24th December 2022, Dr Chee L Khoo
There have been a number of contentious safety concerns regarding the prolonged used of denosumab. The original FREEDOM trial demonstrated efficacy in reducing vertebral, hip and femoral fractures over 3 years of denosumab therapy. There was a further 7 years extension to the original trial and the report was published last year. There were some suggestions a few years ago that patients might, perhaps, need a drug holiday after 5-10 years on denosumab but there is increasing evidence of rapid reduction in bone densitometry (BDM) after denosumab is stopped. Does the reduction in BDM mean an increase in fracture rates? Who can stop their denosumab and who shouldn’t? What do we replace denosumab with after it is stopped? What about the contentious adverse effects after 10 years?
Denosumab is the first line treatment for post-menopausal women at high risk of osteoporotic fractures. It is also indicated for osteoporosis in men, patients with steroid-induced osteoporosis as well as a number of cancer related conditions (bone metastases, women with low bone mass receiving adjuvant aromatase inhibitor therapy for breast cancer and men receiving androgen deprivation therapy for non-metastatic prostate cancer. It is also used in the treatment of Paget’s disease and fibrous dysplasia.
How efficacious is denosumab?
In the FREEDOM trial, 7868 post-menopausal women with osteoporosis randomised to either twice a year denosumab or placebo were followed up for 36 months (1). The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. Denosumab reduced the risk of new radiographic vertebral fracture by 68%, risk of hip fracture by 40% and risk of nonvertebral fracture20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.
The FREEDOM Extension enrolled 4550 subjects who completed the 3-year FREEDOM trial without missing more than one dose (2). Patients who were randomised to the denosumab arm continued to receive 6 monthly denosumab for another 7 years (total of 10 years) while the placebo arm patients received denosumab for 7 years. The low incidence of vertebral fracture incidence remained low after another 7-10 years of denosumab. Nonvertebral fracture rates further decreased with long-term treatment.
The most striking finding from the FREEDOM Extension was that denosumab produced continued and progressive increases in BMD, with mean BMD increments of 21.7%, 9.2%, and 9.0% for lumbar spine, total hip, and femoral neck, respectively, after 10 years of treatment. In a post hoc analysis, improvements in BMD were associated with lower nonvertebral fracture rates beyond 3 years of therapy, a finding replicated in the crossover arm. 95% of participants attained T-score ⩾ −2.5 by year 10 of denosumab treatment.
In other words, denosumab is not only efficacious in reducing fracture rates and improving BDM, the effects were maintained while patients remained on denosumab over the 10 years.
What are the unintended effects?
Denosumab is the first approved monoclonal antibody for osteoporosis, it binds to and inhibits the receptor activator of nuclear factor-κβ ligand (RANKL) inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. RANKL is a member of the tumour necrosis factor (TNF) superfamily and as such can affect the immune system. The safety concerns can be broken down to increased infections, increased malignancy and osteonecrosis of the jaw (ONJ).
Watts et al. in 2012 performed a detailed analysis of FREEDOM specifically regarding incidence of adverse events related to infection (3). Though the rate of serious adverse events of skin infection (cellulitis and erysipelas) occurred in significantly more participants receiving denosumab (15) compared with placebo (3) (0.4% versus <0.1%), the numbers were small and there was no association with timing or duration of exposure to denosumab.
Watts et al. re-examine those adverse events in 2017 and concluded there was no increasing trend amongst events which had displayed imbalances in FREEDOM, specifically the five most frequently reported adverse events of back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia and cystitis as well as other adverse events of interest including malignancy, eczema/dermatitis, pancreatitis, endocarditis, delayed fracture healing and serious adverse events infections, opportunistic infections, and cellulitis or erysipelas (4).
The data from FREEDOM and the extension study revealed no difference in malignancy rate in those receiving placebo compared with those receiving denosumab. The 2014 meta-analysis discussed above also reported a lack of significant difference in rate of incidence of malignancy in denosumab compared with placebo (5). A further 2020 meta-analysis by Rosenberg et al. showed there was no difference in rate of malignancy or malignancy related mortality (6).
Do we need to stop denosumab for dental procedures?
ONJ is defined as: (1) exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider; (2) with history of exposure to an antiresorptive agent; and (3) no history of radiation therapy to the craniofacial region. There were no cases of ONJ reported in the original safety data from the initial 3-year FREEDOM study. Bone et al. published updated figures from the extension study with combined data from up to 10 years of denosumab exposure, reporting the cumulative exposure adjusted incidence as 5.2 per 10,000 participant-years (7).
The majority of ONJ associated with denosumab use occurs in patients taking high dose (120 mg every 4 weeks) for oncology treatment where the incidence is 1–15%. The incidence of ONJ in patients treated with the osteoporotic treatment dose of denosumab (60 mg 6-monthly) is 0.001–0.01% compared with <0.001% in the general population. The main risk factor for ONJ was undergoing an invasive oral procedure and event (OPE) including dental implant, tooth extraction, natural tooth loss, scaling/root planing, or jaw surgery.
Within the world of dentistry the guidance regarding the withholding of antiresorptive treatment (bisphosphonates and denosumab) for invasive dental procedures is unclear; guidelines are contentious and self-admittedly non-evidence based. Consensus guidelines now emphasise the importance of preventive dentistry, recommending the identification and treatment of dental issues prior to initiation of antiresorptive therapy where possible.
What happens when we stop denosumab?
Some physicians had stopped denosumab therapy citing attainment of a BMD above the osteoporosis range, concern re side effects or perceived lack of efficacy for these decisions. The “drug holiday” guidance used for patients on bisphosphonate therapy appears to have been applied erroneously to patients on denosumab in some cases. Other groups of patients delayed or ceased administration upon the advice of their dentist or of their own volition.
It has been recognized for some time that discontinuing therapy with denosumab results in a rapid reversal of its inhibition of bone remodelling, as manifested by an increase in bone turnover markers as soon as the effect of denosumab lapses, that is followed by decline in BMD. This was recognised as early as 2008 when Miller et al. reported on the complete reversibility of BMD gains following cessation of denosumab therapy, but they did not show an increase in fracture risk in these patients, who were followed for 12–24 months post discontinuation (8). Despite these findings, concern remained that at least in theory there may be an increase in fracture risk following denosumab discontinuation.
Indeed, there were case reports of increased rates of vertebral fractures upon discontinuation of denosumab. It was unclear from these case reports whether these patients who stopped denosumab had merely reverted to their baseline risk of a VF, or whether the cessation of denosumab itself had conferred an excess risk. A post hoc analysis of FREEDOM and the extension trial in 2018 confirmed that the rate of VF following discontinuation of denosumab rapidly increased from a low rate on therapy to the incidence seen in the untreated population (9). The VF rate increased from 1.2 per 100 participant-years during the on treatment years to 7.1 in the denosumab discontinuers; this estimate is similar to the rate of 7.0 in the on-placebo years that increased to 8.5 during the post-placebo years. It is thought that this increase in risk of multiple VFs beyond that seen in placebo discontinuers appears more in keeping with the concept of a rebound phenomenon rather than purely the loss of an effective therapy.
What are the recommendations?
An evidence gap exists regarding subsequent management; to date the potential strategies to reduce the rebound effect of stopping denosumab have not been conclusively adjudicated but suggested therapies include oral or intravenous bisphosphonates before or after denosumab with or without reference to bone turnover markers, or SERM after denosumab. Although it is currently recommended to transition to another antiresorptive after discontinuing denosumab, there is a lack of robust evidence supporting this recommendation. Bisphosphonate treatment after denosumab is at least partially effective for maintaining BMD, in particular spinal BMD. Furthermore, bisphosphonates appear to protect against the development of multiple VFs.
Notwithstanding the lack of evidence beyond 10 years of use, there are very few clinical reasons to stop denosumab. Denosumab is an effective antiresorptive with clear benefits in reduced risk of fracture for patients whilst on treatment, and there evidently is an increased risk of multiple VF and perhaps other major osteoporotic fractures.
References:
- Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914. PMID: 19671655.
- Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 2017; 5:513–523.
- Watts NB, Roux C, Modlin JF, et al. Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association? Osteoporos Int 2012; 23:327–337.
- Watts NB, Brown JP, Papapoulos S, et al. Safety observations with 3 years of denosumab exposure: comparison between subjects who received denosumab during the randomized FREEDOM trial and subjects who crossed over to denosumab during the FREEDOM extension. J Bone Miner Res 2017; 32: 1481–1485.
- Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol 2014; 7: 2113–2122.
- Rosenberg D, Avni T, Tsvetov G, et al. Denosumab is not associated with risk of malignancy: systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. Epub ahead of print 3 November 2020. DOI:10.1007/s00198-020-05704-6.
- Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 2017; 5:513–523.
- Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 2008; 43: 222–229.
- Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018; 33:190–198.