4.9 Paget’s disease of bone

In 1876, Sir James Paget presented to the Royal Medical and Chirurgical Society of London an account of his experience with a previously unrecognized disease of the skeleton, which he termed osteitis deformans and has since born his name. Paget’s disease of bone is a focal skeletal disorder which progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular, and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis. The disease is easily diagnosed and effectively treated but its pathogenesis is largely unknown (1–3).

Paget’s disease affects typically the elderly, slightly more men than women, and seldom presents before the age of 35 years. Its prevalence increases with age and it affects 1 to 5% of those above 50 years of age. There is a distinct geographical distribution; the disease is common in central, western, and parts of southern Europe, the USA, Australia, New Zealand, and some countries of South America, while it is uncommon in Scandinavia, Asia, and Africa. There may also be variations within the same country, as shown in studies in the USA, UK, Italy, and Spain. For example, in northeast USA the prevalence is about fivefold higher than in south USA (4) and in parts of northwest England in 1974 the age- and gender-standardized prevalence rate was 8.3% compared to 4.6% in southern towns and cities (5). Interestingly, a more recent radiographic survey in the same centres with identical methodology (6) reported a decline in the overall prevalence of the disease, as has also been observed in other, but not all, regions where comparative studies were performed. In addition, reports from New Zealand, UK, and Spain suggested that the clinical severity of the disease has attenuated in recent years (3). These changes in prevalence and severity of the disease strongly suggest that environmental factors are involved in its pathogenesis.

The adult skeleton is continuously renewed throughout life by the process of bone remodelling. Old bone is removed by the osteoclasts whereas new bone is formed in the same location by the osteoblasts. This occurs in an orderly fashion through temporary anatomic structures called basic multicellular units (BMUs). A basic multicellular unit comprises a team of osteoclasts at the front and a team of osteoblasts at the back supported by blood vessels, nerves, and loose connective tissue. Osteoclasts and osteoblasts are derived from different precursors in the bone marrow. Osteoclasts originate from haematopoietic precursors of the monocyte/ macrophage lineage while osteoblasts originate from multipotent mesenchymal stem cells, which give also rise to bone marrow stromal cells, chondrocytes, adipocytes, and muscle cells. The formation and lifespan of bone cells are controlled by mechanical, systemic, and local factors through mediator molecules in the bone marrow. Important regulators of osteoclast formation and activity belong to a ligand/ receptor/ soluble (decoy) receptor system involving proteins of the TNF receptor superfamily (7, 8). These are RANK-ligand, RANK, and OPG. RANKL is produced by osteoblastic/ stromal cells, reacts with RANK, which is localized in haematopoietic osteoclast precursors, stimulates the formation and activity of osteoclasts, and prolongs their life span. RANKL is essential and sufficient for osteoclastogenesis. Bone resorbing factors up-regulate the expression of RANKL and thereby of osteoclastogenesis. On the other hand, OPG is a soluble receptor which counteracts the biological effects of RANKL preventing its binding to RANK and thereby suppressing bone resorption.

Paget’s disease of bone is a focal disorder of bone remodelling characterized by an increase in the number and size of osteoclasts in affected sites while the rest of the skeleton remains normal. The typically large osteoclasts, which may contain up to 100 nuclei per cell, induce excessive bone resorption associated with an increased recruitment of osteoblasts to the remodelling sites, resulting in increased bone formation and, hence, an overall increase in the rate of bone turnover. The increase in bone formation is thought to be secondary to the increased rate of bone resorption due to the coupling of the two processes. Some evidence, however, suggests that osteoblastic/ stromal cells may also be primarily affected in Paget’s disease and contribute to the increased rate of bone formation (9, 10). The accelerated rate of bone turnover is responsible for the deposition of bone with disorganized architecture and structural weakness. The bone packets lose their lamellar structure and are replaced by woven bone with a characteristic mosaic pattern while bone marrow is infiltrated by fibrous tissue and blood vessels.

In clinical studies the likelihood of a bone being affected by Paget’s disease was related to the amount of bone marrow present in that bone, leading to the postulation that the development of bone lesions may be related to specific properties of pagetic bone marrow (11). In bone marrow cultures from patients with Paget’s disease the rate of formation of osteoclasts and their number is markedly increased, suggesting that intrinsic abnormalities of the bone marrow microenvironment and/or of osteoclast precursors may contribute to the up-regulation of osteoclastogenesis. A number of studies supported these notions and documented two major abnormalities. First, pagetic osteoclasts and their precursors express high levels of osteotropic factors, e.g. IL-6, a bone resorbing cytokine which has been proposed as a possible paracrine/ autocrine factor contributing to the pathogenesis of the disease (10, 12, 13). In addition, enhanced expression of RANKL was detected in bone marrow stromal cells from patients with Paget’s disease and may contribute to the increased number of osteoclasts (14). Second, compared to controls, bone marrow and peripheral cells from patients are hypersensitive to the action of RANKL and calcitriol (15, 16) and there is evidence suggesting that TAFII-17, a component of the transcription complex that binds vitamin D receptor, may be responsible for the hypersensitivity to calcitriol (17). Thus, while the molecular characteristics of the cellular abnormalities of the disease are currently understood, the precise mechanism(s) that trigger these changes remain to be elucidated.

Several, not mutually exclusive, hypotheses have been proposed to explain the pathology of the disease, the most relevant being the viral and the genetic hypotheses. Studies of the distribution of bone lesions in patients with Paget’s disease showed that the probability of a bone being affected is very similar to the probability of a bone being affected with haematogenous osteomyelitis, suggesting that the disease may be caused by a circulating infectious agent. An infection by a slow virus of the paramyxovirus family (measles virus, respiratory syncytial virus, canine distemper virus) was supported by the detection of nuclear and cytoplasmic inclusions resembling paramyxoviral nucleocapsids in osteoclasts and of measles virus nucleocapsid transcripts in bone marrow and peripheral blood monocytes from patients with the disease (18). However, paramyxoviral-like structures have also been found in specimens from patients with other bone diseases, questioning the specificity of this finding. In addition, further search for viral presence in the osteoclasts provided conflicting results (19). However, although the presence or not of paramyxoviruses in pagetic bone is currently debated, there is good evidence that paramyxoviruses and viral proteins can promote the formation of osteoclasts with features similar to those of pagetic osteoclasts (20).

In familial aggregation studies the risk of first-degree relatives of patients with Paget’s disease to develop the disorder was seven to 10 times greater than the risk of individuals without such relatives (21, 22). Furthermore, a positive family history has been reported in up to 25% of patients and a small but detailed study from Spain showed that 40% of 35 patients with Paget’s disease had at least one affected first-degree relative (23). Familial Paget’s disease is inherited as an autosomal dominant trait and initial genetic analyses showed evidence of linkage to chromosome 18q21–22 in some families (24, 25). This chromosome also contains the locus of the rare disease familial expansile osteolysis, which resembles Paget’s disease and was found to be associated with activating mutations in the gene TNFRSF11A, which encodes RANK (26), while abnormalities of the same gene are responsible for another rare skeletal disease, expansile skeletal hyperphosphatasia (27). Subsequent studies, however, failed to detect such mutations in patients with familial or sporadic Paget’s disease. Other abnormal genes that have been identified in diseases with bone phenotypes similar to that of Paget’s disease include TNFRSF11B, which encodes OPG in juvenile Paget’s disease (28), and VCP, which encodes p97 in the syndrome of inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (29). All these genetic defects have in common the up-regulation of the NF-kB-signal transduction, an essential process in the differentiation and activation of osteoclasts. These genes have also been investigated in patients with familial or sporadic Paget’s disease but no mutations were identified. Analysis of families with Paget’s disease identified further possible loci in other chromosomes indicating genetic heterogeneity. However, studies in different parts of the world have now identified mutations in the SQSTM1 gene, located on chromosome 5q35, in up to 50% of patients with familial Paget’s disease and up to 10% of those with sporadic disease (3, 19, 22, 30). Moreover, the most common mutation associated with Paget’s disease (P329L) has been detected in patients from different European countries suggesting a founder gene defect. In addition, animals overexpressing this mutation in cells of the osteoclast lineage formed more osteoclasts, which were hypersensitive to RANKL but did not develop bone lesions resembling those of Paget’s disease in one study while in another they did (19). Whether mutations of genes associated with Paget’s disease are the cause of the disease or whether individuals with a mutation have an increased susceptibility to the disease when exposed to environmental factors, such as paramyxoviruses, is currently unclear. The current view is, therefore, that the disease is caused by interactions between environmental and genetic factors, the nature of which remains to be determined.

The most commonly affected bones are the pelvis (in about two-thirds of patients), the spine, the femora, and the skull but practically any bone of the skeleton may be affected and there is remarkable similarity in the frequency of affected bones in large series of patients from different countries (1, 31, 32). About one-third of patients have only one lesion (Fig. 4.9.1) but the frequency of single lesions varies among series, probably reflecting referral patterns, and is higher in asymptomatic patients. The anatomical spread of the disease is not related to age or gender, shows no particular symmetry in the body, and remains largely unchanged throughout life. The disease progresses slowly within the affected bone but does not generally appear in other bones. Patients with limited bone involvement should, therefore, be reassured that the disease will not progress to other bones with time.

The majority of patients are asymptomatic and the disease may be diagnosed incidentally during investigation of an unrelated complaint by skeletal radiographs or by the finding of an unexplained elevation of serum alkaline phosphatase activity (33). About 5 to 10% of affected patients have symptoms. Skeletal morbidity in Paget’s disease is determined by the damage caused and the progression of the disease in affected sites as well as by the number and the localization of the lesions. Extensive disease, as originally described by Sir James Paget, occurs in about 5% of symptomatic patients. This is in agreement with the limited chance of an individual to develop extensive disease, as predicted by the distribution of lesions, but changing patterns of the disease to milder forms may also contribute to that.

The symptoms and complications of Paget’s disease, summarized in Table 4.9.1, can have a great impact on the quality of life of affected individuals (34, 35). In the majority of patients the presenting complaint is pain. This is related to the extent and site of the disease, it is usually persistent and present at rest, but is not specific. Pain due to secondary osteoarthritis is common and may hamper assessment of the relative contribution of bone and joint pains to the patient’s disability. The origin of such pain can be assessed only retrospectively after treatment which reduces mainly the disease-related pain, having a rather limited effect on the arthritic pain. Deformities are present in about 15% of patients at the time of diagnosis and affect mainly weight bearing bones, the most common deformity being bowing of the lower limbs. About 9% of patients present with fractures, which can be complete or fissure (incomplete) fractures. The latter occur more frequently, can be multiple, can cause pain, and may develop to complete fractures. Fractures heal generally well although in an older, large series of 182 fractures of the femur the incidence of nonunion was 40% (36). The skin overlying an affected bone may be warm as a result of increased blood flow and bone turnover locally and hypervascularity of affected bones may cause ischaemia of adjacent structures (steal syndrome). Irreversible hearing loss is the most common neurological complication occurring in about one-third of patients with skull involvement. This is thought to be related to structural and/or density changes in the cochlear capsule bone (37). Malignant transformation of pagetic bone and development of osteosarcoma is a rare (less than 1%) but extremely serious complication.

Radiographic changes are characteristic of the disease (Fig. 4.9.2). Increased bone resorption may be detected as a decrease in the density of affected bones; sometimes a wedge- or flame-segment of bone resorption may be seen in long bones and extensive osteolytic areas in the skull (osteoporosis circumscripta). The osteolytic changes in long bones progress at a rate of about 1 cm/year. Older lesions usually have a mixed sclerotic and lytic appearance and in the last stage of the disease sclerotic lesions predominate. The involved parts of the skeleton are enlarged and deformed and the cortex can be thickened and dense. The radiological changes can be considered pathognomonic but in some cases differential diagnosis may include fibrous dysplasia and bone metastases, particularly from prostate cancer. Bone scintigraphy is used to assess the extent of the disease. It is not specific but it is more sensitive than plain radiographs; up to 15% of lesions detected by bone scintigraphy may have normal radiographic appearance. Bone scintigraphy should always be included in the investigation of patients with Paget’s disease and plain radiographs of the areas of increased radioisotope uptake should be subsequently made to confirm the diagnosis (Fig. 4.9.3).

The pathology of Paget’s disease is reflected in the proportional increase in biochemical indices of bone turnover (38). Classically, urinary hydroxyproline excretion was used as an index of bone resorption and serum total alkaline phosphatase activity as an index of bone formation. These can be markedly increased in patients with extensive disease but can be also found within the reference range in patients with limited bone involvement. Patients with skull disease tend to have the highest values of serum alkaline phosphatase activity. More specific and sensitive biochemical indices of bone formation include the bone-specific isoenzyme of alkaline phosphatase and the N-terminal extension peptide of collagen type I (procollagen I N-terminal peptide). Serum osteocalcin concentrations are within the normal range in about half of the patients with elevated serum alkaline phosphatase values and should not be used in the management of patients with Paget’s disease. Urinary hydroxyproline is neither specific nor sensitive enough and its determination depends on specific dietary advice. Deoxypyridinoline and peptides of the cross-linking domains of collagen type I, such as the N-telopeptide or the C-telopeptide, measured in urine or serum are the most sensitive biochemical markers of bone resorption. Impaired isomerization of C-telopeptide has been reported in patients with Paget’s disease but not in patients with increased bone turnover from other causes, leading to the postulation that this abnormality may reflect the defect in bone structure (39). Degradation products of collagen type II are not increased in urines of patients (40).

In Paget’s disease, despite the marked changes in the rate of bone and calcium turnover, extracellular calcium homoeostasis is generally maintained but some disturbances may occur. Hypercalcaemia may develop in immobilized patients with active, extensive disease or may be due to concurrent primary hyperparathyroidism, the incidence of which is thought to be higher in Paget’s disease compared to the general population. Secondary hyperparathyroidism is present in about 20% of patients while serum concentrations of calcitriol are generally normal. Hypercalciuria and renal stone disease occur also more frequently in patients with Paget’s disease.

During the past 30 years, the management of patients with Paget’s disease has changed dramatically due to the discovery of the therapeutic potential of the calcitonins and later of the bisphosphonates. Other, less frequently used treatments were plicamycin (mithramycin) and gallium nitrate. Bisphosphonates are currently the preferred treatment of Paget’s disease.

Classically treatment is given to patients with Paget’s disease to relieve symptoms and improve their quality of life. The disease, however, is progressive and patients with symptoms were previously asymptomatic (Fig. 4.9.4). It is currently impossible to identify patients who will develop symptoms and complications and no way to quantify the risk of complications in an individual. Treatment with potent bisphosphonates does not only relieve symptoms due to the disease but restores bone quality and improves or even normalizes radiological appearances. Moreover, the bulk of evidence obtained with bisphosphonates strongly suggests that complications can be prevented if bone turnover is adequately suppressed, whereas there are indications that the contrary is true if bone turnover does not normalize (41). Firm evidence, however, from prospective randomized controlled trials is lacking. Recently, in an attempt to answer this question Langston et al. (42) compared intensive bisphosphonate treatment and symptomatic management in a large cohort of patients with Paget’s disease followed for 3 years and found no differences in clinical outcomes between the two groups. Limitations of the study were the already advanced disease in most of the patients, use of bisphosphonates by the majority of patients before trial entry, and the fact that the disease was in biochemical remission in about half of the patients.

Currently, the following treatment indications are recommended: (1) symptomatic disease; (2) preoperative treatment in preparation for an orthopaedic procedure on pagetic bone to reduce the increased blood flow and excessive bleeding; (3) treatment of asymptomatic patients with skeletal localizations at higher risk of future complications, such as those adjacent to large joints, in the skull, the spine, and the weight-bearing bones; and (4) young patients. The goal of treatment should be to normalize bone turnover, suppress serum alkaline phosphatase activity well within the normal range, and keep it adequately suppressed, if necessary with additional courses of treatment. Retreatment is generally advocated when a previously normal value of serum alkaline phosphatase activity exceeds the upper limit of normal or when it increases by 20 to 25% above its nadir value.

The following properties render bisphosphonates as ideal agents for the treatment of Paget’s disease: selective uptake at active skeletal sites; specific inhibition of bone resorption; short plasma half-life and lack of circulating metabolites; and persistence of the effect after stopping treatment. The general structure of the molecule of germinal bisphosphonates allows numerous substitutions, which has led to the synthesis of a variety of compounds with considerable differences in potency, activity to toxicity ratio, and mechanism of action (43). Bisphosphonates are divided into two groups according to the presence or absence of a nitrogen atom in the molecule. The nitrogen increases the potency of the bisphosphonates and determines their mechanism of action. Compounds without a nitrogen atom in the side chain are etidronate, clodronate, and tiludronate. Nitrogen-containing bisphosphonates include alendronate, ibandronate, incandronate, neridronate, olpadronate, pamidronate, risedronate, and zolendronate. Practically all bisphosphonate, either approved or in clinical development, have been used in the treatment of Paget’s disease, which in turn has served as a human model for investigating the pharmacological properties of these agents. The bisphosphonates approved around the world for the treatment of Paget’s disease are listed in Table 4.9.2.

For the design of optimal therapeutic strategies of Paget’s disease with bisphosphonates their pharmacodynamic properties need to be taken into consideration (44). When a potent bisphosphonate is given to a patient with Paget’s disease, the first measurable effect is the suppression of bone resorption. This occurs within a few days of starting treatment. During this initial period, bone formation does not change. This will decrease secondarily, at a slower rate, due to the coupling of bone resorption to bone formation, so that a new equilibrium will be reached after 3–6 months (Fig. 4.9.5). Thus, adequate suppression of bone resorption will be predictably followed by an adequate suppression of bone formation. Suppression of biochemical indices of bone resorption early during the course of treatment provides, therefore, an indication of the pharmacological efficacy of the bisphosphonate and can subsequently determine the length of treatment (45). Because of the predictable changes in bone remodelling that follow bisphosphonate therapy in Paget’s disease, it is not necessary to prolong treatment until the lowest level of serum alkaline phosphatase is reached and short courses are usually sufficient to achieve remissions. Moreover, the retention of bisphosphonate in the skeleton is proportional to disease activity and inversely proportional to renal function (46). Therefore, dose adjustments may be required in patients with impaired renal function but no specific studies have addressed this issue. These pharmacodynamic principles indicate that bisphosphonate treatment regimens of Paget’s disease should be different from those used in osteoporosis. In addition, the wide variability of disease activity of affected patients strongly suggest that treatment needs to be individualized.

The long-term efficacy of treatment is best assessed by measuring biochemical indices of bone formation, serum alkaline phosphatase activity being still the most commonly used. In the past, the efficacy of treatment was evaluated by its ability to decrease serum alkaline phosphatase activity by more than 50% of its initial value. With the available potent bisphosphonates, this is no longer appropriate and treatment efficacy should be assessed only by its ability to decrease serum alkaline phosphatase values to the normal range (remission). In clinical practice there is no need to measure serum alkaline phosphatase activity earlier than 3 months after the start of treatment, 6 months being the optimal time.

During the initial phase of bisphosphonate treatment, when bone resorption and bone formation are still dissociated, the increased retention of calcium in the skeleton leads to changes in calcium metabolism. There is a fall in serum calcium concentration, which stimulates the secretion of parathyroid hormone secretion and consequently the renal production of calcitriol. These hormones, in turn, increase the renal tubular reabsorption of calcium (parathyroid hormone) and its intestinal absorption (calcitriol). The result is a marked, but transient, increase in calcium balance. The concomitant decrease in serum phosphate concentrations is due to the renal action of parathyroid hormone. Such responses are not observed during etidronate treatment, which has a weak action on bone metabolism. With the attainment of the new equilibrium of bone remodelling, calcium balance returns towards pretreatment levels and the values of the biochemical indices of calcium metabolism normalize. The adaptive changes of calcium metabolism to the marked alterations in bone remodelling prevent the development of symptomatic hypocalcaemia in calcium-replete patients. However, elderly patients frequently have calcium-deficient diets and some investigators advocate the use of calcium supplements during treatment of Paget’s disease with potent bisphosphonates, especially if these are given intravenously or the disease is very active. Support for this logical assumption by clinical trials is, however, limited.

Clinical responses to treatment include the disappearance or clear improvement of pain in more than 80% of treated patients, when this is due to the activity of the disease. A decrease of bone pain is generally observed 1 to 3 months after the start of treatment and the effect is maximal after 6 months and is maintained for as long as biochemical indices of bone turnover remain within the normal range. Soon after the start of therapy with a potent bisphosphonate, particularly if given intravenously, there may be a transient increase in pain at affected sites and patients should be reassured. Pain due to osteoarthritis is unresponsive to treatment in about 75% of patients; nonsteriodal anti-inflammatory drugs can then be used. If the hip joint is affected, hip arthroplasty may be required to control the symptoms. Back pain resulting from involvement of lumbar vertebrae is frequently not relieved by treatment. About half of the patients with pain associated with deformity of the femur or the tibia will respond favourably to bisphosphonate therapy but pain may persist and a corrective osteotomy may be necessary. Deafness is usually not affected but its progression appears to be arrested. There have been also reports of improvement of spinal cord compression with bisphosphonate therapy and fracture frequency of pagetic bones appears to decrease with treatment.

Improvement in bone histology and formation of bone with normal lamellar structure and no evidence of a mineralization defect has been reported with currently used bisphosphonates. Radiologically, an arrest of the progression of the disease is usually seen. Radiological improvement can be dramatic, however, if lesions are lytic and are localized in long bones or in the skull. In other areas, improvement is slow and sometimes difficult to demonstrate by nonexperienced radiologists. Treatment induces an exponential decrease in isotope uptake on bone scintigrams. However, even with normalization of disease activity, only about 10 to 30% of lesions normalize completely and residual uptake (up to 20% of the original) is detected (47). The possible relation of these scintigraphic changes to future recurrences has not been adequately studied but some investigators advocate normalization of bone scintigrams as one of the aims of treatment.

These clinical, histological, and radiological responses emphasize the need for an intervention with a bisphosphonate early in the course of the disease and before the development of complications.

All bisphosphonates given to patients with Paget’s disease significantly decrease biochemical indices of bone turnover (48–55). Considerable differences exist, however, in their ability to induce remissions. Generally, potent bisphosphonates induce better responses. Head to head clinical trials have been performed with etidronate 400 mg daily for 6 months as comparator. In all these clinical trials, etidronate was less effective. The limited efficacy, relative to other bisphosphonates, together with the increased risk of osteomalacia, have made etidronate a treatment of the past. Normalization of serum alkaline phosphatase activity has been reported with tiludronate 400 mg daily for 3 months (35%), clodronate 1600 mg daily for 6 months (up to 70%), alendronate 40 mg daily for 6 months (63%), risedronate 30 mg daily for 2 months (up to 70%), and pamidronate, intravenously or orally in variable regimens (up to 90%). It should be noted that comparison of results obtained in different studies is not appropriate due to different selection criteria and disease activity of treated patients. The results of these studies show, in addition, that despite the availability of effective and convenient treatment regimens with bisphosphonates, there is still need for further improvement. More recently, the efficacy and tolerability of a single 15-min intravenous infusion of zolendronate was compared to oral risedronate 30 mg per day for 2 months in patients with Paget’s disease of moderate activity (56). Results showed that zoledronate was significantly more efficacious than risedronate in inducing biochemical remission associated with improvements in some aspects of the quality of life of the patients. Zoledronate should be currently considered the treatment of choice of Paget’s disease.

Follow-up of patients in remission is indicated every 6–12 months. Remissions, estimated from the time of normalization of serum alkaline phosphatase activity, can be long and can last even longer than 10 years in some patients. We have observed, however, recurrences 12 or 13 years after induction of complete biochemical remission which illustrates the need for continuous follow-up. The duration of remission is determined by the degree of suppression of serum alkaline phosphatase activity and the number of affected bones but is not related to the length or to the mode of treatment (oral or intravenous) as long as a potent, efficacious bisphosphonate is given (57–59). The lower the serum alkaline phosphatase activity reached with treatment, the longer the period of remission. Suppression of serum alkaline phosphatase activity well within the normal range is a prerequisite for long-term remissions and should be part of treatment strategies.

Impaired response to repeated treatment courses with bisphosphonates is usually referred to as acquired resistance and should be distinguished from an intrinsic resistance to a particular compound. Acquired resistance has been reported for etidronate and pamidronate (60, 61) but the underlying mechanism is not known and it is important to differentiate between real and apparent resistance. Some patients may not respond to oral bisphosphonate but may show a prompt response to the same compound given intravenously. In such cases, factors interfering with the already low intestinal absorption of the drug are most likely responsible for the impaired response to oral treatment. Patients retreated with the same bisphosphonate during a recurrence of their disease may show a reduced fractional decrease in biochemical indices of bone turnover compared to earlier treatments. Some consider this response compatible with development of resistance to therapy. However, it has been shown in studies with clodronate and pamidronate that the actual level, rather than the fractional decrease of biochemical indices of bone turnover following every treatment, should be compared to those obtained after the initial therapy (Fig. 4.9.6). This is because patients who are offered a new treatment course have generally a lower rate of bone turnover compared to that before the first treatment. Finally, in patients with Paget’s disease and concurrent hyperparathyroidism, completeness of response is generally less and recurrences occur quicker which might be considered reduced responsiveness. For optimal responses of patients with Paget’s disease and autonomous hyperparathyroidism to be bisphosphonates, parathyroidectomy should be considered. However, real resistance to pamidronate can develop. We showed, for example, progressive reduction in responsiveness to this bisphosphonate, which was mainly related to the extent of skeletal involvement but not to the dose of pamidronate or to the biochemical activity of the disease. Patients with three or more affected bones were most likely to develop resistance to pamidronate, a finding consistent with other reports. These patients respond readily to other bisphosphonates. There are scarce data of resistance to other nitrogen-containing bisphosphonates. Using the same approach as in the pamidronate studies, we found no resistance to consecutive treatments of patients with Paget’s disease with olpadronate. Thus, within the limitations of existing studies, it appears that acquired resistance is specific for pamidronate and is limited to patients with extensive disease. Such resistance does not seem to occur with other nitrogen-containing bisphosphonates but the evidence for that is still weak. Finally, primary resistance to a specific bisphosphonate, if it exists, is rare.

All bisphosphonates given at very high doses can impair the mineralization of newly formed bone and induce osteomalacia. In clinical practice this is, however, relevant only for etidronate. Doses of potent nitrogen-containing bisphosphonates that induce osteomalacia exceed, by many orders of magnitude, those required for effective suppression of bone turnover. Consequently, in all reported controlled studies no adverse effects on bone mineralization have been observed. In only a few patients treated with intravenous pamidronate, at doses higher than those recommended, has impaired bone mineralization been reported. Histological osteomalacia induced by either etidronate or pamidronate is reversible.

In some patients treated for the first time with nitrogen-containing bisphosphonates there is a rise in body temperature and flu-like symptoms during the first 3 days of treatment. These symptoms are transient and subside with no specific measures even when treatment is continued (62, 63). This response is dose-dependent and is associated more frequently with intravenous than oral treatment. Moreover, it does not generally recur upon retreatment, and, if it does, it is of lower intensity. Previous exposure to another nitrogen-containing bisphosphonate, but not to etidronate, precludes the development of this response. Laboratory findings are consistent with an acute phase reaction (63). There is a transient decrease in blood lymphocytes and a transient increase in serum C-reactive protein, possibly due to increases in proinflammatory cytokines, such as IL-6 and TNF-α produced by γ,δ T-lymphocytes in response to a metabolite of the mevalonate pathway, upstream farnesyl pyrophosphate synthase, which is inhibited by nitrogen-containing bisphosphonates (63, 64). Rarely, high doses of nitrogen-containing bisphosphonates may induce ophthalmic reactions such as conjunctivitis, iritis, or uveitis. There are case reports of ototoxicity and central nervous toxicity after intravenous pamidronate. Allergic skin reactions have been occasionally observed with most of the bisphosphonates.

Mild gastrointestinal complaints occur with low frequency with the use of all bisphosphonates. Some nitrogen-containing bisphosphonates can induce more severe symptoms such as heartburn, nausea, and vomiting in a few patients, associated with oesophagitis or gastritis. The use of oral alendonate 40 mg daily was associated with higher frequency of epigastric complaints in an open, but not in a controlled, study and the latter was also the case with oral risedronate 30 mg daily. In a comparative study of alendronate 40 mg/day and risedronate 30 mg/day gastric ulcers and/or large numbers of gastric erosions were detected endoscopically in approximately 3% of patients, and their occurrence was comparable with both bisphosphonates. Nitrogen-containing bisphosphonates should be administered orally with one full glass of water and the patient should remain in an upright position for one half hour to allow quick passage through the oesophagus and to avoid oesophageal irritation. Rapid intravenous injection of bisphosphonates may chelate calcium in the circulation and form complexes, which can be nephrotoxic or can damage directly the renal tubule. Bisphosphonates should, therefore, be given by slow infusion. Zoledronate is administered by short intravenous infusion (15 min) because of the low effective dose. Aminobisphosphonates should not be injected intramuscularly because they can cause severe local irritation and necrosis but clodronate has been given intramuscularly. Osteonecrosis of the jaw is extremely rare in patients with Paget’s disease treated either with oral or intravenous bisphosphonates.