HORIZONS IN MEDICINE Clinical Medicine 2016 Vol 16, No 4: 360–4

Recent advances in the pathogenesis and treatment

of osteoporosis

Authors: Elizabeth M Curtis, A Rebecca J Moon,B Elaine M Dennison,C Nicholas C HarveyD and Cyrus CooperE

Over recent decades, the perception of osteoporosis has and propensity to fracture. Worldwide, there are nearly 9
ABSTRACT

changed from that of an inevitable consequence of ageing, to million osteoporotic fractures each year, and the US Surgeon
that of a well characterised and treatable chronic non-commu- General's report of 2004, consistent with data from the UK,
nicable disease, with major impacts on individuals, healthcare suggested that almost one in two women and one in five men
systems and societies. Characterisation of its pathophysiol- will experience a fracture in their remaining lifetime from
ogy from the hierarchical structure of bone and the role of its the age of 50 years.1 The cost of osteoporotic fracture in the
cell population, development of effective strategies for the UK approaches £3 billion annually and, across the EU, the
identification of those most appropriate for treatment, and estimated total economic cost of the approximately 3.5 million
an increasing armamentarium of efficacious pharmacologi- fragility fractures in 2010 was €37 billion.2 In this article we
cal therapies, have underpinned this evolution. Despite this review the pathogenesis of osteoporosis and approaches to
marked progress, individuals who experience a fragility fracture improving bone strength, aimed at reducing the immense
remain under-treated in many areas of the world, and there is burden of osteoporotic fracture.
substantial need for investment both in secondary and primary
prevention globally. In this brief article, we give an overview of Pathogenesis
the pathogenesis of osteoporosis, and summarise current and
future approaches to its assessment and treatment. Hierarchical structure
Fractures occur when the force applied to a bone exceeds its
KEYWORDS: osteoporosis, epidemiology, pathophysiology,
strength. A bone needs to be both stiff and flexible to resist
treatment, risk assessment, dxa
fracture, which is achieved through a hierarchical structure.
Collagen type-1 fibrils are wound in a triple helical structure,
linked together with non-collagenous proteins, which help to
Introduction prevent shearing. Hydroxyapatite crystals deposited on the
Osteoporosis is characterised by deterioration of bone mass collagen structure add strength, particularly in compression.
and microarchitecture, resulting in increased bone fragility Cross-linkage between collagen fibrils with non-collagenous
proteins is reduced in osteoporotic bone, leading to reduced
tensile strength.3 In addition, larger hydroxyapatite crystals are
found in osteoporosis, making bone more brittle and prone to
Authors: Aacademic clinical fellow, MRC Lifecourse Epidemiology fracture.4
Unit, University of Southampton, Southampton, UK; Bclinical
research fellow, MRC Lifecourse Epidemiology Unit, University of
Bone cells
Southampton, Southampton, UK, and Paediatric Endocrinology,
Southampton University Hospitals NHS Foundation Trust, Osteoblasts, osteocytes and osteoclasts are the three main
Southampton, UK; Cprofessor of musculoskeletal epidemiology, types of bone cells. Osteoblasts are bone forming and
MRC Lifecourse Epidemiology Unit, University of Southampton, may become embedded within bone mineral as mature
Southampton, UK; Dprofessor of rheumatology and clinical osteocytes (comprising 90–95% of the cells within bone)
epidemiology, MRC Lifecourse Epidemiology Unit, University or remain on the surface as bone-lining cells. Osteoclasts
of Southampton, Southampton, UK, and NIHR Southampton are multinucleated cells responsible for bone resorption.
Biomedical Research Centre, University of Southampton and Osteoblasts and osteoclasts work together in a coordinated
University Hospital Southampton NHS Foundation Trust, fashion at specific sites on the surface of trabecular or
Southampton, UK; Edirector and professor of rheumatology, cortical bone, forming ‘bone multicellular units’. During
MRC Lifecourse Epidemiology Unit, University of Southampton, bone formation, osteoblasts lay down new osteoid collagen
Southampton, UK, NIHR Southampton Biomedical Research Centre, matrix and over a period of weeks to months, crystals of
University of Southampton and University Hospital Southampton calcium hydroxyapatite form on the collagen fibrils. Bone is
NHS Foundation Trust, Southampton, UK, and NIHR Musculoskeletal laid down during growth and repair and through adaptation
Biomedical Research Unit, University of Oxford, Oxford, UK to mechanical loading in a process known as modelling.

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 Pathogenesis and treatment of osteoporosis

Remodelling, in contrast, involves a cycle of resorption

Table 2. The spectrum of antifracture efficacy of
and formation of existing bone. Osteocytes play a key
role in the regulation of modelling and remodelling. The pharmacological interventions for osteoporosis.
arrangement of the osteocytes around Haversian canals acts Intervention Vertebral Non-vertebral Hip
as a mechanosensory system and allows communication Alendronate + + +
both directly between neighbouring osteocytes and through
the release of endocrine, paracrine and autocrine signalling Risedronate + + +
factors to other bone cells. The various pathways important Zoledronic acid + + +
to the regulation of osteoblast and osteoclast activity, such Etidronate + – –
as receptor activator of nuclear factor kappa B–receptor
activator of nuclear factor kappa B ligand (RANK–RANKL) Ibandronate + +* –
and Wnt signalling, are increasingly recognised as targets for Raloxifene + – –
anti-osteoporosis agents. Strontium ranelate + + +*
Teriparatide + + –
Changes in bone structure across the life course
Denosumab + + +
The balance of formation and resorption has a critical influence *post hoc analysis in a subset of patients.
on bone mass and strength throughout life. There is a positive
balance during childhood until achievement of peak bone mass
in early adulthood,5 with a subsequent period of stability and
then a negative balance in older age, with osteoclast activity Clinical risk factors
greater than osteoblast activity, leading to bone loss. In women, There are many factors that influence fracture risk, either
this process is accelerated after the menopause. At the level of the through bone mineral density (BMD) or through independent
whole bone, the cellular mechanisms and associated influences mechanisms. These include age, glucocorticoid therapy, a
result in differences in structure between males and females, previous personal history of fracture, a family history of hip
and alterations with advancing age. Males typically have a fracture, current smoking practice, alcohol abuse and certain
larger bone cross-sectional area than females, and in addition diseases associated with osteoporosis eg rheumatoid arthritis,
there is a significant reduction in cortical thickness in females diabetes, osteogenesis imperfecta in adults, untreated long-
following the menopause, contributing to the well established standing hyperthyroidism, hypogonadism or premature
sex differences in fracture risk. The structure of the trabeculae menopause (<45 years), chronic malnutrition, malabsorption
differs between the sexes, with young women having fewer and and chronic liver disease. These are summarised in Table 1,
thinner trabeculae than young men, and a greater reduction in and have, in terms of risk assessment, been incorporated into
trabecular number in women as they age.6 In addition, cortical the FRAX® tool,8 a WHO supported initiative which uses risk
porosity increases at a faster rate in female ageing.7 factors, with or without BMD measurement, to estimate a
10-year probability of either hip fracture or major osteoporotic
Table 1. Risk factors for osteoporosis. fracture. FRAX® is by far the most commonly used such tool
Risk factors independent Risk factors dependent globally, covering 75% of the world's population, and may, as in
of BMD on BMD the UK, be linked to assessment algorithms to define thresholds
for intervention with treatment.9
Age Untreated hypogonadism,
premature menopause
Treatment of osteoporosis
Previous personal history of Malabsorption
fragility fracture Vitamin D and calcium supplementation
Maternal history of hip fracture Endocrine disease eg The role of vitamin D and calcium supplementation has been
– heritable influences hyperthyroidism much debated in recent years with numerous meta-analyses
Glucocorticoid therapy Chronic renal disease suggesting conflicting findings. A large UK randomised
controlled trial demonstrated that supplementation with either
Smoking Chronic liver disease
calcium, vitamin D or both for secondary fracture prevention
Alcohol intake ≥3 units/day Chronic obstructive pulmonary at the population level appeared ineffective,10 although
disease supplementation in high-risk settings where deficiencies are
Rheumatoid arthritis Immobility expected, for example in nursing homes, may be beneficial.11
A recent individual patient data meta-analysis demonstrated
Body mass index ≤19 kg/m2 Drugs eg androgen deprivation
that overall, there appeared to be a modest benefit for combined
therapy, aromatase inhibitors
vitamin D and calcium supplementation for hip fractures,
Falls total fractures and probably vertebral fractures, but that there
Caucasian was no benefit for vitamin D alone.12 Although there has been
Geography – latitudes furthest
discussion from one research group that excess calcium intake
from equator
may be associated with increased cardiovascular risk,13 this
has not been substantiated across many other studies. Indeed,
BMD = bone mineral density.
it is reassuring to note that a recent individual-patient-data

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 Elizabeth M Curtis, Rebecca J Moon, Elaine M Dennison et al

meta-analysis of the anti-fracture studies suggests that calcium for myocardial infarction: 1.6), in addition to the previously
and vitamin D supplementation in combination is associated known risk of venous thromboembolism (VTE). Therefore
with an improvement in mortality, which is not observed its use is now restricted to treatment of severe osteoporosis
with vitamin D supplementation alone.14 Almost all of the in postmenopausal women with high risk of fracture and in
randomised control trial evidence for the efficacy of anti- men at increased risk of fracture, but with no cardiovascular
osteoporosis drugs comes from patients who were prescribed or cerebrovascular disease. However, within this selected
concomitant calcium and vitamin D supplementation; both group of patients, particularly now that many individuals have
should therefore usually be prescribed adjunctively with undergone long-term bisphosphonate treatment, strontium
treatment for osteoporosis. ranelate does still offer a useful alternative.17

Bisphosphonates Selective oestrogen receptor modulators – raloxifene

Bisphosphonates are synthetic analogues of the naturally Raloxifene is a selective oestrogen receptor modulator that
occurring compound pyrophosphate and bind strongly to has antiresorptive oestrogenic effects on the skeleton without
hydroxyapatite, inhibiting bone resorption by inactivating the unwanted risks of oestrogen in the breast. Its use is also
osteoclasts. The most commonly prescribed oral associated with a significant decrease in the risk of breast
bisphosphonate is alendronate. If taken properly (in the cancer. It has been shown to be effective in preventing post-
morning with a glass of water, 45 minutes before food, drink or menopausal bone loss and in preventing vertebral fractures.
other medications and remaining upright for 30–60 minutes However there is no evidence that raloxifene prevents hip or
after the dose), upper GI side effects are uncommon. However, non-vertebral fractures.18 Adverse effects include leg oedema,
for those who are unable to tolerate oral bisphosphonates, or cramps, hot flushes and a two- to three-fold increase in the risk
in whom they are contraindicated (for example malabsorption of VTE.
or dysphagia), then an intravenous bisphosphonate, such as
zoledronate (given yearly in a dose of 5 mg by infusion over a Teriparatide
minimum of 15 minutes) is an alternative.
Teriparatide (recombinant human 1–34 parathyroid-hormone
peptide) is the only agent in current widespread use with truly
Denosumab
anabolic effects on bone. It is administered by subcutaneous
Denosumab, a fully humanised antibody to RANKL, is a injection in daily doses of 20 µg. It increases bone formation
newer antiresorptive agent. RANKL, secreted by osteoblasts, is and produces large increases in BMD, leading to approximately
a major activator of osteoclastic bone resorption and mimics 70% reduction in the incidence of new moderate or severe
the action of osteoprotegerin. Denosumab is administered as a vertebral fractures over 18 months of treatment, together
subcutaneous injection once every six months and its efficacy with reductions in non-vertebral fractures.19 Side effects are
has been demonstrated in patients with renal impairment, uncommon but may include nausea, headache and dizziness;
although due consideration should be given to the possibility in addition, transient hypercalcaemia and hypercalciuria
of underlying renal bone disease in chronic kidney disease may occur. Studies have shown added benefit in combination
4–5. Three-year fracture data show a 68% reduction in treatments such as teriparatide plus denosumab or teriparatide
vertebral fracture and 40% reduction in hip fracture.15 Side plus zoledronate,20 although such approaches are not yet
effects are uncommon, and may rarely include skin infections, approved clinically in the UK, and use of teriparatide in the UK
predominantly cellulitis. This is not typically seen at the is currently limited to those older patients at highest fracture
injection site and may be secondary to an immunomodulatory risk and who may have failed other therapies.
effect of the drug. Hypocalcaemia can also be a risk,
particularly if the patient is vitamin D deficient, or has renal Adverse effects and duration of therapy
impairment.
Atypical femoral factures of the subtrochanteric region
and femoral shaft may also rarely occur in patients taking
Strontium ranelate
bisphosphonates or denosumab. These are usually located
Strontium, an element directly below calcium in group 2 of in the lateral cortex around which endosteal thickening may
the periodic table, is combined with ranelic acid as a carrier be observed prior to fracture occurrence. Individuals may
to form strontium ranelate. It is taken as a single daily oral have prodromal pain and fractures typically are transverse,
dose. Its mechanism of action remains a subject of research, sometimes bilateral and occur after minimal trauma. Although
but there is evidence that it increases bone strength by altering these fractures can occur in bisphosphonate-/denosumab-naïve
bone material properties. Administration of strontium individuals, they appear more commonly in patients taking
ranelate leads to a substantial increase in BMD at the spine these therapies for a prolonged duration. It is thought that the
and hip, though part of this increase is artefactual, due to reason for this increased incidence is related to oversuppression
incorporation of strontium (which has a greater atomic weight of bone turnover. Overall, the fractures prevented greatly
than calcium) into bone. Studies have shown a 36% relative outnumber those atypical events potentially resulting from
risk reduction in hip fracture over three years in osteoporotic medication.21 Osteonecrosis of the jaw is extremely rarely
patients.16 In 2013 a Medicines and Healthcare Products observed during therapy for osteoporosis (as low as 1/100,000/
Regulatory Agency warning on strontium ranelate was issued year for individuals on oral bisphosphonates),22 but appears
due to increased risk of cardiovascular disorders (relative risk more commonly when higher doses of bisphosphonates are

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 Pathogenesis and treatment of osteoporosis

given intravenously for treatment of bone metastases. A Conclusion

causal link to bisphosphonates is unproven but international
guidance suggests a prudent approach, encouraging patients In recent decades, our understanding of the pathogenesis of
to maintain good oral hygiene and have regular dental visits, osteoporosis has dramatically increased, with development of a
with invasive dental work performed before commencement of wide range of effective pharmaceutical approaches to fracture
bisphosphonate or denosumab therapy.23 prevention. Given the enormous prevalence of osteoporosis, and
Current UK guidance has therefore moved towards a frequency and burden of resulting fragility fractures, one of the
reassessment of the need for treatment after three years of key concerns going forward remains the optimal identification of
intravenous bisphosphonate/subcutaneous denosumab, and those requiring treatment.27 The tools for fracture risk assessment
five years of oral bisphosphonate.9 For high-risk patients, are widely available, in the form of the FRAX® calculator, and
continuation of treatment is usually warranted, but where there new medications are undergoing testing. It is vital that awareness
have been no incident fractures and BMD has improved, a of osteoporosis is promoted among all health professionals, in
period without treatment may be recommended. order to ensure closure of the so-called ‘treatment gap’, and with
a consequent reduction in the burden of osteoporotic fracture for
Novel therapies individuals, healthcare systems and societies. ■

Cathepsin-K inhibitors
Acknowledgements
Odanacatib is a once weekly oral treatment for osteoporosis in We would like to thank Medical Research Council (UK), Arthritis
which phase-III clinical trials have recently been performed. Research UK, National Osteoporosis Society (UK), International
It inhibits cathepsin-K, a cysteine protease expressed in Osteoporosis Foundation and NIHR for supporting this work.
osteoclasts which degrades type-1 collagen. In postmenopausal
women with low BMD, 24 months of treatment with odanacatib
was shown to produce increases in lumbar spine and total-hip Note
BMD by 5.5% and 3.2%, respectively, whereas BMD at these This article was originally published in the 2015 Clinical Medicine
sites was essentially unchanged with placebo (−0.2% and supplement Horizons in Medicine 27. All articles in this supplement
−0.9%).24 However, later trial outcomes also demonstrated a are available at www.clinmed.rcpjournal.org/content/15/Suppl_6
possible increase in cerebrovascular events, which has led to a
delay in FDA approval while outcomes are further adjudicated. References
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