Chapter 19: Osteoporosis

Stuart H. Ralston

Chapter Outline

Introduction

Osteoporosis is a common metabolic bone disease characterized by reduced bone mass, microarchitectural deterioration of bone tissue, and an increased risk of fragility fracture.36 The diagnosis is made by measurements of bone mineral density (BMD) using dual energy x-ray absorptiometry (DEXA). Individuals with BMD values more than 2.5 standard deviations below the average in young healthy subjects (T-score <-2.5) are classified as having osteoporosis. People with lesser reductions in BMD (T-score between −1 and −2.5) are classified as having osteopenia whereas people with T-score values between −1 and +2.5 are said to have normal bone mass. Patients with T-score values above +2.5 in the absence of a known cause such as osteoarthritis of the spine considered to have abnormally high bone mass. 
Bone mass increases through growth and adolescence to reach a peak in the early 20s (Fig. 19-1). It remains relatively stable in healthy individuals thereafter until the age of about 45 years when bone loss starts to occur. Although bone is lost with age in both genders, there is an accelerated phase of bone loss after the menopause in women as the result of estrogen deficiency. By the age of 80 years it has been estimated that about 50% of white women and about 20% of men will have osteoporosis as defined on the basis of a T-score of −2.5 or below. 
Figure 19-1
Changes in bone mass with age.
 
Bone mass gradually increases during childhood and adolescence to reach a peak by the age of about 20. Thereafter bone mass is stable until the age of 45 when bone loss starts to occur, particularly in women. By the age of 80 it is estimated that BMD values will have fallen to within the osteoporotic range (T-score < −2.5) in about 50% of all women.
Bone mass gradually increases during childhood and adolescence to reach a peak by the age of about 20. Thereafter bone mass is stable until the age of 45 when bone loss starts to occur, particularly in women. By the age of 80 it is estimated that BMD values will have fallen to within the osteoporotic range (T-score < −2.5) in about 50% of all women.
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Figure 19-1
Changes in bone mass with age.
Bone mass gradually increases during childhood and adolescence to reach a peak by the age of about 20. Thereafter bone mass is stable until the age of 45 when bone loss starts to occur, particularly in women. By the age of 80 it is estimated that BMD values will have fallen to within the osteoporotic range (T-score < −2.5) in about 50% of all women.
Bone mass gradually increases during childhood and adolescence to reach a peak by the age of about 20. Thereafter bone mass is stable until the age of 45 when bone loss starts to occur, particularly in women. By the age of 80 it is estimated that BMD values will have fallen to within the osteoporotic range (T-score < −2.5) in about 50% of all women.
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The clinical importance of osteoporosis lies in the fact that it is a risk factor for fractures and the risk of fracture increases by a factor of 1.5- to 3-fold for each standard deviation reduction in BMD.45 Osteoporosis is classically associated with an increased risk of low-trauma fractures (fragility fractures), but recent studies indicate that perhaps not surprisingly, low levels of BMD are associated with the risk of all types of fractures including high energy fractures.44 
Fractures are a major public health problem in developed countries. For example, it has been estimated that in North America, white women aged 50 have a remaining lifetime risk of 17.5% for hip fracture, 15.6% for clinical vertebral fracture, and 16% for wrist fracture. For men corresponding risks are 6%, 5%, and 2.5%. In the United Kingdom the lifetime risk of any fracture at the age of 50 has been estimated as about 53% for women and 21% for men.34 Although the risk of fracture is significantly increased in patients with osteoporosis as defined by DEXA, most fractures occur in patients who do not have osteoporosis.73 This is because the occurrence of fracture is not only determined by bone strength (which is strongly correlated with BMD) but also other factors such as risk of falling, the type of fall, bone geometry, and bone quality. In keeping with this, it has been shown that reduced BMD values only account for a small proportion of the exponential increase in fracture risk that occurs with increasing age (Fig. 19-2)
Figure 19-2
Relation between BMD, age, and fractures.
 
The incidence of hip fracture increases with age in both genders but is about five times greater in those aged 80 as compared with those aged 60 as BMD values fall below 0.8. (From: De Laet CE, van Hout BA, Burger H, et al. Bone density and risk of hip fracture in men and women: Cross sectional analysis. BMJ. 1997;315:221–225, with permission.)
The incidence of hip fracture increases with age in both genders but is about five times greater in those aged 80 as compared with those aged 60 as BMD values fall below 0.8. (From: De Laet CE, van Hout BA, Burger H, et al. Bone density and risk of hip fracture in men and women: Cross sectional analysis. BMJ. 1997;315:221–225, with permission.)
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Figure 19-2
Relation between BMD, age, and fractures.
The incidence of hip fracture increases with age in both genders but is about five times greater in those aged 80 as compared with those aged 60 as BMD values fall below 0.8. (From: De Laet CE, van Hout BA, Burger H, et al. Bone density and risk of hip fracture in men and women: Cross sectional analysis. BMJ. 1997;315:221–225, with permission.)
The incidence of hip fracture increases with age in both genders but is about five times greater in those aged 80 as compared with those aged 60 as BMD values fall below 0.8. (From: De Laet CE, van Hout BA, Burger H, et al. Bone density and risk of hip fracture in men and women: Cross sectional analysis. BMJ. 1997;315:221–225, with permission.)
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Pathophysiology

Bone Structure

Bone is a composite material comprising matrix and mineral phases. The main component of bone matrix is type I collagen which is a fibrillar protein comprising two alpha 1 and one alpha 2 chains wound together in a triple helix. Bone matrix also contains small amounts of other collagens, growth factors, and other noncollagenous proteins and glycoproteins. The mineral phase of bone consists of calcium and phosphate in the form of hydroxyapatite crystals (Ca10(PO4)6(OH)2) which are deposited in the spaces between collagen fibrils. Mineralization confers upon bone the property of mechanical rigidity, which complements the tensile strength and elasticity derived from bone collagen. Anatomically bone is divided into cortical and trabecular subtypes. Most of the skeleton consists of cortical bone which forms the shafts of the long bones such as the femur, tibia, humerus, and radius and forms a thin envelope around the trabecular bone which is abundant at the metaphyses of long bones and in the vertebral bodies. Both types of bone undergo a process of renewal and repair throughout life as a result of bone remodeling (Fig. 19-3). During bone remodeling old and damaged bone is removed by multinucleated osteoclasts which dissolve bone mineral through secretion of acid and degrade bone matrix through secretion of proteases. Following completion of bone resorption, bone marrow stromal cells are attracted to the resorption lacuna and differentiate into osteoblasts. The osteoblasts lay down new bone matrix which is initially unmineralized (osteoid) and subsequently becomes mineralized to form mature calcified bone. During the process of bone formation some osteoblasts become trapped in the bone matrix and differentiate into osteocytes. Osteocytes are the most abundant cells in bone. They communicate with each other and with cells on the bone surface through long cytoplasmic processes which run through channels in the bone matrix termed canaliculi. Osteocytes play a critical role in the regulation of bone remodeling at a local level. They sense and respond to mechanical stimuli by producing regulatory molecules including receptor activator of nuclear factor kappa B (RANK) which regulates bone resorption and sclerostin (SOST) which regulates bone formation. Osteocytes also have an important endocrine function by producing a circulating hormone called fibroblast growth factor 23 (FGF23) which acts on the renal tubule to regulate serum phosphate levels. 
Figure 19-3
The bone remodeling cycle.
 
The bone remodeling cycle is responsible for renewal and repair of bone throughout life. Bone is removed by multinucleated osteoclasts which are thought to be able to detect and remove areas of microdamage. After about 10 to 12 days osteoclasts undergo programmed cell death (apoptosis) and are replaced by osteoblasts which lay down new bone in the resorption lacuna. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes which are responsible for detecting and responding to mechanical strain. When bone formation is complete the matrix mineralizes and the bone surface becomes quiescent and covered with flat lining cells.
The bone remodeling cycle is responsible for renewal and repair of bone throughout life. Bone is removed by multinucleated osteoclasts which are thought to be able to detect and remove areas of microdamage. After about 10 to 12 days osteoclasts undergo programmed cell death (apoptosis) and are replaced by osteoblasts which lay down new bone in the resorption lacuna. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes which are responsible for detecting and responding to mechanical strain. When bone formation is complete the matrix mineralizes and the bone surface becomes quiescent and covered with flat lining cells.
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Figure 19-3
The bone remodeling cycle.
The bone remodeling cycle is responsible for renewal and repair of bone throughout life. Bone is removed by multinucleated osteoclasts which are thought to be able to detect and remove areas of microdamage. After about 10 to 12 days osteoclasts undergo programmed cell death (apoptosis) and are replaced by osteoblasts which lay down new bone in the resorption lacuna. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes which are responsible for detecting and responding to mechanical strain. When bone formation is complete the matrix mineralizes and the bone surface becomes quiescent and covered with flat lining cells.
The bone remodeling cycle is responsible for renewal and repair of bone throughout life. Bone is removed by multinucleated osteoclasts which are thought to be able to detect and remove areas of microdamage. After about 10 to 12 days osteoclasts undergo programmed cell death (apoptosis) and are replaced by osteoblasts which lay down new bone in the resorption lacuna. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes which are responsible for detecting and responding to mechanical strain. When bone formation is complete the matrix mineralizes and the bone surface becomes quiescent and covered with flat lining cells.
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Bone Resorption

Bone resorption is carried out by osteoclasts which are multinucleated cells derived from the monocytes/macrophage lineage. The RANK signaling pathway plays a critical role in regulating osteoclast differentiation and bone resorption.39 The RANK receptor is a member of the tumor necrosis factor (TNF) receptor superfamily which is expressed on osteoclast precursors and mature osteoclasts. It is activated by a molecule called RANK ligand (RANKL) which is a member of the TNF superfamily (Fig. 19-4). When RANKL binds to RANK several intracellular signaling pathways are activated which cause osteoclast differentiation and bone resorption. Osteoprotegerin (OPG) has homology to RANK, but lacks a signaling domain and acts as a decoy receptor for RANKL. In the presence of OPG, the stimulatory effects of RANKL on osteoclasts are blocked causing osteoclast inhibition. The importance of this system is underscored by the fact that loss of function mutations in RANK and RANKL result in osteoclast poor osteopetrosis due to the failure of osteoclast differentiation,79 whereas loss of function mutations in OPG result in juvenile Paget’s disease, a condition associated with markedly elevated bone turnover, fractures, and bone deformity.42 Rarely, neutralizing autoantibodies to OPG may develop in patients with autoimmune disease and this causes a severe form of osteoporosis with high bone turnover.64 Mature osteoclasts form a tight seal over the bone surface and resorb bone by secreting hydrochloric acid and proteolytic enzymes onto the bone surface. The acid dissolves hydroxyapatite, allowing the proteolytic enzymes to degrade collagen and other bone matrix proteins. Osteoclast-rich osteopetrosis is caused by mutations in the genes that encode molecules which are involved in acid secretion and matrix degradation.79 These include the CA2 gene which encodes carbonic anhydrase type II, which is necessary for acid generation in osteoclasts; the TCIRG1 gene that encodes a 117 kD subunit of the osteoclast proton pump which is necessary for acid secretion; the CLCN7 gene which encodes the osteoclast chloride channel; and the CATK gene which encodes cathepsin K, a protease that is necessary for collagen degradation. 
Figure 19-4
Molecular regulation of bone turnover.
 
Osteocytes play a central role in regulating bone resorption and formation. They regulate bone resorption (left side) by releasing RANKL which binds to RANK on osteoclast precursors triggering osteoclast differentiation and bone resorption, which is mediated by secretion of hydrochloric acid (HCl) and cathepsin K (CatK) onto the bone surface. Osteoprotegerin (OPG) inhibits bone resorption by binding to RANKL and preventing it activating RANK. Other sources of RANKL include T-cells and stromal cells. Osteocytes regulate bone formation by secreting sclerostin (SOST) which binds to the LRP5/frizzled (LRP5/frz) coreceptor, preventing its activation by Wnt family members, thereby suppressing bone formation.
Osteocytes play a central role in regulating bone resorption and formation. They regulate bone resorption (left side) by releasing RANKL which binds to RANK on osteoclast precursors triggering osteoclast differentiation and bone resorption, which is mediated by secretion of hydrochloric acid (HCl) and cathepsin K (CatK) onto the bone surface. Osteoprotegerin (OPG) inhibits bone resorption by binding to RANKL and preventing it activating RANK. Other sources of RANKL include T-cells and stromal cells. Osteocytes regulate bone formation by secreting sclerostin (SOST) which binds to the LRP5/frizzled (LRP5/frz) coreceptor, preventing its activation by Wnt family members, thereby suppressing bone formation.
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Figure 19-4
Molecular regulation of bone turnover.
Osteocytes play a central role in regulating bone resorption and formation. They regulate bone resorption (left side) by releasing RANKL which binds to RANK on osteoclast precursors triggering osteoclast differentiation and bone resorption, which is mediated by secretion of hydrochloric acid (HCl) and cathepsin K (CatK) onto the bone surface. Osteoprotegerin (OPG) inhibits bone resorption by binding to RANKL and preventing it activating RANK. Other sources of RANKL include T-cells and stromal cells. Osteocytes regulate bone formation by secreting sclerostin (SOST) which binds to the LRP5/frizzled (LRP5/frz) coreceptor, preventing its activation by Wnt family members, thereby suppressing bone formation.
Osteocytes play a central role in regulating bone resorption and formation. They regulate bone resorption (left side) by releasing RANKL which binds to RANK on osteoclast precursors triggering osteoclast differentiation and bone resorption, which is mediated by secretion of hydrochloric acid (HCl) and cathepsin K (CatK) onto the bone surface. Osteoprotegerin (OPG) inhibits bone resorption by binding to RANKL and preventing it activating RANK. Other sources of RANKL include T-cells and stromal cells. Osteocytes regulate bone formation by secreting sclerostin (SOST) which binds to the LRP5/frizzled (LRP5/frz) coreceptor, preventing its activation by Wnt family members, thereby suppressing bone formation.
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Bone Formation

Bone is formed by osteoblasts which are mononuclear cells derived from mesenchymal stem cells. Several molecules are involved in regulating osteoblast differentiation. They include core-binding factor alpha 1 (Cbfa1) and osterix which are transcription factors that promote differentiation of mesenchymal stem cells to osteoblasts; bone morphogenic proteins which are members of the transforming growth factor beta superfamily that upregulate Cbfa1 expression in osteoblast precursors; and members of the Wnt superfamily which affect osteoblast differentiation and function by regulating the transcription factor beta-catenin.82 The Wnt molecules are a series of glycoproteins that are highly conserved throughout evolution. They bind to a receptor complex which comprises a member of the frizzled family in a heterodimer with either Lipoprotein receptor-related protein 5 (LRP5) or LRP6 (Fig. 19-4). Binding of Wnt to the frizzled/LRP receptor complex is antagonized by various proteins including Dickkopf 1 (DKK1), secreted frizzled-related proteins (sFRPs) and sclerostin (SOST) (Fig. 19-4). Accordingly, regulation of bone formation by this pathway depends on a fine balance between the stimulatory effects of Wnt and the inhibitory effects of DKK1, sFRP, and SOST on LRP5/LRP6 signaling. 
There are 19 different Wnt genes in mammals and it is currently unclear how many of these interact with frizzled/LRP to regulate bone mass. Experimental evidence has been gained to suggest that at the very least, Wnt3A6 and Wnt10B75 play a role. 
Emerging evidence suggests that production of SOST by osteocytes plays a critical role in regulating bone mass and bone turnover in response to mechanical loading. Mechanical loading of bone inhibits production of SOST by osteocytes and this increases bone formation and reduces bone resorption by increasing levels of OPG.65 The importance of SOST in regulating bone mass is reflected by the fact that recessive (loss of function) mutations in SOST result in bone overgrowth and high bone mass in the syndromes of sclerosteosis and van Buchem disease.35 Similarly, heterozygous mutations in the LRP5 receptor also result in high bone mass by preventing SOST–LRP5 binding, allowing Wnt to activated LRP5 signaling.3 

Systemic Factors that Regulate Bone Remodeling

In addition to the local mediators mentioned above, several systemic hormones regulate bone remodeling. Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D act together to increase bone remodeling allowing skeletal calcium to be mobilized for maintenance of plasma calcium homeostasis. Bone remodeling is also increased by thyroid hormone and growth hormone, but suppressed by estrogen and androgens. These factors are thought to work in part by modulating production of locally produced factors such as RANKL, OPG, and SOST as well as by exerting direct effects on osteoblast and osteoclast activity. 
In addition to suppressing bone turnover, estrogen is also involved in regulating coupling between bone resorption and bone formation such that in states of estrogen deficiency, bone formation fails to keep pace with bone resorption, resulting in bone loss. This is thought to account for the phase of accelerated bone loss that occurs after the menopause in women. 

Risk Factors for Osteoporosis

Osteoporosis is a complex disease with both environmental and genetic components and several risk factors have been identified as summarized in Table 19-1
 
Table 19-1
Risk Factors for Osteoporosis and Fractures
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Table 19-1
Risk Factors for Osteoporosis and Fractures
  •  
    Smoking
  •  
    Excessive alcohol intake (>3 units/day)
  •  
    Low body weight (BMI <19)
  •  
    Early menopause
  •  
    Genetic factors
    •  
      Race
    •  
      Family history hip fracture
  •  
    Diseases
    •  
      Thyrotoxicosis
    •  
      Rheumatoid arthritis
    •  
      Primary hyperparathyroidism
    •  
      Cushing syndrome
    •  
      Hypogonadism
    •  
      Anorexia nervosa
    •  
      Cancer
    •  
      Chronic liver disease
    •  
      Celiac disease
    •  
      Cystic fibrosis
    •  
      Epilepsy
  •  
    Drugs
    •  
      Corticosteroids
    •  
      Thyroxine
    •  
      Gonadotrophin releasing hormone agonists
    •  
      Sedatives
    •  
      Anticonvulsants
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Genetics

Twin and family studies have shown that genetic factors account for between 70% to 85% of the variance in bone mass2 although the heritability of fracture is considerably lower than this especially in the elderly.49 Although the genetic influences on fracture risk are partly mediated by the effects on BMD, other determinants of fracture risk such as bone turnover and bone geometry also have a heritable component.59 Current evidence indicates that BMD is influenced by a large number of genetic variants which individually have a small effect size.59 The same applies to fracture, although fewer variants have been identified.27 It is of interest that many of the genetic variants that are associated with BMD or fractures lie close to genes in the RANK and Wnt signaling pathways.27 

Diet

Most research in this area has focused on calcium intake. Several studies have shown a positive relationship between calcium intake during youth and peak bone mass although there is no convincing evidence linking dietary calcium intake with fracture risk in adults.8 

Mechanical Loading

There is evidence to suggest that mechanical loading increases bone mass whereas immobility causes bone loss.50,74 Population-based studies have also shown an association between increased levels of physical exercise and reduced fracture risk,15 although this is probably due to increased muscle strength and a reduced risk of falling rather than the effects on BMD. 

Smoking

Cigarette smokers are at increased risk of fractures.33,41 The mechanisms are likely to be multifactorial including the fact that female smokers have an earlier menopause, accelerated metabolism of exogenous estrogens, and impaired peripheral conversion of adrenal androgens to estrogen due to reduced body weight. 

Alcohol

Moderate alcohol intake does not seem to affect fracture risk significantly, but there is strong evidence that the risk of fracture increases significantly in those who drink more than 3 units of alcohol per day and is increased substantially in those who drink more than 6 units per day.33 The association between excessive alcohol intake and fracture risk is likely to be multifactorial in nature and probably involves effects on BMD as well as nonskeletal factors such as an increased risk of falling. 

Social Deprivation

Social deprivation is strongly associated with fracture risk.17 The mechanisms are unclear but likely to be multifactorial involving differences in lifestyle factors such as diet, smoking, alcohol, and physical activity. 

Diseases

Diseases that are associated with an increased risk of osteoporosis or fractures are summarized in Table 19-1. The mechanisms underlying these associations are discussed in more detail below. Hypogonadism is an important cause of osteoporosis in both genders. This may be physiologic as in the case of postmenopausal osteoporosis or pathologic as in patients with pituitary disease, Klinefelter syndrome, and Turner syndrome. Hypogonadism during growth predisposes to osteoporosis by reducing peak bone mass whereas hypogonadism in adults predisposes to osteoporosis by causing increased bone loss with uncoupling between bone resorption and bone formation. Although testosterone protects against osteoporosis in men, current evidence suggests that it does so through peripheral conversion to estrogen through aromatization.38 Chronic inflammatory rheumatic diseases such as rheumatoid arthritis and ankylosing spondylitis are associated with an increased risk of osteoporosis and fractures. Several mechanisms are likely to contribute including relative immobility, increased production of proinflammatory cytokines such as interleukin-1 and TNF, and corticosteroid treatment. Similar mechanisms are likely to be responsible for osteoporosis in gastrointestinal (GI) diseases such as Crohn disease and ulcerative colitis. Celiac disease is associated with an increased risk of osteoporosis and fractures presumably due to impaired intestinal absorption of calcium, vitamin D, and other nutrients. Osteoporosis may coexist with osteomalacia in patients with celiac disease and malabsorption or in patients with inflammatory bowel disease. Thyrotoxicosis is associated with osteoporosis due to increased bone turnover as is over-replacement with thyroxine. Primary hyperparathyroidism is associated with osteoporosis due to increased bone turnover with relative uncoupling of bone resorption from bone formation. 

Corticosteroids

Corticosteroids are a strong risk factor for osteoporosis and fractures.78 The risk of fracture is directly related to the dose and duration of therapy. Several mechanisms have been implicated including reduced intestinal calcium absorption, increased renal calcium losses by an effect of glucocorticoids on renal tubular calcium absorption, and reduced bone formation and inhibition of bone formation by apoptosis of osteoblasts and osteocytes. Inhaled corticosteroids are generally considered to be safe with respect to the risk of osteoporosis but high-dose inhaled steroids have been associated with reduced bone mass. 

Thyroxine

Over-replacement with thyroxine in patients with hypothyroidism is associated with reduced bone mass, presumed to be due to a direct stimulatory effect on bone turnover.4 

Other Drugs

Several other drugs including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), and anticonvulsants have been associated with an increased risk of fragility fractures.33 The mechanisms are incompletely understood but are likely multifactorial due to adverse effects on balance and cognitive function and/or direct effects on bone cells. 

Clinical Presentation of Osteoporosis

The most common clinical presentation of osteoporosis is with fractures of various types, details of which are reviewed elsewhere in these volumes. Vertebral fractures deserve special mention since their presence is easily missed. Some patients with vertebral fractures present with acute back pain which can be localized to the affected site or can radiate to the anterior chest wall or abdomen, mimicking intrathoracic pathology or an acute abdomen. In some cases there is a predisposing factor such as bending, coughing, or lifting whereas other fractures occur spontaneously. Many patients with vertebral fractures present insidiously with height loss or kyphosis and chronic back pain. In addition to pain and height loss, patients with multiple vertebral fractures may experience abdominal discomfort and distension due to compression of abdominal organs by severe kyphosis. 

Clinical Assessment

Bone Density

Assessment of BMD by DEXA has a pivotal role in the diagnosis of osteoporosis, in fracture risk assessment, and in selecting patients for treatment. Measurements of BMD are usually made at the femoral neck and lumbar spine in routine practice, but it is also possible to obtain measurements at the wrist and the whole body. Reduced levels of BMD are significantly associated with an increased risk of fracture such that fracture risk increases by a factor of 1.5 to 3-fold for each standard deviation reduction in BMD.45 It is important to emphasize that BMD measurements do not accurately predict fractures occurring since many people with BMD values in the osteoporotic range do not suffer fractures and many people with fractures do not have osteoporosis as defined by BMD measurements. It has been estimated that the sensitivity and specificity of BMD in predicting fractures is similar to that of high blood pressure in predicting stroke, or raised cholesterol in predicting myocardial infarction. 
Osteoporosis is diagnosed if T-score values at either the lumbar spine (typically the average of lumbar vertebrae L1 to L4), femoral neck, or total hip sites lie below −2.5. Although BMD values at these sites are moderately correlated with one another (r = 0.6), it is not uncommon to encounter patients who have low BMD at one site and normal BMD at another. Several factors are thought to contribute to these differences. Trabecular bone has a greater surface than cortical bone and therefore is remodeled more rapidly under states of increased bone turnover such as occurs after the menopause. Accordingly, women with postmenopausal osteoporosis in the 5th and 6th decades often have a greater reduction in spine BMD than hip BMD. There is also evidence that genetic factors may have site-specific effects on BMD depending on the content of cortical and trabecular bone.27 Indications for bone densitometry differ in different countries, depending on the availability of DEXA and economic factors. In the United Kingdom, DEXA is indicated in patients aged 50 years and over who suffer low-trauma fractures and in those with strong clinical risk factors for osteoporosis. In the USA, DEXA is indicated in all women above the age of 65 years and in younger women and men with an equivalent fracture risk. 

Fracture Risk Assessment

Clinical risk factors can be used in the assessment of fracture risk, with or without BMD measurements. Several risk factor tools have been developed, but the ones that are used most commonly are the FRAX tool (www.shef.ac.uk/frax/) and the QFracture score (http://www.qfracture.org/).33 Both provide estimates of 10-year fracture risk by combining information on weight, height, age, and gender with other clinical risk factors such as corticosteroid use, smoking, alcohol intake, and other diseases. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) guidance recommends that fracture risk should be assessed by one of these tools before proceeding to DEXA. It has been suggested that people who have a high absolute fracture risk should be treated for osteoporosis without recourse to a BMD measurement but the evidence base for this is lacking. In one study it was estimated that only 50% of patients over the age of 75 with a history of fragility fractures actually had osteoporosis on a DEXA scan.57 

Radiography

Standard radiographs have poor sensitivity for the detection and monitoring of osteoporosis, since large amounts of bone mineral (up to 30%) must be lost or gained from the skeleton before it can be reliably detected on plain radiographs. The lack of sensitivity of radiographs in detecting early osteoporosis is offset by a relatively high specificity, since most patients who are found to have osteopenia on X-ray do indeed have reduced bone mass on DEXA. The principal application of radiographic examination in the assessment of patients with osteoporosis is in the diagnosis of fractures. The diagnosis of long bone fracture is based on the subjective opinion of a clinician looking for characteristic features such as deformity, displacement, and cortical discontinuity. For vertebral fractures morphometric criteria are increasingly being used for diagnosis and classification.29 

Biochemical Markers

Bone turnover can be assessed biochemically by analysis of bone cell-specific proteins or products of matrix formation and degradation, which are released during bone remodeling. Biochemical markers have been investigated clinically in three main areas: Predicting rates of bone loss, predicting the response to treatment, and assessing compliance with medication. The biochemical markers that are used most commonly in current clinical practice are summarized in Table 19-2. Several investigators have reported a positive correlation between changes in biochemical markers of bone turnover and changes in bone mass in patients who are being treated with antiresorptive agents, but there is limited evidence as yet to show that changes in bone markers are associated with fracture risk reduction. Other studies have investigated the possibility that feedback to patients of biochemical markers might improve adherence but the results have been inconclusive. 
 
Table 19-2
Biochemical Markers of Bone Turnover
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Table 19-2
Biochemical Markers of Bone Turnover
Marker Type Correlates With
Bone Resorption
  •  
    Deoxypyridinoline
Bone collagen degradation
  •  
    Collagen telopeptides (CTX, NTX
     
    )
Bone collagen degradation
  •  
    Tartrate-resistant acid phosphatase
Osteoclast numbers
Bone Formation
  •  
    Total alkaline phosphatase
Osteoblast numbers, liver, and kidney disease
  •  
    Bone-specific alkaline phosphatase
Osteoblast numbers
  •  
    Osteocalcin
Osteoblast numbers
  •  
    Collagen propeptides (PINP, PICP)
Type I collagen synthesis
 

CTX, C-terminal crosslinking telopeptide of type I collagen; NTX, N-terminal crosslinking telopeptide of type I collagen; PINP, N-terminal propeptide of type I procollagen; PICP, C-terminal propeptide of type I procollagen.

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Other Investigations

Several other investigations may be helpful in the assessment of patients with osteoporosis, particularly to exclude secondary causes of the disease such as hypogonadism, primary hyperparathyroidism, thyrotoxicosis, celiac disease, and chronic renal and liver disease. Rarely, transiliac bone biopsy may be required in unusual cases of osteoporosis or in patients where an infiltrative disorder is suspected. 

Systems of Care

Increasing interest has focused over recent years on improving systems of care for patients with osteoporosis and fragility fractures, based on the observation that relatively few patients with fractures related to osteoporosis are appropriately treated. 

Fracture Liaison Service

The fracture liaison service (FLS) was developed in the United Kingdom to try and increase the proportion of individuals with fragility fractures who are investigated for possible osteoporosis and to ensure that they are treated appropriately.46 The FLS system involves offering DEXA examination as a routine to patients above a certain age who suffer low-trauma fractures (typically age >50) and treating those that have osteoporosis with an appropriate therapy. In one study, implementation of an FLS increased the proportion of patients being investigated for osteoporosis from about 10% to over 90%.46 Recent modeling studies indicate that the FLS approach is probably cost effective in reducing overall fracture burden.47 

Population-Based DEXA Screening

No controlled studies have evaluated the effect of screening for osteoporosis on rates of fractures or fracture-related morbidity or mortality. In some healthcare systems such as the United States, it is recommended that DEXA should be performed in all women aged 65 and above and in younger women and men who have similar estimates of fracture risk, although the cost effectiveness of this approach has not been tested.52 

Management

Effective management of osteoporosis depends on correcting modifiable risk factors for the disease, treating secondary causes of osteoporosis where possible, addressing falls risk, and commencing drug therapy where appropriate. 

Lifestyle Modifications and Other Measures

Lifestyle modifications and other measures aimed at reducing the risk of falls or addressing predisposing disease are frequently employed in the management of patients with osteoporosis. 

Diet

Patients with osteoporosis should be advised to take a balanced diet with an adequate protein and energy intake. Adequate amounts of dietary calcium are considered to be important for optimal bone health but the evidence base is poor. In the United Kingdom, the current recommended daily intake for calcium is 700 mg per day, whereas in the United States it has been suggested that premenopausal women and men should take 1,000 mg daily and postmenopausal women 1,500 mg daily.1 Vitamin D is required for optimal absorption of calcium and there is evidence (summarized later) that calcium and vitamin D supplements reduce the risk of fractures. Only a few foods contain substantial amounts of vitamin D, however, and in northern latitudes the amount of vitamin D synthesized by the skin is very limited. The Scientific Advisory Committee on Nutrition in the United Kingdom (www.sacn.gov.uk) recommends a daily intake of 400 International Units of vitamin D to maintain serum 25(OH)D levels above 50 nmol/L which is considered optimal for bone health, but acknowledges that this cannot be achieved easily by dietary means alone. Recent USA-based guidelines recommend 600 International Units of vitamin D up to the age of 70 and 800 International Units of vitamin D thereafter.66 

Exercise

There is no direct evidence that exercise can reduce the risk of osteoporotic fractures, but exercise programs have been shown to reduce falls risk and have potential benefits in terms of improving muscle strength, morale, and general well-being.72 Patients with osteoporosis and a history of fragility fractures should therefore be encouraged to take exercise if possible. Exercise programs have also been shown to be beneficial in improving pain and quality of life after vertebral fractures.7 

Smoking and Alcohol

It is customary to advise patients who have osteoporosis or a history of fragility fractures to reduce cigarette intake or stop smoking, although there is no direct evidence that this affects fracture risk. Similarly patients who consume more than three units of alcohol daily should be advised to reduce intake although it is unclear if this reduces the risk of fractures. 

Falls Reduction

The increased risk of fracture with increasing age is thought to be due in large part to an increase in risk of falling. It is possible to reduce the number of falls significantly by structured multidisciplinary assessment and interventions.14 On this basis, interventions such as correction of cardiovascular or circulatory disorders or poor visual acuity and elimination of environmental hazards should be considered in patients with a history of fragility fracture who have a history of falls. Reduced visual acuity is a risk factor for falls and surgery for cataract has been reported to reduce fracture rates significantly.77 Accordingly, patients with poor vision should be referred to the appropriate specialists for advice and treatment, as appropriate. 

Treatment of Underlying Disease

Patients with osteoporosis should be screened for the presence of predisposing diseases and these should be treated where possible, since in some cases this can avoid the need for drug treatment. Examples include a gluten-free diet and calcium and vitamin D supplements in celiac disease and parathyroidectomy in primary hyperparathyroidism. 

Drug Treatments

Several drug treatments are available for the treatment of osteoporosis (Table 19-3). They can broadly be divided into those that suppress bone resorption (antiresorptive agents) and those that increase bone turnover, but stimulate bone formation more than resorption (anabolic agents). Some agents, such as strontium ranelate, combine a weak antiresorptive effect with a weak stimulatory effect on biochemical markers of bone formation. 
 
Table 19-3
Drug Treatments for Osteoporosis
View Large
Table 19-3
Drug Treatments for Osteoporosis
Antiresorptive agents
Bisphosphonates
 Etidronate
 Alendronic acid
 Risedronate
 Ibandronate
 Zoledronic acid
Denosumab
Hormone replacement therapy
Raloxifene
Tibolone
Anabolic agents
Parathyroid hormone 1-34
Parathyroid hormone 1-84
Other agents
Strontium ranelate
Nutritional supplements
Calcium and vitamin D
Vitamin D
Active vitamin D metabolites
X

Bisphosphonates

Bisphosphonates are stable analogues of pyrophosphate, a naturally occurring inhibitor of mineralization and ectopic calcification. They share in common a central core structure of phosphorus–carbon–phosphorus atoms to which are attached various side chains at the R1 and R2 positions (Fig. 19-5). Bisphosphonates bind strongly to calcium ions causing the drugs to preferentially target bone and become incorporated within hydroxyapatite. The binding affinity for hydroxyapatite varies widely between drugs, but is particularly high for zoledronic acid. The potency with which bisphosphonates inhibit bone resorption is highly variable, and mainly determined by the chemical structure of the side chains. Specifically, incorporation of nitrogen into the side chain markedly increases potency. After oral or intravenous administration, the bisphosphonate is targeted to bone surfaces at sites of increased bone turnover. When bone containing the bisphosphonate undergoes resorption, the drug is released at high concentration within the osteoclast, causing osteoclast inhibition and inhibition of bone resorption. 
Figure 19-5
Structure of bisphosphonates.
 
Bisphosphonates are based on the structure of pyrophosphate, an endogenously produced inhibitor of mineralization. The carbon atom in bisphosphonates renders the drugs resistant to hydrolysis.
Bisphosphonates are based on the structure of pyrophosphate, an endogenously produced inhibitor of mineralization. The carbon atom in bisphosphonates renders the drugs resistant to hydrolysis.
View Original | Slide (.ppt)
Figure 19-5
Structure of bisphosphonates.
Bisphosphonates are based on the structure of pyrophosphate, an endogenously produced inhibitor of mineralization. The carbon atom in bisphosphonates renders the drugs resistant to hydrolysis.
Bisphosphonates are based on the structure of pyrophosphate, an endogenously produced inhibitor of mineralization. The carbon atom in bisphosphonates renders the drugs resistant to hydrolysis.
View Original | Slide (.ppt)
X

Etidronate

Etidronate is now seldom used in the treatment of osteoporosis due to the fact that it has not been shown to prevent nonvertebral fractures.18 It is given in a dose of 400 mg daily for 2 weeks followed by calcium supplementation of 500 mg daily for 11 weeks (Didronel PMO). The etidronate component should be given on an empty stomach at least 2 hours before eating, with a glass of water. 

Alendronic Acid

Alendronic acid is one of the most widely used treatments for osteoporosis. It has been shown to reduce vertebral fractures by about 50%, nonvertebral fractures by about 17%, and hip fractures by 40% in women with postmenopausal osteoporosis when given in a dose of 10 mg daily in combination with calcium and vitamin D supplements (NICE, systematic review 2008). Alendronic acid has also been shown to increase BMD in corticosteroid induced osteoporosis68 and men with osteoporosis,53 but evidence for antifracture efficacy in these indications is lacking. 
Alendronic acid in a dose of 70 mg once weekly has been found to give an equivalent increase in BMD as 10 mg daily71 and on this basis, the once-weekly dosing regimen is now used virtually in all patients. Alendronic acid is poorly absorbed from the GI tract and should be taken at least 30 minutes before food or other medication with a large glass of water and the patient instructed to remain upright during this time. The most common adverse effect of alendronic acid is upper GI upset which resolves when the treatment is stopped. Less commonly severe esophagitis and esophageal ulcers may occur especially in patients with swallowing difficulty and those who fail to take the drug correctly. Rare adverse effects include osteonecrosis of the jaw,37 and atypical subtrochanteric femoral fractures.70 

Risedronate

Risedronate has similar antifracture efficacy to alendronic acid in patients with postmenopausal osteoporosis when given in a dose of 5 mg daily in combination with calcium and vitamin D supplements.19 Efficacy has also been demonstrated in the prevention of vertebral fractures in corticosteroid-induced osteoporosis.80 Risedronate increases BMD in male osteoporosis but there are no data on fracture prevention. Risedronate in a dose of 35 mg weekly has been found to give an equivalent increase in BMD as 5 mg daily and once-weekly dosing is used most commonly in routine clinical practice. Adverse effects are as described for alendronic acid although there is weak evidence from observational studies that risedronate may have a slightly better upper GI tolerability than alendronic acid.58 

Zoledronic Acid

Zoledronic acid is an effective treatment for osteoporosis. When given intravenously at a dose of 5 mg once a year, along with calcium and vitamin D supplements, it has been shown to reduce the risk of vertebral, nonvertebral, and hip fractures in patients with postmenopausal osteoporosis.10 Zoledronic acid is the only agent that has been shown to reduce mortality in osteoporosis. When administered to men and postmenopausal women who had suffered hip fractures, treatment reduced overall mortality by 28% and reduced the risk of recurrent fracture by about 35%.43 It has also been shown to be effective in the prevention and treatment of glucocorticoid-induced osteoporosis with effects on BMD that are superior to those of risedronate.62 The most common adverse effect is a transient influenza-like illness for 2 to 3 days after the first infusion which is self limiting. This reaction can occur after subsequent infusions but is milder and usually asymptomatic. Other less common adverse effects include hypocalcemia, atrial fibrillation, and renal impairment. Rare side effects include osteonecrosis of the jaw and uveitis. Prior to administration of zoledronic acid renal function should be checked and the drug administered only if the estimated GFR is greater than 35 mL/min. Vitamin D deficiency should also be corrected to reduce the risk of hypocalcemia. 

Ibandronate

Ibandronate can be given orally or intravenously in the management of osteoporosis. A randomized controlled trial in patients with postmenopausal osteoporosis showed that it reduced the risk of vertebral fractures by about 50% when given orally in a dose of 2.5 mg daily.23 However no overall reduction in the risk of nonvertebral or hip fractures was found in this study. As with other bisphosphonates, bridging studies have shown that 150 mg monthly gives an equivalent or greater increase in BMD as 2.5 mg daily60 and this is the dose that is used in routine clinical practice. Intravenous ibandronate is given in a dose of 3 mg every 3 months in osteoporosis. The antifracture efficacy of the 3-mg/3-month regimen has not specifically been investigated but a post hoc analysis of data from patients treated with oral ibandronate 150 mg monthly and various doses of intravenous ibandronate showed evidence of efficacy at preventing vertebral and nonvertebral fractures with higher cumulative doses of the drug.32 Adverse effects and dosing instructions for administration of oral ibandronate are as described for alendronate. Patients who receive intravenous ibandronate may experience a transient “flu-like illness” as described for zoledronic acid. 

Denosumab

Denosumab is a fully humanized monoclonal antibody directed against RANKL, a key stimulator of bone resorption (see above). It has powerful inhibitory effects on bone resorption and is given subcutaneously in a dose of 60 mg every 6 months in the treatment of osteoporosis. Large-scale clinical trials have shown that denosumab reduces the risk of vertebral fractures by about 68%, hip fractures by 40%, and nonvertebral fractures by 20% in patients with postmenopausal osteoporosis.22 Although adverse effects are uncommon, it is important to ensure that patients are vitamin D replete at the time of therapy to reduce the risk of hypocalcemia. Osteonecrosis of the jaw has been reported in patients receiving long-term treatment with denosumab, but this is rare.55 Denosumab is not subject to clearance by the kidney and because of this can be used in osteoporotic patients with renal impairment, although care should be exercised in such patients to ensure they do not have renal osteodystrophy since this is predicted to increase the risk of hypocalcemia considerably. Unlike bisphosphonates, the effect of denosumab on bone resorption is relatively short lived and when treatment is stopped there is a rebound increase in bone turnover with significant bone loss. Accordingly, treatment must be given on a continuing basis for a sustained therapeutic effect. 

Strontium Ranelate

Strontium ranelate has weak inhibitory effects on bone resorption and weak stimulatory effects on biochemical markers of bone formation. It is also incorporated into bone, substituting for calcium in hydroxyapatite crystals. Randomized trials have shown that strontium ranelate 2 g daily reduces the risk of vertebral fractures by about 50% and nonvertebral fractures by about 16% in women with postmenopausal osteoporosis.48,56 The pivotal trials of strontium ranelate showed no overall efficacy at preventing hip fractures but a positive effect was identified in a post hoc subgroup analysis of patients with hip BMD values less than −3. Absorption of strontium is inhibited by food and it is usually given as a single dose at night at least 2 hours after eating. The most common side effect is diarrhea and other GI side effects, but other less common adverse effects include skin rashes and venous thrombosis. Strontium ranelate has recently been found to increase the risk of myocardial infarction and is contraindicated in patients with known cardiovascular disease and those with strong risk factors for cardiovascular disease such as diabetes. Patients who are treated with strontium often have large increases in BMD as assessed by DEXA. This however is mainly due to the fact that strontium ions (atomic mass, 87.6) substitute for calcium ions (atomic mass, 40.1) in hydroxyapatite. In view of this it is difficult to truly assess bone mass in patients who have been receiving strontium. The effects of strontium on bone density persist for about 12 months after stopping treatment and there is evidence that antifracture efficacy is also sustained during this time. 

Parathyroid Hormone

PTH differs from the other drugs mentioned above in that it is an anabolic agent which works by stimulating bone remodeling and producing new bone.61 Although bone resorption and bone formation are both increased by PTH, the cyclical mode of administration causes bone formation to increase more than bone resorption, resulting in a net gain of bone. This differs from the situation in primary hyperparathyroidism where the sustained elevation in PTH levels causes bone resorption to increase more than bone formation resulting in bone loss, especially in cortical bone. Two types of PTH are currently licensed, the 1-34 fragment and the full length molecule (1-84). PTH 1-34 20 mcg daily given by subcutaneous injection has been shown to be effective in reducing the risk of vertebral fractures by 65% and nonvertebral fractures by 50% in women with postmenopausal osteoporosis.51 The 1-34 fragment has also been shown to be effective in male osteoporosis with regard to the effects on BMD, although there are no fracture studies in males.54 PTH 1-34 is effective in the treatment of corticosteroid-induced osteoporosis and has been shown to be superior to alendronic acid at reducing the risk of vertebral fractures in this situation.69 The 1-84 fragment of PTH has been shown to reduce the risk of vertebral fractures by about 60% but there are no data on efficacy for nonvertebral fractures.31 Adverse effects of PTH include headache, muscle cramps, and mild hypercalcemia which is usually asymptomatic and does not require therapy to be stopped. The recommended duration of therapy is 2 years at which point patients should be given an antiresorptive agent to prevent loss of the bone that has been newly formed. Raloxifene, alendronic acid, and zoledronic acid have all been reported to be effective at maintaining the increases in bone mass and preventing bone loss in patients previously treated with PTH.9,26,40,63 There is evidence to suggest that concurrent administration of alendronic acid blunts the anabolic effect of PTH by inhibiting bone formation30 and that previous treatment with oral bisphosphonates results in a slightly blunted anabolic response.11 Interestingly, concomitant administration of intravenous zoledronic acid with PTH does not appear to blunt the anabolic response.16 

Calcium and Vitamin D

There is evidence to suggest that combined calcium and vitamin D supplements can reduce the risk of nonvertebral fractures with effects that are most pronounced in elderly institutionalized patients who are at risk of vitamin D deficiency.13 Calcium and vitamin D supplements are seldom used as stand-alone therapy for younger patients with osteoporosis but are frequently used as an adjunct to other osteoporosis treatments including bisphosphonates, strontium ranelate, denosumab, and PTH. 

Calcitonin

Intranasal calcitonin (200 units/day) has been shown to reduce the risk of vertebral fractures by about 30% in postmenopausal women with osteoporosis but it does not appear to be effective at preventing nonvertebral fractures.12 Calcitonin has a number of side effects including flushing and nausea, and recently long-term use of calcitonin was reported to be associated with an increased risk of cancer resulting in withdrawal of authorization for its use in the treatment of osteoporosis in Europe. 

Hormone Replacement Therapy

Hormone replacement therapy (HRT) is effective at preventing postmenopausal bone loss and has been shown to be effective in preventing vertebral fractures, nonvertebral fractures, and hip fractures in postmenopausal women,76 even if they have not been diagnosed with osteoporosis on the basis of DEXA.67 Although HRT is clearly effective at preventing fractures, it is seldom used clinically in the treatment of osteoporosis because long-term use in older women has been associated with an increased risk of cardiovascular disease, venous thrombosis, and breast cancer. It remains an option in younger women (age <60) with osteoporosis and is the treatment of choice for preventing bone loss in women with an early menopause. 

Raloxifene

Raloxifene belongs to a class of compounds termed selective estrogen receptor modulators (SERM). It acts an estrogen receptor agonist in bone and as an antagonist in other tissues, most notably the breast. Raloxifene, given orally at a dose of 60 mg/day, has been shown to reduce the risk of vertebral fractures in postmenopausal women with osteoporosis by about 30%.28 No efficacy has been demonstrated for nonvertebral and hip fractures and because of this it is used infrequently. Adverse effects include hot flushes, muscle cramps, and an increased risk of venous thrombosis. 

Tibolone

Tibolone is a steroid hormone which acts as a partial agonist at estrogen, progesterone, and androgen receptors. It alleviates vasomotor symptoms and enhances libido in postmenopausal women with similar efficacy to HRT. Tibolone has been shown to reduce the risk of vertebral fractures by about 45% and nonvertebral fractures by about 26% in a randomized trial of older (age >65) postmenopausal women with osteoporosis.20 In this study tibolone treatment was associated with a reduced risk of breast cancer (68% reduction) but an increased risk of stroke (119% increase), although the number of events were small. Currently tibolone is mainly used as an alternative to HRT in postmenopausal women with low BMD and menopausal symptoms. 

Testosterone

Testosterone replacement therapy is often used in the treatment of osteoporosis in men who have hypogonadism where it has added benefits of increasing muscle strength and general well-being. Treatment can either be given by injection every 4 to 6 weeks or by transdermal patches. Testosterone has no clear role in the treatment of male osteoporosis in the absence of hypogonadism. 

Combination Therapy

There is no clear indication for using combination therapy in the treatment of osteoporosis. Although several clinical trials have been performed using combination therapy these have not been powered to look at fractures and so the clinical value of this approach remains uncertain. 

Monitoring Response to Treatment

It remains uncertain whether patients on treatment for osteoporosis should be monitored or how this should best be achieved. Although most drug treatments for osteoporosis have stimulatory effects on BMD, the role of BMD monitoring remains controversial since changes in BMD are poorly associated with fracture risk reduction.21,81 This may be partly because of limitations in the precision of BMD measurements and the fact that fracture risk is only partly explained by BMD. Biochemical markers of bone turnover have also been explored as a means of predicting good and poor responders to treatment in terms of fracture risk reduction. Although pretreatment levels of bone turnover as assessed by biochemical markers have been associated with subsequent risk of fracture on alendronate therapy,5 clinical trials designed to investigate the effectiveness of feeding back the results of biochemical markers to patients on therapy showed no significant benefit in terms of fracture risk reduction.24 In clinical practice, repeat DEXA measurements are often performed in patients on treatment to assess response. Such measurements should not normally be repeated within 2 years of starting antiresorptive therapy since the precision of the measurement is such that significant changes are unlikely to be detected before this time. 

Treatment Failure

Treatment failure has recently been defined as the occurrence of two or more fragility fractures in a patient who has been established on therapy or the occurrence of one fragility fracture in a patient who has experienced bone loss or failed to respond in terms of biochemical markers of bone turnover.25 It is unclear how patients with treatment failure should best be managed. There are several potential options including switching from one oral agent to another, switching from an oral agent to a parenteral agent, or switching from an antiresorptive to an anabolic agent. In the absence of an evidence base the author’s personal approach is to first ensure that the patient is taking oral medication correctly. This is especially important with oral bisphosphonates and strontium ranelate. If the treatment is being taken properly then I recommend a switch to a parenteral therapy, except in patients with severe osteoporosis (T-score −4 or below) where I would offer treatment with PTH. 

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