Журнал «Боль. Суставы. Позвоночник» 2 (10) 2013

Продовження. Початок у № 1(9), 2013

Vitamin D

Rickets and osteomalacia are the diseases traditionally associated with severe vitamin D deficiency, defined as 25(OH) vitamin D levels below 10 ng/ml (25 nmol/l). A growing body of evidence has emerged indicating that less severe degrees of vitamin D deficiency between 10 and 20 ng/ml (25 and 50 nmol/l) and even vitamin D insufficiency, defined as 25(OH) vitamin D levels between 20 and 30 ng/ml (50 and 75 nmol/l), impair gastrointestinal absorption of calcium and bone mineralization, contributing to the pathogenesis of osteoporosis in older people [60]. Vitamin D has an impact on bone density and bone quality. In addition, by increasing muscle strength, adequate vitamin D status reduces the risk of falling in older individuals (see below). Therefore, vitamin D has a dual benefit for prevention of fractures in the elderly, a benefit on bone density and on muscle strength [61]. The importance of vitamin D for the prevention and treatment of osteoporosis has notably been reviewed in a previous Consensus of the Belgian Bone Club [1].

Furthermore, many studies have implicated vitamin D and its metabolites in the pathogenesis of a wide variety of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and several common cancers. The principal non-classical targets will be reviewed in this section. Whilst the evidence on bone and muscle health is based on randomised clinical trials, the evidence on other disease areas is nevertheless of a lower level. Most trials are small to moderate sized, and the outcomes of interest are only secondary outcomes. Interestingly, a meta-analysis of 18 randomised clinical trials including 57,311 individuals nevertheless concluded that vitamin D supplementation was associated with a decrease in total mortality (RR 0.93; 95% CI 0.77–0.96 compared to the control group) that could be due to effects of vitamin D on the musculoskeletal system or, as summarized below, on various non-skeletal diseases [35].

Vitamin D and muscular function

Vitamin D receptors have been shown to be present in muscle tissue [62], and a direct effect of vitamin D on muscle physiology is probable [63]. In muscle, vitamin D activates protein kinase C, which promotes calcium release, increasing the calcium pool that is essential for muscle contraction [64]. The potential cell signalling pathways affected by vitamin D in muscle have been recently reviewed [65]. Vitamin D deficiency has long been clinically associated with impaired muscle strength [66] and is also associated with loss of muscle mass [67]. With ageing, the number of vitamin D receptors in muscle decreases and the number of type II fibres, the first to be recruited to avoid falls, also decreases [68]. Treatment of elderly stroke survivors with 1,000 IU of vitamin D₂ daily increases mean type II muscle fibre diameter by 2.5-fold over a 2-year period [69]. Because muscle weakness is a major risk factor for falls, it is not surprising that low vitamin D status is associated with an increased falls risk, as notably shown in a longitudinal study [70]. A meta-analysis including seven randomised, double-blind trials evaluating a daily dose of 700–1,000 IU/day of vitamin D demonstrated that falling was significantly reduced by 19 % (RR 0.81; 95% CI 0.71–0.92) in vitamin D supplemented individuals compared with those receiving calcium or placebo [71]. This benefit may not depend on additional calcium supplementation, was significant within 2–5 months of treatment and extended beyond 12 months of treatment.

Vitamin D insufficiency and deficiency are associated with an increase in muscle fat as demonstrated by a significant negative relationship between circulating 25(OH) vitamin D levels and computed tomography measures of percent muscle fat (p < 0.001) [72]. Most studies have not found a significant relationship between baseline 25(OH) vitamin D levels and muscle strength [73]. However, correction of vitamin D deficiency has most often been associated with an improvement in muscle strength. Vitamin D supplementation in vitamin D-deficient Asian Indians during 6 months has thus shown an enhancement in skeletal muscle strength and physical performance [74]. A recent randomised, placebo-controlled, double-blind trial of 1,000 IU/day of vitamin D for 1 year showed a significant increase in muscle strength and mobility in subjects in the lowest tertile of baseline 25(OH) vitamin D values [75]. A longer duration trial showed that vitamin D and calcium supplementation during 20 months were superior to calcium alone in reducing fall frequency and improving muscle function in community-dwelling elderly subjects with 25 (OH) vitamin D levels below 31 ng/ml [76]. These studies are in agreement with a recent systematic review and metaanalysis where the authors confirmed a beneficial effect of vitamin D supplementation on proximal muscle strength in adults with vitamin D deficiency but no significant effect on muscle strength in vitamin D replete adults [77].

Vitamin D and cardiovascular risk

A low level of 25(OH) vitamin D could be an independent risk factor for cardiovascular events, although a causal relationship has yet to be supported by large interventional trials. The evidence supporting a link between vitamin D deficiency and myocardial diseases has recently been reviewed [78]. In addition to possible direct effects due to the presence of the vitamin D receptor and of the 1-alpha hydroxylase enzyme in cardiac myocytes and other cells of the cardiovascular system [79], vitamin D has significant effects on several cardiovascular risk factors. Studies, ranging from animal studies to clinical trials, have shown that pharmacological doses of vitamin D notably reduce inflammation [80], improve endothelial function [81], control the secretion of insulin and improve insulin sensitivity [82].

Furthermore, as recently reviewed, vitamin D status has been linked to arterial hypertension [83]. Several observational studies suggest that 25(OH) vitamin D levels less than 15 ng/ml are associated with an excess risk of cardiovascular events when compared to levels > 30–40 ng/ml. A nested case–control study in 18,225 men in the Health Professionals Follow-up Study (men aged 40–75 years, free of cardiovascular disease at baseline) showed that men with a 25(OH) vitamin D level ≤ 15 ng/ml had an increased risk for myocardial infarction relative to men with a level ≥ 30 ng/ml (RR 2.42; 95% CI 1.35–3.84) [84]. Even men with a 25(OH) vitamin D level 22.6–29.9 ng/ml had an increased risk (RR 1.60; 95% CI 1.10–2.32) compared with those with a level ≥ 30 ng/ml. In the Framingham offspring cohort study, 25(OH) vitamin D was measured in 1,739 participants without prior heart disease. At a mean follow-up of 5.4 years, amongst those with hypertension, there was a 2-fold increase in the risk of cardiovascular events for the participants with a 25(OH) vitamin D level < 15 ng/ml compared to those with a level ≥ 15 ng/ml [34]. The Ludwigshafen Risk and Cardiovascular Health Study, a prospective cohort comprising 3,300 patients referred to coronary angiography and followed for 7.7 years, demonstrated a strong association between vitamin D status and several cardiovascular outcomes, such as cardiovascular mortality [85], stroke [86], heart failure and sudden cardiac death with the lowest risk amongst those with the highest 25(OH) vitamin D levels [87]. However, such associations have not been found in other studies. In the Osteoporotic Fractures in Men Study, vitamin D intake was evaluated in 3,094 men and 25(OH) vitamin D was measured in 813 men. The authors found no association between vitamin D intake or 25(OH) vitamin D levels and incidence of cardiovascular disease during a median follow-up of 4.4 years [88]. Similarly, serum levels of 25(OH) vitamin D levels were not independently associated with cardiovascular mortality in the prospective Rancho Bernardo study including 1,073 community-dwelling older adults followed up to 10.4 years [89]. On the other hand, in a cross-sectional study of 2,722 subjects, the prevalence of hypertension was found to be increased in subjects with 25(OH) vitamin D levels < 40 ng/ml; odds ratios were 2.7 (1.4–5.2), 2.0 (1.4–5.2) and 1.3 (1.2–1.6) for 25(OH) vitamin D levels < 15, 15–29 and 30–39 ng/ml, respectively, compared with the >40 ng/ml group [90]. This inverse relationship between 25(OH) vitamin D levels and hypertension has been recently confirmed in a meta-analysis of 18 studies [91]. These various sets of data raise the question of whether vitamin D supplementation can prevent hypertension and cardiovascular events.

The evidence of benefit of vitamin D supplementation from randomised trials is, however, scarce. In a small trial, 8 weeks of supplementation with vitamin D₃ (800 UI/day) and calcium was reportedly more effective in reducing systolic blood pressure than calcium alone [92]. In the Women’s Health Initiative trial, including 36,282 postmenopausal women, vitamin D₃ plus calcium supplementation did not reduce blood pressure, nor the risk of developing hypertension over 7 years of follow-up; however, in this trial, supplementation consisted only of 400 IU/day and adherence to supplementation was only around 60 % [93]. A recent metaanalysis of eight randomised clinical trials in patients with a mean baseline blood pressure above 140/90 mmHg concluded that vitamin D reduces blood pressure modestly but significantly [94]. In summary, results from different studies are conflicting and trials specifically assessing effects of vitamin D on cardiovascular diseases as a primary endpoint are lacking. It is therefore premature to recommend supplemental vitamin D intake for the prevention of cardiovascular diseases or hypertension [95].

Vitamin D and the immune system

Vitamin D receptors are present in almost all immune cells, including activated T and B lymphocytes and antigenpresenting cells. Immune cells also express vitamin Dactivating enzymes, allowing local conversion of inactive vitamin D into calcitriol within the immune system [96]. Several autoimmune diseases such as type 1 diabetes mellitus or multiple sclerosis are more frequent in countries with less sunshine, and vitamin D deficiency in early life increases the risk of autoimmune diseases and infections later on [96, 97]. There are several epidemiological studies that have reported an association between vitamin D deficiency and susceptibility to respiratory infections, especially tuberculosis and Gram-negative infections [98]. Studies using animal models of autoimmune diseases have identified vitamin D as a potential modulator of differentiation, proliferation and secretion processes in autoimmune reaction [96]. Supplementation in humans might thus be preventive in a number of autoimmune disorders.

A Finnish birth-cohort study, including > 10,000 children born in 1966, showed that vitamin D supplementation during the first year of life (2,000 IU/day) was associated with a risk reduction of 78 % for developing type 1 diabetes (followed up until end 1997) compared to no supplementation or use of lower doses [99]. A meta-analysis of data from four case-control studies and one cohort study support the beneficial effects of vitamin D in prevention of type 1 diabetes [100]. A more recent supplementation study, however, was negative [101]. Data indicate that treatment with vitamin D could be beneficial in reducing the risk of developing multiple sclerosis and diminishing its exacerbations [102]. Although contradictory data exist concerning supplementation benefits in rheumatoid arthritis (RA) and systemic lupus erythematosus, an association between low levels of 25(OH) vitamin D levels and activity of both diseases has been reported [103, 104]. Furthermore, an inverse association between higher intake of vitamin D and risk of rheumatoid arthritis was demonstrated in the Iowa Women’s Health Study [105]. However, we still lack non-biased large cohort studies that can sustain the proposed benefits of vitamin D supplementation for optimal immune function. Large-scale intervention trials in humans that support the findings in preclinical or observational studies are lacking [96].

Vitamin D and cancer: treatment and prevention

Many experimental data show that calcitriol stimulates apoptosis and differentiation and inhibits angiogenesis and proliferation in tumour cells [106]. Numerous association studies suggest that serum 25(OH) vitamin D levels are inversely associated with the risk of many types of cancer. Further, in some studies of patients with cancer, an association between low 25(OH) vitamin D levels and poor prognosis has been observed [107, 108]. A meta-analysis of available studies indicated that there is a trend for lower incidence of colorectal carcinoma and adenoma with 25(OH) vitamin D levels > 20 ng/ml in a dose-response association [109]. For breast cancer, a pooled analysis of two studies with 880 cases and 880 controls demonstrated that individuals with sufficient serum 25(OH) vitamin D levels had 50 % lower risk of breast cancer than those with levels < 13 ng/ml [110]. In addition, a large case-control study on 1,394 post-menopausal breast cancer patients and 1,365 controls also showed that the 25(OH) vitamin D level was significantly associated with lower breast cancer risk, particularly at levels above 20 ng/ml [111]. Most evidence concerning the link between vitamin D and cancer is derived fromlaboratory studies and observational investigations of 25(OH) vitamin D levels in association with cancer incidence and outcome. There are, however, several possible confounding factors and association cannot prove causation. Moreover, results from prospective studies only are more heterogeneous and do not support a significant association between vitamin D status and breast cancer [112].

There have been no clinical trials with cancer incidence or mortality as a primary outcome to support causality between vitamin D status and cancer. One population-based randomised clinical trial found that calcium plus vitamin D supplementation decreased cancer incidence as a secondary outcome. In that study including 1,179 healthy postmenopausal women aged >55 years, the mean level of 25(OH) vitamin D at baseline was 29 ng/ml. Supplementation with 1,100 IU vitamin D/day increased serum 25(OH) vitamin D to 38 ng/ml. After 4 years of treatment, the supplemented group had a 60 % lower risk of developing cancer than the placebo group [113]. However, a recent reanalysis has indicated that this inverse association between vitamin D levels and cancer incidence disappeared after adjustment for BMI and physical activity [9, 112]. In another randomised trial, the Women’s Health Initiative, no effect of calcium and 400 IU vitamin D/day was found on the incidence of colorectal or breast cancer, which were secondary outcomes [114]. However, the dose of 400 IU used in that trial may have been inadequate to raise 25(OH) vitamin D blood levels significantly, particularly after factoring in adherence levels. A recent review of randomised vitamin D supplementation trials with cancer incidence as a secondary endpoint concluded that the results were null [112]. Moreover, the recent large-scale «Cohort Consortium Vitamin D Pooling Project of Rarer Cancers» showed no evidence linking higher serum 25(OH) vitamin D levels to reduced risks of less common cancers, including endometrial, gastric, kidney, pancreatic and ovarian cancers [115]. In summary, the available evidence that vitamin D reduces cancer incidence is inconsistent and inconclusive. Randomised controlled trials assessing vitamin D supplementation for cancer prevention are in progress. Their results are to be awaited before promoting vitamin D supplementation to reduce cancer risk.

As a general conclusion, the importance of vitamin D for bone health and the prevention of osteomalacia and osteoporosis are well recognized. More recently, vitamin D deficiency has been associated with other chronic conditions, including cardiovascular disease, autoimmune diseases and cancer. However, most evidence for the importance of vitamin D in these conditions comes from laboratory studies and observational investigations. Randomised controlled trials are needed to determine whether long-term supplementation with vitamin D has a favourable impact on the development or clinical course of non-skeletal diseases [116].

Bisphosphonates

BPs are the mainstay in the treatment of osteoporosis and other metabolic bone diseases such as Paget’s disease, as well as in tumoural conditions such as multiple myeloma, bone metastases and cancer-induced hypercalcaemia. Their efficacy and safety have been thoroughly established on the basis of multiple large pivotal trials dealing with their main indications. Their daily use in clinical medicine since 1969 has confirmed the general conclusions of the trials. Their strong affinity for the skeleton partially explains their excellent safety profile for other systems of the body. Even at high pharmacologic doses, their bone affinity grossly precludes tissue uptake outside the skeleton. First of all, intestinal absorption after oral administration is weak, on the order of less than 1 %, even under ideal conditions (after a prolonged fast, with a full glass of water, and remaining fasting for at least 30 min in an upright position before any other food or beverage intake), leading to very low peak values in the plasma. After intravenous administration, however, if the plasma peak levels are higher, these levels are transient and short-lived. Similarly to what is observed after oral administration, serum levels rapidly decrease due to their rapid adsorption on the surface of bone (± 50 %). The rest is cleared by both glomerular filtration and proximal tubular secretion (± the remaining 50 %) [117]. The retention time in the skeleton is extremely long and depends on the individual bone affinity of the various BPs. Part of the released BPs from the skeleton can be re-uptaken, and part is eliminated in the urine. Even if their terminal half-life is long, plasma levels remain very low. However, small amounts have been detected in body fluids up to 8 years after stopping the drug [118, 119]. This justified some warning regarding the use of BPs in premenopausal women of child bearing age. Even if there has been no demonstrated adverse foetal events in humans, large controlled studies are lacking to confirm their widespread safe use [120]. Some caution to restrict the use BPs to severe condition is still justified.

Bisphosphonate and acute phase reaction

After the first intravenous administration of a nitrogencontaining bisphosphonate (n-BP) (e.g. disodium pamidronate, zoledronic acid, ibandronate), about 25 % of patients experienced flu-like symptoms, consisting of transient and self-limited fever, myalgias and/or arthralgias for 2 to 3 days. Acute phase reaction (APR) has been associated with the release of serum inflammatory cytokines such as tumour necrosis factor (TNFa) and IL-6, but not IL-1 [121]. The origin of these pro-inflammatory agents was homed on monocytes and/or macrophages [122] but also in human peripheral blood gd T cells, which could constitute the trigger for activation of the former cells [123]. The APRs were absent or at least strongly attenuated with subsequent infusions with n-BPs. The APR has also been observed after high-dose oral monthly ibandronate [124]. The postinfusion syndrome can be reduced by acetaminophen [125]. It has been suggested that the co-administration of statins could prevent this reaction [123, 126], but this preventative effect does not seem to be systematic [127]. On the contrary, concomitant glucocorticoid (GC) therapy did not alle­viate it [128]. Depletion in 25(OH)D could constitute a factor favouring the occurrence of APR after n-BPs infusion in n-BP-naive patients, but this remains to be confirmed [129].

Bisphosphonate and musculoskeletal pain

Some cases of prolonged musculoskeletal pain have been reported [130] in up to 20 to 25 % of patients on alendronate and risedronate, as well as zoledronic acid [128, 131]. The majority of patients experienced gradual relief of pain after discontinuation of the drug. A few patients redeveloped pain following re-challenge of the drug. No plausible explanation has been proposed for their occurrence, and the association between BPs and musculoskeletal pain has therefore been questioned [132].

Bisphosphonate and the risk of renal failure

In line with the renal elimination of BPs, it is not recommended to prescribe BPs to patients with a creatinine clearance less than 30 ml/min, and this is specified in the Summary of Products Characteristics of BP who were granted an European Marketing Authorisation. In all pivotal studies of BPs, chronic kidney diseases (CKD) constituted an exclusion criterion, based on the calculated estimated glomerular filtration rate using the formula of Miller et al. [133]. In these large studies, however, several patients with CKD, but without other calcium metabolism abnormalities, notably in serum calcium, phosphate, alkaline phosphatase, vitamin D and PTH were included. Some exceptions to this 30 ml/min rule could therefore be theoretically possible [133–135]. Even if clinical trials and clear recommendations in the population with CKD are lacking, many clinicians suggested to halve the dose or reduce the frequency of administration of BPs in CKD [135]. Potential indications of BPs in CKD are the prevention of bone loss in kidney after transplantation. However, in these cases, no antifracture efficacy has so far been demonstrated with BP use [136–138]. Moreover, some patients treated with IV pamidronate developed low-bone turnover adynamic bone [137]. Calciphylaxis is a rare complication of CKD. Case reports have suggested the potential usefulness of BPs in its treatment [139, 140]. Proteinuria and proximal tubular necrosis has been described in mice and rats after parenteral doses of pamidronate sodium and clodronate five to 20 times higher than clinical doses used in humans [141]. However, acute renal toxicity was also reported in humans after rapid infusion of high doses of non-n-BPs [142]. Renal function deterioration, defined by elevations in the serum creatinine level, was observed in up to 15 % of the patients receiving 4 mg of zoledronic acid over 15 min in trials of treatment for bone metastases (compared with 6.7 % to 11.5 % in patients on placebo) [143]. In the doses registered for the treatment of postmenopausal osteoporosis, oral BPs did not adversely affect the renal function. With intravenous zoledronic acid infusions, with infusion times of 15 min, short-term increases in serum creatinine have been observed for 9 to 11 days in a small subset of patients [144]. It seems therefore justified that patients be well hydrated and avoid simultaneous therapeutic agents at risk of impairing renal function. Patients with a glomerular filtration rate less than 30 ml/min should ideally be excluded, the precise diagnosis of bone loss in such patients being uncertain. Other kinds of bone disease than osteoporosis could be present [144]. As there exists no head-to-head comparative trial, it is not possible to determine whether intravenous n-BPs such as pamidronate disodium or ibandronate would have a different renal safety profile than zoledronic acid [144].

Bisphosphonate and ocular risk

Cases of iritis, episcleritis and scleritis, but also conjunctivitis, have been reported after therapy with n-BPs (mainly alendronate, pamidronate disodium and zoledronic acid) in up to 1 % [145–147]. This does not seem to constitute an exclusive complication for n-BPs, but they were rarely reported with first-generation BPs [148]. Eye inflammation can resolve after local GC administration, but some patients can recur after BP rechallenge. In severe cases of uveitis and scleritis, it could be better to discontinue IV BP [149].

Bisphosphonate and the gastrointestinal tract

Digestive problems are at the origin of most drug withdrawals with oral n-BPs, mainly due to oesophageal irritation and upper gastrointestinal side effects [150]. They are poorly absorbed by the gastrointestinal tract, of the order of about 1 %. Moreover, their absorption is further reduced if they are taken with food and beverage such as coffee, milk, orange juice etc. Hence, the recommendation is to take them in a fasting condition with a glass of water and to remain fasting in an upright position for at least 30 min after swallowing the drug until the first meal of the day. These precautions help to prevent most upper gastrointestinal side effects [151]. Moreover, the availability of weekly and monthly BPs has further decreased the frequency of the upper gastrointestinal tract symptoms [152–157]. It has been suggested that a lot of adverse events in upper gastrointestinal tract might be already present prior to start BPs therapy [158] and that clinicians and patients may sometimes inappropriately attribute gastrointestinal complaints to therapy [159]. Irrespective of whether gastrointestinal symptoms in individual patients are linked with oral BPs or not, it should be remembered that such a link has not been reported with intravenous therapy.

A study based on the General Practice Research Database containing anonymised patient records of about six million people in UK suggested a doubling of the incidence of oesophageal cancer with 5 years’ use of oral BPs [160], but this was not confirmed in another analysis of the same database [161]. No excess of gastric and colorectal cancer was found. Moreover, in patients with Barrett’s oesophagus on oral BPs, no increased risk of oesophageal adenocarcinoma was observed [162]. Even if no definitive conclusion can be drawn from these studies, upper gastrointestinal investigation is recommended if a patient on BPs develops dysphagia and pain.

Bisphosphonates and cardiovascular risk

In the pivotal study of zoledronic acid versus placebo in postmenopausal osteoporotic women, atrial fibrillation reported as serious adverse events (SAEs) was more frequent in the actively treated patients (1.3 % versus 0.5 %; p < 0.001). This was not observed in the HORIZON recurrent fracture trial, in which a similar frequency of ‘serious’ atrial fibrillation was observed both in actively treated and placebotreated patients (1.1 % versus 1.3 %) [163]. Post hoc analyses of previous main trials on alendronate, risedronate and ibandronate having involved about 30,000 patients did not show any clear-cut association with atrial fibrillation [164–166]. It is possible that a lot of BP-treated patients have increased risks of cardiovascular events already before the start of therapy [167, 168]. Also, any potential cardiovascular risk should be weighted against the benefits of BP therapy. These include the well-documented antifracture efficacy, of course, but may also include additional benefits like the mortality benefit after hip fracture with zoledronic acid therapy, a 30 % mortality reduction not simply attributable to anti-fracture efficacy [163, 169].

Bisphosphonate and hypocalcaemia

BPs and in particular n-BPs are potent inhibitors of osteoclastic bone resorption. They can therefore provoke hypocalcaemia, hypocalciuria and PTH reaction in some cases. Etidronate, however, did not induce any fall in serum and urine calcium because it acutely impaired the accretion of calcium into bone, offsetting a hypocalcaemic response [170]. Even with intravenous potent n-BPs, symptomatic hypocalcaemia rarely occurs in the treatment of osteoporosis under usual conditions, i.e. with supplemental calcium and vitamin D, lack of pre-existing hypoparathyroidism and/or renal failure.

Miscellaneous

— Skin reactions like rash, pruritus and urticaria have been rarely reported with BP use. Re-challenge was positive in some cases [171]. Change of BP was not always accompanied by resurgence of symptoms, suggesting that BP-induced cutaneous reactions are probably not attributable to a class effect [171].

— Extremely rare case reports of damage to the oral mucosa, apparently not related to osteonecrosis of the jaw, have been reported with the incorrect administration of n-BPs. Discontinuation of the inappropriate use allowed healing of the mucosa ulcers, even with maintained oral intake, but taken according to the prescription instructions [172].

— A few reports of transient hepatitis after months to years of alendronate and/or risedronate, with liver biopsies compatible with a drug-induced toxicity, have been described [173, 174]. Healing occurred soon or later after stopping the drug.

Bisphosphonates and cancer

BPs constitute an efficacious therapy in order to prevent skeletal complications in patients with bone metastases. They might help to maintain functional independence and quality of life [175]. Several BPs have shown some efficacy in this regard, but owing to its easy mode of administration and its potency, zoledronic acid became the most used drug. Improved quality of life and prolonged disease-free survival have been observed with adjuvant therapy with zoledronic acid. In addition, zoledronic acid has shown a direct inhibition of tumorigenesis and cellular growth in preclinical models. So far, clinical results remain controversial [160, 176–183].

SAPHO syndrome

Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome is a rare condition consisting of sterile inflammatory osteoarticular disorders, frequently associated with skin lesions resistant to conventional anti-inflammatory therapy [184]. Several case reports have shown successful therapy with infusions of pamidronate disodium and zoledronic acid [185, 186].

Multicentric reticulohistiocytosis

Multicentric reticulohistiocytosis is a rare systemic condition characterized by erosive polyarthritis frequently progressing to arthritis mutilans and papulonodular lesions on the skin. Alleviation of the arthritis and concurrent reduction of the size and number of cutaneous nodules have been observed in single case reports with therapy with alendronate, pamidronate and zoledronic acid [187].

Hypertrophic osteoarthropathy

Hypertrophic osteoarthropathy can be disabling and resistant to analgesic and anti-inflammatory drugs. Clubbing, arthralgias, cutaneous and osseous (periosteal) proliferation in the upper and lower extremities are frequently associated with bronchogenic carcinoma and right-to-left cardiac shunts. A few case reports have shown an effective alleviation of symptoms after pamidronate disodium and zoledronic acid in both benign and malignant conditions [188].

There are potentially other indications for BPs such as periodontitis leading to local bone loss. However, there is not yet enough evidence to recommend a wide use of BPs in the treatment of this condition. Moreover, the theoretical albeit questioned risk of osteonecrosis of the jaw could deter clinicians to use them thoughtlessly [189].

To be continued in the next issue