Dr Kevin McCarroll is a consultant physician and geriatrician specialising in osteoporosis at St James’s Hospital, Dublin where he is a Clinical Lead of the Bone Heath Unit. He also co-runs the orthogeriatric service and is a Clinical Senior Lecturer in Medical Gerontology at Trinity College. He is a co-investigator in the Trinity, Ulster, Dept Agriculture (TUDA) study of over 5000 patients in which research on bone health and vitamin D is being conducted.
Osteoporosis is common and affects an estimated 300,000 people in Ireland. It is defined as decline in bone mass associated with a microarchitectural deterioration in bone resulting in increased risk of fragility fracture. In practise, the diagnosis can be made when the lowest T score on DXA is ≤-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. Fragility fracture is one that occurs from a fall from standing height or due to trauma not normally expected to cause a fracture. Osteopenia is defined when the T score is between -1.0 to < -2.5. In premenopausal females and males aged under 50, a Z score < -2.0 indicates low bone mass which may due to osteoporosis though other causes such as osteomalacia need to be considered.
Who to treat?
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 calcuated using tools such as FRAX (4) osteopenia 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 then 10 year fracture risk for hip is 5.4% and 20.3% for major osteoporostic fracture. In patients with no fracture history but with moderate osteopenia (T score < 1.5 -2.0) and on drugs causing bone loss (eg. aromatase inhibitors, steroids) antiresorptive therapy can be started.
Factors to consider
Up to 50% of fragility fractures occur in patients with osteopenia as other factors influence risk. While about 70% of bone strength relates to BMD, other factors collectively determining ‘bone quality’ are important, especially in the spine. For example, patients on steroids, aromatase inhibitors and androgen deprivation therapy have a higher risk of fracture independent of BMD resulting from their negative effects on bone quality. For recurrent fallers (≥2 per year), FRAX estimated fracture risk may be increased by 30%. Prior recent fracture (within 2 years) is a big predictor of imminent fracture. The majority (70%) of vertebral fractures do not present clinically but are associated with increased incident vertebral fracture risk by a factor of 2-5. For this reason, any previous radiological imaging which includes the spine should be reviewed. In patients at very high risk of fracture (FRAX risk 60% above treatment threshold), T score ≤ -3.5 or recent vertebral fractures, parenteral or anabolic therapy should be considered.
Vitamin D / calcium and lifestyle factors should be addressed including avoidance of smoking, alcohol in moderation and weight bearing exercise (at least 30 mins/day). Resistive exercises to improve muscle strength and balance are advised and where appropriate multi disciplinary 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 / calcium supplements. However, not everyone needs supplemental calcium and the dose should be tailored to the individual. In general, total calcium intake should be 1000 mg combining diet and and /or supplements. Patients should have a serum 25-hydroxyvitamin D level of at least 50 nmol/l which can usually be achieved with 800-1000 IU of vitamin D per day.
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 up 50% an forearm by about 25%. However, use is contraindicated in renal impairment (<35 ml/ min), GORD and oesophageal disorders (Barretts and achalasia). Unfortunately, persistence with bisphosphonates is low at about 50% at one year, highlighting the importance of selecting the appropriate patients for treatment: avoid if difficulty remembering to take or comply with instructions (sit upright for at least 30 mins, full glass of water, no food) and if 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.
Zolendronic acid is an alternative therapy when there are GI contraindications to oral bisphosphonates. It has also been recommended as a first line initial treatment for patients in hospital with a 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 mins. It has similar antifracture efficacy at the hip and forearm but is superior at reducing vertebral fractures (about 70% reduction). Standard therapy is for 3 years though in patients with severe osteoporosis and high risk of fracture, it may be considered for up to 6 years. About 25% of patients experience a mild acute phase reaction after the initial infusion (musculoskeletal pain and fever) which usually resolves with simple analgesics within 72 hrs.
Drug holidays, when and for how long?
Bisphosphonates have a long half life in bone (10 years) with anti-resportive and anti-fracture effects persisting for a period after therapy cessation. For this reason, patients may have a break from treatment or ‘drug holiday’ though this needs to be closely monitored. Importantly, the concept of ‘drug holiday’ does not apply to other osteoporosis treatments where BMD drops after therapy cessation. Treatment with oral bisphosphonates is typically for 5 years and for 3 years with zolendronic 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 yrs for alendronate and 6 yrs for zoldenronic acid). Fracture risk can also be reassessed using FRAX and applying standard treatment thresholds. Drug holidays are typically for 1.5 to 3 years (18 -24 months with oral therapy and for up to 3 years with zolendronic acid) followed by repeat BMD assessment. In patients where there is a significant decline in BMD or rise in bone markers, treatment may be need to be restarted.
This is not clearly defined but may be considered to occur when there is a decine in BMD, no improvement in bone markers or ≥2 fractures on therapy. It should always prompt an investigation into potential reasons including poor compliance, malabsorption and secondary causes (endocrine and medications).
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’s a monoclonal antibody that blocks the action of the cytokine (RANK), resulting in profound inhibition of bone resorption. It has a similar potency and antifracture efficacy to zoledronic acid but can be used in renal impairment (eGFR< 30 ml/min). Treatment for 3 years reduces fracture risk in spine by 68%, 40% at the hip and 20% at nonvertebral sites. Therapy can be continued for up to 10 years (based on trial data) where there is sustained rises in BMD and antifracture efficacy. Serum calcium should be normal and vitamin D >50 nmol/l prior to starting so as to avoid hypocalcaemia. Denosumab is associated with an increased risk of cellulits and possibly other infections and for this reason might not be as suitable for some patients.
Rebound bone loss and fracture risk on stopping denosumab
Stopping denosumab results in rapid rebound bone loss, decline in BMD and increased vertebral fracture risk, occurring as early as 1-3 months after discontinuation. In fact, all BMD gains from several years of treatment can be lost within 24 months. For this reason denosumab must not be stopped unless patients are switched to alternative therapies. The greatest predictor of bone loss after stopping denosumab is duration of use. However, as data on safety and efficacy is lacking beyond 10 years , there are concerns about continuing therapy indefinitely. Despite this, for patients already on denosumab and at high risk of fracture remaining on treatment may be the best option. If stopping denosumab, recent NOGG guidelines suggest transitioning to zolendronic acid with close monitoring of bone turnover markers (BTM). Further zoledronic acid therapy at 6 months is advised if there is inadequate suppression of bone turnover, or in patients at higher risk of fracture when BTM are not accessible. Alternatively, for patients, on densumab for shorter periods (2.0- 2.5 years), oral bisphosphonate (if no contraindication) after 6 months of their last injection can be considered with BTM monitoring to ensure treatment efficacy. Despite bisphosphonate therapy, there is still a risk of bone loss for some patients. For these reasons, 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, it is a good choice.
Teriparatide is a recombinant parathyroid hormone administered as a daily subcutaneous injection. 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. It is the only anabolic therapy available in Ireland and reduces vertebral fracture risk by abut 70-80%. However, it’s effect on hip BMD is modest where it is not 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 though adverse effects include nausea, dizziness, musculoskeletal pain, palpitations and low mood. For patients who have severe osteoporosis of both the spine and hip, bisphosphonate treatment may be more appropriate followed by teriparatide. Alternatively, dual 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 6 months) and hip (at 12 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.
Atypical fractures are a rare and possible adverse effect of bisphosphonates (incidence of 1/ 1000 after 10 years of oral therapy). They are a type of stress fracture of the subtranchanteric femur. Though rare, the risk increases substantially after 5 years and is greater in Asians and patients on steroids. Fractures often occur spontaneously or with minimal trauma and may be bilateral (25%). As there is often a prodrome of pain in the groin/ thigh, patients on bisphosphonates for 5 or more years should have a femur x-ray if clinically indicated. This can identify ‘incomplete AFF’ which is generally an indication for prophylactic femoral nailing to prevent fracture propagation. When AFF occurs, isphosphonates are generally stopped, with future AFF risk appearing to decline substantially. However, in those at high risk of fragility fracture due to their osteoporosis, the optimal future treatment strategy is unclear. AFF have also been reported with denosumab though with a lower incidence.
Osteonecrosis of the Jaw (ONJ)
This is a rare occurrence in the treatment of osteoporosis and is more common with potent antiresorptives (denosumab and zoledronic acid). In the majority of cases, it is precipitated by dental surgery, particularly dental implants or extractions. However, poor dental hygiene, diabetes, and steroids are risk factors. If using these parenteral therapies it is advisable to maintain good dental hygiene and consider dental treatments (if required) prior to their initiation. When ONJ occurs, bisphoshonates may be stopped though this needs to balanced against risk of fracture. For patients on denosumab therapy who are at higher risk of ONJ, some guidelines suggest doing elective dental procedures between 5-6 months after administration of their last injection and to restart treatment 2- 4 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.
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