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Irish Osteoporosis Society Annual Medical Conference for Health Professionals, 17 October 2020
Prof Bernard Walsh, Director of the Bone Health and Osteoporosis Unit at the Mercer’s Institute, St James’s Hospital, Dublin, and Trinity College Dublin, addressed the issue of bone health treatment during the coronavirus pandemic in a comprehensive presentation. He noted that by 17 June, Ireland had 25,341 cases of Covid-19 and 1,710 associated deaths, “which is very similar to the number of osteoporotic fractures which occur each year in Ireland (30,000-40,000), and the number of people who die following that fracture”.
Prof Walsh then outlined the details of the Joint Guidance on Osteoporosis Management in the Era of Covid-19 from the American Society for Bone and Mineral Research (ASBMR), American Association of Clinical Endocrinologists (AACE), Endocrine Society, European Calcified Tissue Society (ECTS) and National Osteoporosis Foundation (NOF), which has been created to assist clinicians in the management of patients with osteoporosis in the era of Covid-19. The current pandemic has necessitated the implementation of social distancing strategies that have the potential to disrupt the medical care of patients with osteoporosis. The guidance creators acknowledge that there is a paucity of data to provide clear guidance, thus their recommendations are based primarily on expert opinion.
The guidelines say that initiation of oral bisphosphonate therapy can be done via telephone or video visit and should not be delayed in patients at high risk for fracture (eg, in patients who have recently sustained an osteoporotic fragility fracture). Bone mineral density (BMD) examinations may need to be postponed when public health guidance recommends the halting of elective procedures. When possible to do safely, patients who are already taking osteoporosis medications should continue to receive ongoing medications including oral and intravenous (IV) bisphosphonates, denosumab, oestrogen, raloxifene, teriparatide, abaloparatide, and romosozumab (approved in 2019 in Europe but not yet reimbursed in Ireland). There is no evidence that any osteoporosis therapy increases the risk or severity of Covid-19 infection or alters the disease course (in either a positive or negative way), the document notes. However, there are early signals that Covid-19 may be accompanied by an increased risk for hypercoagulable complications, in which case caution should be used for oestrogen and raloxifene, both of which may modestly increase thrombotic risk.
To facilitate social distancing guidelines and to minimise patient exposure at phlebotomy centres, the guidelines state standard pre-treatment labs (such as calcium, 25-hydroxyvitamin D, and/or creatinine) prior to IV bisphosphonate and/or denosumab administration can be avoided if labs within the preceding year were normal and it is the clinical judgement of the medical provider that a patient’s health has been stable. However, laboratory evaluation is recommended for patients with fluctuating renal function and those who are at higher risk of developing hypocalcaemia, such as those with malabsorptive disorders, hypoparathyroidism, advanced renal dysfunction (chronic kidney disease stage 4 or 5), or taking loop diuretics.
Alternative methods of delivering parenteral osteoporosis treatments
The guidelines acknowledge that it may not be possible to safely provide parenteral osteoporosis treatments that are not self-administered (eg, IV bisphosphonates, denosumab, or romosozumab) in all geographic locations during the current Covid-19 pandemic.
Alternative delivery methods include:
- Off-site clinics: Administration of treatments at locations geographically isolated from Covid-19 ‘hot-spots’ should be considered whenever possible. However, recognise that this may disadvantage socioeconomically challenged communities if public transportation options are not available.
- Home delivery and administration: This is a feasible option if available and could include a visiting nurse, home health aide, home-visiting medical staff or family healthcare provider.
- Self-injection of denosumab (and/or romosozumab) has been proposed and is reportedly available in some locales. However, there are important medico-legal issues to consider surrounding the proper product handling and administration, including the small risk of drug-related hypersensitivity reactions in the absence of a medical provider, although steps to mitigate such potential risks may be in place in some communities.
- Drive-through administration of denosumab and/or romosozumab: This may also be logistically difficult to arrange. Further, it is recommended that patients be monitored by a medical provider for 15 minutes after injection in the unlikely event of a hypersensitivity reaction.
Specific recommendations for management of patients who are unable to receive ongoing non-oral osteoporosis medications during the Covid-19 pandemic
The guidelines recommend frequent re-evaluation of patients in whom treatment was disrupted with the goal to resume the original osteoporosis treatment plan once circumstances allow.
Denosumab is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss which is administered six-monthly and via subcutaneous injection. For patients in whom continued treatment with denosumab is not feasible within seven months of prior denosumab injection, strongly consider transition to oral bisphosphonate if possible (such as weekly alendronate). For patients with underlying gastrointestinal disorders, such as gastroesophageal reflux disease (GORD), achalasia or active peptic ulcer disease, consider monthly ibandronate or weekly/monthly risedronate.
For patients with chronic renal insufficiency [estimated glomerular filtration rate (eGFR) levels < 30-35mL/min], consider an off-label regimen of lower dose oral bisphosphonate (eg, alendronate 35mg weekly, or alendronate 70mg every two weeks). There is evidence that denosumab discontinuation causes rebound high bone turnover and rapid bone loss within one year, and increases the risk of multiple vertebral fractures particularly among those with existing vertebral fractures. Reports of vertebral fractures after denosumab discontinuation have occurred as early as seven months after the last denosumab injection.
The optimal regimen of bisphosphonate to mitigate the ‘rebound phenomenon’ that characterises denosumab discontinuation is currently unknown. Limited evidence suggests that oral alendronate may provide protection from denosumab-discontinuation rebound bone loss, particularly in patients who have received only a short period of previous denosumab treatment.
However, multiple vertebral fractures have been described in two patients provided with alendronate following treatment with denosumab for an average of 3.5 years. There is conflicting evidence regarding whether zoledronic acid can prevent rebound bone loss following denosumab discontinuation, with most data showing that zoledronic acid was less effective in maintaining BMD when previous denosumab treatment exceeds two years. Additional unknowns include the optimal bisphosphonate timing relative to denosumab discontinuation, and whether less potent anti-resorptives (such as raloxifene) may prevent the high bone turnover state after denosumab discontinuation.
Teriparatide or abaloparatide
For patients in whom continued treatment with teriparatide or abaloparatide is not feasible, consider a delay in treatment. If this delay exceeds two-to-three months, consider a temporary transition to oral bisphosphonate. There is evidence that BMD progressively declines after teriparatide discontinuation. Similar declines are expected with abaloparatide discontinuation. Hence, treatment with either skeletal anabolic agent should be followed by treatment with an antiresorptive agent to prevent bone loss.
For patients in whom continued treatment with romosozumab is not feasible, consider a delay in treatment. If this delay exceeds two-to-three months, consider a temporary transition to oral bisphosphonate. There is evidence that bone loss occurs rapidly following romosozumab discontinuation, although there is no indication that discontinuation leads to increased fracture risk. There is evidence that transitioning from romosozumab to alendronate can lead to continued gains in BMD.
Intravenous (IV) bisphosphonates
For patients in whom continued treatment with intravenous (IV) bisphosphonates is not feasible, delays of even several months are unlikely to be harmful. There is evidence that the skeletal protective effects of bisphosphonate treatment linger for many months, and potentially years, after bisphosphonate administration. As per the guidance, Prof Walsh strongly emphasised the need for patients to continue taking denosumab, “at all costs. I think it is absolutely crucial for patients to get their denosumab” to avoid rebound and increased fracture risk. “It is our most potent drug for bone suppression but rebound is the big worry. It can come on very quickly and we have all seen rebound fractures and people who have just missed one dose in three months.
That message must get out there: There is no reason for stopping denosumab if people are tolerating it and they are still osteoporotic and have had fractures,” Prof Walsh said, adding that if people have to be taken off denosumab they have to take an alternative therapy (eg, bisphosphonate) to suppress the rebound issue and to be monitored. Echoing Prof Walsh, Dr Kevin McCarroll, Consultant, Medicine for the Elderly, St James’s Hospital, Dublin, also strongly advised against drug holidays of denosumab, noting that missing an injection is a particular risk during Covid-19. He emphasised the need to replace denosumab with a bisphosphonate and to continue checking bone markers if it was stopped. However, BMD loss can continue despite taking zoledronic acid after denosumab; so if it is being tolerated well in older patients, to continue it, Mr Carroll stated. He also outlined the risks of medication-induced bone loss, citing steroid (>5mg for >three months), aromatase inhibitors, and androgen deprivation therapies as particular offenders, stressing the need for adequate BMD monitoring and appropriate anti-resorptive prescriptions, where indicated, in those at moderate/high risk of fractures.