Joint Guidance on COVID-19 Vaccination and Osteoporosis Management from the American Society for Bone and Mineral Research (ASBMR), American Association of Clinical Endocrinology (AACE), Endocrine Society, European Calcified Tissue Society (ECTS), the International Osteoporosis Foundation (IOF), and the National Osteoporosis Foundation (NOF) 

The guidance below has been created to assist clinicians in the management of patients with osteoporosis who will receive vaccination against COVID-19.  

The current pandemic has necessitated the implementation of strategies that have disrupted medical care for patients with osteoporosis.(1,2) We acknowledge that there is a paucity of data to provide clear guidance. Thus, the below recommendations are based primarily on expert opinion.

General Recommendations

Osteoporosis per se does not appear to increase the risk for infection with or complications from COVID-19. Therefore, it is not necessary to prioritize patients with osteoporosis for COVID-19 vaccination only on the basis of that condition. However, any decision to prioritize patients with osteoporosis for vaccination should be based on indications specific to each country.

General bone health measures (i.e., calcium and vitamin D supplementation, weight-bearing exercises, and maintenance of a balanced diet) should not be interrupted at the time of vaccination or thereafter.

There is no evidence that any osteoporosis therapy either increases the risk or severity of COVID-19 infection, alters the disease course, or interferes with the efficacy or side effect profile of COVID-19 vaccination.

Considering limited COVID-19 vaccine availability, vaccine dosing may need to be prioritized over potential slight alterations in standard osteoporosis regimens (as detailed below).

Medication specific recommendations for management of patients with osteoporosis in relation to COVID-19 vaccination  

• Oral bisphosphonates [alendronate (Fosamax^®), risedronate (Actonel^®), and ibandronate (Boniva^®)]

We recommend that oral bisphosphonates should be continued without interruption or delay in patients receiving COVID-19 vaccination. 

Evidence: Oral bisphosphonates rarely cause an acute phase reaction,(3,4) and there is no evidence that COVID-19 vaccination will lead to bisphosphonate intolerance or that bisphosphonate treatment will diminish COVID-19 vaccine effectiveness.

• Intravenous (IV) bisphosphonates [zoledronic acid (Reclast^®) and ibandronate (Boniva^®)]

We recommend a one week interval between IV bisphosphonate infusion and COVID-19 vaccination to allow for distinguishing between putative acute phase reactions resulting from either IV bisphosphonate administration or COVID-19 vaccination.

Evidence: The development of a post-infusion inflammatory reaction, particularly in treatment-naive patients, is a well-recognized side effect of IV bisphosphonate administration, with median duration approximately three days after zoledronic acid infusion.(5,6)  Since acute phase reactions are a reported side effect of both recombinant adenovirus vector-based(7) and mRNA-based(8) COVID-19 vaccines, it seems prudent to stagger the timing of administrations of an IV bisphosphonate and a COVID-19 vaccine. However, no current data suggests that concurrent administration might alter the side effect profile and/or reduce the efficacy of either the IV bisphosphonate or COVID-19 vaccine. Given the long skeletal biologic half–life of zoledronic acid,(9,10)  patients who have received previous zoledronic acid treatment may delay subsequent infusions for several months if necessary.

• Denosumab (Prolia^®)

We recommend an interval of 4-7 days between treatment with denosumab and COVID-19 vaccination to allow for the potential occurrence of injection site reactions with either treatment. Alternatively, denosumab treatment could be administered in the contralateral arm or alternative site (abdomen or upper thigh) if it is necessary to administer concomitantly with COVID-19 vaccine. We also recommend that while denosumab timing may be slightly adjusted to account for vaccine timing, denosumab injections should not be delayed more than 7 months after the previous denosumab dose.

Evidence: Denosumab functions by inhibiting RANKL. In addition to its role in osteoclast biology, RANKL also plays an important role in human T-cell activation.(11) Current data do not show that denosumab is associated with increased COVID-19 infection risk (12) or respiratory infections in osteoporosis patients.(13) Delayed or discontinuation of denosumab therapy is associated with increased bone resorption and increased vertebral fracture risk,(14) with fractures reported as early as seven months following the last denosumab injection.(15)

• Teriparatide (Forteo^®) or abaloparatide (Tymlos^®)

We recommend that both teriparatide and abaloparatide should be continued in patients receiving COVID-19 vaccination.

Evidence: Neither medication has been associated with an increased risk of infection or immunomodulatory effects, nor does either cause acute phase reactions. Although both teriparatide and abaloparatide may induce local injection site reactions, they are not typically administered at the same site as COVID-19 vaccines (which are typically delivered in the upper arm).

• Romosozumab (Evenity^®)

We recommend an interval of 4-7 days between provision of these injections, or consideration for injection in the abdomen (except for a two-inch area around the navel) or thigh if administered concomitantly. 

Evidence: Romosozumab inhibits the activity of sclerostin. It is provided as a once monthly subcutaneous injection. There is no evidence for infection risk or acute phase reactions with romosozumab treatment.(16) Upper arm injection site reactions (pain, swelling and erythema) have been reported as potential side effects of both romosozumab and COVID-19 vaccination.(7,8,16)

• Raloxifene

We recommend that raloxifene should be continued in patients receiving COVID-19 vaccination.

Evidence: There is no known interaction between raloxifene and COVID-19 vaccines, and raloxifene therapy does not cause an acute phase reaction.

References:
1.    Yu EW, Tsourdi E, Clarke BL, Bauer DC, Drake MT. Osteoporosis management in the era of COVID-19. J Bone Miner Res. 2020;35(6):1009-13. 
2.    Napoli N, Elderkin AL, Kiel DP, Khosla S. Managing fragility fractures during the COVID-19 pandemic. Nat Rev Endocrinol. 2020;16(9):467-8. 
3.    Hagino H, Kishimoto H, Ohishi H, Horii S, Nakamura T. Efficacy, tolerability and safety of once-monthly administration of 75mg risedronate in Japanese patients with involutional osteoporosis: a comparison with a 2.5mg once-daily dosage regimen.  Bone. 2014;59:44-52.
4.    Saag K, Lindsay R, Kriegman A, Beamer E, Zhou W. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density.  Bone. 2007;40(5):1238-43.
5.    Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab. 2010; 95(9):4380-7.
6.    Reclast® (zoledronic acid) Injection Full Prescribing Information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021817s027lbl…
7.    Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020;395(10240):1845-54.
8.    Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403-16.
9.    Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(2):243-54.
10.    Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015;30(5):934-44. 
11.    Sobacchi C, Menale C, Villa A. The RANKL-RANK axis: a bone to thymus round trip. Front Immunol. 2019;10:629.
12.    Blanch- Rubió J, Soldevila-Domenech N, Tío L, et al. Influence of anti-osteoporosis treatments on the incidence of COVID-19 in patients with non-inflammatory rheumatic conditions. Aging (Albany NY). 2020;12(20):19923-37.
13.    Dirk-Cohen T, Rosenberg D, Avni T, Shepshelovich D, Tsvetov G, Gafter-Gvili A. Risk for infections during treatment with denosumab for osteoporosis: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2020;105(5):dgz322.
14.    Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS. J Clin Endocrinol Metab. 2020;doi: 10.1210/clinem/dgaa756 [Epub ahead of print].
15.    Gonzalez-Rodriguez E, Aubry-Rozier B, Stoll D, Zaman K, Lamy O. Sixty spontaneous vertebral fractures after denosumab discontinuation in 15 women with early-stage breast cancer under aromatase inhibitors. Breast Cancer Res Treat. 2020;179(1):153-9.
16.    Kaveh S, Hosseinifard H, Ghadimi N, Vojdanian M, Aryankhesal A. Efficacy and safety of romosozumab in treatment for low bone mineral density: a systematic review and meta-analysis. Clin Rheumatol. 2020;39(11):3261-76.