Zoledronsyra

Additional information

Female sex is one of the risk factors for osteoporosis fragility fractures. The same type of fractures occurs in men and women with osteoporosis. Women are more prone to spinal fractures, due to a relatively abrupt bone density loss after menopause. Men have a higher peak bone mass (in general), and the bone density deteriorates more successively from the age of 40 [1].

Osteoporosis in men is largely underdiagnosed and undertreated. Also, in those men with a history of fractures and a high risk of new fractures. Although there are differences between men and women in the pathophysiology of osteoporosis, such as in the pattern of bone loss, similarities like clinical risk factors predominate. Drug approval for osteoporosis treatment in men has generally been based on small-scale bridging trials with bone mineral density (BMD) endpoint for substances previously shown to reduce fracture risk in postmenopausal osteoporosis [2, 3].

Pharmacokinetics and dosing

The total body clearance of zoledronic acid is 5.04 ± 2.5 L/hour, independent of dose, and unaffected by patient’s sex, age, body weight and race. The clinical studies have shown effect with similar doses in men and women and no sex differentiation in dosing has been suggested [11].

Effects

A post hoc analysis (265 men, 568 women) evaluated the effects of a single dose of IV zoledronic acid 5 mg versus oral risedronate 5 mg/day on lumbar spine BMD. Zoledronic acid treated patients had a higher increase in lumbar spine BMD in both men and women at month 12 compared to risedronate [12].

The effect of zoledronic acid on fracture healing in osteoporotic patients with intertrochanteric fractures was investigated in an open label study (19 men, 24 women). A single injection of zoledronic acid 5 mg was administered intravenously to all the patients after fixation during hospital stay. There was no correlation between a patient’s sex and the time taken to fracture union [13].

A post hoc analysis (347 men, 1139 women) of the HORIZON Recurrent Fracture Trial was done to determine the effect of zoledronic acid on total hip and femoral neck BMD in subgroups with low‐trauma hip fracture.  A greater effect was observed for total hip BMD at month 12 in women [14].

Adverse effects

Bisphosphonates

The data supporting the algorithm of long-term osteoporosis management with bisphosphonates, up to a total of 10 years, is described in a report by the American Society for Bone and Mineral Research (ASBMR) Task Force. The report stated that there is no evidence of sex differences in the risk of associated atypical femur fracture and osteonecrosis of the jaw from long-term bisphosphonate treatment. Men on long-term bisphosphonate therapy presumably have similar safety issues as postmenopausal women [4].

In a systematic review on the effect of anti-resorptive drugs on the development of medication-related osteonecrosis of the jaw in osteoporosis patients, patients’ sex was reported in 587 cases (38 men, 549 women). The majority of cases were found in women with a male-to-female ratio of 1:14 [5]. Another systematic review on medication-related osteonecrosis of the jaw from anti-resorptive drugs treatment found no significant interactions for patient’s sex (6 men, 53 women) [6]. The low number of men in these reviews does not allow any speculation on sex difference with regard to bisphosphonate-related osteonecrosis of the jaw.  In a survey sent to all oral and maxillofacial surgery clinics and hospital dental clinics in Sweden requesting reports of all new cases of bisphosphonate-related osteonecrosis of the jaw during 2007 and 2008, women accounted for 22 of the 26 oral bisphosphonate-related osteonecrosis of the jaw cases in 2007 and 25 of the 29 cases in 2008. Women were prescribed bisphosphonates 7.5 times more frequently than were men during 2007 and 2008 in Sweden. However, the number of men with osteonecrosis of the jaw was too few for a valid determination of the male incidence  [7]. 

Radiographs of Swedish women and men ≥55 years (n=5,342) with femoral shaft fractures during a 3-year period were reviewed. Atypical fractures were found in 12 men and 160 women. The age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39-79) in women and 54 (CI: 15-92) in men. In bisphosphonate users, the risk of atypical fracture was higher in women than men (RR=3.1, CI:1.1-8.4) [8].

In a study evaluating oral bisphosphonates and reported clostridium difficile infection (CDI), CDI adverse drug reactions were more common for women (0.45% [93/20,586]) compared to men (0.25% [4/1568]) [9]. 

No sex differences were found in a population-based, international case-control study (134,475 men, 738,397 women) on the risk of valvulopathy among bisphosphonate users [10].In a German register study, patients (382 men, 573 women) with cancerous disease and an osteonecrosis of the jaw during intravenous bisphosphonate treatment were analyzed stratified by patient’s sex, type of bisphosphonate, and type of cancer in regard to duration of bisphosphonate treatment until first diagnosis of osteonecrosis of the jaw and osteonecrosis of the jaw-free survival. In the subgroup of patients with kidney cancer under single dose zoledronic acid treatment, the occurrence of an osteonecrosis of the jaw was significantly shorter (median of 9.0 vs. 14.0 months) in men than in women [15] . Another study attempting to identify co-factors to the development of bisphosphonate-related osteonecrosis of the jaw in patients treated with bisphosphonates (48 men, 121 women) showed no correlation between sex and the occurrence of bisphosphonate-related osteonecrosis of the jaw [16].

In a retrospective case-control study in patients with multiple myeloma treated with anti-resorptive drugs, the dental charts of non-bisphosphonate-related osteonecrosis of the jaw patients (41 men, 59 women) and bisphosphonate-related osteonecrosis of the jaw patients (10 men, 6 women) were reviewed. Male sex was found to be associated with medication-related osteonecrosis of the jaw [17]. Another case-control study in myeloma patients (108 men, 93 women) investigating the role of intravenous dosage regimens of bisphosphonates in relation to other etiological factors in the development of osteonecrosis of the jaw, showed no correlation between patient’s sex and the development of bisphosphonate-related osteonecrosis of the jaw [18].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

A retrospective study (58 men, 356 women) investigating long-term adherence to and persistence with zoledronic acid treatment in a real-world setting showed no difference in the sex ratio between the group with full treatment (>3 years adherence and persistence) and the group with early treatment termination [19].

The ASBMR Task Force report stated that continued treatment with bone protective therapy is indicated in women taking glucocorticoids long-term in a dose >5 mg/day of oral prednisolone or equivalent. Men ≥50 years who are treated with long-term glucocorticoids >5mg/day are also at increased risk of fracture and may benefit from continuation of therapy [4].

In a Spanish population-based cohort study trends of use of anti-osteoporosis drugs were analyzed. Out of 1.5 million participants, 135,410 received anti-osteoporosis drug treatment during 2001–2013. Prevalence was higher in women (6.1%) compared to men (1.1%). The incidence rate (IR) was 24.90 in women and 2.77 in men. IRs were highest for bisphosphonates along the years (ranging 3.70–14.73 and 0.57–1.75 in women and men respectively) [20].

In an observational study using Hungarian national prescription data, male patients had disproportionately fewer bisphosphonate prescriptions for osteoporosis in all age groups [21].

Patients with bone metastases from solid tumors who initiated treatment with a bone-targeted agent, the denosumab patients (762 men, 832 women) were less likely to switch bone-targeted agent and more compliant with treatment compared to intravenous bisphosphonate patients (883 men, 1092 women). These findings were consistent between men and women [22].