‘Bone Health—Across a Woman's Lifespan’

ABSTRACT

Despite a high burden of osteoporosis and minimal trauma fractures worldwide, there is still a treatment gap in timely diagnosis and optimal treatment. There is also a lack of international consensus and guidelines on the management of bone fragility in premenopausal women. This review article provides an overview of the current understanding of factors impacting women's bone health across the adult lifespan, as well as dilemmas in the diagnosis, assessment and management of osteoporosis in premenopausal and postmenopausal women, premature ovarian insufficiency and bone health following breast cancer.

1. Introduction

Osteoporosis, characterised by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue, leads to an increased risk of fragility (minimal trauma) fractures. Osteoporosis (defined as T‐score < ‐2.5 standard deviations (SD) on dual‐energy x‐ray absorptiometry (DXA) or history of minimal trauma fracture) affects one in two women over the age of 50 [1]. In premenopausal women, the definition of osteoporosis is less clear, though commonly defined as previous fragility fracture or Z‐score ≤ ‐2 SD on DXA; it particularly occurs in the context of chronic disease and medications that affect bone metabolism. The incidence of minimal trauma fractures increases with age. In older women, the lifetime risk of a minimal trauma fracture is higher than the risk of ischaemic heart disease or breast cancer (~ 44%) [2].

Despite a high burden of osteoporosis worldwide, there is still a treatment gap in timely diagnosis and optimal treatment of this condition. Bone fragility in premenopausal women, in particular, is poorly understood and under‐represented in guidance documents on the management of bone fragility. We aim to provide an overview of the current understanding of factors impacting women's bone health across the adult lifespan, as well as discuss current dilemmas in the diagnosis, assessment and management of osteoporosis. This review article will focus on bone health in ciswomen (assigned female at birth). There is a growing understanding of the importance of bone health and the impact of hormone therapy on BMD in transwomen ‐ outlined further by Rothman & Iwamoto in 2019 (https://doi.org/10.1007/s12018-019-09261-3).

1.1. Overview of Osteoporosis

International guidelines recommend fracture risk assessment in all post‐menopausal women, with consideration given to the assessment of clinical risk factors and secondary drivers of osteoporosis and accelerated bone loss (as described in Table 1) [3, 4, 5, 6]. Where there is clinical concern, DXA screening is advised along with optimisation of relevant modifiable risk factors. Following a minimal trauma fracture, all patients should be screened for risk factors, regardless of BMD, to mitigate risk of future fractures.

TABLE 1.

Clinical risk factors and potential secondary drivers of osteoporosis and accelerated bone loss.

Non‐Modifiable
Age
Sex (female)
Paternal or maternal history of hip fracture
Family history of osteoporosis
Race (Caucasian, Asian)

Modifiable
Smoking
Alcohol
Low BMI
Low calcium and vitamin D intake
Prolonged immobility

Secondary causes of osteoporosis
Endocrine
Primary hyperparathyroidism
Hyperthyroidism
Cortisol excess
Premature menopause or hypogonadism
Gastrointestinal
Liver disease
Inflammatory Bowel Disease
Coeliac disease and other malabsorptive diseases
Haematological
Disorders of red blood cells such as thalassaemia
Multiple myeloma and myeloproliferative diseases
Renal
Chronic kidney disease
Hypercalciuria
Other
Rheumatoid arthritis and other inflammatory arthritis
Anorexia Nervosa and other eating disorders
Neuromuscular disease
Post‐transplant
Medications
Glucocorticoids
Antiepileptics
SSRIs
PPI
Intramuscular medroxyprogesterone acetate (Depo‐provera)
Aromatase inhibitors

A comprehensive clinical assessment including DXA is recommended in premenopausal women with fragility fracture, or an underlying chronic disease affecting bone metabolism (see Table 1) [4, 7]. However, routine DXA screening is not recommended in premenopausal women without risk factors. For those without a clear underlying cause for fragility fracture, genetic screening may be appropriate particularly in the presence of clinical and biochemical characteristics which increase suspicion of a genetic condition such as osteogenesis imperfecta, hypophosphatasia or other genetic syndromes with a phenotype of increased fracture risk [8]. The yield has been shown to be higher if testing is targeted in young adults < 55yo with two or more peripheral fractures, high normal BMI, and/or a positive family history of osteoporosis [9]. Important considerations in determining whether genetic testing is pursued include the likelihood of changes to management, potential impact on family planning and, of course, accessibility of tests.

2. Changes in Bone Mass Across the Lifespan

2.1. Peak Bone Mass

Peak bone mass (PBM) is the maximum amount of bone an individual has by the time a stable skeletal state has been reached during young adulthood. During childhood, bone mass slowly increases but then doubles during puberty between the ages of 8–18 years [10, 11]. The Canadian CaMOS study found the timing of PBM was dependent on skeletal site and sex. Areal BMD (aBMD) at the femoral neck peaked at ages 16–19 in females and 19–21 years in males, whereas lumbar spine aBMD peaked at ages 33–40 in females and 19–33 in males [12].

Genetic factors account for up to 80% of the variance in PBM [13]. However, modifiable factors such as weight bearing physical activity, hormonal status and calcium intake influence whether the genetically pre‐determined PBM is obtained, as shown in Figure 1. Altered pubertal development can have long lasting consequences on adult bone health, which has been demonstrated in a wide range of conditions including Turner syndrome, Klinefelter syndrome and hypogonadotrophic hypogonadism seen in anorexia [14]. Chronic illness in childhood may impact nutrition, physical activity levels and hormonal status leading to poor accrual of bone, which is further compounded by factors specific to the disease, such as inflammation and medication use (particularly glucocorticoids). Conditions listed in Table 1 can all negatively impact PBM and lead to the earlier development of osteoporosis.

FIGURE 1.

Bone mass across the lifespan.

The National Osteoporosis Foundation found high grade evidence for calcium intake and physical activity for development of peak bone mass in a recent systematic review [11]. Recommended daily intake (RDI) of calcium in children aged 9–18 ranges between 1000 and 1300 mg per day. Levels of physical activity and type of physical activity most beneficial to bone health have not been determined, although randomised control trials identified in children beneficial to bone health mostly focused on jumping. Vitamin D supplementation has variable effects on bone density dependent on baseline vitamin D level, calcium intake, stage of puberty and compliance [11, 15]. Improvements in BMD with vitamin D supplementation are small and mostly seen in those who are vitamin D deficient < 50 nmol/L [15].

Large population studies show that following PBM accrual, trabecular bone loss commences from the third decade of life, continuing post‐menopause [16]. However, these changes in bone mass early in life are not typically associated with fracture.

Pregnancy and breastfeeding induce physiological changes to calcium metabolism to nourish the growing foetus and neonate respectively. Maternal intestinal calcium absorption is increased, mediated largely by increased parathyroid hormone‐related peptide (PTHrP) and 1,25(OH)₂‐Vitamin‐D₃ levels which peak in third trimester. Changes to placental lactogen, insulin growth factor‐1 (IGF‐1), oestradiol and prolactin in pregnancy also may have effects on bone metabolism in the pregnant woman. Studies assessing changes to aBMD in pregnancy are limited and report conflicting data. Longer term, pregnancy is thought to protect against aBMD loss [7], while other studies demonstrate an association between high parity (> 5) have shown lower aBMD in these women [17].

During lactation, skeletal demineralisation supports the growing foetus and is moderated through mammary PTHrP. Intestinal absorption of calcium is not increased in lactating women, contributing further to the imbalance in skeletal mineral content, and thus aBMD can reduce up to 10% during breastfeeding. However, bone density recovers within 12 months of weaning; measurement of aBMD within this timeframe is therefore not recommended [18].

2.2. Important Considerations for Osteoporosis in Premenopausal Women

2.2.1. Diagnostic Challenges

There is a lack of international consensus regarding appropriate diagnostic criteria for osteoporosis in premenopausal women. The International Osteoporosis Foundation (IOF) and the European Calcified Tissue Society together recommend the diagnosis of osteoporosis in premenopausal women with vertebral and/or multiple fragility fractures with low aBMD, defined by the IOF as a Z‐score ≤ ‐2 prior to 20 years of age, and a T‐score < ‐2.5 in older premenopausal women who have attained peak bone mass [19]. The IOF also recognises aBMD T‐score < ‐2.5 at the spine or hip in a premenopausal woman with an underlying chronic disease affecting bone metabolism, as consistent with osteoporosis [8]. The IOF recommends use of T‐scores in premenopausal women to maintain consistency with the World Health Organisation criteria for postmenopausal osteoporosis but acknowledges the recommendations by the International Society of Clinical Densitometry to report Z‐scores rather than T‐scores in premenopausal women [20]. For Z‐scores, a comparison to average age‐matched and sex‐matched BMD, a score ≤ ‐2 is classified as ‘below the expected range for age’. This is particularly relevant when assessing younger adults as factors other than osteoporosis may also contribute to low bone density, such as low peak bone mass and osteomalacia due to an underlying chronic disease or other factors described above [20]. For clarity and to maintain consistency with much of the published literature, we have used the term osteoporosis in premenopausal women presenting with fracture (regardless of bone density) and ‘low bone density’ to identify premenopausal women presenting with aBMD Z‐score ≤ ‐2 without fracture.

Central to the controversy surrounding diagnosis of osteoporosis is the low rate of incident fracture in premenopausal women. As a result, the correlation between low aBMD and incident fracture is weak [21]. However, it is also important to recognise that premenopausal women who fracture are at 30% higher risk of sustaining a fracture in their early postmenopausal years, although there is no data to determine whether early intervention attenuates this risk [22].

Despite these complexities, the limited available guidance recommends assessment with DXA in premenopausal women presenting with fragility fracture and that a bone health assessment investigating for a secondary cause is conducted in all premenopausal women with fragility fracture and/or low bone density on DXA without a clear secondary driver [8, 16, 19].

Low bone density without fracture is a challenging clinical entity in premenopausal women. While in postmenopausal women, low bone mass is largely due to increased bone resorption, in premenopausal women, reduced PBM can also contribute. This may be due to physiological factors such as small bone size, genetics and constitutional leanness which are not typically associated with increased risk of fracture. Isolated low BMD is also associated with delayed menarche, oestrogen deficiency, androgen excess, low BMI, low muscle mass and a family history of osteoporosis; the predictive value of these factors along with low bone density in identifying women at higher risk of incident fragility fracture has not been ascertained. It is prudent to ensure that osteomalacia, risk factors for low PBM attainment and secondary causes for osteoporosis are excluded in women with isolated low bone density. Importantly, premenopausal women with isolated low bone density and those presenting with fragility fracture without an underlying cause (i.e. idiopathic osteoporosis (IO)) have both shown evidence of reduced mineralisation [23] and microarchitectural changes [24] affecting cortical and trabecular bone.

IO in premenopausal women is rare and is associated with reduced bone formation secondary to osteoblast dysfunction [25]. Bone turnover in IO is heterogeneous with groups of women demonstrating low‐normal bone formation rate while others have high bone‐formation rates. Teriparatide has shown to be effective in improving aBMD at the lumbar spine (+ 13.2% (95% CI: 10.3, 16.2) and femoral neck 5.0% (95% CI: 3.2, 6.7) in premenopausal women [26]. The implications of the varied bone formation rates require further delineation.

2.3. Causes of Secondary Osteoporosis Specific to Premenopausal Women

2.3.1. Menstrual Disorders

Functional hypothalamic amenorrhoea (FHA) is commonly associated with elite athletes. However, FHA should be considered in any woman who presents with low bone density/fracture, oligo/amenorrhoea and caloric deficit in the absence of other explanations. FHA requires multidisciplinary input with dietician and physiotherapist involvement to aid in assessment and management of relative caloric deficit and moderation of exercise, respectively. Suppression of the hypothalamic‐pituitary‐gonadal (HPG) axis is responsible for menstrual disruption, oestrogen balance, bone accrual and turnover. At non‐weight bearing sites, amenorrhoeic adolescents and young adult females have lower stiffness and failure load than eumenorrheic controls [27]. Caloric (and weight) restoration is key in caring for women with FHA, with psychological input important in the context of an eating disorder, and guidance around moderation of exercise to aid in menstrual resumption. If unsuccessful, or where delays to achieving these are likely, transdermal oestrogen replacement is recommended. Data for use of the combined oral contraceptive pill (COCP) for bone health in these women is not as robust and suppresses the physiological HPG axis and is therefore not recommended for women with FHA. Non‐oestrogen‐based contraception should be considered.

2.3.2. Contraception

There is robust evidence for the detrimental effects of intramuscular medroxyprogesterone acetate (DMPA) on bone density and fracture risk [28]. DMPA suppresses gonadotrophin secretion, inhibiting ovarian oestradiol production and has consistently shown to reduce aBMD with prolonged use. Women under 30 years of age exposed to DMPA for > 3 years were found to have three times higher risk of incident fracture [29].

For women at high risk of bone loss or fracture, there is conflicting data surrounding the use of the COCP for contraception, with no robust data to suggest that it benefits bone density [30].

2.3.3. Pregnancy and Lactation Induced Osteoporosis (PLO)

Fracture during pregnancy, particularly the third trimester, and lactation are rare but occur in the context of extreme changes to bone metabolism during this time, in women with or without prior low bone density. Vertebral fractures are commonly reported in PLO, although underdiagnosis and delayed diagnosis is common as symptoms overlap with expected musculoskeletal changes and ionising radiation is avoided in pregnancy. Musculoskeletal changes occurring in pregnancy are also thought to contribute to peri‐partum hip and lower limb fractures.

It is important to counsel affected women on the impact of continued breastfeeding on progressive bone loss, and an individualised approach which considers fracture risk, symptoms as well as the benefits of continued breastfeeding to both mother and baby is required.

Teriparatide improves aBMD in women with PLO [31], with reports of symptomatic relief within 1‐3 months of teriparatide commencement. Evidence for fracture prevention is lacking. Intravenous zoledronic acid and alendronate has also been used [32], but careful consideration is needed with counselling regarding the lack of robust foetal safety data. Avoiding conception within 12 months of treatment is recommended [33].

2.4. Breast Cancer

Breast cancer is the most common cancer in women globally, with an expected incidence of 3.2 million by 2050 [34]. Due to improved access to screening and therapeutic options, breast cancer survival continues to improve. Recognition of the adverse effects of breast cancer therapies on bone health is important and has led to international guidelines to prevent and manage bone fragility in these women [35, 36].

Mechanisms leading to bone loss in breast cancer include oestrogen deprivation secondary to therapies (chemotherapy, ovarian ablation and adjuvant endocrine therapies); menopause and concomitant medications such as high‐dose glucocorticoids. The majority of breast cancers are oestrogen receptor positive and the use of adjuvant endocrine therapy with tamoxifen, gonadotropin‐releasing hormone (GnRH) agonists and aromatase inhibitors (AIs) improves disease free survival.

In premenopausal women, tamoxifen is associated with bone loss, whereas it is bone‐sparing in postmenopausal women (see Figure 2). Aromatase inhibitors (AIs) improve disease‐free survival compared with tamoxifen but are associated with significant bone loss and increased fracture risk [37]. A meta‐analysis of adverse effects of adjuvant endocrine therapy reported a 47% increased fracture risk with AI use compared with tamoxifen [38]. AIs are also used in association with GnRH agonists in premenopausal women and induce profound oestrogen deficiency with a 17.3% loss of BMD within 3 years compared with baseline.

FIGURE 2.

Annual lumbar spine BMD change with adjuvant endocrine breast cancer therapy. Adapted and updated from ‘Assessment and management of bone health in women with oestrogen receptor‐positive breast cancer receiving endocrine therapy: Position statement of the Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society, the Australasian Menopause Society and the Clinical Oncology Society of Australia’.

2.5. Premature Ovarian Insufficiency

Premature ovarian insufficiency (POI), defined as the loss of ovarian function before the age of 40, affects approximately 4% of women globally [39]. Among the various physical and psychological consequences of POI, the impact on bone health is particularly significant due to hypoestrogenism and other POI‐associated factors. While the degree of bone health impairment relates to the duration of amenorrhea, in typical postmenopausal women annual bone loss of up to 2% has been reported [40, 41]. Depending on age of onset, bone health deficits may result from a combination of impaired bone accrual and increased bone resorption.

As shown in Figure 3, the net effect of decreased oestrogen levels at the cellular level is increased osteocyte and osteoblast apoptosis, decreased osteoclast apoptosis, and increased RANKL‐mediated differentiation [42]. Women with POI face initially more rapid trabecular bone loss followed by prolonged slower loss of cortical bone, contributing to long‐term bone fragility and increased fracture risk [42].

FIGURE 3.

The impact of oestrogen deficiency and menopause on bone mineral density and bone turnover.

The prevalence of osteoporosis, with increased fracture risk, is increased in women with POI [43]. However, data on fracture prevalence in this population remains limited. One longitudinal study of Australian women, with a mean age of 68 years and a 23‐year follow‐up, found that women with POI or early menopause (EM) have a higher risk of fracture (odds ratio 1.45; 95% CI 1.15–1.81) compared with those experiencing menopause at the typical age [44]. Additionally, a meta‐analysis indicated that early menopause is associated with an elevated fracture risk compared to menopause at the usual age [45].

Conventional BMD measurements have previously shown significantly lower BMD (spine and hip) in POI compared to women with usual age at menopause [46]. Further research tools have shown lower trabecular bone score (TBS), altered geometry, and reduced bone strength [47, 48]. However, validated fracture risk score mechanisms in these young women require more research, as FRAX and other scores are not validated in women < 40 years.

2.6. Postmenopausal Osteoporosis

Fragility fractures in older adults remain a significant burden with an estimated 1 in 2 lifetime risk of sustaining an osteoporotic fracture after the age of 50 years in women [1]. Risk factors for osteoporosis in older adults vary significantly from those affecting younger adults < 50 years old, although there is a legacy BMD effect from risk factors causing accelerated bone loss earlier in life. Oestrogen is one of the major regulators of bone health and metabolism in women (as described in Figure 3), reducing bone resorption, lowering bone mass sensitivity to PTH, improving intestinal calcium resorption, and reducing renal calcium excretion [49].

Following the initial rapid trabecular loss with 1%–2% annual BMD decline immediately following menopause, there is a longer 10–20 year period of slower bone loss, affecting both cortical and trabecular compartments (age‐related bone loss) with attenuated rates of bone loss [40].

After menopause, there is enhanced endocortical resorption but decreased periosteal apposition, resulting in thinned cortices. This is reflected in a marked increase in bone resorption with C‐telopeptide and urinary N‐telopeptide, markers of bone resorption, rising by ~90%, outpacing bone formation (osteocalcin rising by 45%), resulting in net bone loss [49, 50].

3. Management of Osteoporosis

3.1. Lifestyle Factors

Achieving optimal PBM is important to protect against future osteoporosis—PBM is usually achieved by age 40 in women. To reduce the future risk of developing osteoporosis and for optimal bone maintenance, addressing lifestyle factors that may impact BMD is important.

3.1.1. Dietary Calcium Intake

The RDI of calcium for women under 50 years is 1000 mg/day and 1300 mg/day in > 50 years, equivalent to 3–4 servings of dairy [51]. However, only 19% of older adults meet this recommendation [51]. Patient education is vital to achieve calcium RDI, and calcium supplements advised for those unable to reach targets.

3.1.2. Vitamin D

Vitamin D is important for gastrointestinal calcium absorption and bone mineralisation. The major source of vitamin D is sunlight exposure, however balancing detrimental solar UV effects with vitamin D absorption can be difficult. Maintaining vitamin D status > 50 nmol/L is recommended for bone health at all ages, with appropriate sun exposure or vitamin D supplementation ‐ if required, 800–1000 international units per day is usually sufficient [51].

3.1.3. Protein

Adequate intake of dietary protein is important for acquisition and maintenance of bone density and skeletal muscle mass, to prevent bone loss and sarcopenia. The RDI of protein for adults is 0.8 g/kg/day data, however protein needs are increased in older adults and in pregnant and breastfeeding women [52]. In pregnancy, RDI increases to 1.1 g/kg/day and 1.3 g/kg/day for breastfeeding women [52]. In older adults, intake of 1–1.2 g/kg/day is recommended for bone health and to prevent sarcopenia [51, 52].

3.1.4. Weight‐Bearing Exercise

Progressive resistance training and weight‐bearing impact exercises have beneficial effects to increase and maintain bone density, structure and strength in all age‐groups [53]. Muscle resistance (strength) training should be regular (minimum twice per week), moderate to vigorous intensity and progressively increase in resistance load. Weight‐bearing impact exercises (e.g. jumping) should be performed most days and include moderate‐to‐high loads in a variety of movements. Balance training in isolation does not improve BMD but may aid in falls prevention. In frail patients, supervision is recommended for exercise programs to reduce falls risk. Walking, cycling and swimming are insufficient to impact and improve BMD, though they have other cardiovascular benefits.

3.1.5. Smoking Cessation

Cigarette smoking accelerates bone loss and increases fracture risk, particularly hip fractures [51]. Smoking cessation is advised.

3.1.6. Alcohol Intake

More than two standard alcoholic drinks per day is associated with increased fracture risk and potentially decreased osteoblast function [51].

3.2. Medical Therapies for Osteoporosis

Pharmacological options for osteoporosis are summarised in Table 2 [54]. Detailed discussions about efficacy of individual treatments are discussed further in relevant lifespan subheadings.

TABLE 2.

Pharmacological options for the prevention and treatment of osteoporosis.

Treatment	Mechanism of action	Practice points	Side effects and contraindications
Antiresorptive therapy
Bisphosphonates Oral	Binds to calcium hydroxyapatite in bone and inhibits farnesyl pyrophosphate synthase. This inhibits attachment of osteoclasts to bone and decreases osteoclast activity. Retained skeletal activity for years (> 10).	Oral bisphosphonates have poor intestinal absorption (~ 1%). In women of childbearing age, avoid where possible. * Crosses placenta. If needed, consider cessation at least 12 months prior to pregnancy.	Oral: Oesophagitis. Contraindicated in active upper gastrointestinal disease. Intravenous: Nephrotoxic. Acute phase reaction is common ‐ usually with the first dose. * Symptoms may improve with short course of glucocorticoids [54]. Both: Atypical femoral fracture (AFFa). Medication‐related osteonecrosis of the jaw (MRONJb).
− Alendronate − Risedronate − Ibandronate − Etidronate Intravenous − Zoledronic acid − Pamidronate
Selective oestrogen receptor modulators (SERM c ) − Raloxifene − Bazedoxifene (+/‐ CEEd)	Bind weakly to oestrogen receptors in the body and act as a partial oestrogen agonist in bone in postmenopausal women.	Reduce risk of vertebral but not non‐vertebral fractures.	Increased risk of venous thromboembolism (VTEe). Raloxifene: Increased hot flashes.
Menopause hormone therapy (MHT f ) (Oestrogen +/‐ progesterone), tibolone	Acts on oestrogen receptors in bone to slow bone turnover by decreased osteocyte and osteoblast apoptosis, increased osteoclast apoptosis, and decreased RANK ligand‐mediated differentiation.	Indicated for conditions of oestrogen deficiency (POIg, FHAh). Effective and appropriate for postmenopausal osteoporosis before age 60 years (or within 10 years after menopause).	Risks and benefits of MHTf will depend on individual risk profile and choice of agent used. − Breast cancer: Potential increased risk (depending on duration of treatment, progestogen, and patient risk factors). − VTE d and stroke: Increased risk with oral oestrogen. − Cardiovascular disease (CVD i ): Increased risk when MHTf is started > 10 years after menopause.
Denosumab	Human monoclonal antibody against RANK‐ligand, decreasing osteoclast action and inhibiting bone resorption.	Rapid offset of action ‐ requires timely dosing every 6 months. − Do not delay doses for > 1 month. Discontinuation causes rapid rebound increase in bone resorption and can cause vertebral fractures. − bisphosphonates may mitigate bone resorption, depending on duration of denosumab therapy.	Increased risk of hypocalcaemia, particularly in patients with severe renal impairment. * Sufficient calcium and vitamin D levels must be confirmed before dose. Risk of rebound vertebral fractures with discontinuation. AFFa MRONJb
Anabolic treatment
PTH/PTHrP analogues − Teriparatide − Abaloparatide	Teriparatide ‐ recombinant 1–34 fragments of PTH. Increases bone formation through osteoblast action. Abaloparatide ‐ synthetic PTHrP analogue. Activates PTH‐1 receptors to increase bone formation.	Daily subcutaneous self‐administered injection. Recommended cumulative use over lifetime < 24 months. Requires consolidation of BMD gains with antiresorptive therapy. Reduced efficacy if given following antiresorptive agent. Insufficient to prevent bone resorption following denosumab discontinuation.	Mild hypercalcaemia (less with abaloparatide), hypercalciuria and hyperuricaemia. Contraindicated in malignancy with bone metastases, and in those with risk factors for osteosarcoma, such as Paget's disease and prior external beam radiotherapy.
Romosozumab	Human monoclonal antibody against sclerostin. Sclerostin inhibits the Wnt signalling pathway, which is involved in osteoblastogenesis. Increases bone formation (anabolic) and decreases bone resorption (antiresorptive).	Monthly subcutaneous injection, administered by a health professional. ‐ 12‐month course. Requires consolidation of BMD gains with antiresorptive therapy. Reduced efficacy if given following bisphosphonate. Insufficient data on efficacy following denosumab.	Potential increase in major adverse cardiovascular events. Contraindicated in those with a history of myocardial infarction or stroke. Increased risk of hypocalcaemia, particularly in patients with severe renal impairment. * Consider risk of CVDh in those with severe renal impairment. AFFa MRONJb

^a AFF ‐ atypical femoral fracture.

^b MRONJ ‐ medication‐related osteonecrosis of the jaw.

^c SERM ‐ selective oestrogen receptor modulator.

^d CEE ‐ conjugated equine oestrogen.

^e VTE ‐ venous thromboembolism.

^f MHT ‐ menopause hormone therapy.

^g POI ‐ premature ovarian insufficiency.

^h CVD ‐ cardiovascular disease.

3.3. Premature Ovarian Insufficiency

Besides optimising lifestyle factors, as described earlier, the cornerstone of the management in POI is oestrogen‐based hormone therapy which in the absence of contraindications, should be administered at least until the average age of menopause (50–51 years) [41]. Moderate to high‐quality evidence supports that HT not only alleviates hypoestrogenic symptoms but also helps preserve BMD [41]. The ideal hormone therapy formulation is still debated.

Previous studies have assessed various oestrogen formulations, with or without progesterone, to determine their impact on BMD as the main outcome. A 2023 systematic review of 16 studies involving women with idiopathic POI found that menopause hormone therapy (MHT) regimens containing 2 mg oestradiol, 1.25 mg conjugated equine oestrogens (CEE), 100 µg transdermal oestradiol, or continuous COCP with 30 µg ethinylestradiol were associated with increased BMD in the femoral neck and lumbar spine. In contrast, lower doses of oestradiol/CEE, tibolone, or cyclic COCP use did not demonstrate similar BMD benefits [55].

Testosterone, a potent anabolic agent for bone and muscles, has been studied in women with POI, albeit with small doses showing no substantial effects on BMD [56]. Larger RCTs are ongoing. Data regarding other osteoporosis‐specific therapies including denosumab, selective‐oestrogen receptor modulators (SERMs) and anabolic agents are lacking in POI.

3.4. Postmenopause

In the immediate peri‐menopausal period, MHT with oestrogen +/‐ progesterone has been shown to improve BMD and prevent fractures. In one meta‐analysis including approximately 10,000 women, bone density was significantly higher in the MHT group (both opposed and unopposed oestrogen) at all measurement sites [50]. After 2 years of MHT, BMD increased by 6.8% at the lumbar spine, 4.5% at the forearm, and 4.1% at the femoral neck [50]. In another meta‐analysis of those using MHT, there was a 37% reduction in vertebral fractures and a 28% reduction in hip fractures [57]. Tibolone—a synthetic steroid with oestrogenic, progestogenic and androgenic effects ‐ has efficacy in prevention of bone loss and has been shown to reduce the risk of vertebral fractures by 45% and non‐vertebral fractures by 26% in older women with osteoporosis [58]. Raloxifene—a SERM—reduces the risk of vertebral fractures but not non‐vertebral fractures [59]. Its decreased efficacy for fracture prevention and side effect profile limits utility in clinical practice.

Once oestrogen and MHT are withdrawn (usually over age 60 years or within 10 years of menopause), BMD gains disappear rapidly within 3–4 years of treatment cessation. In those at high risk of fracture, other sequential osteoporosis therapies should be considered with a four‐pillared approach to general management of osteoporosis. These include appropriate dietary calcium and protein intake, weight‐bearing exercise, appropriate vitamin D status and pharmacological agents, as appropriate.

3.4.1. Antiresorptive Therapy

Bisphosphonate therapy reduces the risk of vertebral and nonvertebral fractures in women. Duration of treatment depends on ongoing fracture risk, balanced against the small but potentially significant risk of side effects such as AFF and MRONJ, which rise with increased bisphosphonate exposure.

For women with osteoporosis at increased risk of minimal trauma fracture, the use of alendronate over 2–3 years reduces risk of vertebral fracture by 47% (number needed to treat [NNT] ‐ 72) and reduces non‐vertebral fracture by 51% (NNT 24) [60]. Similar improvements in risk of secondary fracture for postmenopausal women have been seen with risedronate with 39% reduction in vertebral morphometric fracture and 20% reduction in non‐vertebral fractures [61].

Zoledronic acid has excellent efficacy in fracture risk reduction in post‐menopausal osteoporosis with significantly reduced (70%) rates of vertebral morphometric fractures and 41% reduced hip fracture risk following three infusions of 5 mg zoledronic acid at baseline, 12 and 24 months, compared to placebo [62]. Optimal dosing interval remains an area of ongoing research and ongoing post‐hoc analyses have shown similar improvement in BMD, reductions in bone turnover markers, and decreased vertebral fracture risk persisting beyond 12–18 months following a single dose of zoledronic acid [63].

Denosumab is a potent antiresorptive, improving mass and strength in both cortical and trabecular bone. It has been shown to significantly reduce the risk of hip, morphometric vertebral and non‐vertebral fractures by 40%, 68% and 20% respectively [64]. However, unlike bisphosphonates which are sequestered in bone, the effect of denosumab on bone wanes rapidly with strict 6‐monthly administration required. Once started, denosumab therapy should not be interrupted due to an increased risk of rebound fractures (highest in those with previous vertebral fracture) with rapid increase in bone resorption following cessation. Currently, definitive measures to mitigate this rebound fracture risk are unclear but alternative antiresorptive treatment, such as zoledronic acid, should be given 6 months after the final denosumab injection [65]. Following a dose of zoledronic acid, the effect can be monitored with BTMs at 3 and 6 months: in the case of increased BTMs (i.e. above the mean found in age‐ and sex‐matched cohorts), repeated infusion of zoledronate should be considered [65]. As such, the use of denosumab should be carefully considered in those who may require prolonged treatment for osteoporosis and reserved as first‐line only for older patients and in those where bisphosphonate and/or osteoanabolic treatment is inappropriate.

3.4.2. Osteoanabolic Agents

There is increasing evidence to support the use of osteoanabolic agents which increase BMD, particularly romosozumab, as initial therapy for women with severe osteoporosis, with sequential antiresorptive to consolidate BMD gains.

In patients without recent use of osteoporosis therapies, romosozumab, a potent anabolic agent with some antiresorptive effect, reduced vertebral and clinical (predominantly non‐vertebral) fractures by 73% and 36% within 12 months of treatment [66]. Fracture risk reduction for non‐vertebral fractures was not statistically significant at 12 or 24 months, however this may be related to a low rate of non‐vertebral fractures in the placebo group. When romosozumab efficacy was directly compared to 2 years of alendronate therapy, 12 months of romosozumab followed by alendronate showed superior vertebral, non‐vertebral and hip fracture risk reduction by 48%, 19% and 38%, respectively [67]. BMD gains are superior for romosozumab, compared to alendronate and teriparatide, at the lumbar spine (11.4%), total hip (4.1%) and femoral neck (3.7%) [68].

Teriparatide, recombinant human parathyroid hormone, increases cortical width and trabecular thickness. Teriparatide has good efficacy in reducing both vertebral (65% risk reduction) and non‐vertebral fractures (53% risk reduction) in postmenopausal women with previous vertebral fractures [69]. Meta‐analysis showed significant improvements ( ~ 10%) in lumbar spine BMD and smaller, but still significant improvements (2.8%–3.9%) in femoral neck BMD [69]. Abaloparatide, a PTHrp analogue, reduced the risk of new morphometric vertebral fractures by 86%, and the risk of non‐vertebral fractures by 43% following 18 months of treatment [70]. Abaloparatide appeared more effective than teriparatide to reduce major osteoporotic fractures, but further head‐to‐head trials are needed [70].

Though there is strong evidence supporting use of anabolic therapy as initial osteoporosis treatment, its use in clinical practice has been curtailed by high drug costs. When used sequentially following bisphosphonate therapy, osteoanabolic effects of both romosozumab and teriparatide appear to be ‘blunted’ with attenuated BMD gains at all sites, though romosozumab appears more effective than teriparatide [71].

The optimal sequential treatment in osteoporosis remains a current area of research. In women treated with 24 months of denosumab followed by the sequential use of teriparatide alone for 24 months, total hip BMD progressively declined following switch in treatment [72]. Teriparatide alone may not be sufficient to mitigate rapid bone resorption following denosumab discontinuation. Using teriparatide and denosumab concurrently showed sustained anabolic effect on BMD more than either drug alone, without the increase in bone resorption seen with sequential use [73]. There is a paucity of data reviewing the transition from denosumab to romosozumab, an effective osteoanabolic agent, or combination therapy, however concern remains that romosozumab may be insufficient to suppress rebound bone resorption following denosumab discontinuation if used alone.

3.5. Osteoporosis Therapy in Breast Cancer

To optimise bone health in breast cancer survivors, international guidelines recommend optimisation of lifestyle including a well‐balanced diet and exercise, as previously discussed. Exercise has multiple benefits including improved BMD, quality of life, reduced aromatase inhibitor‐associated arthralgia, and possible improved breast cancer outcomes. Antiresorptive medication initiation with AI is recommended in the setting of: T‐score < ‐2 or where ≥ 2 fracture risk factors are present (age > 65 years, BMI < 20, T score < ‐1.5, family history of hip fracture, personal history of fragility fracture after age 50, current/previous smoking and oral glucocorticoid use > 6 months). Bisphosphonates and denosumab both increase BMD but fracture outcomes for bisphosphonates are lacking. Reduced fracture risk has been reported with denosumab compared with placebo in women treated with AIs, but improved survival has been observed in women receiving bisphosphonates [74, 75].

Recommended therapies include weekly alendronate and risedronate, monthly ibandronate, and 6 monthly zoledronic acid and denosumab [74]. Concerns about discontinuation of denosumab exist as they do in the general population, with more research needed regarding the optimal transition to bisphosphonates if denosumab is discontinued. Teriparatide is contraindicated in women with a prior history of radiotherapy. There is insufficient evidence to make a recommendation regarding romosozumab.

3.6. Frail and Older Patients Over 75 Years of Age

Absolute fracture risk rises with age and is highest in the older adult population, largely related to the risk of falls. A multidisciplinary and holistic approach is needed to address fracture prevention in older adults, beyond osteoporosis medications alone.

Consideration should be given to reducing falls risk with review of:

• 1.Environmental risks (including the need for mobility aids),
• 2.Risk for sarcopenia and consideration of dedicated, supervised exercise programs for falls risk reduction (particularly focusing on strength and balance),
• 3.Nutrition, particularly protein and dietary calcium intake, and risk factors for malabsorption,
• 4.Vitamin D status, sun exposure and supplementation as required,
• 5.Potential ‘falls‐risk increasing drugs’, such as psychotropics or sedatives, and the cumulative effect of polypharmacy.

Choice of osteoporosis therapy depends on patient factors, including competing health issues, medication adherence, and life expectancy. Antiresorptives and osteoanabolic agents are effective for vertebral fracture risk reduction in older populations and zoledronic acid and risedronate have shown efficacy in reducing non‐vertebral fractures.

4. Conclusion

Osteoporosis and associated fractures represent a significant disease burden for women with increasing prevalence with age. Optimisation of modifiable risk and lifestyle factors remain important across the lifespan, and a holistic approach to osteoporosis is required (as shown in Figure 4). During the menopause transition period and with premature oestrogen deficiency, oestrogen‐based hormone therapy remains an effective treatment option. In older adults, the focus of pharmacological management shifts to antiresorptive and osteoanabolic therapies with a focus on falls prevention.

FIGURE 4.

Overview of bone health across the lifespan in women.

Author Contributions

Gabrielle Stokes: writing – original draft, review and and editing, data curation, visualisation. Madhuni Herath: writing – original draft, review and editing. Navira Samad: writing – original draft, review and editing. Anne Trinh: writing – original draft, review and editing, conceptualisation, supervision. Frances Milat: writing – original draft, review and editing, conceptualisation, supervision.