Reference: June 2025 | Issue 6 | Vol 11 | Page 23
Osteoporosis is common and affects up to 500,000 people in Ireland. Fragility fractures are a serious consequence, with over 32,000 occurring annually, and may incur costs of up to €1 billion.
Osteoporosis is defined as decline in bone mass associated with a microarchitectural deterioration in bone, resulting in increased risk of fragility fracture. The diagnosis can be made using DXA: Lowest T score ≤-2.5 at any of three sites (total hip, neck of femur, or lumbar spine).
However, a clinical diagnosis of osteoporosis can also be made without bone mineral density (BMD) measurements in patients who have a fragility fracture of the hip or spine. A fragility fracture is one that occurs after a fall from standing height or due to trauma which is not normally expected to cause a fracture.
Osteopaenia is indicated by a T score between -1.0 and >-2.5. In premenopausal females and males under 50, a Z score ≤-2.0 indicates low bone mass which may indicate osteoporosis, although other causes such as osteomalacia should be excluded.
Osteoporosis therapy may in general be initiated when there is: (1) clinical diagnosis due to low-trauma hip or vertebral fracture; (2) diagnosis based on DXA criteria; (3) high fracture risk as calculated using tools such as FRAX; or (4) osteopaenia with high risk of fracture. The FRAX tool can be used to estimate 10-year fracture risk with or without BMD. The threshold to start therapy varies by country and guidelines.
The National Osteoporosis Guideline Group (NOGG) in the UK have established age-dependent thresholds. For example, in adults aged 70+, therapy is recommended when the 10-year fracture risk for hip is 5.4 per cent and 20.3 per cent for major osteoporotic fracture. In patients with no fracture history but with moderate osteopaenia (T score ≤-1.5-2.0) and on drugs causing bone loss (eg, aromatase inhibitors, steroids), antiresorptive therapy is indicated.
Fracture risk
About 50-70 per cent of fragility fractures occur in patients with osteopaenia, as this is more prevalent, but also because other factors influence fracture risk. About 70 per cent of bone strength relates to BMD but other factors collectively determining ‘bone quality’ are important, especially in the spine.
For example, diabetes and endocrine disorders increase fracture risk independent of BMD. This is also true of some medications (eg, steroids, aromatase inhibitors, and androgen deprivation therapy) that impair bone quality.
A history of a fragility fracture is one of the most important risk factors and at least doubles future fracture risk whilst a prior vertebral fracture increases the risk by up to five-fold. However, the majority (70 per cent) of vertebral fractures do not present clinically and for this reason, any previous radiological imaging which includes the spine should be reviewed. Importantly, the highest risk for re-fracture (>10 per cent) occurs in the first two years after a fragility fracture, highlighting the need for prompt treatment.
The FRAX+ tool includes additional risk factors to calculate 10-year fracture risk including falls, diabetes, fracture recency, and hip axis length. It also includes trabeculae bone score (TBS), a tool available on some DXA machines which utilises lumbar spine images to assess bone microarchitecture and quality.
Guidelines also increasingly advise on stratifying fracture risk into the categories of ‘high-risk’ or ‘very high-risk’ to guide decisions on therapy. ‘High-risk’ patients are typically defined as those meeting minimum intervention thresholds for treatment. In contrast, ‘very high risk’ includes patients with additional factors such as a recent major osteoporotic fracture, very low T-scores, or multiple clinical risk factors. In those at very high risk (eg, FRAX risk 60 per cent above minimum intervention threshold), T score ≤-3.5 or recent vertebral fractures, parenteral or anabolic therapy should be considered.
Lifestyle factors
Vitamin D, calcium and lifestyle factors should be addressed including avoidance of smoking, alcohol in moderation, and weight-bearing exercise (at least 30 minutes per day). Resistive exercises to improve muscle strength and balance are advised and, where appropriate, multidisciplinary input to reduce falls risk.
Secondary causes of osteoporosis should be looked for, especially in younger patients or those with very low T scores. Most trials of osteoporosis medications have included patients on vitamin D and calcium supplements.
However, not everyone needs supplemental calcium and the dose should be tailored to the individual. In general, total calcium intake should be 1,000mg combining diet and/or supplements. Patients should have a serum 25-hydroxyvitamin D level of at least 50nmol/l which can usually be achieved with 800-1,000IU of vitamin D per day.
Bisphosphonates
First-line therapy for osteoporosis is usually oral bisphosphonates which are also indicated for prevention of steroid-induced osteoporosis. They reduce the risk of fractures of the hip and spine by about 50 per cent and in the forearm by 25 per cent. However, in patients at very high risk of fracture more potent therapies should be considered.
Bisphosphonates are contraindicated in renal impairment (eGFR <35ml/min), gastro-oesophageal reflux disease (GORD), and oesophageal disorders (Barretts and achalasia). Unfortunately, persistence with bisphosphonates is low at about 50 per cent at one year, highlighting the importance of selecting the appropriate patients for treatment.
Avoid prescribing if the patient has difficulty remembering to take or comply with instructions (sit upright for at least 30 minutes, full glass of water, no food) and if there are GI intolerance/malabsorption syndromes. Alendronate may have superiority over risedronate in BMD gains but there is no evidence of any difference in antifracture efficacy. Ibandronate can be taken once monthly as an alternative for some patients with mild GORD.
Zoledronic acid is an alternative therapy when there are GI contraindications or failure of oral treatment. It is also specifically recommended as a first-line initial treatment after hip fracture and can be considered in those at very high fracture risk. It is given as a once yearly intravenous infusion over 15-30 minutes. It has similar antifracture efficacy at the hip and forearm but is a more potent antiresorptive and is superior at reducing vertebral fractures (by about 70 per cent).
Standard therapy is for three years though in patients with severe osteoporosis and ongoing high risk of fracture, it may be considered for up to six years. About 30 per cent of patients experience a mild acute phase reaction after the infusion (musculoskeletal pain and fever) which usually resolves with simple analgesics within 72 hours.
Drug holidays
Bisphosphonates have a long half-life in bone (10 years) with antiresporptive and anti-fracture effects persisting for a period after therapy cessation. For this reason, patients may have a break from treatment (drug holiday), though this needs to be closely monitored. However, the concept of drug holidays does not apply to other osteoporosis treatments where BMD drops after therapy cessation.
Treatment with oral bisphosphonates is typically for five years and for three years with zoledronic acid, after which a drug holiday should be considered. Drug holidays may be appropriate in patients who, after treatment, have a T score at the hip or spine of >-2.5, no recent fractures, and are at lower risk of future fracture.
However, in older patients at high risk of fracture (fallers, previous hip or recent fractures) or on drugs causing bone loss, therapy may need to be continued (up to 10 years for alendronate and six years for zoledronic acid). Fracture risk can also be reassessed using FRAX and applying standard treatment thresholds.
Drug holidays are typically for 1.5 to three years (18-24 months with oral therapy and for up to three years with zoledronic acid) followed by repeat BMD assessment. Where there is a significant decline in BMD or rise in bone markers, treatment may be need to be restarted.
Denosumab
Denosumab is the most potent antiresorptive used in the treatment of osteoporosis and is administered by subcutaneous injection twice yearly. It can also be used for the prevention of bone loss in patients on aromatase inhibitors or androgen deprivation therapy. It is a monoclonal antibody that blocks the action of the cytokine RANKL, resulting in profound inhibition of bone resorption (70-80 per cent). It has a similar potency and antifracture efficacy to zoledronic acid but can be used in renal impairment (eGFR<30ml/min).
Treatment for three years reduces fracture risk in spine by 68 per cent, 40 per cent at the hip, and 20 per cent at nonvertebral sites. Long-term therapy up to 10 years (based on trial data) results in sustained rises in BMD and antifracture efficacy. Serum calcium should be normal and vitamin D >50nmol/l prior to starting so as to avoid hypocalcaemia. Denosumab is associated with an increased risk of cellulitis and possibly other infections and for this reason might not be suitable for some patients.
Stopping denosumab results in rapid rebound bone loss, decline in BMD, and increased vertebral fracture risk (especially multiple vertebral fractures), occurring as early as one to three months after discontinuation. In fact, all BMD gains from several years of treatment can be lost, with the greatest decline in the first 12 months, though persisting for up to two years. For this reason denosumab must not be stopped unless patients are switched to an antiresorptive therapy.
The greatest predictor of bone loss after stopping denosumab is duration of use, while prior vertebral fracture is a strong predictor of incident vertebral fracture in the rebound period. As data on safety and efficacy is lacking beyond 10 years, there is uncertainty about longer-term therapy. However, some patients have been taking denosumab for up to 14 years with no reported increase in adverse effects.
For some patients already on denosumab and at high risk of fracture (especially if they have had recent vertebral fractures), remaining on treatment indefinitely or at least until T scores improve and fracture risk reduces may be the best option. If patients do achieve a low fracture risk, then stopping denosumab can be considered. However, despite bisphosphonate therapy, there is still a risk of bone loss. If stopping, NOGG guidelines suggest switching to zoledronic acid with close monitoring of bone turnover markers (BTMs). Further zoledronic acid therapy is advised if there is inadequate suppression of bone turnover, or six months later in patients at higher risk of fracture when BTMs are not accessible.
In fact, after stopping >five years of denosumab therapy, a mean drop in lumbar spine T score of 0.5 in the first year is reported despite two zoledronic acid infusions six months apart. Clinical experience and observational data also show that three infusions of zoledronic acid in the first year after stopping longer-term denosumab may be required to maintain BMD. Alternatively, for patients on denosumab for shorter periods (2-2.5 years), oral bisphosphonate (if no contraindication) after six months of their last injection can be considered, although BTM monitoring is needed to ensure treatment efficacy.
For this reason, in younger patients and those with mild osteoporosis, starting denosumab may not be a good option. Conversely, in older patients with severe osteoporosis and/or life expectancy of up to 10 years or more, it may be a good choice. Importantly, unlike bisphosphonates where BMD gains plateau after three to five years, there are sustained rises for up to 10 years with denosumab, making it a better choice for some patients with lower T scores.
Teriparatide
Teriparatide is a recombinant parathyroid hormone that has anabolic effects on bone and is administered as a daily subcutaneous injection. It results in large gains in BMD at the spine and a reduction in vertebral fractures by about 70-80 per cent. It should be considered as a first-line therapy in patients with severe osteoporosis of the spine and/or with low trauma or spontaneous vertebral fractures.
However, its effect on hip BMD is modest and it has not been conclusively shown to reduce fracture. Contraindications include unexplained raised ALP, Paget’s disease, prior radiotherapy hypercalcaemia, hyperparathyroidism, haematological or active malignancy, and renal calculi. Most patients tolerate it well, although adverse effects include nausea, dizziness, musculoskeletal pain, palpitations, and low mood.
For patients who have severe osteoporosis of both the spine and hip, combination therapy with denosumab and teriparatide for two years may be considered in a specialised setting. Of note, switching from denosumab to teriparatide is associated with a decline in BMD at the spine (at six months) and hip (for up to 24 months) and is not advisable in patients with severe hip or spine osteoporosis. Importantly, teriparatide must be followed up with further treatment (typically bisphosphonates) to consolidate BMD gains.
Romosozumab
Romosozumab is a monoclonal antibody that targets sclerostin and is unique in having both anabolic and antiresorptive effects. It is regarded as the most potent osteoporosis drug, producing the largest BMD gains at both the hip and spine. It is administered once monthly (dose of 210mg) as two consecutive subcutaneous injections in the abdomen, thigh, or upper arm for a total of 12 months.
Treatment results in a reduction in vertebral fractures by 73 per cent and clinical fractures by 36 per cent. When followed by one year of alendronate, it has been shown to reduce hip fractures by 38 per cent compared to alendronate therapy over two years.
In Ireland, it is indicated for postmenopausal women with severe osteoporosis (T score ≤–2.5 at hip or lumbar spine, or distal forearm where the latter is not available) and who have sustained a major osteoporotic fracture (hip, vertebral, proximal humerus, or distal radius) within the past 24 months. It is available with a high-tech prescription under a HSE Managed Access Programme and can be prescribed by consultants in a specialism relevant to osteoporosis (eg, geriatricians, endocrinologists, rheumatologists) who are registered and approved.
Romosozumab therapy should be followed by an antiresorptive agent such as a bisphosphonate or denosumab, otherwise BMD gains can dissipate. A potent intravenous bisphosphonate (eg, zoledronic acid) is generally considered prudent in this setting, though alendronate and ibandronate are also shown to further increase BMD.
Transitioning to denosumab is also a good option and results in the greatest BMD gains. One year of romosozumab followed by denosumab for 12 months results in improvements at the total hip and spine equivalent to nearly seven years of denosumab. However, the decision to use denosumab needs to be carefully considered, as if stopped at a future point, bisphosphonates may not prevent subsequent bone loss.
Romosozumab is well tolerated, with only about 5 per cent discontinuing the drug due to adverse effects. These include injection site reactions (5 per cent), nasopharyngitis (10 per cent) and arthralgia (10 per cent). The main concern around use is a possible increase in cardiovascular events which were identified in one of the pivotal trials. The potential mechanism is unclear and may involve sclerostin-mediated pathways that might increase the risk of vascular calcification. However, studies on the effect of sclerostin on cardiovascular risk are conflicting and it remains to be seen whether the drug is implicated.
In Europe, romosozumab is contraindicated in any patient with a history of myocardial infarction or stroke. Clinicians must balance the benefits of fracture risk reduction against cardiovascular risk before using it. Caution should be exercised in those with established cardiovascular disease; and in other patients, clinical risk factors such as hypertension, diabetes, hyperlipidaemia, smoking, and family history need to be considered.
Treatment failure
This is not clearly defined but may be considered to occur when there is a decline in BMD, no improvement in bone markers or ≥2 fractures on therapy despite good compliance. It should always prompt an investigation into potential reasons including malabsorption and secondary causes (endocrine and medications).
Atypical fractures
Atypical femoral fractures (AFFs) are a rare and possible adverse effect of bisphosphonates (incidence of 1/1,000 after 10 years of oral therapy). They are a type of stress fracture of the subtrochanteric femur. Though rare, the risk increases substantially after five years and is greater in Asians and patients on steroids. Fractures often occur spontaneously or with minimal trauma and may be bilateral (up to 50+ per cent).
As there is often a prodrome of pain in the groin/thigh, patients on bisphosphonates for five or more years should have a femur x-ray if clinically indicated. This can identify ‘incomplete AFF’ where prophylactic femoral nailing to prevent fracture propagation needs to be considered. When AFF occurs, it is advised to stop bisphosphonates, after which future AFF risk appears to decline substantially. However, in those at high risk of fragility fracture due to their osteoporosis, the optimal treatment strategy is unclear. Teriparatide therapy after surgically treated AFF may reduce time to fracture healing. While AFF may occur on denosumab and romosozumab, the incidence is lower than with bisphosphonates.
Osteonecrosis of the jaw
Medication-related osteonecrosis of the jaw (MRONJ) is a rare occurrence in the treatment of osteoporosis and appears more common with denosumab. In the pivotal trial of denosumab, 0.68 per cent of patients having a dental-related procedure developed MRONJ. More recently, in some clinical case series, up to 1.0 per cent of patients undergoing dental extractions on denosumab for osteoporosis developed MRONJ. However, with bisphosphonates, the risk is very low. The majority of cases are precipitated by dental surgery, particularly dental implants or extractions but the cause is multifactorial, with oral infection being a big factor. Poor dental hygiene, diabetes, and steroids are also risk factors.
If using parenteral therapies, it is especially advisable to maintain good dental hygiene and consider dental treatments (if required) prior to their initiation. When MRONJ occurs, bisphosphonates may be stopped, though this needs to balanced against the risk of fracture. However, stopping denosumab may not be advisable and patients should seek expert opinion from a specialist in osteoporosis.
For patients on denosumab therapy who are at higher risk of MRONJ, some guidelines suggest doing elective dental procedures between five to six months after administration of their last injection and to restart treatment two to four weeks later.
Osteoporosis in younger adults
The majority of cases of osteoporosis in younger adults are associated with secondary causes including drugs, premature menopause, amenorrhoea, anorexia, and endocrine disorders. Osteomalacia resulting from vitamin D deficiency and/or low calcium intake will also result in low BMD and should not be mistaken for osteoporosis.
In patients at very high risk of fracture and where other causes have been addressed or treated, bisphosphonates may be cautiously considered. However, females of child-bearing age should be counselled on the potential risk of teratogenetcity and to avoid pregnancy while on treatment.
