effect seems to differ between endogenous and exogenous female hormones and seems to depend on the age, and as a result influence the biomechanical properties of the ligaments and tendons differentially. Since it seems to play a significant role with regard to skeletal muscle protein turnover, estrogen/hormonal replacement therapy may counteract the degenerative changes in skeletal muscle [19]. Women differ from men with regard to muscle and tendon, most likely because of sex differences in estrogen. Experimental findings support the hypothesis that estrogen has an anabolic effect on muscle primarily by lowering the protein turnover and enhancing sensitivity to resistance training. Furthermore, estrogen may reduce the stiffness of tendons, an effect that may be modified by physical training [20].
In response to acute estrogen treatment, FOXO3 activation (dephosphorylation) and MuRF1 protein expression were shown to decrease in early postmenopausal women but increase in late postmenopausal women (p < 0.05). Preliminary studies suggest the effects of estrogen treatment on skeletal muscle protein breakdown markers are dependent on time since menopause [21].
Nevertheless, there is a need for greater insight into the direct and indirect mechanistic effects of female hormones before any evidence-based recommendations regarding type, dose, duration and timing of hormone replacement therapy can be provided.
Treatment and Alternatives
As long as their benefits and risks are assessed on an individual basis, and each patient is aware of the risks, older women with continuing symptoms should not be denied MHT. In fact, the key recommendation of most societies, including the British Menopause Society, is that all women should be able to access advice on how they can optimize their menopause transition and beyond, with particular reference to lifestyle and diet and an opportunity to discuss the pros and cons of complementary therapies and HRT [22]. A global consensus statement on menopausal MHT concludes that it is effective and appropriate for the prevention of osteoporosis-related fractures in at-risk women before age 60 years or within 10 years after menopause [23].
Effective prophylactic strategies are needed for the suppression of age-related muscle wasting and bone loss after menopause. The effect of exercise is now taking a more central role in the prevention and as an adjuvant treatment for postmenopausal-related musculoskeletal degeneration. Higher volumes of exercise, especially impact exercise, lead to a smaller decline in total bone mineral density, which may remain following intervention completion [24]. Aerobic dance intervention was also shown to result in a lower incidence of bone fracture through increasing BMD and decreasing fall risk for postmenopausal women [25]. In ovariectomized rats, interval running significantly inhibited the expression of inflammatory molecules, and improved antioxidant activity via down-regulation of mitogen-activated protein kinases (MAPKs) in the ageing-induced ovariectomized rats skeletal muscle. When compared with continuous running, interval running improved muscle mass and growth in these rats by promoting muscle growth-related factors including MyoD, myogenin, phospho-mechanistic target of rapamycin (p-mTOR), sirtuins (SIRTs), and bone morphogenic proteins (BMPs). This also effectively reversed bone loss via the down-regulation of bone resorption and osteoclast formation in receptor activator of nuclear factor κB ligand (RANKL)-treated bone marrow macrophages (BMMs). There was also an increased expression of SIRT1 and 6, which promoted osteogenic differentiation and bone formation via modulating the BMP signalling pathway compared with continuous training [26].
The use of calcium with or without vitamin D supplements is associated with less BMD loss of the lumbar spine and femoral neck, especially in premenopausal women [27].
Selective estrogen receptor modulators (SERMs), such as raloxifene, now have a more central role in the prevention and management of postmenopausal osteoporosis. SERMs act through estrogen receptors and are agonists for bone and antagonists for breast and uterine tissue. Bisphosphonates are also widely used. Zoledronic acid infusion combined with percutaneous kyphoplasty could provide more benefits in the treatment of T12 or L1 osteoporotic vertebral compression fracture [28]. Also there are newer drugs which act by interplaying with cytokines [29] (Table 13.1).
Table 13.1 Current pharmacological agents indicated for the treatment of postmenopausal osteoporosis
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