Osteoporosis

Abstract

Osteoporosis is a progressive skeletal disorder that is characterised by compromised bone strength that leads to an increased susceptibility to fractures. With an ageing population in the UK and a prevalence rate of 34% in people over the age of 50 years, the health and financial burden of the disease is significant. Osteoporosis develops due to an imbalance in bone remodelling, leading to a decrease in bone mineral density and alterations in the micro-architecture of bone. Diagnosis of osteoporosis involves a thorough assessment to identify patients at risk of developing osteoporosis, as it is often asymptomatic. Bone density measurements through dual-energy x-ray absorptiometry (DXA) scans are the gold-standard diagnostic modality. Treatment of osteoporosis is guided by the symptomatology of patients in addition to their T-score from the DXA scan. Oral bisphosphonates are the first-line therapy in addition to oral calcium and vitamin D supplementation to halt bone resorption and reduce fracture risk.

Clinical case scenario

Maria is a 78-year-old woman with a history of wrist and vertebral fractures and presents to her GP with low back pain. On examination, she has kyphosis and tenderness over the lumbar spine. Given her history of smoking and hyperthyroidism, a dual-energy x-ray absorptiometry (DXA) scan is requested, and this shows a T-score of −2.8, confirming osteoporosis. Treatment is initiated with oral bisphosphonates along with oral calcium and vitamin D, as she was deficient. Her GP discusses the importance of treatment adherence and schedules a medication review in 1 month. When next seen, Maria reports improved back pain, but has severe dyspepsia since starting alendronic acid. Her GP reviews her technique of taking bisphosphonates and finds no issues of concern. However, the adverse effects are affecting her adherence and Maria requests an alternative. Her GP refers her to the specialist geriatrician for advice on alternative anti-osteoporotic treatment. The geriatrician suggests a switch to once weekly oral bisphosphonate and Maria continues on oral calcium and vitamin D supplementation. Maria tolerates the once weekly oral bisphosphonate and her GP arranges to see her in 2 years for a repeat DXA scan to reassess her bone mineral density.

Introduction

Globally, osteoporosis affects approximately 18% of the population. This condition can have significant health implications for patients, including a significant decrease in quality of life and increased morbidity, mortality, and disability. These therefore present a significant financial burden (Porter and Varacallo, 2023). According to the International Osteoporosis Foundation, the estimated annual cost for treating osteoporotic fractures is £4.5 billion accounting for 2.4% of the healthcare budget in 2019 (International Osteoporosis Foundation, 2022). Given the limited resources available within the National Health Service (NHS) and an ageing population, this article will provide a greater understanding of the implications of osteoporosis. Early diagnosis and management are vital to achieving better health outcomes.

Pathophysiology

Osteoporosis results from an imbalance in bone remodelling processes, leading to low bone mass or abnormal bone architecture. This causes bone fragility and increased risk of fracture. Bone strength is influenced by several factors such as bone mineral density, the size and shape of bone, bone turnover and the micro-architecture of bone (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001).

Bone is in a constant state of remodelling in response to mechanical and hormonal changes. The remodelling of bone is initiated by specialised cells, called osteocytes, which regulate local mineral deposition at the bone matrix by osteoclasts and osteoblasts (Turner et al., 2002). Osteoclasts are large, multinucleated cells which are responsible for the breakdown of bone tissue, also referred to as bone resorption. Osteoclasts attach themselves to the surface of the bone tissue, creating a specialised compartment where they can secrete enzymes, such as cathepsins and matrix metalloproteinases (Goto et al., 2003). These enzymes degrade the organic matrix of bone. Additionally, osteoclasts secrete acids that dissolve the mineral components of bone, leading to the release of calcium and other minerals. Other molecules, including interleukin 1 (IL-1), 1,25 dihydroxy-vitamin D (calcitriol), prostaglandin E2 and IL-6 are involved in promoting osteoclast differentiation activity, thereby enhancing bone resorption (Kitaura et al., 2020; Takeda et al., 1999). The activity of osteoclasts is regulated by a variety of cellular and signalling pathways, with disruptions in these pathways resulting in osteoporosis.

Osteoblasts, on the other hand, are specialised cells responsible for the formation of new bone tissue through the synthesis and secretion of bone matrix. These cells are derived from mesenchymal stem cells and differentiate into osteoprogenitors, a crucial component in bone growth, repair and remodelling (Florencio-Silva et al., 2015). Once activated by transcription factors, such as Runx2 and osterix, osteoblasts produce a range of molecules for bone formation, including enzymes, growth factors (TGF-β, IGFs) and other proteins.

The Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) and the Osteoprotegerin (OPG) signalling pathway are key factors in bone remodelling. RANKL is produced by osteoblasts, which bind to RANK receptors on osteoclasts, promoting their differentiation and bone resorption activity. OPG can act as a decoy receptor, thereby inhibiting RANKL from activating osteoclasts (Tobeiha et al., 2020). An imbalance in RANKL or OPG can contribute to developing conditions such as osteoporosis. Other important cellular pathways involved in bone formation include the functions of parathyroid hormone (PTH) and TGF-β (Ottewell, 2016). PTH is a hormone that stimulates both bone formation and resorption. The anabolic or catabolic effects of PTH are dependent on the frequency and duration of exposure to PTH. Continuous exposure to PTH generally activates osteoclasts and favours bone resorption, whereas intermittent exposure promotes bone formation by stimulating the activity of osteoblasts (Silva and Bilezikian, 2015). TGF-β is another growth factor produced by osteoblasts that is involved in bone metabolism. It is stored in the bone matrix and released during bone resorption, acting to recruit stem cells and promote their differentiation into osteoblasts. Following the completion of bone formation, osteoblasts will either become dormant in the lining cells on the bone surface and undergo apoptosis or further differentiate into osteocytes where they become embedded into the bone matrix.

Lastly, it is important to note the role of oestrogen in bone remodelling. At the cellular level, oestrogen functions to inhibit the differentiation of osteoclasts: a process mediated by cytokines, such as IL-1 and IL-6. Collectively, this reduces the amount of active remodelling units. In menopausal women, the associated oestrogen deficiency can result in cancellous, in addition to cortical bone loss. Thus, decreased bone mass, disturbed architecture, and reduced bone strength are common observations in this population (Väänänen and Härkönen, 1996).

Risk factors

The risk of developing an osteoporotic or fragility fracture is influenced by a complex interaction of primary and secondary variables. Primary risk factors can be considered to be those that are directly related to bone health, whereas secondary risk factors are external factors that may impact bone health. These can be categorised into modifiable or non-modifiable risk factors (Table 1).

Table 1.

Summary of risk factors for developing osteoporotic or fragility fractures.

Modifiability	Risk factors	Description
Primary non-modifiable	Age	Greater risk for women over 50 and men over 65 years of age
	Gender	Women have higher risk due to menopause
	Family history	Increased risk with family history of osteoporosis
Primary modifiable	Low BMI	Risk increases with BMI less than 20 kg/m²
	Alcohol and tobacco	Excess consumption linked to higher risk
	Low calcium and Vitamin D	Risk can be modified with supplementation
Secondary non-modifiable	Endocrine diseases	Affects bone metabolism
	Chronic diseases	Liver, kidney, and lung diseases increase risk
Secondary modifiable	Medications	Proton pump inhibitor, steroids, anti-epileptics
	Immobilisation	Reduced stress on bone impacts remodelling
	Nutrient malabsorption	Risk can be modified with treatment

Adapted from NICE (2023)

Primary non-modifiable risk factors

Age is a primary, non-modifiable risk factor, as bone mineral density (BMD) naturally tends to decline with age. Women over the age of 50 and men over the age of 65 are at a greater risk as compared with other age groups. Gender is another primary, non-modifiable risk factor for developing osteoporosis. Women are at a greater risk of developing osteoporosis and fragility fractures, due to lower peak bone mass and undergoing hormonal changes during menopause, which significantly reduces oestrogen level, which is vital for bone health (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). A family history of osteoporosis and a maternal history of hip fractures are other primary, non-modifiable risk factors for developing osteoporosis.

Primary modifiable risk factors

A low body mass index (BMI) is a primary, but modifiable, risk factor. A BMI of less than 20 kg/m² has been associated with a more rapid decline in BMD. However, this risk factor can be modified with nutritional intervention and lifestyle changes (ACOG, 2021). Excess alcohol consumption and tobacco use have also been associated with an increased risk of developing osteoporosis. However, studies have demonstrated that moderate alcohol consumption has positive effects on the declining rate in BMD. Other primary, modifiable risk factors include low calcium intake and vitamin D deficiency (Jackson et al., 2006). These risk factors lead to reduced BMD, thereby increasing the risk of osteoporotic and fragility fractures.

Secondary non-modifiable risk factors

The development of certain medical conditions can increase the risk of developing osteoporosis and are considered as secondary, non-modifiable risk factors. This includes chronic liver disease, chronic kidney disease and rheumatoid arthritis.

Secondary and modifiable risk factors

Various pharmacological therapies and treatments can influence bone health and can be classified as secondary, modifiable risk factors for developing osteoporosis. Medications include proton pump inhibitors, corticosteroids (minimum 3 month course of a steroid dose equivalent to 7.5 mg prednisolone) and some anticonvulsants (carbamazepine) that have all been linked with reduced BMD (Mazziotti et al., 2006). Endocrine diseases such as diabetes mellitus, hyperthyroidism and hyperparathyroidism can interfere with bone metabolism. For example, diabetes mellitus causing impaired glucose tolerance can affect collagen formation in bones (Saito et al., 2014). However, treatment for these conditions can mitigate the risk of osteoporosis.

Other risk factors may include prolonged immobilisation, which reduces the mechanical stress on the bone, thereby reducing the need for bone remodelling. Nutrient malabsorption from gastrointestinal conditions such as Crohn’s disease, ulcerative colitis and coeliac disease are also risk factors for developing osteoporosis (NICE, 2023). Nutritional supplementation and medical therapies can be used to reduce the risk of osteoporosis.

Diagnosis

Osteoporosis is often asymptomatic until a fracture occurs; therefore, a thorough clinical assessment is important in diagnosing this condition in patients with risk factors. Clinical evaluation is based on a thorough history and identifying the presence of risk factors. Diagnostic studies are also implemented to exclude reversible secondary causes of low bone mass in patients deemed to be low-risk based on their FRAX or Z scores with suspicious symptoms or fragility fractures. The key components to include in the history are age, sex, ethnicity, whether women are postmenopausal, history of immobilisation and if there is a history of previous fractures (ACOG, 2021). Physical examination may reveal a reduced BMI or spinal kyphosis, which may indicate an asymptomatic fracture. Secondary causes of osteoporosis should also be investigated where appropriate and can include conditions such as hypogonadism in either sex, the presence of endocrine conditions and haematological conditions such as multiple myeloma and haemoglobinopathies.

Patients who present with a risk for fragility fractures should be assessed to exclude non-osteoporotic causes for fragility fractures. These conditions include metastatic bone disease, which is suggested by bone pain, history of cancer (particularly cancer of the breast, kidney, lung, prostate and thyroid) or other constitutional symptoms such as fever, night sweats and weight loss (NICE, 2023). Other non-osteoporotic causes for fragility fractures include multiple myeloma, osteomalacia and Paget’s disease. Multiple myeloma should be considered in the presence of bone pain, recurrent infections, anaemia, hypercalcaemia or renal impairment. Osteomalacia presents with bone and muscle pain or proximal muscle weakness, whereas Paget’s disease is suggested by bone pain or deformity.

The gold-standard method of measuring the bone mineral density of patients is through a dual-energy x-ray absorptiometry (DXA) scan to confirm osteoporosis in the absence of an osteoporotic fracture. DXA scans have become the gold-standard diagnostic test for osteoporosis due to their notably shorter scan times, being comparatively inexpensive and reduced radiation exposure compared with other imaging modalities (Krugh and Langaker, 2023). It is of note that although the DXA scan is highly specific it has a low sensitivity, meaning a large number of fragility fractures occur in women who do not have osteoporosis, as defined by the T-score. Therefore, a diagnosis of osteoporosis should encompass a risk factor assessment, in addition to DXA scan findings.

The initiation of drug treatments without a preceding DXA scan is considered acceptable for patients who present with a vertebral fracture. The DXA scan assesses the BMD at the spine and hip and generates a T-score that compares the patient’s BMD with that of a healthy young adult of the same sex. A T-score of −1.0 or above is considered normal, between −1.0 and −2.5 indicates low bone mass (osteopenia) and a score below −2.5 is diagnostic of osteoporosis (Sheu and Diamond, 2016). Osteopenia is described in the literature as the precursor to osteoporosis, and is used in individuals with below normal BMD reference values but not yet low enough to meet the diagnostic criteria to be considered osteoporotic (Varacallo et al., 2023). Therefore, individuals presenting with osteopenia can benefit from therapeutic interventions to prevent their condition from becoming osteoporotic. The World Health Organization (WHO) has added a fourth category for T-scores where a score of −2.5 or more with the presence of a fragility fracture indicates severe or established osteoporosis (WHO, 2000). In addition to the T-score, DXA scans can provide a Z-score, which is a comparison of the patient’s BMD to the average BMD of people of the same age, sex and ethnicity. Although the T-score is used to diagnose osteoporosis, a negative Z-score of −2.5 or less should raise the suspicion of a secondary cause of osteoporosis.

For all other patients who have risk factors for osteoporosis, but do not have a vertebral fracture, a 10-year fragility fracture risk should be calculated prior to arranging a DXA scan. National guidance (NICE, 2023) suggest patients should be offered a DXA scan to measure their BMD without calculating their fragility risk if they are over the age of 50 years with a history of fragility fractures or are younger than 40 years and have a major risk factor for fragility fractures. Two commonly used online risk stratification tools include QFracture® and FRAX®; however, the former is preferred in the UK.

These risk stratification tools are able to predict the absolute risk of hip fractures and major osteoporotic fractures of the spine, wrist, hip or shoulder over the following 10 years. The QFracture® is a web-based risk calculator specifically developed for the UK population and is considered as the preferred risk stratification tool in the UK. The tool defines the cut-off for women at the top 10% highest risk of developing a fracture at 10 years a score of 11.1%, whereas for men, the cut off for the top 10% at highest risk is a score of 2.6% (Hippisley-Cox and Copeland, 2012). The FRAX® was developed by the WHO to assess the risk of fracture and integrates clinical risk factors and BMD scores at the neck of femur to calculate a 10-year fracture probability (Silverman and Calderon, 2010). FRAX® does not provide explicit thresholds for intervention, thereby allowing clinicians to use their judgement to decide on initiating therapy (Fig. 1). Limitations of the FRAX® score include: the assumption that BMI and mortality are constant across different ethnic and racial groups and also it is known to exclude some variables that are known to be associated with fracture risk. For example, the evidence suggests that white, Asian, Hispanic, and Native American women are at increased risk of osteoporosis compared with black women (Pothiwala et al., 2006). Additionally, unlike QFracture®, FRAX® does not offer gender-specific thresholds. Nevertheless, FRAX® is a validated tool for multiple ethnicities and is used worldwide. Table 2 (adapted from NICE (2023)) provides a review of the interpretation of fragility fracture risk scores from both of the risk stratification tools.

Figure 1.

FRAX^® fragility fracture risk intervention thresholds.

Table 2.

Interpretation of fragility fracture risk scores.

Risk	QFracture®	FRAX®
High risk	Risk score is 10% or greater	Red zone of risk chart
Intermediate risk	Risk score is close to, but below 10%	Orange zone of risk chart
Low risk	Risk score is below 10%	Green zone of risk chart

Other diagnostic methods in assessing patients with suspected osteoporosis include laboratory investigations to identify deficiencies in vitamins and minerals such as vitamin D and calcium. People aged over 65 years or those with minimal exposure to sunlight are at risk of vitamin D deficiency and NICE (2023) advise a daily calcium intake of 1000 mg/day for those who are at increased risk of a fragility fracture. If there is a suspicion of a secondary cause, the following tests should be considered: assessing testosterone deficiency in men, thyroid function tests, PTH levels, serum cortisol levels and serum/urine protein electrophoresis.

Management

Management of osteoporosis is multi-faceted and includes pharmacological therapies and lifestyle modifications to manage risk factors. Those at high risk who undergo a DXA scan and the T-score is −2.5 or less, bone-sparing drug treatments, such as bisphosphonates should be commenced. Bisphosphonates are a widely established treatment that is used to treat osteoporosis through suppression of the protein geranylgeranylation, an essential cellular process required for osteoclastic bone resorption (Reszka and Rondan, 2003). This is particularly relevant in postmenopausal women and men aged over 50 years with a low BMD score. Recommended bisphosphonates include Alendronate (10 mg once daily or 70 mg once weekly) or Risedronate (5 mg once daily or 35 mg once weekly). Oral bisphosphonates are licensed for use in postmenopausal women, but only specific forms are licensed for use in men (once daily alendronate and Risedronate are licensed in men). Oral bisphosphonates may also be prescribed to patients who are on high dose oral corticosteroids. Adherence of oral bisphosphonates should be considered as they must be taken on an empty stomach in the morning with a full glass of water and patients must be sat up for 30 minutes to minimise adverse effects (Joint Formulary Committee, 2023). If the T-score is above −2.5, management strategies should focus on modifying risk factors and treating possible underlying conditions. For these patient groups, a repeat DXA scan should be considered after 2 years. If standard oral bisphosphonates are not tolerated or contra-indicated, referral to specialist services should be considered for treatment with options such as zolendronic acid, denosumab, strontium ranelate, raloxifene and teriparatide.

Following the initiation of bone-sparing treatments such as bisphosphonates, medication reviews and dental screenings should be conducted to anticipate and monitor for adverse effects such as dyspepsia, reflux or symptoms suggestive of an atypical fracture, or osteonecrosis of the jaw. Contraindications also include a history of hypersensitivity to the bisphosphonate, hypocalcemia, and chronic kidney disease. Patient adherence to treatments should be investigated and consideration of alternative treatments should be made if adverse effects are unacceptable. Patients who are taking oral corticosteroids should continue treatment with bisphosphonates and/or calcium and vitamin D until steroids have stopped then reassess the risk of fragility fractures to determine the need for treatment continuation. Patients who are started on oral bisphosphonates should be reviewed after 3–5 years and reassessed for their risk of fragility fractures and if bisphosphonates are still indicated (NICE, 2023). People who sustain an osteoporotic fracture despite being on bone-sparing therapy should be investigated for secondary causes for osteoporosis. If secondary causes are excluded, referral to a specialist for drug advice should be considered.

Low-risk patients should receive lifestyle modification advice and a follow-up appointment within 5 years. Assessment of vitamin D and calcium levels is essential for all patients at risk of osteoporosis. If a patient is not exposed to large amounts of sunlight, but has adequate daily calcium intake, initiating 400 international units (IU) of vitamin D is recommended without calcium supplementation. However, if calcium intake is inadequate, 400 IU of vitamin D with 1000 mg of calcium daily is recommended (NICE, 2023). Hormonal replacement therapy should be considered for younger postmenopausal women to reduce the risk of fragility fractures and to relieve menopausal symptoms.

Primary and secondary prevention

Primary prevention strategies for osteoporosis include focussing on achieving peak bone mass and maintaining bone quality through patient education, engaging in regular physical activity and dietary supplementation. Raloxifene, a bone resorption inhibitor, has been found to increase BMD in certain postmenopausal women. However, its adverse effects must be considered carefully prior to treatment initiation (Delmas et al., 1997). The risk of glucocorticoid-induced osteoporosis can be mitigated with initiation of bisphosphonates, particularly for patients with prolonged treatment or prior fractures.

Secondary prevention strategies focus on reducing the risk of falls among patients who have already been diagnosed with osteoporosis. Falls risk assessments, multi-disciplinary health care team approaches and targeted interventions can all help reduce the risk of falls. Holistic approaches to improving the gait and mobility status of patients at risk of falls with the aid of therapists, balance and weight-bearing exercises can all help reduce the risk of falls thereby reducing the risk of fractures.

Key points

Osteoporosis is a chronic condition that is characterised by reduced BMD and compromised bone strength, leading to an increased risk of fractures

Osteoporosis develops from an imbalance between bone formation and resorption, leading to weakened bone structure

DXA is the gold-standard diagnostic modality and measures BMD

First-line treatment includes oral bisphosphonates such as alendronate and risedronate, other treatments include vitamin D and calcium supplementation

Patient adherence to medication is vital for treatment efficacy – alternative therapies or weekly dosing can be considered for those with adverse effects

Lifestyle interventions such as physical exercise, eating a balanced diet and adequate intake of calcium and vitamin D play a key role in prevention of osteoporosis

Footnotes

ORCID iDs

Dr Muataz Khalid

Dr Ahmed Elhamalawy

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