Answer:
This was addressed previous in "Ask the Expert" question. I also included at the end an additional reference that I was able to locate.
"There are reports of skin reactions including urticaria associated with bisphosphonates, although I could not find reports with zoledronic acid. All of the bisphosphonates share a similar chemical structure suggesting susceptibility to cross reactivity for immunologically mediated reactions (see figure in Phillips article). Intravenous administration seems to be a greater risk. Testing has been described (Pala et al; Phillips et al). The report by Phillips et al describes both testing and challenge/desensitization protocols.
Testing has been reported in a subject with suspected inhalational exposure to sodium alendronate (Pala et al). The authors report both prick skin tests and patch tests being positive. This subject experienced rhinitis without urticaria but was inhaling the medication at work and not ingesting.
In summary, there are reports of urticaria with bisphosphonates including alendronate. Testing, both by prick and patch testing have been reported. Cross-reactivity would be expected but desensitization/challenge has permitted oral tolerance after a reaction (Phillips et al).
References:
1. Phillips, Elizabeth, et al. "Skin reactions associated with bisphosphonates: a report of 3 cases and an approach to management." Journal of Allergy and Clinical Immunology 102.4 (1998): 697-698.
2. Rolla, Giovanni, Caterina Bucca, and Luisa Brussino. "Bisphosphonate-induced bronchoconstriction in aspirin-sensitive asthma." The Lancet 343.8894 (1994): 426-427.
3. Papapetrou, Peter D. "Bisphosphonate-associated adverse events." Hormones (Athens) 8.2 (2009): 96-110.
4. Pala, G., et al. "Occupational rhinitis to sodium alendronate." Allergy 63.8 (2008): 1092-1093.
Sodium alendronate (SA) is a low-molecular-weight (LMW) compound inhibiting bone resorption, used to treat osteoporosis, recognized as an irritant of the respiratory system and skin. A few cases of skin reaction after oral intake of bisphosphonate have already been reported (1, 2). To our knowledge, no report exists on occupational respiratory allergy caused by this compound.
A 40-year-old woman was referred to our department for suspected work-related rhinitis and asthma. Since 1995 she had been employed in a pharmaceutical company, assigned to the tablets packaging department of SA (about 1 week each month) and other drugs, and particularly during the 3 months before our observation she was employed exclusively on the SA line. The product line was enclosed, provided with local exhaust fans, and the subject wore a mask without a particle filter. One month after being moved exclusively to the SA line, she started to complain of nasal itching, rhinorrhoea and dry cough. Symptoms appeared every Monday, 1 h after starting her work, improved during weekends and resolved during holidays. Symptoms were more severe during day shifts than during night shifts, when only less number of lines was involved in the production. No similar symptoms were reported by other employees.
The patient came to our observation 1 month after the symptoms’ onset; she had worked until the day before our consultation.
The clinical history reported wheals after strawberry ingestion, palmo-plantar erythema after intake of an unspecified antibiotic, eczema after use of latex gloves and sneezing upon exposure to cats. She had never taken SA.
Lung function tests were normal, skin prick tests (SPTs) were positive to cat dander and grass pollens, serum IgE levels were 36.8 kU/l and peripheral eosinophilia was 4.3%.
Both SPTs and patch tests with SA in saline (1: 100 and 1: 10 w/v) were positive, and showed negative results when performed on 10 nonexposed subjects.
A specific Inhalation Challenge (SIC) was performed, out of grass pollens period, with occupational method (3). After a control day, exposure for 60 min to SA 10 mg dissolved in lactose provoked a significant increase in nasal symptoms’ score and a significant decrease in peak nasal inspiratory flow (PNIF) at 15, 30 and 240 min, but no change in forced expiratory volume in 1 s (FEV1). After SA exposure, provocative dose of methacholine producing a 20% fall in FEV1 (PD20 FEV1) decreased from 1636 µg before challenge to 704 µg and induced sputum (IS) eosinophils increased from 1.2% to 7.9% (4).
The SIC repeated after premedication with oral levocetirizine induced no significant change in PNIF. SIC was also performed in a healthy control with no significant change.
A diagnosis of allergic occupational rhinitis (OR) caused by SA was made (5). During follow-up visit, the patient had ceased exposure to SA and was completely free of symptoms.
Among LMW-chemicals, several drugs are well-known to induce work-related respiratory allergy (6). To our knowledge, this is the first case, described in the literature, of OR caused by SA The patient’s history, SPTs, patch tests and the SIC results fulfilled the criteria for the diagnosis of OR caused by SA (5). The presence of a latency period, the dual nasal response to SIC, the absence of symptoms in other exposed workers suggest an allergic mechanism.
Interestingly, sensitization occurred despite the enclosure of the production process and the use of a personal protective device (mask). It may be suggested that during the loading phase of tablets, some powder disperses into the environment and the mask proved inadequate. The observed decrease in PD20 FEV1 and increase in IS eosinophils may be related to lower airways’ inflammation induced by the nasal response and/or may have represented an early, preclinical marker of occupational asthma (OA). The negative response to SIC after levocetirizine suggests that mast cells may play a role in the response.
I hope this information is of help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI
Minciullo PL, Allegra A, D'Angelo A, Musolino C, Gangemi S.Challenge test to bisphosphonates in patients with hypersensitivity reactions to drugs. Allergol Immunopathol (Madr). 2015 Mar-Apr;43(2):127-30
I hope this has been helpful.
Andrew Murphy, MD FAAAAI
Minciullo PL1, Allegra A2, D'Angelo A1, Musolino C3, Gangemi S4.