Denosumab (Prolia) for postmenopausal osteoporosis

• A biological agent
  Denosumab is the first monoclonal antibody for the treatment of postmenopausal osteoporosis.
• Novel mechanism of action
  Denosumab decreases bone resorption and bone loss by inhibiting RANKL, a protein essential for the activation and function of osteoclasts.
• Subcutaneous injection once every 6 months
  Patients should continue taking prescribed calcium and vitamin D supplements.
• Reduced the risk of vertebral, hip and non-vertebral fracture in a large randomised trial
  Twenty-one women needed to be treated with denosumab instead of placebo for 3 years to prevent one new radiographically detected vertebral fracture.
• Direct comparisons with bisphosphonate used a surrogate outcome
  Denosumab increased bone mineral density more than alendronate.
• Skin disorders are common
  Rash, dermatitis and eczema are not restricted to the injection site; manage with standard care.
• Serious skin infections may occur, but are uncommon
  Bacterial skin infections leading to hospitalisation were reported more frequently with denosumab than placebo.
• Long-term safety profile is not fully characterised
  Rare events of hypocalcaemia, pancreatitis and osteonecrosis of the jaw have been reported. Malignancy and infection are potential safety issues, for which a causal relationship has not been established.

Authority required (streamlined)

Primary prevention

Treatment as the sole PBS-subsidised anti-resorptive agent* for osteoporosis in a woman aged ≥ 70 years with a bone mineral density (BMD) T-score of ≤ –2.5.^1,2 The date, site (femoral neck or lumbar spine) and score of the qualifying BMD measurement must be documented in the woman's medical record when treatment is initiated.

Secondary prevention

Treatment as the sole PBS-subsidised anti-resorptive agent for established postmenopausal osteoporosis in a woman with fracture due to minimal trauma.^† The fracture must have been demonstrated radiologically and the year of plain X-ray, computed tomography or magnetic resonance imaging must be documented in the woman's medical record when treatment is initiated.¹

May be prescribed by nurse practitioners (continuing therapy only)

Authorised nurse practitioners may prescribe continuing therapy of this medicine after it has been initiated by a medical practitioner. See the PBS website for more information on nurse practitioner PBS prescribing.

* Anti-resorptive agents in established osteoporosis include alendronate sodium, risedronate sodium, disodium etidronate, raloxifene hydrochloride, strontium ranelate, zoledronic acid and denosumab.

^†A vertebral fracture is defined as a ≥ 20% reduction in height of the anterior or mid-portion of a vertebral body relative to the posterior height of that body, or a ≥ 20% reduction in any of these heights compared with the vertebral body above or below the affected vertebral body.

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended the listing of denosumab on a cost-minimisation basis — that is, similar efficacy and cost — compared with zoledronic acid.¹ The equi-effective doses for this comparison were denosumab 60 mg every 6 months and zoledronic acid 5 mg once yearly.

In March 2012 the PBAC recommended a change in the required BMD T-score from ≤ –3.0 to ≤ –2.5. This was on the basis that in postmenopausal osteoporosis denosumab 60 mg once every 6 months has a similar effect to that of alendronate 70 mg once weekly, at a similar cost.²

Denosumab is a human IgG2 monoclonal antibody that targets RANKL (receptor activator of nuclear factor kappa B ligand). Inhibition of RANKL prevents the formation, function and survival of osteoclasts, thereby decreasing bone resorption and bone loss.

RANKL also plays an important role in B-cell, T-cell and dendritic cell differentiation and maturation, but it is not known if denosumab affects these processes.^3,4

Denosumab is only approved for the treatment of osteoporosis in postmenopausal women.

The key clinical trial that examined the effect of denosumab on fracture rate included a mixed population of postmenopausal women (60–90 years of age) with and without a prior fracture.⁵

Clinical trials have assessed the effect of denosumab on bone loss associated with hormone ablation therapy for prostate cancer and breast cancer, but these indications are not approved in Australia.

Denosumab is given as a subcutaneous injection once every 6 months. The denosumab PBS listing does not place any restriction on the duration of therapy, or the extent to which a patient has been pre-treated with other anti-resorptive therapies.

Ensure adequate calcium and vitamin D intake

Women enrolled in denosumab clinical trials received supplemental calcium and vitamin D.^5–7 Use supplements if daily requirements cannot be met through diet and sunlight exposure alone.

The recommended daily intake of calcium for women aged ≥ 50 years is 1300 mg.⁸ At least 400–800 units (10–20 micrograms) of vitamin D are required daily, or 800–2000 units (20–50 micrograms) for those with limited sun exposure.⁸

Denosumab reduces the risk of radiographically detected vertebral fracture compared with placebo.⁵ Evidence from the same trial indicates that it reduces the risk of non-vertebral and hip fracture in postmenopausal women with osteoporosis.

Denosumab is an alternative to existing therapies for postmenopausal osteoporosis. Some women may find the 6-month dose interval more convenient than oral dosing schedules.

Women with the highest risk of fracture generally derive the greatest benefit from osteoporosis treatment. Before prescribing denosumab for postmenopausal osteoporosis consider that:

• its long-term safety profile is yet to be characterised
• the anti-fracture efficacy of denosumab has not been directly compared with that of other anti-resorptive therapies.

There are no head-to-head trials comparing the anti-fracture efficacy of denosumab with other osteoporosis therapies. The primary outcome of trials that compared denosumab with alendronate was change in BMD.^6,7

Denosumab reduces vertebral fracture risk compared with placebo

The 3-year FREEDOM trial assessed the effect of denosumab (60 mg once every 6 months) on vertebral fracture in postmenopausal women.⁵ The study enrolled a mixed population of 7868 women with or without a previous fracture, all of whom had a BMD T-score of < –2.5 at the lumbar spine or total hip. About 13% of women in the trial had taken an oral bisphosphonate for less than 3 years, but not in the 12 months before enrolling.⁹ Women who had taken oral bisphosphonates for more than 3 years were excluded.

At study's end the incidence of new vertebral fracture was 2.3% in the denosumab group and 7.2% in the placebo group (RR 0.32, 95% CI 0.26 to 0.41). Denosumab reduced the risk of non-vertebral fracture and hip fracture by 20% and 40%, respectively, relative to placebo (Table 1).

Table 1.
FREEDOM trial: effect of denosumab on fracture rates in postmenopausal osteoporosis

*Non-vertebral and hip fractures reported as hazard ratios
†Number who needed to be treated with denosumab 60 mg every 6 months instead of placebo to prevent one fracture over 3 years of treatment
‡Defined as an increase of at least one grade in a vertebral body that was normal at baseline by semi-quantitative grading scale

There were no significant differences in health-related quality of life outcomes between denosumab and placebo treatment arms, or between women without any fractures and those with an incident fracture.¹⁰

Denosumab increases bone mineral density more than alendronate

Two randomised trials investigated change in BMD in postmenopausal women (T-score ≤ –2.0) receiving denosumab or alendronate.^6,7 In the DECIDE study, a minority of women (about 12%) had previously used oral bisphosphonates for 6–8 months but had discontinued more than 2 years before the trial began.⁶ All women enrolled in the STAND study had been taking alendronate for at least 6 months (median 36 months) immediately before the trial began.⁷ Both studies included a mixed population of women with or without a previous fracture.

After 12 months, treatment with denosumab was associated with a modest, but significant, absolute increase in total hip BMD (≤ 1% in both studies) compared with alendronate.^6,7 The clinical significance of this change in BMD, a surrogate efficacy endpoint in studies of osteoporosis, is unclear.

Skin disorders, including dermatitis, eczema, rash and pruritus, were reported in more women receiving denosumab than placebo (12.0% vs 9.1%, RR 1.8, 95% CI 1.34 to 2.36) in postmenopausal osteoporosis studies (pooled data from two trials; n = 8091).⁴ Most of these events were not specific to the injection site; some resolved spontaneously.^4,11

Report suspected adverse reactions to the TGA online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Be vigilant for hypocalcaemia

There were rare, transient cases of hypocalcaemia in postmenopausal osteoporosis trials.^11,12 Patients with abnormal renal function experienced more frequent and severe hypocalcaemia in a phase one study in which calcium and vitamin D were not routinely supplemented (see Dosing issues). ¹¹

Denosumab is contraindicated in women with hypocalcaemia.¹² Low serum calcium levels should be corrected before starting denosumab; supplemental calcium and vitamin D is required in patients predisposed to hypocalcaemia (see Ensure adequate calcium and vitamin D intake).

Serious skin infections may occur, but are uncommon

Bacterial skin infections leading to hospitalisation, including cases of cellulitis and erysipelas, were reported more frequently with denosumab than placebo in the FREEDOM trial (0.3% vs < 0.1%; p = 0.002).⁵ The overall rate of serious infections did not differ between treatment arms.

Although denosumab does not appear to be associated with opportunistic infection, it should be used cautiously in patients with impaired immune function or those receiving immunosuppressive therapy.

Pancreatitis is a possible adverse effect

In postmenopausal osteoporosis studies, eight patients receiving denosumab developed pancreatitis (nine events), compared with four patients in the placebo group.⁴ All events in the denosumab group, and one in the placebo group, were considered serious.

Previous episodes of pancreatitis may have been contributing factors in three of the denosumab-treated patients, and gallstones in one other.^4,11

Limited data on osteonecrosis of the jaw

Osteonecrosis of the jaw occurs rarely with antiresorptive therapy, including denosumab.¹² Prescribers are advised to consider the same recommendations for patients beginning bisphosphonate therapy, and ensure that all necessary dental work is completed before starting denosumab.¹³

The risk of developing osteonecrosis of the jaw appears to be greater at high doses (i.e. when used to manage bone loss associated with hormone ablation for prostate cancer or breast cancer), but cases have occurred in patients treated with 60 mg denosumab every 6 months for osteoporosis.¹² One report, from an open label extension of the FREEDOM trial, described osteonecrosis of the jaw in an 83-year-old woman. Onset was 18 months after the first dose of denosumab. Other factors may have contributed including a history of multiple tooth extractions and dental procedures, breast cancer, cardiovascular disease and dementia, and previous use of alendronate for about 3 months.^11,14

It is not known if the risk of osteonecrosis of the jaw differs from that with bisphosphonates in women treated for osteoporosis. Nor is it known if previous treatment with a bisphosphonate affects risk in women receiving denosumab.

Malignancy and infection are potential safety issues, but a causal relationship has not been established

There are no data from preclinical or clinical studies to confirm an association between denosumab therapy and malignancy or infection*. However, women treated with denosumab had a slightly increased incidence of cancer and infection compared with those in placebo groups. It has been suggested that denosumab may increase the risk of cancer or infection by disrupting an immune signalling pathway regulated by RANKL.¹⁵

In postmenopausal osteoporosis trials there were more new cases of breast cancer, pancreatic cancer, gastrointestinal cancer and reproductive cancers among women receiving denosumab than placebo.⁴ The numerical differences were small. The only malignancy that occurred more often in the placebo arm was respiratory neoplasm. There was no significant difference in the overall incidence of malignancy in the anti-fracture efficacy trial.⁵

The incidence of serious infections of the ear, joints, abdomen and urinary tract was modestly higher with denosumab than placebo.⁴ Endocarditis, although rare, was reported more frequently with denosumab than placebo.

*Excluding bacterial skin infections.

Effects of long-term suppression of bone turnover are unclear

As with bisphosphonates, treatment with denosumab results in significant suppression of bone remodelling.^6,7 Full evaluation of bone formation and turnover in 36-month biopsies from the FREEDOM trial was hindered by inadequate tetracycline labelling of mineralised bone (two of 17 denosumab specimens evaluable; 22 of 22 placebo specimens evaluable).⁴ Insufficient labelling is of concern because it suggests reduced bone remodelling and formation; however, this did not translate into an increased risk of fracture for these women.

Bisphosphonate-induced suppression of bone turnover has been associated with atypical fracture in postmenopausal women with osteoporosis, but the evidence is inconclusive.^16–18 Whether an association exists with denosumab is yet to be determined.

There were six reports of delayed fracture healing in the FREEDOM trial, two in the denosumab treatment arm and four in the placebo arm.⁵

The recommended dose of denosumab is 60 mg once every 6 months, administered as a subcutaneous injection to the top of the thigh, the abdomen or back of the arm.

Denosumab is supplied as a single-use pre-filled syringe containing 60 mg denosumab in 1 mL water for injection (60 mg/mL).¹² Neither patients nor carers should administer denosumab unless they have received appropriate training. Consider the dose interval and the patient's dexterity and ability to recall injection technique before discussing the possibility of self-administration.

No dose adjustment is necessary in older patients or those with renal impairment.¹² However, calcium level monitoring is recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Be aware that the needle cover of the pre-filled syringe contains a latex derivative that can cause allergic reactions.

Denosumab should be stored in a refrigerator between 2^oC and 8^oC.

Denosumab does not appear to be immunogenic

No antibodies with denosumab-neutralising activity have been detected in patients treated with denosumab.^11,14 Binding antibodies were present in < 1% of patients during clinical studies.

Provide patients and their carers with the following information.^12,19,20

• Denosumab is an injection to the top of the thigh, the abdomen or back of the arm. It is given once every 6 months.

• Stop taking bisphosphonates or other antiresorptive medicines before the first denosumab injection.

• Continue taking calcium and vitamin D if these have been prescribed.

• Maintain good oral hygiene and complete necessary dental work before starting denosumab. Consider providing patients with a referral letter stating that denosumab is indicated.

• Report fever, chills and hot or tender skin to their doctor immediately.

• Rash and itchy dry skin are common and not restricted to the injection site.

• Denosumab is a new medicine with a novel mechanism. Its long-term side effects are not yet known.

Discuss the Prolia Consumer Medicine Information (CMI) leaflet with the patient.

Medicine Update

An NPS Medicine Update article on denosumab is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with other medicines.

Updated 1 March 2012 to reflect changes to PBS listing including streamlined authority and addition to nurse practitioner schedule. Evidence since the original release date has not been reviewed.

First released 1 December 2010.