Bone mineral density testing by dual energy X-ray absorptiometry is recommended every 2–3 years to help monitor adherence and response to therapy.23 More frequent testing every 12 months may be needed if there is a significant change in therapy or the patient’s health, or the use of drugs which decrease bone density, for example corticosteroids.23 The frequency of bone density testing has come under question. Given that changes to bone density generally occur slowly and allowing for measurement error of the testing, there is little evidence to support annual testing unless there have been major changes in treatment or health status. Some would argue that, once a diagnosis has been made and treatment started, no further testing is necessary given the weak concordance between fracture risk reduction and bone density changes, together with the lack of clear evidence that monitoring improves compliance.24 However, most specialists still monitor bone mineral density to gauge adherence and response to treatment after two years and then again at five years to aid decisions about treatment duration.
Table 2 shows the number of patients that must be treated for 36 months in order to prevent one fracture.25-28
Table 2 Efficacy of antiresorptive drugs
Drug
|
Vertebral fractures (NNT)
|
Hip fractures (NNT)
|
Patient population studied (to determine NNT)
|
Oral bisphosphonates25
|
15–20
|
91
|
Bone mineral density (T-score –2.0 to –4.0) Low-trauma fracture
|
Intravenous bisphosphonates25
|
14
|
91
|
Bone mineral density (T-score –2.0 to –4.0) Low-trauma fracture
|
Raloxifene26
|
29
|
n/a
|
Low bone mineral density (T-score less than –2.5) Low-trauma fracture
|
Denosumab27
|
21
|
200
|
Bone mineral density only (T-score –2.5 to –4.0)
|
Teriparatide28
|
11
|
n/a
|
Low bone mineral density (mean T-score –2.6) Low-trauma fracture
|
Oral bisphosphonates
Bisphosphonates block osteoclast activation and thus slow bone resorption. They slow bone loss, improve bone mineral density and reduce fracture rates. Most bisphosphonates have similar degrees of efficacy, whether they are used intravenously or orally. Head-to-head evidence for oral bisphosphonates is lacking. Oral drugs alendronate and risedronate are the preferred first choice due to their low cost and ease of use with once-weekly dosing. There are other oral bisphosphonates, however they are uncommonly used in the treatment of osteoporosis.
The use of oral bisphosphonates is limited by their adverse effects in renal impairment and they are absolutely contraindicated if the estimated glomerular filtration rate (eGFR) is below 35 mL/minute/1.73 m2. They also have significant upper gastrointestinal adverse effects. Dysphagia, achalasia, or an inability to remain upright for 30 minutes after tablet ingestion, are absolute contraindications.
Intravenous bisphosphonates
Intravenous bisphosphonates can overcome the gastrointestinal limitations, however this therapy has other potential adverse effects, notably the risk of flu-like reactions with intravenous infusions of zoledronic acid. Other symptoms such as joint and muscle pains can be prolonged. Patients with renal impairment can be at greater risk of these reactions, and in such cases the infusion rate could be reduced. Intravenous bisphosphonates are not recommended when the eGFR is below 35 mL/minute/1.73 m2. Zoledronic acid has not been tested to any great extent in people with eGFR below 30 mL/minute/1.73 m2. It may be directly nephrotoxic or may worsen already low bone turnover, however these issues do not appear to be of concern when using the osteoporosis regimen of 5 mg annually. Some clinical experience with zoledronic acid was reported in a cohort with eGFR in the 20–30 mL/minute/1.73 m2 range without untoward effects although reduced dosing was recommended. As zoledronic acid is renally cleared it has generally been recommended to use a reduced dose or a slower infusion rate in older patients with reduced renal function but no sound evidence exists for this.29 A different class of drug that is not affected by renal function, such as denosumab, should be considered. There may also be a slight risk of atrial fibrillation with intravenous zoledronate.
The recommended duration of therapy with oral bisphosphonates is five years and perhaps less (3 years) for intravenous bisphosphonates.30-35 Safety data are robust for up to five years of treatment, but extending treatment beyond this has questionable benefit and possible harm. Harms such as osteonecrosis of the jaws and atypical femoral fractures occur very infrequently but are more likely with longer periods of antiresorptive treatment. Osteonecrosis of the jaws is more likely to be seen in patients with cancer receiving frequent doses of bisphosphonates, but other risk factors include dental extractions, dental implants, poorly fitting dentures, and pre-existing dental disease, glucocorticoid use and smoking (see Dental note in this issue).
More research is required to determine optimum duration of bisphosphonate therapy. Each patient should be reviewed after five years and a decision regarding ongoing treatment based on their individual needs and fracture risk profile. If they remain at high risk, most specialists would continue treatment. Treatment may be safely extended or alternative treatments used if:
- the femoral neck T-score** is less than –2.5 without prevalent vertebral fractures
- the femoral neck T-score is less than –2.0 with prevalent vertebral fractures
- there has been a recent fracture.
Denosumab
Denosumab is a monoclonal antibody that reversibly inhibits bone resorption by reducing osteoclast formation and differentiation while increasing osteoclast apoptosis. It increases bone mineral density at the lumbar spine and hip, and reduces vertebral, non-vertebral and hip fractures. In contrast to bisphosphonates, denosumab can be used in chronic kidney disease, however these patients are particularly at risk of hypocalcaemia so baseline assessment of calcium and vitamin D status should be undertaken before starting therapy. Denosumab’s effect will wear off as it does not accumulate.
It is therefore given regularly as a six-monthly subcutaneous injection.
Raloxifene
Raloxifene is a selective oestrogen receptor modulator that reduces postmenopausal bone loss. It reduces the risk of vertebral fractures, but it does not reduce non-vertebral fractures. Raloxifene is an alternative to bisphosphonates or denosumab (if they cannot be tolerated) for women with postmenopausal osteoporosis and is most appropriate for treating younger postmenopausal women with spinal osteoporosis. It increases the incidence of hot flushes, which can be a significant problem in young postmenopausal women. Raloxifene reduces the risk of breast cancer, so it can be considered in women with a high risk of breast cancer. It is, however, known to increase the risk of deep venous thrombosis and other evidence suggests a slightly increased mortality after stroke.
Strontium
Strontium ranelate reduces bone resorption but its mechanism of action is unknown. A 2008 Cochrane systematic review36 of three randomised controlled trials reported a 37% reduction in vertebral fractures and a 14% reduction in non-vertebral fractures over three years when strontium was used for established osteoporosis. However, monitoring of bone mineral density while on therapy is difficult to interpret. Up to 50% of any increase in spinal bone mineral density is due to the atomic weight of strontium and the distribution across the skeleton can be highly variable.
Recent data have raised significant safety concerns, particularly the risk of myocardial infarction. This has curtailed the use of strontium with contraindications in patients with a history of ischaemic heart disease, venous thromboembolism, peripheral vascular or cerebrovascular disease. Strontium use is declining in Australia, but it remains an option for people unable to tolerate other drugs and who have a low cardiovascular risk.37
Teriparatide
Teriparatide is a synthetic form of parathyroid hormone and is the only currently available drug that increases bone formation. As a last line of therapy, teriparatide is used to treat severe osteoporosis and is subsidised in Australia when people continue to fracture despite receiving at least 12 months treatment with first-line therapies.
The rate of vertebral fractures may be reduced by up to 65%. There is an overall reduction in non-vertebral fractures, but the rate of hip fractures is not reduced.
Contraindications include patients younger than 25 years, known or suspected Paget’s disease or previous radiotherapy to bone. Additional contraindications include pre-existing hypercalcaemia, malignancy, kidney disease and primary hyperparathyroidism. Rat studies have shown a risk of bone sarcomas and this is the only basis for the recommended lifetime exposure to teriparatide being limited to 18 months. Following a course of teriparatide, patients should receive antiresorptive therapy (e.g. raloxifene, a bisphosphonate, denosumab, strontium ranelate) to further increase bone mineral density and maintain the anti-fracture effect.
New drugs
There are some drugs in development, but their role is currently uncertain. Cathepsin K is elevated in women with postmenopausal osteoporosis. It is a cysteine protease that cleaves collagen 1, the major collagen type in bone. Bone mass can therefore be preserved by inhibiting cathepsin. Clinical trials with cathepsin K inhibitors, such as odanacatib, have shown improvements in bone mineral density at the spine and hip. These trials have also found a reduction in bone resorption markers with minimal effect on bone formation.
Another target for therapy is sclerostin. It is produced by osteocytes as a glycoprotein inhibitor of osteoblast signalling. Romosozumab is an anti-sclerostin monoclonal antibody that increased bone formation and bone mineral density in phase I and phase II trials. Further evaluation of the efficacy and safety of this drug in a large phase III controlled study is awaited. These interventions appear to be promising drugs for the treatment of osteoporosis.38,39