Abstract
Osteoporosis is a systemic skeletal disease that is a cause of morbidity and mortality. It can affect all ages but most frequently postmenopausal women. It is a silent condition, however, osteoporotic fractures can lead to significant pain and disability. In this review article, we aim to review the clinical approach to the management of postmenopausal osteoporosis. We include risk assessment, investigations, and the various pharmacological and non-pharmacological options used in the treatment of osteoporosis. We have discussed the pharmacological options individually including their mechanism of action, safety profile, effects on bone mineral density and fracture risks, and duration of use. Potential new treatments are also discussed. The importance of sequence in the use of osteoporotic medicine is also highlighted in the article. An understanding of the different treatment options will hopefully help in the management of this very common and debilitating condition.
Keywords
Osteoporosis is a cause of significant morbidity and mortality
Osteoporosis has been defined by various consensus development conferences as “a systemic, skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility.” 1
The clinical significance of osteoporosis only becomes apparent when it results in fractures. This is because it is a condition that is silent until a fracture arises with resultant pain and possible disability. Accelerated bone loss occurs as people get older, which consequently increases the incidence of fractures. Fragility fractures most commonly affect the hip, spine, and distal forearm. The consequences of such fractures are evident in terms of mortality, morbidity, and economic cost. 2
Worldwide estimates suggest that 1 in 3 women and 1 in 5 men, aged greater than 50 years, will suffer from an osteoporotic fracture as they advance in years. 3 Osteoporosis disproportionately affects the older population, who may already have substantial difficulty with frailty and reduced functional capacity. As a result, the impact of these fractures can be devastating.
Although evidence shows osteoporosis affects men less frequently than women, some evidence suggests that men tend to have more complications and a poorer quality of life associated with osteoporosis. 4 Approximately half of all the patients who sustain a hip fracture lose the ability to live independently. In the year immediately after their fracture up to 20% die, with women having a significantly lower mortality rate than men. 5
The European Community Report states that in Ireland, patients with osteoporotic fractures occupy an increasing number of hospital beds. However, there are not enough hospital beds in the Irish hospital system to meet the demand for care. This necessitates a review of priorities within the Irish healthcare system. At present the main groups at risk are men between the ages of 40 and 75 years of age and women aged 35–65 years. 6 Therefore, preventive health measures need to target these age groups.
In the European Union (EU), there were approximately 5.5 million men and approximately 22.1 million women with osteoporosis in 2010. 7 Parallel statistics for Ireland for 2010 were 37,127 men and 129,309 women have osteoporosis. This accounts for 3.7% of all men in Ireland over the age of 50 years and 20% of all women over 50 years. 8 Over an individual’s lifetime, the risk is high, ranging from 40% to 50% in females and 13%–22% in males. Life expectancy is increasing throughout the developed world. It is estimated that the number of individuals aged 65 years and older will escalate from the current figure of 323 million to 1555 million by the year 2050. 9 If it is the case that the age-standardized incidence rates from 2009 onwards remained constant over the next 20 years, it is estimated there would be an increase by 2025 of 79% in the rates of hospitalizations for all osteoporotic-type nonhip fractures in the Republic of Ireland and an increase of 88% in the number of hip fractures. 8
Consequently, the economic burden is expected to increase, as the workforce population will decrease in size. It was noted by the Office of the Surgeon General (US), in 2004 that osteoporosis is costly in terms of effects on society. This is in addition to direct healthcare expenses and indirect expenses, as well as lost productivity/workdays for people with osteoporosis and their careers. 10
From an individual’s perspective, osteoporosis can have an enormous effect on both patients and their families. It does not directly result in death, however, it can lead to a significant impact on both the physical and mental health that progresses over time potentially being associated with increased mortality. 10 Osteoporosis also dramatically affects functional status. Many who sustain fractures experience considerable pain and loss of height. As a result, it can affect their functional ability to carry out their activities of daily living. In addition, osteoporotic fractures can affect an individual’s confidence, body image, and mood. 11 Fear of falling is a common consequence in people who sustain falls and suffer fractures. This can lead to feelings of isolation and helplessness.
Clinical evaluation of a patient with osteoporosis
A detailed history and clinical examination are essential for choosing whom to evaluate with further diagnostic tests and deciding which patients need preventive intervention or therapy. Clinical symptoms and signs of osteoporosis include fracture, pain, loss of height, kyphosis, respiratory difficulty, and gastrointestinal symptoms. Some of the modifiable risk factors of osteoporosis include diet and lifestyle-related factors such as smoking, a sedentary lifestyle, and excess alcohol intake. However, some risk factors are non-modifiable, 12 these include age, small skeletal size, family history, female sex, postmenopausal status, previous fracture, and race. Commonly, the Caucasian race is listed as a risk factor for osteoporosis, however, Asian individuals have a comparable risk for the development of osteoporosis and related fractures. 13
The predictors of fractures in perimenopausal women are bone mineral density (BMD), age, and a previous fracture. The presence of one vertebral fracture doubles the risk of a future vertebral fracture. 14
Primary osteoporosis refers to osteoporosis that results from bone loss associated with aging. It also refers to the additional losses related to menopause that occur in women. Secondary osteoporosis refers to bone loss associated with underlying medical conditions or certain medications. When undergoing an osteoporosis assessment, up to 30% of postmenopausal women and 50%–80% of men are found to have clinical risk factors thought to be partially contributing to the disease. 15 Generally speaking, in an otherwise healthy individual with no clinical signs, the causes of secondary osteoporosis should be ruled out. 16 Detailed clinical history, including drug history and clinical exam, should be performed. There are no specific guidelines in terms of appropriate investigations. The following investigations are recommended: serum calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone (PTH), liver and renal function, full blood count, and thyroid-stimulating hormone. 16 Additional tests can be considered in patients with severe osteoporosis, including, serum protein electrophoresis, free light chain assay, markers of inflammation, coeliac serology and total IgA, sex steroids (testosterone in men and oestradiol in women), and 24-h urinary-free cortisol. 16
The most common cause of secondary osteoporosis is glucocorticoid-induced osteoporosis (GIOP), especially in younger patients. It is the most common drug-induced cause. 17 Patients taking glucocorticoids for long-term for conditions such as Crohn’s disease, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis (RA) should be evaluated for osteoporosis. The principal effect of glucocorticoids is on the osteoblast, a cell that is involved in bone formation. This results from the reduced generation of osteoblast precursors, and amplified apoptosis of osteoblasts and osteocytes. 17 Several inflammatory and autoimmune disorders, which increase the risk for osteoporosis, are often treated with glucocorticoids which can magnify their underlying risk. These disorders include systemic lupus erythematosus (SLE) inflammatory bowel disease (IBD), and RA among other inflammatory conditions, which are linked with bone loss due to the systemic release of inflammatory cytokines with substantial effects on bone remodeling; 18 this is in addition to any impact from steroid medication.
Methods of assessing BMD based on X-ray can be divided into methods applying to the central skeleton (dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT)) and methods applied to the peripheral skeleton (peripheral QCT, DXA, single-energy photon absorptiometry, radiographic absorptiometry, radiogrametry, single-energy X-ray absorptiometry). The most commonly used method is DXA.
Risk assessment for osteoporosis
We know that individuals who are at an increased risk of sustaining additional fractures are those who have sustained a previous fracture. 14 For example, half of all patients who sustain a hip fracture had a prior fracture. 19 This initial fracture is sometimes called a sentinel fracture or sentinel event. In the immediate interval after a first fracture, the re-fracture risk is highest. Therefore, capturing the patient very early after their fracture is essential. 20 Knowing that half of all hip fracture patients have had a warning fracture, we should then be able to predict who is at risk of a hip fracture and take steps to prevent such occurrences. History of fracture at other sites also increases the risks of future fractures, for example, one study showed that after sustaining a distal forearm fracture, the incidence of a subsequent fracture was 55% by 10 years and 80% by 20 years. 21 Similarly, the risk of another vertebral fracture after a spinal fracture is particularly high. In one study, a previous vertebral fracture increases the risk of a subsequent vertebral fracture to fivefold. 22 Vertebral fractures are associated with significant morbidity and mortality. They can occur in the absence of significant trauma, so their identification is typical via radiographic means. 22 However, using only a visual inspection of a spinal X-ray to diagnose the vertebral fracture can lead to disagreement, as this approach can be subjective. 23 Hence, several standardized approaches have been proposed to describe vertebral fractures. One of the widely used semi-quantitative fracture assessment methods was proposed by Genant et al. 24
Unlike the other approaches, in Genant’s visual semi-quantitative assessment, the type of deformity, wedge, biconcavity, or compression is not linked to the grading of a fracture. Instead, each vertebra receives a severity grade depending on the visually apparent degree of vertebral height loss. 25 In this approach, using visual inspection and without direct vertebral measurement, thoracic and lumbar vertebrae from T4 to L4 are graded. The measurements are as follows: normal which is called grade 0, mildly deformed (grade 1, which is the reduction of 20%–25% of the height and 10%–20% of the projected vertebral area), moderately deformed (grade 2, which is the reduction of 26%–40% of the height and 21%–40% of the projected vertebral area), and severely deformed (grade 3, which is the reduction of >40% of the height and projected vertebral area. Grade 0.5 is a “borderline” vertebra that shows some deformation but cannot be assigned to grade 1 fractures. 25
Although measurement of BMD with DXA is the so-called gold standard for diagnosis of osteoporosis, it is recognized that some patients are at a higher risk of fracture despite normal BMD results. Several clinical factors have been identified as having a larger contribution to higher fracture risk than would be expected with BMD alone. 26 As a result, several fracture risk calculators were developed including the Fracture Risk Assessment Tool (FRAX), which was developed to help formulate a system to better predict fracture risk.
FRAX is a computerized system developed in 2008 that analyzes individualized 10-year probability of both hip and major osteoporotic fracture (clinical spine, distal forearm, and proximal humerus). 27 FRAX consists of several clinical risk factors for osteoporosis. These include prior fragility fracture, smoking, parental hip fracture, excess alcohol intake, systemic glucocorticoid use, RA, and additional secondary causes of osteoporosis. In addition, age, sex, body mass index (BMI), and geographic area are also taken into account to calculate an estimated 10-year fracture probability, which is independent of BMD. 28 Due to the differences in bone density in different ethnic groups and across different countries, FRAX models are currently available for 73 countries across the world with additional country-specific models likely to be made available in future versions. If there is no FRAX model available for a patient’s country, it is recommended that a similar country for which the epidemiology of osteoporosis is similar to the patient’s country should be chosen.
FRAX has been approved and shown to be a reliable assessment tool by the National Institute for Health and Care Excellence, UK and the Food and Drug Administration. 29 It is easily accessible online and is on most DXA software. It is predominantly used as a clinical tool to assist physicians when making decisions regarding treatment and advising patients. As it is also used in national guidelines, clinicians must have a good understanding of its strengths and limitations. Any risk assessment tool should not replace clinical judgment and DXA measurements where appropriate. Clinicians should be aware of the limitations discussed below.
The FRAX calculator does not take into account how long has passed since a previous fracture. This is important as we know the risk is highest in the first 5 years and fluctuates with time. 30 The amount and duration of smoking, alcohol, and steroid use are not incorporated and need to be considered, for example, when looking at a heavy smoker compared with an occasional or ex-smoker. 31 A further limitation is that the FRAX algorithm uses T-Scores for femoral neck BMD and not the lumber spine. This therefore may not always reflect the severity of the patient’s condition, for example, some patients may have a significantly lower BMD at the lumber spine compared with the femoral neck, and therefore the FRAX score will not reflect their risk adequately.
The database incorporated within the FRAX model has been constructed from rates of hip fractures from around the world as it is the case that all patients with a hip fracture are admitted to hospital. 32 However, patient’s non-hip fractures are usually treated as outpatients, resulting in an underestimation of the incidence of wrist or proximal humeral fractures. 30 The reported rates of fractures at other sites are much more difficult to accurately assess as not all are inpatients and properly captured on hospital systems. 33 In addition, vertebral fractures may not present clinically and often are incidental findings.
Other important risk factors that are not included in the FRAX calculation tool include physical activity, serum hydroxyvitamin D, risk of falls, biochemical bone markers, and other comorbidities. Therefore, an individual’s calculated risk may differ from the actual risk.
Treatment choices available for the prevention of fragility fractures
Less than half of males and females with a diagnosis of osteoporotic fractures take their medication as prescribed (poor compliance) and 47% stop their medication within 6 months (lack of persistence). 34 Non-adherence to treatment especially in chronic diseases leads to a lack of treatment efficacy, increased healthcare costs, and associated morbidity and mortality. Patient education is an important aspect of the role of the clinician who can guide patients toward relevant information. This helps include the patient in decisions regarding their healthcare. Such education includes advising the patient and any caregiver about osteoporosis and its consequences, discussion of lifestyle issues, the modification of risk factors, and importantly, compliance with their medication.
The overall aim of osteoporosis treatment, including both pharmacological and non-pharmacological approaches and treatments, is to prevent fractures. Modifiable risk factors such as nutrition, hormonal status, physical exercise, past medical history, drug abuse, and alcohol or tobacco use can interfere with achieving peak bone mass. 35 Therefore, the patient should be educated on non-pharmacological treatment routes. Part of the consultation process should include advice regarding smoking cessation and moderate alcohol consumption. Reduction of caffeine intake and increased weight-bearing activities should also be encouraged. Falls prevention strategies should be discussed with patients. An important part of such a strategy is assessing their home environment. Falls are among the chief cause of morbidity and disability in older people. Over one-third of people aged 65 years or older fall every year, and in half of these cases the falls are recurring. 36 It is recognized that hip protectors are a cost-effective means of decreasing the risk of hip fractures. However, there have been concerns with adherence to wearing hip protectors among both patients themselves and healthcare staff. 37
Medical conditions that contribute to falls risks such as dizziness, postural hypotension, poor vision, and inadequate footwear must also be addressed. Physical exercise programs including strength training and weight-bearing exercises in addition to balance and coordination training may help to maintain or increase spine and hip BMD, as well as decrease the frequency of falls among patients with low BMD. 38
Calcium is important at all stages of life for bone health. The development of peak bone mass and preservation of bone mass in adults is reliant on adequate calcium intake in addition to other factors. Calcium is an important component of bone, accounting for over one-third of its mass and much of its strength. 39 Daily calcium consumption recommendations vary from country to country and studies indicate that even in countries with lower recommended amounts, many people are not consuming enough calcium. 40 Adequate calcium and vitamin D are necessary to maximize the effectiveness of the pharmacological intervention. Supplementation may be necessary where there is inadequate intake. In recent years, controversy has arisen based on reports of increased cardiovascular risk associated with calcium supplementation. In October 2016, the American Society of Preventative Cardiology (ASPC) and the National Osteoporosis Foundation (NOF) came together to review the existing data on the effect of both vitamin D and calcium on health outcomes including cardiovascular disease. Following this, they released a position statement on the lack of evidence linking calcium (with or without vitamin D supplementation) to cardiovascular disease. The NOF and ASPC statement concluded that there is “moderate-quality evidence that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) with the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time.” 41 Following this, the NOF recommends that women aged 50 and younger get 1,000 mg of calcium from all sources daily and that women aged 51 and older get 1,200 mg of calcium daily. 42
Vitamin D also plays an important role in bone health throughout life for several reasons. It is used to help with calcium absorption and bone mineralization and its effects on muscle help reduce fall risk. Vitamin D receptors are present throughout the body in many different tissue and cells. Sufficient vitamin D status is necessary for the optimal functioning of these tissues and cells. A sizable body of research has gathered over the past number of years providing new evidence regarding the role of vitamin D in the prevention of a wide-ranging number of diseases. 43 Only a limited number of food products contain vitamin D, so on average we would need to get 70%–80% of our vitamin D from sun exposure. Hence the reason many patients require oral supplementation. Vitamin D can be given on its own or in combination with calcium. The NOF recommends for those over 50 years of age that 800–1000 units of vitamin D supplementation should be taken daily. 42
Antiresorptive agents
Nonhormonal pharmacological agents are often divided into those that are antiresorptive and those that are anabolic agents. Nitrogen-containing bisphosphonates are the most commonly used. These drugs act by binding to hydroxyapatite and inhibiting the enzyme farnesyl diphosphate synthase in the cholesterol biosynthetic pathway. The osteoclasts are the cells involved in bone resorption. This action of the bisphosphonates results in the suppression of osteoclastic bone resorption (as well as coupled bone formation).44,45
The most frequently prescribed medications for osteoporosis are bisphosphonates. Although they have a good safety profile, the concerns regarding atypical femoral fractures have contributed to reduced use of bisphosphonates. 46 In one study of 196,129 women on bisphosphonates, 277 atypical femoral fractures occurred. 46 The incidence of atypical fractures increased as the duration of bisphosphonate use increased, from 0.07 per 10,000 person-years among women with less than 3 months of bisphosphonate use to 13.10 per 10,000 person-years among those with 8 years or more of use. 46 The study found that the risk of atypical femur fracture increased significantly with a longer duration of bisphosphonate treatment, particularly beyond 5 years of use. 46 The use of potent bisphosphonates has also been associated with the development of osteonecrosis of the jaw. The prevalence of this condition is estimated to be around 1 in every 10,000 patients with malignancies treated with high-dose intravenous bisphosphonates. On the contrary, in patients with osteoporosis and Paget’s disease, the prevalence appears to be less than 1 in 60,000. 47 It is important to emphasize that the fracture prevention role of bisphosphonates in the treatment of osteoporosis far outweighs the risk of atypical femoral fractures or osteonecrosis of the jaw in patients with doses recommended for osteoporosis.
Despite their common mechanisms of action, the different bisphosphonates (which include Alendronate, Risedronate, Ibandronate, and Zoledronic acid) vary considerably in terms of anti-remodeling potency and also the degree of their persistence in the skeletal matrix. 44 Bisphosphonates reduce the risk of osteoporotic fracture. In a systemic review of 24 studies, it was noticed that the overall rate of vertebral fracture was lower in the bisphosphonate group when compared with the placebo group, at 5.9% and 10.3%, respectively. The overall rate of non-vertebral fracture was 6.0% in the bisphosphonate group and 9.6% in the placebo group. 48 Depending on the formulation used, they can be taken weekly or monthly orally and there are also intravenous options, which can be given annually, or every 3/12. Strict instructions need to be given to patients on how to take oral medication due to its bioavailability. Patients should be advised to take it 30 min before food while sitting up and not to take it with any other medications.
Denosumab is another frequently prescribed antiresorptive medication with a different mechanism of action to bisphosphonates, a monoclonal antibody against the receptor activator of nuclear factor kB ligand (RANKL). It is a powerful antiresorptive agent that greatly suppresses bone turnover markers and constantly increases BMD. As a result, it has been shown to reduce fracture risk. In the FREEDOM trial, 7868 women were randomized to receive either denosumab 60 mg subcutaneously 6-monthly or a placebo. 49 They were followed for 36 months. Reduction in the new radiographic vertebral fractures was seen in the denosumab group (2.3%) as compared with placebo (7.2%). In terms of BMD, as compared with placebo there was a relative increase in BMD in the denosumab group, with an increase of 9.2% noted in lumbar spine BMD and an increase of 6% noted in hip BMD. 49
The safety data extends to 10 years and it is reassuring that denosumab has a good safety profile. 50 Denosumab has been associated with osteonecrosis of the jaw; however, a systemic review of the literature from January 2003 to April 2014 noticed that osteonecrosis of the jaw occurred at doses of denosumab or bisphosphonates that were used for oncology indications. 51 In the oncology patient population, where high doses of these medications are used at frequent intervals, the incidence of osteonecrosis of the jaw is more and was 1%–15%. However, the incidence of osteonecrosis of the jaw is estimated only at 0.001%–0.01% in the osteoporosis patient population, marginally higher than the incidence in the general population (<0.001%). 51 Atypical femoral fractures have also been reported in patients treated with denosumab. In the FREEDOM extension trial, eligible participants were those who had received either denosumab 60 mg subcutaneously or placebo for 3 years while participating in the FREEDOM trial. 49 The two groups in the FREEDOM extension trial received denosumab 60 mg subcutaneously and were observed for another 7 years. The incidence of atypical femoral fractures was low in those treated with long-term denosumab, with one case seen in each group in the 10 years follow-up study. 52
Denosumab is most likely cleared by the reticuloendothelial system with minimal renal filtration, and therefore can be used in patients with mild to moderate renal impairment. 53 Although denosumab treatment has many benefits, a prospective cohort study published in 2016 found that approximately 25.9% of patients treated with denosumab develop persistent hypocalcemia due to its antiresorptive properties. 54 The risk is most severe in patients with chronic kidney disease. To prevent this complication careful baseline assessment, calcium, and vitamin D supplementation if appropriate, and observation, is warranted for all patients treated with denosumab. Those most at risk, in particular, those with chronic kidney disease should have serum calcium checked. 55 An important consideration in treatment with denosumab is that in contrast to stopping bisphosphonates, there is a very rapid increase in bone turnover and a decrease in BMD after stopping denosumab because the drug is not retained in bone. 56 Based on available evidence, the European Calcified Tissue Society (ECTS) advised that a re-evaluation should be performed after 5 years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10 years or be switched to an alternative treatment. For patients at low risk, denosumab could be discontinued after 5 years but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. 56 In practice, all patients should be advised not to discontinue denosumab treatment without consideration being given to a replacement.
Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. 57 Because of their estrogen activity in bone, they help reduce bone loss and improve BMD. 57 They also reduce the risk of vertebral fractures. 57
The most commonly used SERM, raloxifene, is indicated in patients who are at high risk of fractures (determined by BMD and risk factors). SERMs are to be used primarily in postmenopausal women of younger age. SERMs are known to help reduce the risk of breast cancer, in some individuals this and other non-skeletal effects of SERMs are an important consideration in the selection of patients. 58
Raloxifene has been proven to reduce the risk of vertebral fracture but does not affect non-vertebral fracture risk. In one of the largest trials comparing raloxifene with placebo, the vertebral fracture risk was 5.4%6.6% in women taking 60 and 120 mg of Raloxifene respectively. The risk was 10.1% in the placebo group. However, the risk of non-vertebral fracture was similar in both groups. 59
Raloxifene has been proven to improve BMD. Multiple trials have been done to show the improvement in BMD with the use of Raloxifene. In the MORE trial (Multiple Outcomes of Raloxifene Evaluation), compared with placebo, raloxifene increased BMD in the femoral neck by 2.1% (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg). 59 It is taken as a 60 mg tablet once a day. The treatment is intended for long-term use.
The adverse effects are due to the agonist or antagonist effect of raloxifene on a particular end organ. The common side effects include hot flushes, leg cramps, and peripheral edema. Because of its estrogen agonist effects, raloxifene increases the risk of venous thromboembolism in patients. 60 Hence, it should be used with caution with a patient at risk of venous thromboembolism. It should also be discontinued in the event of an illness or a condition leading to a prolonged period of immobilization.
Hormone replacement therapy
Hormonal therapies are not usually used as the first-line treatment for osteoporosis; however, postmenopausal women may already be taking hormonal replacement therapy (HRT). The benefit they offer in terms of bone health is an important added benefit of this therapy. During menopause, the drop in estrogen level can affect bone remodeling and bone health. HRT causes estrogen levels to increase, this can help prevent bone loss and reduce the risk of osteoporosis. Hence, in postmenopausal women use of HRT not only improves menopausal symptoms but also reduces the risk of osteoporosis.
HRT is available in different combinations, but the common ones are estrogen-only therapies or those in combination with progesterone. In addition, estrogen-based HRT can be taken in different forms including pills, patches, topical, and vaginal estrogen.
HRT has evidence of improving BMD. In one study of 120 postmenopausal women with low bone density, the comparison was made between treatment with exercise and either placebo, calcium, or estrogen. The findings of the study suggested that in postmenopausal women with low bone density, bone loss can be slowed down or prevented by exercise plus calcium supplementation or estrogen–progesterone replacement. Although the exercise-estrogen regimen was more effective than exercise and calcium supplementation in increasing bone mass, it also caused more side effects. 61
The Women’s Health Initiative (WHI) trial of estrogen plus progesterone was a randomized, controlled, double-blind trial designed to determine the effects of estrogen plus progesterone compared with a placebo on several important chronic diseases of older women. It found that combined estrogen–progesterone treatment reduced hip and vertebral fracture risk by 34% and total osteoporotic fractures by 24%. 62
Risk factors associated with HRT in certain high-risk individuals are endometrial cancer, increased risk of blood clots, stroke, breast cancer, and heart diseases. These adverse effects are among the reasons that HRTs are not the first-line choice for the primary treatment of osteoporosis. The use of HRT for the management of osteoporosis should be discussed on a case-by-case basis. A risk assessment for contraindications should be done before starting a patient on this treatment.
Anabolic agents
Anabolic agents are usually only recommended for people with severe osteoporosis. In contrast to antiresorptive medications (e.g. bisphosphonates), anabolic agents work by stimulating bone production. The anabolic therapies that are currently in use are as follows:
PTH/teriparatide/abaloparatide;
Romosozumab (currently awaits Health Technology Assessment with National Center for Pharmacoeconomics, Ireland).
PTH
Teriparatide
PTH is an anabolic bone agent that has been approved for use in postmenopausal osteoporosis. While continuous PTH exposure is catabolic in bone (such as in primary or secondary hyperparathyroidism), intermittently administered (such as PTH via daily subcutaneous injection) has the paradoxical effect of stimulating new bone formation. 63 The dose of PTH is 20 mcg daily by subcutaneous injection and it is typically used for 2 years. There is growing support for extending the treatment duration if necessary, however, the license is still restricted to 2 years in Ireland. The use of an anabolic agent should be followed by a switch to an antiresorptive drug to maintain gains made in BMD.
PTH reduces the risks of both vertebral and non-vertebral fractures and increases BMD. Two randomized control trials compared teriparatide with alendronate in terms of improving lumbar spine bone density. The study comparing 20 mcg of sub-cutaneous teriparatide per day with 10 mg of alendronate (Fosamax) orally (PO) per day noticed that spinal BMD in the PTH group was 4.8% more than that of alendronate (Fosamax) group. 64 Another study comparing 40 mcg of teriparatide per day versus 10 mg of alendronate per day for glucocorticoid-induced osteoporosis noted that increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for the lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck. 65
In terms of the prevention of vertebral fractures, teriparatide is perhaps a better option than bisphosphonates. A study in the patient population of glucocorticoid-induced osteoporosis to access the efficacy of 20 mcg of teriparatide per day compared with 10 mg of alendronate per day noticed fewer new vertebral fractures in the teriparatide group (1.7%) as compared with the alendronate group (7.7%). The incidence of nonvertebral fractures was similar between the two groups and not statistically significant. 65 Both drugs increased BMD; however, teriparatide had a more significant improvement than alendronate.
In terms of adverse effects, PTH may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia. It should be avoided in patients with hyperparathyroidism, who may often have associated hypercalcemia. In animal studies, the risk of osteosarcoma was observed when treated with teriparatide (Forsteo/Forteo); however, an increased risk of osteosarcoma has not been observed in observational studies in humans. 66 Caution should be taken in patients on digoxin as PTH-induced hypercalcemia can cause digoxin toxicity. Other common side effects noted with PTH therapy include headache, nausea, and cramps.
Abaloparatide
Abaloparatide is a synthetic peptide analog of human PTH -related protein. It is given at a dose of 80 mcg as a subcutaneous injection into the periumbilical region of the abdomen. 67 It has been shown to reduce the risk of new vertebral and nonvertebral fractures, along with clinical and major osteoporotic fractures compared with placebo in the abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE); 68 86% relative risk reduction (RRR) in new vertebral fractures and 43% RRR in nonvertebral fractures were observed in the ACTIVE trial.
The use of abaloparatide is not recommended for more than 2 years during a patient’s lifetime. 68
Abaloparatide can cause nausea, dizziness, headache, palpitations, and hypercalciuria. 69 The black box warning regarding the risk of osteosarcoma has been removed.
Romosozumab
Romosozumab is a humanized monoclonal antibody that targets sclerostin receptors (which are endogenous inhibitors of bone formation). It works by speeding up the osteoblasts and slowing down the osteoclasts. Hence, it not only prevents bone loss but also helps in increasing bone strength. It is taken as monthly subcutaneous injections (210 mg per month) for a year.
Romosozumab reduces the risk of fractures. In one study, 1 year of treatment with romosozumab followed by 1 year of alendronate reduced the risk of a new vertebral fracture by 48% compared with 2 years of alendronate alone. The risk of nonvertebral fractures was 19% lower in the romosozumab-to-alendronate group than in the alendronate-alone group. Patients who received romosozumab had greater gains in BMD compared with alendronate at all measured sites and all-time points. 70
In another study, 1 year of treatment with romozumab (210 mg) lowered the risk of a new vertebral fracture by 73% compared with a placebo. Romosozumab was then followed by 1 year of denosumab and compared with placebo followed by denosumab. It was shown that the improvement in fracture reduction was maintained in this second year of the trial. 71
Regarding side effects, in randomized controlled studies, an increase in serious cardiovascular events (myocardial infarction and stroke) has been observed in romosozumab treated patients compared with the controls. Romosozumab is contraindicated in patients with previous myocardial infarction or stroke. 72 It has been noticed to cause hypocalcemia in patients receiving the therapy. It is important to ensure that any hypocalcemia should be corrected before starting the therapy. Significant hypersensitivity reactions were observed with romosozumab in clinical trials. Although rare, osteonecrosis of the jaw has been observed in clinical trials of romosozumab. It is important to do a risk evaluation of patients before starting them on romosozumab. Patients should be advised to keep good dental hygiene and have a regular dental checkup. Atypical femoral shaft fractures were also seen rarely with romosozumab use. 72
Potential new treatments
Odanacatib
Odanacatib is a cathepsin K inhibitor. Cathepsin K is a lysosomal cysteine protease. It is expressed by osteoclasts during the process of bone resorption. It acts as the major collagenase responsible for the degradation of the organic bone matrix during the bone remodeling process. 57 It is currently being developed for the treatment of osteoporosis and bone metastasis. In a phase II clinical trial, weekly doses of odanacatib reduced bone turnover markers in postmenopausal women with low BMD and increased BMD. 73
Treatment threshold in treatment of postmenopausal osteoporosis
The treatment initiation for osteoporosis is guided by clinical risk factors and BMD. Bone health and osteoporosis foundation recommendations advise starting pharmacological treatment in postmenopausal women and men aged 50 and above who have any of the following: 74
T-score ⩽ 2.5 at the femoral neck, total hip, lumbar spine, 33% radius by DXA.
Low bone mass: T-score between −1.0 and −2.5) at the femoral neck or total hip by DXA, and based on FRAX model, having a 10-year hip fracture risk ⩾ 3% or a 10-year major osteoporosis-related fracture risk ⩾ 20%.
Fracture of the hip or vertebra regardless of BMD.
Fracture of the proximal humerus, pelvis, or distal forearm in persons with low bone mass (T-score between −1.0 and −2.5).
The decision to treat should be individualized in persons with a fracture of the proximal humerus, pelvis, or distal forearm who do not have low BMD.
In addition, there are situations where clinical judgment is required to treat individuals at risk of fracture but who don’t have a diagnosis of osteoporosis e.g.
Individuals with low bone mass (T Score < –1.0) and other clinical risk factors for example, undergoing hormonal cancer treatment or with active inflammatory arthritis.
Individuals with low BMD in their AP spine.
Individuals on long-term steroids. Treatment for postmenopausal women on steroid use for more than 3 months should be considered. FRAX scores can help make the decision. However, certain high-risk groups, including the patient with a prevalent fracture, age more than 70 years, or use of steroid dose of 7.5 mg or above can be considered for treatment without a FRAX score. 75
The treatments of premenopausal osteoporosis or male osteoporosis are beyond the scope of this article.
The sequence order of osteoporosis treatments
The effects of anabolic medications (teriparatide) are blunted in patients who have received recent treatment with potent antiresorptive compared with those who did not receive antiresorptive treatment. 76 The reduced impact of this sequence of treatment is less noticeable on spine BMD compared with hip BMD. 76 Patients who switched from antiresorptive therapy to teriparatide had a decline in hip BMD seen in the first 12 months. This effect was more prominent if the antiresorptive therapy was denosumab, in which case the hip BMD continued to decline for 24 months. In contrast, the combination therapy of antiresorptive and teriparatide noted an increase in hip BMD when compared with switching therapy from antiresorptive to teriparatide. If it is thought that an anabolic agent is likely to be needed at some stage, it will have a more significant impact on BMD if it is used before the antiresorptive treatment. However, in patients where an antiresorptive has been used first and there is an inadequate response, the use of combination therapy of an anabolic and antiresorptive has more benefit in terms of improving BMD, especially at the hip. 77
Limitations of this review article
This article is limited to osteoporosis treatment for postmenopausal women. Specific discussions on male osteoporosis and premenopausal osteoporosis were beyond the scope of this article. The renal bone disease was also not covered in this article as it would need a more focused discussion due to its complexity and necessity for renal input. The treatments discussed were mainly restricted to those that are available in Ireland with a more limited discussion on romosozumab and abaloparatide.
Conclusion
Osteoporosis is a common condition affecting over one-third of postmenopausal women. The consequences for patients on a personal level and society as a whole are enormous, resulting from fractures and in some cases hospitalizations. The resulting morbidity and loss of independence and functional decline can be life-changing for many otherwise healthy individuals. Increasing evidence points to the benefit of preventive lifestyle measures in helping to improve bone density and reduce falls risks. This, in combination with pharmacological and non-pharmacological interventions, together with appropriate patient and healthcare professional education, will help to reduce the global burden of osteoporosis.
