Drugs & Aging (2025) 42:395–412

https://doi.org/10.1007/s40266-025-01205-5

THERAPY IN PRACTICE

Treatment Considerations for Severe Osteoporosis in Older Adults

Heidi See1 · Emma Gowling1 · Evie Boswell1 · Pritti Aggarwal2,3 · Katherine King1 · Nicola Smith1 · Stephen Lim1,4,5 ·
Mark Baxter1,4 · Harnish P. Patel1,4,6

Accepted: 26 March 2025 / Published online: 16 April 2025

© The Author(s) 2025

Abstract
Osteoporosis, a chronic metabolic bone disease, increases the predisposition to fragility fractures and is associated with consider-
able morbidity, high health care cost as well as mortality. An elevation in the rate of incident fragility fractures will be observed
proportional with the increase in the number of older people worldwide. Severe osteoporosis is currently defined as having a bone
density determined by dual-energy X-ray absorptiometry that is more than 2.5 standard deviations (SD) below the young adult
mean with one or more past fractures due to osteoporosis. Nutrition, physical activity and adequate vitamin D are essential for
optimal bone strength throughout life. Hormone (oestrogen/sex steroid) status is also a major determinant of bone health. This
review explores mechanisms involved in bone homeostasis, followed by the assessment and management of severe osteoporosis,
including an overview of several treatment options in older people that range from anti-resorptive to anabolic therapies.

1 Introduction
Key Points
Populations are ageing. Current estimates place the num-
ber of people aged 65 or older at 761 million [1]; this age The number of individuals who have a high risk of frac-
bracket is the fastest growing worldwide, and for the first ture is increasing commensurate with an ageing popula-
time in history, there are more people aged 65+ years than tion. However, many people at risk or have sustained an
children under 5 years [2]. Life expectancy has increased osteoporosis related fracture remain untreated.
by over 6 years from 2000 to 2019, to 73.4 years [3], and
A clinical and radiological assessment of primary and
secondary fracture risk should form part of a compre-
hensive geriatric assessment in older people.
Heidi See, Emma Gowling and Evie Boswell are Joint authors.
Evidence now exists for the anti-fracture effect for a
* Harnish P. Patel range of anti-osteoporotic agents ranging from anti-
[email protected]
resorptive to osteoanabolic therapies that can be con-
1
Medicine for Older People, University Hospital sidered in older people. Choice of treatment should
Southampton NHS Foundation Trust, Tremona Road, be based on shared decision making with respect to
Southampton SO16 6YD, UK preference, presence of comorbid diseases, polyphar-
2
Living Well Partnership, Southampton, UK macy burden, quality of life, social and psychological
3
School of Primary Care, Population Sciences and Medical circumstances. Vitamin D 800–1000 international units
Education, University of Southampton, University Road, and 1200 mg calcium a day are important adjuncts to
Highfield, Southampton SO17 1BJ, UK anti-osteoporotic treatments.
4
Academic Geriatric Medicine, University of Southampton,
Southampton General Hospital, Tremona Road, Mailpoint
63, G Level West Wing, Southampton SO16 6YD, UK
5
NIHR Applied Research Collaboration, University
of Southampton, Southampton, UK
6
NIHR Biomedical Research Centre, University Hospital
and University of Southampton, Tremona Road,
Southampton SO16 6YD, UK

Vol.:(0123456789)
396 H. See et al.

current population projections estimate that by 2050, peo- assistance with their mobility as well as aspects of activi-
ple over 65 years will account for 16% of the total popu- ties of daily living.
lation (1.6 billion people), equivalent to one in every six
persons [4, 5] whilst the number of people aged over 80
will triple, reaching 426 million. Whilst these milestones 2 Bone Remodelling
are testament to advances in current clinical care, living
longer has ramifications on physical and mental health. Bone is a multifunctional connective tissue composed of
Especially, the associated morbidity and mortality of organic and inorganic components including but not limited
non-communicable diseases, such as those affecting the to collagen, non-collagenous proteins, calcium and phospho-
musculoskeletal (MSK) system, is one of the leading con- rus in the form of hydroxyapatite [16]. There are two main
tributors to global disease burden [6]. It is estimated that types of bone in the adult skeleton: cortical bone constitutes
1.71 billion people live with a MSK disorder [7], and in approximately 80% of the adult bone mass whilst trabecular
the UK, MSK conditions currently account for the third- bone constitutes the remaining 20%. Cortical bone is dense
largest area of the National Health Service (NHS) budget, and has a low turnover rate of approximately 3% per year.
as well as a loss of 30 million working days each year [8, In contrast, trabecular bone has a turnover rate of approxi-
9]. Not only osteoporosis but also osteoarthritis and sar- mately 26% per year, has a lower mineral content and is
copenia constitute the largest portion of MSK disorders. more metabolically active and responsive to hormonal stim-
Osteoporosis, a common metabolic bone disease char- uli [17]. Whilst cortical bone confers mechanical strength
acterized by low bone mass and disruption of bone micro- and bone integrity, trabecular bone, found in long bones and
architecture, contributes annually to 8.9 million fractures vertebrae, undergoes remodelling more than cortical bone,
worldwide, leading to reduced physical and psychological which are the sites most commonly at risk of sustaining fra-
health, lower quality of life and shorter life expectancy gility fracture [16, 17]. Osteocytes, osteoblasts and osteo-
[10–13]. Osteoporosis is also associated with a high health clasts are the main cells within bone (Fig. 1). Osteocytes
care cost. For example, in the year 2019, osteoporosis found in the lacunae of the matrix have a mechano-sensory
incurred an estimated direct total fracture cost approach- function, and osteoblasts synthesize osteoid whilst osteo-
ing £5 billion in the UK [14]. The prevalence of not only clasts enzymatically resorb bone [18]. All three cell types
osteopenia and osteoporosis but also sarcopenia, the loss are important for bone growth and remodelling occurring
of muscle function and mass, increases with age. In com- continuously throughout the skeleton in response to mechan-
bination with other comorbid conditions and presence of ical demand, stress or injury that not only shapes skeletal
frailty, both older women and men are at increased risk of mass, size and shape but also maintains serum calcium and
sustaining fragility fractures, defined as fractures conse- phosphate homeostasis. A remodelling cycle on the bone
quent to low energy transfer trauma, such as falling from surface occurs through five sequential stages: activation,
a standing height or less. In the UK, it is estimated that resorption, reversal, formation and termination and involves
the lifetime probability of a major osteoporotic fracture is coordinated actions of osteoclasts with osteoblasts [19].
22% in men and 46% in women. Approximately 549,000 Systemic regulators of bone remodelling, such as the
fragility fractures occur each year, equating to over one a sex steroids, act in concert with local regulators such as
minute that are accounted by 105,000 hip fractures, 86,000 cytokines and growth factors including but not limited to
vertebral fractures and 358,000 other fractures encompass- sirtuins, protein kinases such as mechanistic target of rapa-
ing fractures of the pelvis, ribs, humerus, forearm, tibia, mycin (mTOR), Forkhead proteins, M-CSF, wnt and the
fibula, clavicle, scapula and sternum. RANK/RANKL/OPG system to maintain bone homeostasis.
Hip and vertebral fractures are the most serious of all Oestrogen has a significant role in preventing bone resorp-
fragility fractures. Rates of hip fracture increase exponen- tion by inhibiting osteoclasts [20, 21]. Sclerostin, a key
tially from the age of 50 years, with two women for every glycoprotein secreted by osteocytes is a potent inhibitor of
man affected. Fractures are associated with substantial osteoblastogenesis and bone formation [22, 23]. In midlife/
morbidity, whilst mortality after a hip fracture is greatest post menopause and later in men, this homeostatic balance
in the first 12 months post fracture at a rate approach- between formation and resorption is disrupted. Alterations
ing 26% and is considerably elevated by the presence in cellular activity, i.e. increased osteoclastic activity, will
of co-morbidity [14, 15]. In the UK, the mean length of lead to increased bone resorption and decreased bone for-
stay in hospital following a hip fracture is 20 days, which mation, resulting in a net loss of bone. Bone volume and
accounts for half a million bed days each year. Each day, mass decline in older individuals and in all ethnicities. An
3600 hospital beds in the UK are occupied by patients imbalance in remodelling within the microenvironment
who have sustained a hip fracture. Of those independently in older people is also driven by mesenchymal stem cell
mobile pre-fracture, around half will require ongoing (MSC) senescence and a shift in differentiation to favour
Treatment Considerations for Severe Osteoporosis in Older Adults 397

Fig. 1  Resorption dominates over formation, driven in part by cells. Osteoblasts produce extracellular proteins, alkaline phosphatase
increased osteoblastic apoptosis, osteocyte senescence and an and collagen—collectively known as the bone matrix, which at first
increased predilection for bone marrow stem cells to differentiate into is unmineralized osteoid that subsequently accumulates calcium
adipocytes in older people. Osteoclasts originate from haematopoi- phosphate in the form of hydroxyapatite. A subpopulation of mature
etic stem cells and degrade bone via secretion of acids and proteo- osteoblasts further differentiate into osteocytes within the mineralized
lytic enzymes that dissolve collagen and matrix proteins during bone bone.
resorption. Osteoblasts arise from committed mesenchymal precursor

adipogenesis within the bone marrow at the expense of oste- 3 Osteoporosis in Context of the Lifecourse
oblast generation (Fig. 1) [24]. Consequently, not only tra-
becular but also cortical thinning, as well as increased corti- When considering the lifecourse, the concept of peak bone
cal porosity, contributes to lower bone quality and strength, mass, defined as the maximum amount of skeletal tissue an
and unless this imbalance is disrupted by intervention(s), individual will have in their life at the termination of skel-
higher fracture risk at all sites in older people of both sexes etal maturation, is thought to be attained between 25 and 30
will be observed. years of age, and males attain higher bone mineral density
(BMD), compared with females [25]. ‘Bone health’ in older
age is, therefore, a function of the ‘peak’ attained in early
life and the extrinsic and intrinsic changes operating through
middle years into old age. Conditions which hinder an indi-
vidual’s ability to maximize peak adult bone mass, such
as undernutrition, inter-current illness and socioeconomic
398 H. See et al.

deprivation, and also low levels of physical activity could, number of standard deviations (SD) a patient’s BMD is
therefore, increase the probability of developing osteopo- below the mean reference value of a healthy young female
rosis in later in life. Similarly, in later life, lifestyle factors population. A T-score ≤ 2.5 SD below the reference value
such as steroid use, malabsorption syndromes (e.g. coeliac indicates osteoporosis, and where this is accompanied by
disease), anorexia, malnutrition, smoking, excess alcohol one or more fractures, this indicates severe osteoporosis
intake and physical inactivity, as well as other intrinsic and [28]. However, a majority of fractures occur in individu-
extrinsic risk factors, all contribute exponentially to the als who have osteopenia, defined by a T-score of between
increase fracture risk in older people, more so in those with 1.0 and 2.5 SDs below the mean reference value. However,
lower peak bone mass [26]. DXA results in older people should be interpreted in con-
Bone mass decreases at a rate of 0.5% a year after peak text of the presence of degenerative spine disease that can
levels are attained. Women have an increased risk of primary artificially elevate BMD. Conversely, total bone matrix can
osteoporosis as they reach a lower peak bone mineral density be markedly lower in osteomalacia [29]. In this condition,
compared with men, but this risk is further increased by the there is a defect in mineralization of bone matrix because
post-menopausal decline in oestrogen. Bone loss in women of vitamin D deficiency, secondary to a variety of causes
is most evident in the trabecular vertebral bodies as they are seen in older people including malnutrition, malabsorption,
more metabolically active and are sensitive to oestrogen. chronic renal disease and poorer exposure to sunlight, e.g.
Thus, women aged 50 years or over have a four-fold higher being housebound.
rate of osteoporosis and two-fold higher rate of osteopenia
than men [11]. However, it is noteworthy that approximately 4.2 Assessment of Risk
20% of men who have osteoporosis also live with lower sex
steroid levels highlighting requirements for detailed serum Women aged 65 years and above, all men aged between 70
investigations as part of a holistic assessment [26]. The gen- and 75 years and above and younger patients with risk fac-
eral observation of morbidity from osteoporosis and associ- tors should receive a form of osteoporosis risk assessment
ated fractures in women probably reflects their longer life across health care settings. Age, sex, smoking, alcohol use,
expectancies. previous and family history of a fracture and the use of oral
glucocorticoids, history of rheumatoid arthritis and the pres-
ence of secondary osteoporosis are data that can be input to
4 Osteoporosis: Diagnosis and Management calculate the FRAX score. These are relevant risk factors to
be considered when assessing an older person’s individual
4.1 Diagnosis fracture risk [29]. This tool estimates the 10-year probability
of osteoporotic-related fracture and is externally validated,
Osteoporosis is most often underdiagnosed and undertreated calibrated and applicable in many countries across the globe
as it progresses without symptoms unless the patient pre- (https://​frax.​shef.​ac.​uk/​FRAX/) [30, 31]. The output from
sents with a fragility fracture usually at an older age or a FRAX assessment can also be modified by bone mineral
routine clinical assessment concludes information on bone density values obtained from DXA at the femoral neck
health is needed. Dual-energy X-ray absorptiometry (DXA) where available. The QFracture and Garvan fracture risk
to determine bone densitometry is the gold standard method prediction algorithms or calculators are other assessment
for diagnosing osteopenia and osteoporosis. DXA also tools which have shown good predictive value in specific
provides the opportunity for vertebral facture assessment countries/populations but have limited utility in diverse pop-
(VFA). VFA in conjunction with plain radiography has been ulations [32, 33]. Furthermore, all risk calculators generate
recommended by the International Osteoporosis Foundation a risk score rather than indication for treatment and are not
(IOF) and adopted UK National Osteoporosis Guidelines comparable with each other [33]. Knowledge of individual
Group (UK NOGG) as well as the Royal Osteoporosis Soci- T-scores, other risk factors and ascertainment of patient pref-
ety (ROS) to be used in high-risk individuals to detect mod- erences will inform lifestyle changes and treatment strategies
erate or severe vertebral fractures and identify those who are appropriate for the patient through shared decision making
at risk of further fracture in the spine or other skeletal sites. (SDM) [34]. This takes into consideration what matters most
Other risk factors for current and future vertebral fracture to the patient, presence of comorbid diseases (e.g. chronic
include a history of measured height loss, self-reported prior kidney disease (CKD)), consequent polypharmacy burden
fracture after the age of 50 years, kyphosis and long-term and their social and psychological circumstances. Patients
glucocorticoid therapy [27]. who have a higher future risk of osteoporotic fracture should
The diagnosis of osteoporosis is made using DXA scan- be treated according to respective local or national osteopo-
ning to measure the bone mineral density (BMD) of the rosis guidelines to reduce their future risk.
proximal femur to obtain a T-score, which represents the
Treatment Considerations for Severe Osteoporosis in Older Adults 399

Given the impact both osteopenia and osteoporosis have the progression towards the severe category of osteoporosis
on fracture risk, primary prevention through screening and [42–50].
intervention for individuals at high risk could significantly
reduce morbidity associated with fragility fractures. The 4.3 Non‑pharmacological Options Supporting
seminal study: screening in the community to reduce frac- the Treatment of Severe Osteoporosis
tures in older women (SCOOP) showed that screening with
FRAX and pharmacological intervention for postmenopau- Physical inactivity in older age translates to decreased
sal women aged 70–85 years at high risk of fracture was mechanical loading on bone that reduces the stimulus on
associated with a reduction in hip fracture rates. This inter- osteoblasts resulting in reduced OPG secretion and increased
vention was also found to be cost-effective compared with expression and secretion of RANKL, as well as the pro-
the standard care [35]. inflammatory interleukins IL-1, IL-6 and TNF-α. The
Older people presenting with a hip fracture are more combined effect of this imbalance is increased osteoclast
likely to be osteoporotic, sarcopenic and live with frailty. differentiation, formation and activity with ensuing bone
In these situations, implementing the process of compre- resorption [26] and low bone mass. Conversely, physical
hensive geriatric assessment (CGA) by multidisciplinary activity stimulates bone growth and preserves bone mass.
team, comprising but not limited to orthopaedic surgeons, Physical activity and exercise to correct biomechanical
older people’s specialist teams, pharmacy, therapists, nurses, imbalance in the abdominal trunk as well as to strengthen
mental health professionals, dietitians, speech and language hip flexion and knee flexion is recommended to reduce the
therapists, is considered best practice [36]. While CGA is risk of falls and for the prevention of osteoporosis. In addi-
the gold standard for patients with hip fracture, input from a tion to preserving skeletal muscle, resistance exercise has
multidisciplinary fracture liaison service (FLS) can be ben- been shown to increase bone strength through repeated
eficial for individuals with other fragility fractures, such as mechanical loading, thereby improving bone mineral den-
wrist, shoulder or vertebral fractures. FLS are specifically sity [51]. In support of this notion, a systematic review of
in place to systematically assess, identify and advise on risk 59 studies (20 randomized controlled trials (RCTs)) com-
factor management to reduce the risk of subsequent, more posed of 1560 participants pertaining to the effect of physi-
debilitating fractures [37]. General principles employed by cal activity on the prevention of osteoporosis in individuals
the FLS include preserving bone mineral density through ≥ 65 years concluded that physical activity is very likely to
recommending pharmacological and non-pharmacological
interventions, such as improving muscle strength and bal-
ance, managing falls and other risk factors. Global initiatives Table 1  Secondary causes of osteoporosis relevant for older people
such as the International Osteoporosis Foundation’s Capture Endocrine Gastrointestinal disorders
the Fracture initiative (capturethefracture.org) support the
expansion of FLS widely within the hospital setting. Hypogonadism Malabsorption
Another important concept is the ‘imminent fracture Inflammatory bowel disease
risk,’ which highlights individuals at high risk of fracture Oestrogen deficiency Chronic liver disease
within 12–24 months after a sentinel fracture. For example, Cushing’s disease Eating disorders
in a study of 377, 561 older women ≥ 65 years who had Hyperparathyroidism
sustained a vertebral and non-vertebral fracture, the cumu- Vitamin D deficiency Others
lative risk of subsequent hip and other fractures at 2 and 5 Growth hormone deficiency Rheumatoid arthritis
years was 18% and 31%, respectively [38]. Imminent risk of Diabetes Ankylosing spondylitis
fracture in older people is elevated by recent prior fracture, Multiple sclerosis
fracture site, biological sex, age, osteoporosis and comorbid- Haematological disorders Sarcopenia
ities such as cognitive dysfunction, polypharmacy, reduced Multiple myeloma Drug/toxin related
physical activity, poorer general health and falls [39]. This Chronic haemolytic anaemia Alcohol
concept emphasizes the importance of early identification, Anti-epileptic drugs
assessment and treatment of those at high risk to reduce Connective tissue disorders Androgen deprivation therapies
future morbidity and mortality from fracture [40, 41]. Ehlers–Danlos syndrome Glucocorticoids
Several illnesses as well as drug treatments associated Marfan’s syndrome Heparin
with osteoporosis (secondary causes of osteoporosis) are Proton pump inhibitors
listed in Table 1 and serve as a reminder to clinicians to Selective serotonin reuptake
inhibitors (SSRI)
address these risk factors when conducting their compre-
Tobacco smoking
hensive geriatric assessment, medicines rationalization or
Thyroxine
therapeutic deprescribing with the ultimate aim of halting
400 H. See et al.

be beneficial, where increases in BMD were reported more fortification or pharmacologically, restoring serum 25-OH-D
at the lumbar spine over the femoral neck. Furthermore, levels to at least or above 50 nmol/L [63].
increases in BMD were more pronounced when multiple as In terms of fracture prevention and effects on skeletal
well as resistance exercise regimes were employed [52]. In muscle, in a systematic review and meta-analysis of 33 ran-
another a systematic review of 43 randomized controlled tri- domized controlled trials (RCTs), comprising 1145 partici-
als, the most effective type of exercise for increasing femoral pants, primary use of routine calcium and vitamin D sup-
neck bone mineral density was high force exercise, such as plements was not associated with lower risk of total, hip,
progressive resistance strength training of the lower limbs vertebral or non-vertebral fractures in community dwelling
[53]. The effect of exercise training on increased BMD at older adults [64]. Vitamin D has not been shown to be ben-
the femoral neck, lumbar spine and trochanter in older post- eficial in the general population for musculoskeletal heath
menopausal women between 60 and 82 years was seen in despite basic science studies postulating the physiological
a further systematic review and meta-analysis of 53 RCTs effects of vitamin D acting through its receptor on muscle
comprising 2896 participants [54]. health [63, 65, 66]. In another systematic review and meta-
Exercise programmes should be personalized to the nalysis of 81 RCTs comprising 53, 537 participants, vitamin
patient to ensure that they are safe, sustainable and repro- D did not have any effects on fracture prevention or prevent
ducible, e.g. avoidance of sudden rotational movements or falls [67]. Further systematic reviews and metanalyses have
severe flexion of the spine to reduce the risk of vertebral shown that vitamin D with or without calcium had no effect
compression. Holistic reviews focusing on addressing foot- on muscle strength measures or physical performance, e.g.
wear, home environment and polypharmacy with particular appendicular lean mass, grip strength or physical perfor-
attention to medications with a high anti-cholinergic burden mance measures [68, 69]. Calcium intake, although can lead
and deprescribing are also key components of assessment to modest increased in BMD, does not clinically reduce the
of an older person at risk of fracture [55–57]. Furthermore, risk of future fracture [70, 71]. Previous studies of calcium
smoking cessation, avoiding excess alcohol and optimizing supplementation suggested an increased risk of cardiovas-
nutrition are modifiable factors contributing to the manage- cular disease, including myocardial infarction [72]. How-
ment of osteoporosis. ever, other studies found no association between calcium
supplementation and risk of cardiovascular disease [73, 74].
4.4 Treatments Used to Manage Severe Calcium and vitamin D should be given to older people with
Osteoporosis insufficiency and who are at risk of or are being treated for
osteoporosis, who have sustained a fragility fracture and are
4.4.1 Calcium and Vitamin D prescribed glucocorticoids or other treatments that affect
vitamin D metabolism, such as anti-convulsant therapy [75,
Dietary or supplemental calcium is essential for bone min- 76].
eralization. Bone also acts as a calcium reservoir, restoring
physiological levels when serum calcium is low through 4.4.2 Pharmacological Options for the Treatment of Severe
the action of parathyroid hormone [58]. For example, when Osteoporosis
dietary calcium is insufficient to meet calcium demand, i.e.
during periods of undernutrition or malabsorption often seen There are various pharmacological options for the treatment
in older people. In addition to ultraviolet B radiation induced of severe osteoporosis that aim to reduce the risk of pri-
synthesis, vitamin D may be obtained from egg yolks, salt- mary or secondary fractures depending on assessment of the
water fish and liver, as well as in supplements purchased in patient. These include:
isolation or combined with other vitamins [59–61]. Serum
vitamin D (25-OH-D) deficiency (< 25 nmol/L) in older (i) Anti-resorptive therapy—bisphosphonates and deno-
people is common, not only secondary to physiological sumab
changes in the ability of the skin to synthesize 25-OH-D (ii) Parathyroid hormone (PTH) analogues
but also particularly in those who are malnourished, have (iii) Romosozumab
chronic kidney disease, are institutionalized or are house-
bound. Intakes of 1000 mg of calcium in combination Importantly, strontium ranelate is no longer used world-
with 400 international units (IU) of vitamin D per day are wide for the treatment of severe osteoporosis given the asso-
generally recommended [62]. However, recommendations ciation with stroke and ischaemic cardiac events.
for housebound older people or those living in a nursing Anti-resorptive therapy—bisphosphonates (alendronic
home are 800–1000 IU of vitamin D and 1200 mg calcium acid, risedronate sodium and zoledronic acid) Bisphospho-
per day [63] through supplementation either through food nates bind strongly to hydroxyapatite and inhibit osteoclast-
mediated bone resorption thereby reducing bone turnover
Treatment Considerations for Severe Osteoporosis in Older Adults 401

and increase bone mineral density within 1–2 years of com- bisphosphonates, geographical region as well as diverse pop-
mencement, reaching peak action within 3–4 years [77, 78]. ulations, did not demonstrate a reduction in mortality risk
Bisphosphonates have been shown to reduce the risk of hip [88]. Consequently, the authors recommend continued use
and non-vertebral fractures, even those living with frailty of bisphosphonates to reduce fracture risk but that further
[79–81]. For example, evidence shows 10 mg of alendronate studies investigating the association between bisphosphonate
daily for 10 years increased bone mineral density by 13.7% use and mortality are needed.
at the lumbar spine, 10.3% at the trochanter, 5.4% at the There is a paucity of studies examining the anti-fracture
femoral neck and 6.7% at the total proximal femur. Obser- efficacy of bisphosphonates in men. One multicentre RCT
vational data suggest a lower mortality risk associated with of zoledronic acid in men aged 50–85 years demonstrated
oral bisphosphonate use in the treatment of osteoporosis a significant reduction in the rate of vertebral fractures in
after hip fracture [82, 83]. Notably, in the observational men with osteoporosis [89]. Given limited evidence from
study conducted by Sambrook et al. [83] 2005 institutional- trials, current approaches compare BMD responses as an
ized older individuals (mean age 85.7 years) prescribed oral outcome from treatment with anti-osteoporosis agents in
bisphosphates were followed up for 5 years and monitored men and women with similar fracture risk. A recent sys-
for incident hip fractures and mortality. Bisphosphonate tematic review and meta-analysis of 21 RCTs revealed that
use was associated with a 27% reduction in death compared bisphosphonates, amongst other anti-osteoporosis agents
with non-users (adjusted hazard ratio 0.73, 95% confidence significantly enhanced BMD at the spine, total hip and femo-
interval (CI) 0.56–0.94, P = 0.02). Similar associations have ral neck compared with placebo in men [90]. Therefore, the
been observed in several other observational studies. How- assessment and management of osteoporosis in men should
ever, caution should be exercised when drawing conclusions align with diagnostic and treatment algorithms utilized for
on the relationship between bisphosphonate use and mortal- women, and this view is supported by a recent consensus
ity due to residual or unmeasured confounding [84]. guideline from the European Society for Clinical and Eco-
In a landmark randomized placebo-controlled trial con- nomic Osteoporosis, Osteoarthritis, and Musculoskeletal
ducted by Lyles et al. [85] involving over thousand patients Disease (ESCEO) [91].
in each arm, intravenous zoledronic acid (5 mg) was admin- Alendronate 10 mg once daily or 70 mg once weekly or
istered up to 90 days after repair of low-trauma hip fractures risedronate sodium 5 mg once daily or 35 mg once weekly
and repeated yearly for the 1.9-year follow-up. This treat- is recommended for postmenopausal women and men over
ment was associated with a 28% reduction in death from all 50 years of age, who have confirmed osteoporosis on DXA.
causes in both men and women (P = 0.01). Additionally, Reevaluation of BMD is usually recommended between 3
zoledronic acid reduced the rate of new clinical fractures and 5 years. Thereafter, treatment is continued for up to 10
compared with placebo (8.6% versus 13.9%), representing years if the patient continues to be risk of fracture or has
a risk reduction of 35%. Furthermore, a lower rate of new commenced on corticosteroid therapy. On review, if the
clinical vertebral fractures (1.7% versus 3.8%, P = 0.02) and T-score is > −2.5, a drug holiday ranging 1–2 years may
rates of new non-vertebral fractures (7.6% versus 10.7%, P be recommended pending further evaluation of BMD and
= 0.03) were observed. Notably, there were no significant fracture risk [92]. However, discontinuation of bisphospho-
reductions in new hip fractures. nates in women at this time may be associated with up to
Meta-analyses have further explored associations between 40% higher risk of new clinical fractures compared with
bisphosphonate use and mortality with varied results. For those who continue bisphosphonates, and alternatives should
example, following the observations of Lyles et al., an analy- be considered as part of risk factor assessment and shared
sis of eight eligible randomized controlled trials revealed decision making [93].
that treatment with bisphosphates amongst other agents Adverse effects of oral bisphosphonates include gastro-
including intravenous zoledronic acid and denosumab was intestinal symptoms, bone/joint pain, oesophageal ulcera-
associated with a reduced mortality of approximately 11%, tion and, rarely, osteonecrosis of the jaw (ONJ). The risk
justifying the use of anti-osteoporotic agents in older indi- factors for ONJ include concurrent duration and treatment
viduals living with frailty and who have a high fracture risk for cancer, smoking and poor dental hygiene. In the absence
[86]. In another meta-analysis, a non-significant decrease of cancer, i.e. for the treatment of osteoporosis, the risk of
in cardiovascular mortality was observed, while a clinically ONJ is minimal, estimated at around 1 in 100,000. Risk fac-
significant reduced risk of all-cause mortality was found in a tors include chronic ear infections, recent ear operation or
diverse patient population, including those with osteoporosis suspected cholesteatoma [94]. Atypical femoral fractures
and cancer treated with bisphosphonates (pooled risk ratio (AFF)—atraumatic transverse fractures of the lateral sub-
(RR) of 48 trials: 0.90, 95% CI 0.84–0.98) [87]. However, a trochanteric femur requiring surgical fixation—can occur
recent metanalysis of 47 placebo-controlled RCTs involving after prolonged use of bisphosphonate with a rate approach-
59,437 participants, which accounted for the use of various ing 1.74 fractures per 10,000 person years for women over
402 H. See et al.

50 years [95]. In a North American study, the risk of AFF with frailty and sarcopenia. Cockcroft and Gault estimation
increased with longer duration of bisphosphonate use. Haz- of GFR is, therefore, necessary to use in these situations.
ard ratio compared with less than 3-month use increased Denosumab is a humanized monoclonal antibody that
from 8.86 (95% CI 2.79–28.20) for 3–5-year use to 43.50 blocks RANKL and hence osteoclastic activity within 3 days
(95% CI 13.70–138.15) when bisphosphonates were used for of administration [77] (Table 2). It is given via a subcutane-
8 years or more. Discontinuation of bisphosphonates in this ous injection (60 mg) on a 6-monthly basis. Even though no
study was associated with a rapid decrease in AFF rate [96]. dose adjustment is needed in patients with renal impairment,
Similar findings were also observed in a study conducted in those with severe renal impairment (creatinine clearance
in Denmark where prolonged use of bisphosphonates was < 30 mL/min, on dialysis or in individuals with an eGFR
associated with a seven-fold increase in AFF in adults ≥ 15–29 per min per 1.73 m ­ 2, the risk of hypocalcaemia is
50 years [97]. Importantly, in this study oral glucocorticoid higher, requiring frequent (at least prior to the next dose)
use and proton pump inhibitor use were independently asso- monitoring of serum calcium. Thus, supplemental calcium
ciated with increased AFF risk—drugs that are commonly and vitamin D should be taken concurrently. The pivotal
used by older people. Oral bisphosphonates should be taken Fracture Reduction Evaluation of Denosumab (FREEDOM),
on an empty stomach, in an upright position, with a glass of multicentre placebo-control trial showed a reduction in frac-
water [98]. Adherence to bisphosphonates may be challeng- ture incidence of 68% for vertebral fractures, 40% for hip
ing in older people because of this complex dosing regime fractures and 20% for non-vertebral fractures, in the first 3
and can be complicated by the presence of polypharmacy, years, in postmenopausal woman taking denosumab [104].
impaired cognition and physical care needs. Furthermore, In the 10 year follow-up, a continued lower fracture inci-
they should be separated from other medications since they dence and an increase in BMD without plateau was observed
may be mistaken for regular medication and taken concomi- [105]. Denosumab is often used as an alternative when oral
tantly. In older people with severe gastro-oesophageal reflux, bisphosphonates are not tolerated or are contraindicated or
dysphagia or cognitive impairment, alternative preparations, where other social and psychological problems preclude
i.e. intravenous (IV) yearly or 18 monthly infusions of zole- bisphosphonate therapy, e.g. cognitive impairment. Treat-
dronic acid or alternatives to bisphosphonates, may be used ment is usually for 5–10 years, after which an assessment
[99]. of BMD is usually indicated to plan continuation of therapy
Zoledronic acid is a potent and long-acting bisphospho- with another anti-osteoporosis treatment based on specialist
nate and is licensed for use in the primary or secondary pre- recommendation [106]. This is because the anti-resorptive
vention of post-menopausal osteoporosis, not only used in effects of denosumab rapidly diminishes after treatment ces-
men with osteoporosis but also used in cancer, myeloma and sation because of the loss of osteoclast inhibition. [107].
Paget’s disease [99]. As an example, intravenous zoledronic Consequently, fracture risk rapidly returns to pre-treatment
acid 5 mg can be used as first line treatment, particularly levels within 12 months of cessation. Spontaneous rebound
post-hip fracture repair in hospital. As the rate of incident vertebral fractures have been documented to occur as early
fracture in the 5-year post-sentinel hip fracture approaches as 7 months after the last dose of denosumab, so 6-monthly
25% attention to fracture risk reduction is an important pri- patient and physician reminders with clinical and biochemi-
ority [38]. In this regard, a single infusion of zoledronic acid cal reviews are of vital importance [108, 109]. This contrasts
was associated with a 23% reduction in fracture by 6 months with bisphosphonates where BMD is maintained for at least
(hazard ratio 0.77, 95% CI 0.57–1.03, P = 0.080) and 25% 2–5 years after treatment cessation. In FREEDOM, more
(hazard ratio 0.75, 95% CI 0.61–0.92, P = 0.005) by 12 cases of cellulitis in the denosumab then placebo group were
months [100]. This 20–30-min infusion is an option for older observed, but the overall numbers were extremely small
individuals living with advanced frailty or dementia who leaving open the question whether the effect was causal or
may be restricted to their own home or have a shortened life simply a chance finding [110]. Denosumab, similar to bis-
expectancy [101, 102]. It is worth noting that intravenous phosphonates, is also associated with very rare long-term
preparations may elicit an acute phase response resulting in side effects including osteonecrosis of the jaw and atypical
fever and myalgia that is short lived and responsive to simple femoral shaft fractures.
analgesia and dexamethasone [103]. When initiating denosumab or other anti-resorptive ther-
Bisphosphonates are renally excreted and should be apy, it is important to ensure that patients have any necessary
avoided in renal impairment. For example, alendronic acid, dental checks or tooth extractions performed, have normal
risedronate sodium and zoledronic acid should be avoided serum calcium levels and are replete in serum 25-OH-D at or
when creatinine clearance is below 30–35 mL/min per 1.73 above 50 nmol/L [31]. This lowers the risk of severe hypoc-
­m2. However, it is important to note that eGFR calculations alcaemia during treatment. Multiple loading regimes exist
may not be accurate in older people, especially those living for those who are vitamin D deficient. In clinical practice, a
single dose of 100,000 IU of colecalciferol for individuals
Table 2  Main pharmacological interventions for osteoporosis in older adults
Treatment Indications/advantages Side effects and contraindica- Guidance Dosing Duration of treatment
tions

Calcium and vitamin D Reduce the risk of hip fracture Gastrointestinal symptoms and Housebound older people or 1200 mg of calcium in Lifelong unless contraindicated
and of total fracture in those renal stones those living in a nursing combination with 800 IU of
who are deficient Contraindicated in pre-existing home are advised to take vitamin D, daily
Reduces risk of hypocalcaemia hypercalcaemia 800–1000 IU of vitamin D
during treatment with anti- and 1200 mg calcium per
resorptive agents day
Oral Bisphosphonates Treatment of postmenopausal, Gastrointestinal symptoms For postmenopausal women Alendronate 10 mg PO, once 5 years followed by fracture
male and glucocorticoid Bone/muscle/joint pain and men over 50 years of daily or 70 mg once weekly risk assessment and history of
induced osteoporosis Hypocalcaemia age, diagnosed with osteo- Risedronate sodium 5 mg PO, steroid use that informs con-
Osteonecrosis of the jaw (rare) porosis once daily or 35 mg PO, tinuation for another 5 years
Atypical femoral fractures Ensure patients have normal once weekly or drug holiday of 6 months
Contraindicated in renal serum calcium levels have to 3 years
impairment creatinine clear- vitamin D level at least or
ance < 35mL/min; condi- above 50 nmol/L. Tooth
tions impairing gastric emp- extraction if needed, good
tying (achalasia, oesophageal dental hygiene and well-
Treatment Considerations for Severe Osteoporosis in Older Adults

stricture) and hypocalcaemia fitting dentures are recom-

mended
Intravenous zoledronic acid Treatment of osteoporosis and Gastrointestinal symptoms Give in patients with recent Zoledronic acid 5 mg IV 3 years followed by fracture risk
steroid induced osteoporosis including oesophagitis fragility fracture annually or 5 mg every 18 assessment that informs con-
in men and post-menopausal Bone/muscle/joint pain Administer at least 14 days months for fracture preven- tinuation for another 5 years
women Hypocalcaemia after hip fracture repair tion in osteopenia or drug holiday
Fracture prevention in women Osteonecrosis of the jaw (rare) Ensure patients have normal
with osteopenia of the hip or Atypical femoral fractures serum calcium levels have
femoral neck Contraindicated in renal vitamin D level at least or
impairment creatinine above 50 nmol/L
clearance < 35mL/min and
hypocalcaemia; caution
advised in decompensated
heart failure
Denosumab Reduces the risk of vertebral, Hypocalcaemia Alongside calcium and vita- 60 mg SC (6 monthly) 10 year treatment without any
hip, non-vertebral fractures Abdominal discomfort min D supplementation drug holidays. Follow treat-
Increase in BMD without Increased risk of bacterial Alternative when oral bisphos- ment with other anti-osteopo-
plateau in postmenopausal infections phonates are not tolerated or rosis agents
women, male and glucocor- Skin rash are contraindicated
ticoid induced osteoporosis Osteonecrosis of the jaw (rare) Tooth extraction if needed,
and in patients with a risk of Atypical femoral fractures good dental hygiene and
fracture well-fitting dentures are
recommended
Ensure patients have normal
serum calcium levels have
vitamin D level at least or
above 50 nmol/L
403
Table 2  (continued)
404

Treatment Indications/advantages Side effects and contraindica- Guidance Dosing Duration of treatment
tions

Teriparatide Treatment of post-menopausal, Nausea If intolerant or severe side 20 mcg SC daily (maximum Up to 2 years, followed by
male, and glucocorticoid Chest pain effects occur from first line 24 months) another anti-osteoporotic
osteoporosis and patients at Pain in limbs therapies described agent
high fracture risk Gastrointestinal disorders Evidence suggests teriparatide
Recommended for post-men- Headache use as first line for the treat-
opausal women with severe Dizziness ment of severe osteoporosis
osteoporosis who have previ- Contraindicated in hyperpar- in a case-by-case basis
ously experienced a fragility athyroidism, Paget’s disease, Ensure patients have normal
fracture and are at risk of previous bone radiation serum calcium levels have
another within 24 months therapy or malignancies with vitamin D level at least or
bony metastases and severe above 50 nmol/L
renal impairment
Abaloparatide Treatment of post-menopausal Injection site reactions, dizzi- Ensure patients have normal 80 mcg SC daily for 18 Up to 2 years, followed by
osteoporosis and patient ness, headache, nasopharyn- serum calcium levels have months another anti-osteoporotic
with high fracture risk. gitis, joint pain, bronchitis vitamin D level at least or agent
Lower risks of new vertebral and hypertension above 50 nmol/L
fractures Contraindicated in patients
Reduction in risk of non-ver- with open epiphyses, Paget’s
tebral, vertebral and clinical disease, bone malignancies
fracture and severe renal impairment
Romosozumab Treatment of post-menopausal Cardiovascular and cer- Ensure patients have normal 210 mg (2 × 105 mg injec- 12 months, followed by
osteoporosis and patients ebrovascular events seen in serum calcium levels have tions sequentially) SC into sequential treatment with na
with high fracture risk pivotal trials vitamin D level at least or the abdomen, thigh or upper anti-resorptive agent
Reduces the risk of vertebral Headache and injection site above 50 nmol/L arm monthly for 12 months
and non-vertebral fractures reactions QRISK3 could be calculated
There is a potential theoretical when considering treatment
risk when combined with
other drugs that can potenti-
ate hypocalcaemia
Contraindicated in patients
with hypocalcaemia or his-
tory of stroke or myocardial
infarction in the past year

BMD bone mineral density, IU international units, mg milligrams, mcg micrograms, DXA dual-energy X-ray absorptiometry, PO per oral, IV intravenous, SC subcutaneous
H. See et al.
Treatment Considerations for Severe Osteoporosis in Older Adults 405

who have sustained a fragility fracture, e.g. of the hip, impairment. BMD gains are noticeable after 3 months of
appears to be well tolerated. This should be then followed commencement and last 1–2 years after cessation of teri-
with a combination supplementation with calcium and vita- paratide where a switch to another agent becomes necessary.
min D (800–1000 IU of vitamin D and 1200 mg calcium). Side effects may include skin reactions, nausea, arthralgia,
Alternative loading regimens include 20,000 IU three headache, dizziness and gastrointestinal symptoms.
times a week for a total of 6–7 weeks, followed by 800–1000 Abaloparatide is an analogue of parathyroid hormone-
IU/day to maintain a serum vitamin D level at or above 50 related peptide, is dosed at 80 mcg once daily for a maxi-
nmol/L [111]. Vitamin D in excess is associated with hyper- mum duration of 18 months and is given subcutaneously.
calcemia, hypercalciuria and mineral deposits in soft tis- It is associated with lower risks of new vertebral fractures
sues. Importantly, analyses of supplementation studies of when compared with both placebo. Additionally, a lower
vitamin D and calcium by Dawson–Hughes shows a nonlin- risk of non-vertebral fractures in comparison with placebo
ear, U-shaped association between 25-OH-D levels, falls and and a significant increase in BMD amongst 2463 post-men-
fracture. The association with increased morbidity appears opausal women aged 49–86 years in the ACTIVE study was
to occur at higher serum values approaching 100–150 observed. Furthermore, analysis of data from the ACTIVE
nmol/L, suggesting caution must be exercised when ongo- trial suggested a lower number needed to treat to prevent
ing intermittent high bolus doses of vitamin D are prescribed one vertebral or non-vertebral, clinical or major osteoporo-
for an older person. Global data are needed on these associa- tic fracture for abaloparatide compared with teriparatide,
tions to inform more precise estimates, but the notion that suggesting better efficacy compared with teriparatide [117,
higher levels of serum 25-OH-D contributes to increased 118]. The ACTIVExtend study, where alendronic acid was
falls and fracture rates is a relevant and important consid- administered for 24 months after the initial 18 months of
eration during clinical assessment, treatment and follow-up abaloparatide, found that this treatment sequence increased
[63]. The postulated mechanism for increased musculoskel- BMD as well as reduced the risk of vertebral, non-vertebral,
etal morbidity from high bolus doses involves down regula- clinical and major osteoporotic fractures in the participants
tion of 1-α-hydroxylase activity leading to reductions in 1,25 [119]. Finally, a randomized, double-blind, placebo-con-
dihydroxy-vitamin D activity, decreased calcium absorption, trolled study evaluated the efficacy and safety of abalopara-
increased bone turnover and bone loss [76, 112]. tide in men and showed significant increases in BMD at
Parathyroid hormone analogues (teriparatide and aba- the lumbar spine, total hip and femoral neck compared with
loparatide) Teriparatide, a synthetic parathyroid hormone, placebo. Adverse effects may include injection site reactions,
is anabolic (activates osteoblasts) in bone rather than anti- dizziness, nasopharyngitis, joint pain and headache [120]
resorptive and should be administered subcutaneously in the (Table 2).
abdomen or thigh at a dose of 20 mcg daily for of 24 months Romosozumab Romosozumab is a monoclonal anti-
or more in select countries that have approved longer term sclerostin antibody that has both anabolic and anti-resorp-
use. Teriparatide is currently used to treat postmenopausal tive effects that is cleared by hepatic proteolysis and not by
women with high risk for fracture, men with primary or the kidneys [77]. Administration is via two 105 mg sub-
hypogonadal osteoporosis at high risk of fracture and men cutaneous injections into the abdomen or thigh, totalling
and women with glucocorticoid-induced osteoporosis at a monthly dose of 210 mg for a maximum of 12 months.
high risk for fracture [113]. In a seminal randomized pla- Significant gains in BMD are typically observed within 6
cebo-controlled trial with postmenopausal women with at months of starting treatment and can be maintained post
least one prior vertebral fracture, teriparatide was shown treatment cessation by an anti-resorptive agent. It is gen-
to decrease the risk of new vertebral fractures by 65% and erally well tolerated, with 4–5% of patients experiencing
non-vertebral fragility fractures by 53%. Furthermore, an injection site skin reactions [121]. Other potential reac-
increase in BMD was observed at both the lumbar spine tions include arthralgia, headaches or infections. Supple-
(9%) and femoral neck (3%) [114]. It can be used in men and mentation with calcium and vitamin D is recommended,
women who are intolerant or who suffer severe side effects and although romosozumab has a good safety profile in
from first line therapies described above. individuals with reduction in renal function, monitoring of
The analyses from the VERtebral fracture treatment serum calcium is recommended in individuals with severe
comparisons in Osteoporotic women (VERO) trial of the renal impairment [122].
effects of teriparatide and risedronate sodium in post-men- Several clinical trials have evaluated the efficacy of
opausal women with severe osteoporosis suggest teripara- romosozumab. The FRAME study, an international, ran-
tide can be used first line in those with severe osteoporosis domized double-blind, placebo-controlled trial, assessed
[115, 116]. Teriparatide is contraindicated in patients with romosozumab in postmenopausal women aged 55–90 years
metabolic bone diseases such as Paget’s disease, skeletal with osteoporosis. The romosozumab group had a 75%
metastases, previous bone radiation therapy and severe renal lower risk of new vertebral fractures at 24 months [123].
406 H. See et al.

The 2018 FRAME extension study further examined the and BRIDGE trials reported an increase in cardiovascular
efficacy, safety and fracture risk following 1 year of romo- and cerebrovascular events linked to romosozumab use. In
sozumab, followed by 2 years of denosumab, and found a the ARCH study, 16 patients (0.8%) in the romosozumab
lower incidence of fractures in the romosozumab–deno- group experienced cardiac ischemic events compared with
sumab group compared with the placebo–denosumab 6 (0.3%) in the alendronic acid group (odds ratio 2.65, 95%
group: new vertebral fractures were 1.0% versus 2.8% (P CI 1.03–6.77) and 16 patients (0.8%) in the romosozumab
< 0.001), clinical fractures were 4.0% versus 5.5% (P = group versus 7 (0.3%) in the alendronic acid group reported
0.004) and non-vertebral fractures were 3.9% versus 4.9% cerebrovascular events (odds ratio 2.27, 95% CI 0.93–5.22).
(P = 0.039), respectively [124]. The BRIDGE study suggested a numerical imbalance in
The 2017 ARCH study compared postmenopausal serious cardiovascular adverse events, with 4.9% of patients
women treated with alendronic acid for 24 months against in the romosozumab group experiencing such events com-
women who received romosozumab for 12 months fol- pared with 2.5% in the placebo group [127, 130]. A potential
lowed by alendronic acid for another 12 months. Notably, mechanism for cardiovascular effects was put forward by
the romosozumab-to-alendronic acid group demonstrated Zheng et al. [131] postulating that lower sclerostin levels
48% lower risk of new vertebral fractures (P < 0.001) and might elevate the risk of hypertension, type 2 diabetes, myo-
a 27% lower risk of clinical fractures (P < 0.001). The cardial infarction and increased coronary artery calcifica-
risk of non-vertebral fractures was reduced by 19% (P = tion. However, further research will be necessary to clarify
0.04), while the risk of hip fracture decreased by 38% (P the association between romosozumab and cardiovascular
= 0.02) [123, 125]. as well as cerebrovascular events [130].
The STRU​CTU​RE trial in 2017 evaluated the efficacy Support for the use of osteoanabolic agents in postmeno-
of romosozumab compared with teriparatide in postmen- pausal women was reinforced by a recent network meta-anal-
opausal women with osteoporosis transitioning from oral ysis of 69 trials involving over 80,000 patients. The authors
bisphosphonate therapy. After 1 year of treatment, the concluded that osteoanabolic agents, such as romosozumab
romosozumab group showed significantly greater increases and parathyroid hormone receptor antagonists, were more
in areal bone mineral density (BMD) measured by DXA at effective than bisphosphonates in preventing clinical and
both the hip and spine. Specifically, the mean percentage vertebral fractures. Additionally, denosumab treatment was
change from baseline in total hip areal BMD was 2.6% (95% associated with reduced rates of vertebral fractures com-
CI 2.2–3.0) for romosozumab, whereas teriparatide showed pared with bisphosphonates [132].
a decrease of −0.6% (95% CI −1.0 to −0.2) [126]. In summary, romosozumab is recommended for postmen-
The 2018 BRIDGE trial was a smaller randomized pla- opausal women who have sustained a major osteoporotic
cebo-controlled study that found 12 months of romosozumab fracture within the last 24 months but have not experienced
treatment resulted in significant increases in spine and hip a recent stroke or myocardial infarction in the past year. It
BMD compared with placebo in men with osteoporosis. is suitable for those with a T-score ≤ −3.5 at the hip or
The mean percentage change from baseline in lumbar spine spine or a T-score ≤ −2.5 at the hip or spine with either
and total hip BMD was notably higher with romosozumab: a vertebral fracture, a history of two or more osteoporotic
12.1% versus 1.2% for the lumbar spine and 2.5% versus vertebral fractures or high fracture risk indicated by FRAX.
−0.5% for the total hip (P < 0.001) [127]. From a pragmatic and therapeutic point of view, a QRISK3
A review of the effectiveness of sequential treatments calculation to estimate an individual’s risk for developing
utilized by FRAME, ARCH and STRU​CTU​RE, by Cos- a heart attack or stroke over the next 10 years when con-
man et al. [128], indicated that initiating treatment with sidering romosozumab therapy can be conducted to inform
romosozumab for 1 year leads to substantial BMD gains at clinical decision making [133]. Continuation with either
both the total hip and lumbar spine, suggesting that sequen- bisphosphonates or denosumab should follow in sequence
tial treatment of romosozumab followed by anti-resorptive (Table 2). Further trial data for the efficacy of romosozumab
agents may be more effective in preventing fractures than on fracture reduction in men are required.
the reverse sequence. This ‘anabolic first’ approach could be
particularly advantageous for older individuals with severe
osteoporosis and is the subject of recent European guidance 5 Frailty, Cognitive Impairment, Dementia
[129]. and Fragility Fracture
There are conflicting findings regarding cardiovascular
adverse effects associated with romosozumab. While the Frailty, a syndrome defined as a state of heightened physi-
FRAME, FRAME extension and STRU​CTU​RE studies ological vulnerability to stressors, becomes more prevalent
found no significant differences in cardiovascular events with increasing age and is very often associated with mul-
between the romosozumab and placebo groups, the ARCH timorbidity [134]. Physical dysfunction that characterizes
Treatment Considerations for Severe Osteoporosis in Older Adults 407

frailty is often seen in parallel with cognitive impairment those who are insufficient and if calcium intake is inad-
and or dementia. This cognitive decline is often accompa- equate, and individuals should be encouraged to modify
nied behavioural problems, visual and motor impairments their diet.
and an increased risk of falls. Moreover, the high prevalence
of malnutrition and sarcopenia among patients living with Declarations
dementia significantly elevates the likelihood of osteoporosis Funding No funding was granted for this publication. This is an
and confers a higher risk for incident and future fractures. independent commissioned review by Drugs and Aging and reflects
The presence of these conditions presents a unique thera- the clinical, medical and research roles of all authors within the UK
peutic challenge, as this vulnerable group of older people are National Health Service.
least likely to receive fracture risk assessments or receive
longer-term primary or secondary prevention medications. Conflict of interest H.P.P. has received lecture fees from Abbott, Pfizer
and HC-UK conferences outside of the submitted work. All other au-
Several contributing factors contribute to this disparity, thors declare that they have no conflicts of interest in relation to this
including delirium, worsening cognitive decline, institu- work. H.S., E.G., K.K., N.S., S.L., M.B. and H.P.P. are supported by
tionalization, poor adherence and competing polypharmacy the Department of Medicine for Older People, University Hospital
[135]. Additionally, altered pharmacokinetics due to age and Southampton, Southampton, UK. E.B. and P.A. are supported by the
Faculty of Medicine, University of Southampton. H.P.P. is supported
other systemic physiological changes in the body with age by the NIHR Southampton Biomedical Research Centre, Nutrition and
increase the risk of adverse drug reactions (ADRs) in this the University of Southampton. S.L. is supported by the NIHR Ad-
group of patients. vanced Fellowship scheme. This report is independent research, and
Anti-resorptive and anabolic agents may be prescribed to the views expressed in this publication are those of the authors and not
necessarily those of the NHS, the NIHR or the Department of Health.
these patients. Vitamin D and calcium supplementation (800 These funding bodies had no role in writing of the manuscript or deci-
IU of vitamin D3 and 1200 mg of calcium) has been shown sion to submit for publication. For the purpose of Open Access, the au-
to lower hip and other fracture risk in older female nursing thor has applied a Creative Commons Attribution (CC BY) licence to
home residents who are deficient [136]. In this regard, CGA any Author Accepted Manuscript version arising from this submission.
can be beneficial for this group of vulnerable patients and Availability of data and material Not applicable
can identify achievable goals to improve bone health in the
short and medium term, considering the broader medical, Ethics approval Not needed
social, physical and psychological aspects of their health,
Authors’ contributions H.S., E.G., E.B., P.A., K.K., N.S., S.L., M.B.
including life expectancy [36]. and H.P.P. all contributed to the preparation of the manuscript. All
authors reviewed and approved the final manuscript, providing com-
ments and amendments. H.P.P. edited the final draft. All authors agree
6 Conclusions to be accountable for the work.

The prevalence of osteoporosis rises with age, predispos- Open Access This article is licensed under a Creative Commons Attri-
bution-NonCommercial 4.0 International License, which permits any
ing to fractures that have significant impact on the lives of non-commercial use, sharing, adaptation, distribution and reproduction
older people. Osteoporosis is often underdiagnosed and in any medium or format, as long as you give appropriate credit to the
untreated; therefore, bone and muscle health assessment original author(s) and the source, provide a link to the Creative Com-
should be part of a holistic comprehensive geriatric assess- mons licence, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative
ment in primary and secondary care. Nutrition, physical Commons licence, unless indicated otherwise in a credit line to the
activity, exercise, gait and balance interventions benefit material. If material is not included in the article’s Creative Commons
both bone and muscle health and can reduce the risk of licence and your intended use is not permitted by statutory regula-
falls. These interventions should be combined with other tion or exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this licence, visit
lifestyle measures to improve overall bone health. Bone http://creativecommons.org/licenses/by-nc/4.0/.
sparing agents are beneficial for fracture risk reduction.
But for older people who have a high fracture risk, factors
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