Zoledronic acid
Bisphosphonates are synthetic analogues of pyrophosphate and bind to bone mineral with high affinity. They are taken up by osteoclasts during bone resorption and either inhibit the adenosine triphosphate (etidronate or clodronate) or farnesyl pyrophosphate synthase (aminobisphosphonates) pathways.3 This inhibits bone resorption through reduced recruitment of osteoclasts and decreased osteoclast activity, with formation of giant dysfunctional osteoclasts.4
Zoledronic acid is the most potent bisphosphonate and has the longest skeletal half-life. It is administered as an intravenous infusion (5 mg in 100 mL) over at least 15 minutes once per year, for a maximum of three years. Patients must be appropriately hydrated before the infusion, especially the elderly and those with renal impairment or receiving diuretic therapy. Treatment is contraindicated when creatinine clearance is less than 35 mL/minute. Hypocalcaemia and vitamin D deficiency (25(OH)D <50 nmol/L) should be corrected before the infusion. Adequate calcium and vitamin D supplementation should also be recommended after starting therapy.
Efficacy
In a large placebo-controlled clinical trial, zoledronic acid treatment reduced vertebral fractures by 70% (10.9% vs 3.3%, p<0.001), non-vertebral fractures by 25% (10.7% vs 8.0%, p<0.001) and hip fractures by 41% (2.5% vs 1.4%, p=0.002) over three years in postmenopausal women with osteoporosis.5 All-cause mortality decreased by 28% (13.3% vs 9.6%, p=0.01) and all clinical fractures by 35% (13.9% vs 8.6%, p=0.001) in older men and women who received zoledronic acid 5 mg versus placebo within three months of sustaining a hip fracture.6 The mechanisms responsible for mortality reduction in patients treated with zoledronic acid remain unclear, but may be related to an effect on reducing cardiovascular events and pneumonia7 If treatment was deferred for two weeks after the fracture, the improvements in bone mineral density and reductions in mortality and re-fracture rate were greater. 8
Adverse effects
Infusion-related acute-phase reactions are common, occurring in about a third of patients after the first infusion, and only 7% and 3% of patients after the second and third infusion, respectively.5 Symptoms including fever, myalgia, influenza-like symptoms, headache, nausea and arthralgia occur for 1–3 days. Giving paracetamol shortly after the infusion reduces these symptoms. Zoledronic acid may also increase serum creatinine concentrations, particularly in patients with pre-existing renal impairment.
In postmenopausal women with osteoporosis, the incidence of serious atrial fibrillation was increased versus placebo (1.3% vs 0.5%, p<0.001).5 However, as this was not found in the other zoledronic acid trials, the association remains uncertain and a report from the Food and Drug Administration found no association between bisphosphonates and atrial fibrillation. Rare events reported with both oral and intravenous bisphosphonates include severe ocular inflammation, and severe and incapacitating musculoskeletal pain. In this trial, atypical femoral fractures did not occur.5
In osteoporosis trials of zoledronic acid, there was only one case of osteonecrosis of the jaw reported in each of the treatment and placebo groups. The risk is estimated to be very low (about 1:10 000) and is most strongly associated with high cumulative intravenous bisphosphonate doses in patients with malignancy, rather than in patients with osteoporosis.
Denosumab
Denosumab is a fully human monoclonal antibody to RANKL (receptor activator of nuclear factor-κβ ligand) that prevents its interaction with osteoclasts. It reversibly inhibits bone resorption by reducing both osteoclast formation and differentiation and increasing osteoclast apoptosis (New drugs, Aust Prescr 2010;33:193-8).
The potential benefits of denosumab include the absence of gastrointestinal adverse effects that may limit oral bisphosphonate use, and the ease of administration by family doctors, which may lead to improved adherence. Also dose adjustment is not necessary in patients with renal impairment.
Vitamin D deficiency should be corrected before initiating denosumab therapy. Adequate calcium and vitamin D supplementation should also be recommended after starting therapy. As hypocalcaemia may be exacerbated by denosumab, patients with conditions that predispose them to hypocalcaemia (such as hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, severe renal impairment – creatinine clearance <30 mL/min, or renal dialysis) should be aware of the symptoms of hypocalcaemia and be monitored regularly.
Efficacy
When given as a 60 mg subcutaneous injection every six months, compared with placebo, denosumab increases the bone mineral density at the lumbar spine and hip, with associated relative risk reductions of 68% (7.2% vs 2.3%, p<0.001) for vertebral fractures, 20% (8.0% vs 6.5%, p=0.01) for non-vertebral fractures and 40% (1.2% vs 0.7%, p=0.04) for hip fractures.9,10 Additionally, comparison trials with alendronate, either in treatment-naïve patients or in patients pre-treated with alendronate, have shown non-inferiority in bone mineral density increases at all sites compared with denosumab.10-12 No head-to-head studies with primary fracture outcomes have been performed.
Adverse effects
Denosumab is well tolerated with adverse effect rates generally similar to placebo.9,11-16 The most common adverse reactions include musculoskeletal pain, hypercholesterolaemia and eczema, and discontinuation should be considered if the latter is severe.13 Hypocalcaemia may rarely occur, especially in patients with stage 5 chronic kidney disease. Pancreatitis has also been reported. Denosumab has the potential to increase the risk of infection and neoplasia. Increased rates of serious skin infections, predominantly cellulitis, have been observed in trials and patients should seek prompt medical attention if they develop signs and symptoms of infection. No significant increases in malignancy rates have been noted to date. Atypical fractures and delayed fracture healing have not been observed in trials.
Osteonecrosis of the jaw has rarely been reported (two cases) and a routine oral examination is recommended before starting treatment.17 In patients with bone metastases from breast or prostate cancer, osteonecrosis of the jaw may be associated with denosumab treatment, suggesting decreased bone turnover may be an important contributing factor.
Strontium ranelate
Although the mechanism of action of strontium is unclear, this orally administered daily treatment decreases bone resorption, increases bone formation markers and maintains bone microarchitecture. It should be administered two hours after the evening meal for optimal absorption and should not be taken at the same time as calcium supplements.
Efficacy
Strontium increased spinal and hip bone density and reduced vertebral fractures by 41% (32.8% vs 20.9%, p<0.001) and nonvertebral fractures by 16% (12.9% vs 11.2%, p=0.04) in postmenopausal women with osteoporosis over three years in the SOTI trial,18 and for up to five years in the TROPOS trial.19 A post hoc analysis showed it also reduces hip fractures in women aged 74 years and over with a T-score of –3.0 or less.19 Strontium also reduces vertebral and non-vertebral fractures and improves quality of life in women aged over 80 years20,21 and reduces vertebral fractures in postmenopausal women with or without prevalent fractures and osteopenia.22 Although the increases of spinal and hip bone mineral density appear to be greater than for other osteoporosis treatments, just under 50% of the increase in spinal bone mineral density is artefactual and is related to the substitution of strontium, a heavier element, for calcium in hydroxyapatite crystals in bone. Nevertheless, increases in bone mineral density after strontium treatment are related to fracture risk reduction.
Adverse effects
The annual incidence of venous thromboembolism over five years was 0.9% with strontium ranelate versus 0.6% with placebo (relative risk of 1.4).23 Strontium has also been associated with rare and potentially fatal cases of hypersensitivity reactions with eosinophilia and systemic symptoms. The incidence of this adverse reaction is extremely low, estimated at 1:54 000 patient-years of treatment. Patients should be warned of the possibility of a rash and it may be prudent to stop strontium if this occurs within the first 6–8 weeks of treatment. Diarrhoea and nausea also occur. Initiating treatment every second day for one month may reduce these adverse effects.
Teriparatide
Anti-catabolic therapies like zoledronic acid and denosumab prevent bone loss but do not add new bone, nor do they restore disrupted bone microarchitecture. In severe osteoporosis, preventing further bone loss may not be enough to stop further fractures. In these cases, treatments that stimulate bone formation and reverse skeletal deterioration may be a valuable option. Teriparatide or human parathyroid hormone (1–34) is the only anabolic drug currently approved for treatment of osteoporosis in Australia.
Continuous high circulating parathyroid hormone has catabolic effects on bone as seen in people with primary hyperparathyroidism. However, low-dose intermittent parathyroid hormone (20 microgram per day subcutaneously) has an anabolic effect.24 Based on bone marker studies, teriparatide increases both bone formation and resorption. However, during the first three months of treatment parathyroid hormone stimulates bone formation to a greater extent than bone resorption, suggesting that teriparatide could initially induce bone apposition without previous bone resorption through modelling-based formation.25 ,26 After 3–6 months of teriparatide treatment, the bone remodelling rate is globally increased, with bone formation favoured over bone resorption resulting in a net gain of bone deposited in each basic multicellular unit.
Treatment needs to be initiated by a specialist and treatment duration is limited to 18 months.
Efficacy
Teriparatide therapy increases spine and hip bone mineral density and reduces vertebral and non-vertebral fractures in postmenopausal women.27 It has similar effects in men but there are no data on non-vertebral fractures.28,29 The effect of teriparatide on hip fracture reduction has not been reported for men or women. Decreases in vertebral fractures of 65% (14% vs 5%, p<0.001) and non-vertebral fractures by 53% (6% vs 3%, p=0.02) compared with placebo in postmenopausal women are similar to those seen with zoledronic acid and denosumab. A meta-analysis has shown that severe back pain was reduced by 61% with teriparatide compared to the comparators (placebo, alendronate or hormonal therapy).30 The risk reduction for back pain was evident after only six months of teriparatide.
Adverse effects
Adverse reactions reported during phase III trials with teriparatide generally have been mild. The most frequent events were dizziness, headache and leg cramps in fewer than 10% of patients. Injection site hypersensitivity occurred in a small number of patients. Allergic reactions, including dyspnoea, urticaria and chest pain, occurred in less than one in 1000 patients.31 About 5% of recipients experienced mild transient hypercalcaemia which resolved within 24 hours. If hypercalcaemia occurs, it is generally recommended to reduce calcium intake to 1000 mg daily or less or to decrease the frequency of injections. Monitoring of serum calcium is not routinely needed, however it may be worth measuring serum calcium at baseline and after a month of therapy. A recent study evaluating the effect of teriparatide on urinary calcium at one, six and 12 months27,28 showed small increases in urinary calcium excretion, with less than 1% of the participants requiring a dose change in calcium or teriparatide due to hypercalciuria.
Osteosarcoma was reported in a rat oncogenicity model. However, only two cases have been reported in patients during postmarketing studies of approximately one million patients to date. This frequency is less than anticipated for people aged over 60 years. Each patient commencing teriparatide must sign a consent form acknowledging they are aware of this risk and treatment should be avoided in patients at increased baseline risk for osteosarcoma, such as children, and those with Paget's disease, unexplained elevations in alkaline phosphatase, or prior radiation therapy involving the skeleton.
AUSTRALIAN PRESCRIBER
