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Osteoporosis International https://doi.org/10.1007/s00198-018-4476-y

REVIEW

Understanding osteoporotic pain and its pharmacological treatment R. Vellucci 1 & R. Terenzi 2 & J. A Kanis 3,4 & H. G. Kress 5 & R. D. Mediati 1 & J.-Y. Reginster 6 & R. Rizzoli 7 & M. L. Brandi 2 Received: 8 January 2018 / Accepted: 6 March 2018 # International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Abstract Osteoporosis, a disorder that affects millions of people worldwide, is characterized by decreased bone mass and microstructural alterations giving rise to an increased risk of fractures. Osteoporotic fractures can cause acute and chronic pain that mainly affects elderly patients with multiple comorbidities and commonly on different drug regimens. The aim of this paper is to summarize the pathogenesis and systemic treatment of osteoporotic pain. This narrative review summarizes the main pathogenetic aspects of osteoporotic pain and the cornerstones of its treatment. Osteoporotic fractures induce both acute and chronic nociceptive and neuropathic pain. Central sensitization seems to play a pivotal role in developing and maintaining chronicity of post-fracture pain in osteoporosis. Antiosteoporosis drugs are able to partially control pain, but additional analgesics are always necessary for pain due to bone fractures. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors reduce acute pain but with a poor effect on the chronic neuropathic component of pain and with relevant side effects. Opioid drugs can control the whole spectrum of acute and chronic bone pain, but they differ with respect to their efficacy on neuropathic components, their tolerability and safety. Chronic pain after osteoporotic fractures requires a multifaceted approach, which includes a large spectrum of drugs (antiosteoporosis treatment, acetaminophen, NSAIDs, selective COX-2 inhibitors, weak and strong opioids) and nonpharmacological treatment. Based on a better understanding of the pathogenesis of osteoporotic and post-fracture pain, a guided stepwise approach to post-fracture osteoporotic pain will also better meet the needs of these patients. Keywords Analgesic treatment . Chronic pain . Opioids . Osteoporotic fracture pain . Osteoporotic pain mechanism . Osteoporotic pain treatment

* M. L. Brandi [email protected] 1

Palliative Care and Pain Therapy Unit, University Hospital of Careggi, Florence, Italy

2

Department of Surgery and Translational Medicine, University of Florence, AOU Careggi Largo Brambilla n.3, 50134 Florence, Italy

3

Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK

4

Institute for Health and Ageing, Catholic University of Australia, Melbourne, Australia

5

Department of Special Anaesthesia and Pain Medicine, Medical University/AKH of Vienna, Vienna, Austria

6

University of Liège, Liège, Belgium

7

Service of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, 1211 Geneva 14, Switzerland

Introduction According to the World Health Organization (WHO), osteoporosis is described as a systemic skeletal disease characterized by decreased bone mass and altered microarchitecture of the bone tissue, leading to enhanced bone fragility and risk of fractures [1]. Bone loss is asymptomatic and progresses without pain and other symptoms until the occurrence of a fracture. It is estimated that almost 30 million people in Europe suffer from osteoporosis [2]. Fragility fractures are the most feared and frequent complications of osteoporosis: In 2010, the number of new fractures in Europe was estimated to be 3.5 million [2]. Fragility fractures are usually characterized by acute and chronic pain that is generally not controlled by anti-osteoporosis drugs (Table 1). Sensory nerve fibres do not appear to decline with

Oral 150 mg/month; i.v. 3 mg i.v. 5 mg/year

Ibandronate

Raloxifene

SERM

Anti-RANKL antibody Denosumab

Oral 60 mg/day

s.c. 60 mg/every 6 months

Oral 35 mg/week; oral 75 mg/2 tbs/month

Risedronate

Zoledronate

Oral 70 mg/week

Alendronate

Nitrogen-containing bisphosphonates

Route of administration and dose

+

1. Prospective, uncontrolled, multicentre, observational study; treatment with raloxifene for 6 months; 3299 adults, postmenopausal osteoporotic women, mean age 67.6 years (89.4%: reduced bone mineral density, 39.8%: pre-existing fractures and 93.4%: skeletal pain). Median pain intensity on VAS was 66.0 mm [8]

1. Retrospective, uncontrolled, single-centre study; 80 patients treated with denosumab or alendronate after recent vertebral fracture due to osteoporosis (10 men, 70 women) [6] 2. Observational, uncontrolled, single-centre prospective study; 60 women with post-menopausal osteoporosis related to glucocorticoids therapy (30 patients) or not (30 patients) treated for 12 months with denosumab [7]

International, multicentre, randomized, double-blind, placebo-controlled trial (HORIZON); subjects randomly assigned to receive either i.v. administration of zoledronate 5 mg/year or placebo; 285 postmenopausal osteoporotic women (zoledronate group, mean age 73.4 years), 277 postmenopausal osteoporotic women (placebo group; mean age 73.1 years) [5]

+

+

No studies

A randomized controlled trial; treatment with alendronate (35 mg/week for 6 months) compared to elcatonin (i.m. 20 units/week); 97 adults, postmenopausal osteoporotic women with back pain, mean age 79.8 years, range 60–96 years [3] Prospective study; treatment with risedronate for 4 months; 27 adults, postmenopausal osteoporotic women, mean age 70.6 years, range 58–83 years, with low back pain, without acute or chronic vertebral fractures of the thoracic and lumbar spine [4]

Type study

Bone pain effects in osteoporosis

+

+

+

Anti-vertebral fracture efficacya

Antiosteoporosis drugs and their effects on fracture risk and bone pain

Antiresorptive drugs

Type drug

Table 1

1. Raloxifene treatment was associated with a marked reduction of skeletal pain and analgesic consumption and an improvement in subjective sleep quality. After 6 months of raloxifene treatment, the frequency and intensity of pain and use of analgesics for skeletal pain decreased consistently by approximately 50%. The median decrease in pain intensity from baseline to 6 months was 27.0 mm (46%) [8]

1. Pain relief was obtained at a mean of 3.3 weeks with denosumab and 5.4 weeks with alendronate [6] 2. Denosumab treatment gave a substantial decrease in bone pain at month 12 in both group of patients. The effect was present also in patients with prior osteoporotic fracture [7]

Treatment with zoledronate over 3 years was associated with improvements in specific domains of quality of life (using OQLQ) versus placebo, particularly in patients sustaining incident fractures, with significant differences favouring zoledronate in pain, and standing pain [5]

An improvement was described after risedronate treatment in low back pain, evaluated with the assessment of the VAS score, RDQ, and SF-36 A decrease in serum and urinary NTx was associated with improvement of low back pain [4] No studies

Alendronate suppressed bone turnover, reduced back pain, and improved QOL (SF-8) more markedly than elcatonin [3]

Results

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20 mcg/day

Route of administration and dose

+

Anti-vertebral fracture efficacya

2. Raloxifene group effect greater than other group was more evident by EAM than VRS and during months 3–6 than for 1–2 months. Raloxifene group appeared to be more effective on the bone and joint pain than other group in postmenopausal women according to both EAM and VRS measurements [9]

2. Pilot study; 24 adults (postmenopausal women with back and/or knee pain, with osteoporosis and/or osteoarthritis) randomly divided into two groups, to be treated with 60 mg raloxifene and 1 mcg alfacalcidol/day, or 1 lg alfacalcidol alone/day, respectively, for 6 months. Pain following KL by standing up from a chair and bending the knee by squatting, KSL by walking horizontally and ascending and descending stairs, and by lying down supine on a bed and leaving the bed to stand was evaluated by EAM, based on measurement of the fall of skin impedance, and a VRS, recording subjective pain on a scale of 0–100 between no pain and unbearable pain [9] Type study 1. A secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial; treatment with teriparatide 20 mcg/day (n = 541 subjects) or placebo (n = 544 subjects) for a median of 19 months; postmenopausal osteoporotic women with prevalent vertebral fractures [10] 2. Prospective, multinational and observational study; treatment with teriparatide 20 mcg/day for up to 18 months and followed up for a further 18 months; 1161 postmenopausal osteoporotic women pre-treated with bisphosphonates (median duration 36 months). Data on prior bisphosphonate use, clinical fractures, back pain VAS and HRQoL (EQ-5D) were collected over 36 months [11]

2. Significant reductions in back pain and improvement in HRQoL were described for up to 18 months of teriparatide treatment; these outcomes were still evident for at least 18 months after teriparatide was discontinued [11]

1. Teriparatide-treated women had reduced risk for moderate or severe back pain, severe back pain and back pain associated with vertebral fractures (57)

Results

Results

Type study

Bone pain effects in osteoporosis

tbs tablets, + anti-fracture efficacy described, i.v. intravenous, s.c. subcutaneous, i.m. intramuscular, QOL quality of life, SF-8 Short-Form Health Survey, VAS visual analogue scale, RDQ Roland Morris Disability Questionnaire, SF-36 Short Form-36, NTx N-terminal telopeptide of type I collagen, HORIZON The Health Outcomes and Reduced Incidence with Zoledronic acid ONce, OQLQ miniosteoporosis quality of life questionnaire, KL knee loading, KSL knee and spine loading, EAM electroalgometry, VRS visual rating scale, HRQoL health-related quality of life

Osteoformative drug Teriparatide

Antiresorptive drugs

Type drug

Table 1 (continued)

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age, whereas density of bone mass decreases [12]. The occurrence of a fracture induces acute pain determined and maintained by mechanical, inflammatory and also neuropathic components. Very often, acute pain evolves into a chronic pain. Over time, additional mechanisms, e.g. continuous contraction of the para-spinal musculature resulting in fatigued and painful muscles, may contribute to a multifaceted chronic pain syndrome [13]. Vertebral fractures can induce a series of alterations that end up in chronic pain, having great individual and socioeconomic impact. Focusing on spinal fractures, the acute phase is followed by a musculoskeletal chronic pain component and then by a cascade of events characterized by multiple vertebral compressions, dorsal kyphosis, decreased height, exaggerated lordosis, mechanical compression of nerve roots or spinal cord, with the induction of continuous abnormal stress on spinal muscles, facet joints and ligaments [14]. The coexistence of one or more of these factors causes a pain worsened by movement, giving rise to loss of functional capacity, physical disability and low self-esteem. Evaluation of chronic pain after osteoporotic fractures requires a clear understanding of the nature of the pain and its underlying pathophysiology. The identification of the nature of chronic pain of osteoporotic origin should always determine the way to its management.

Mechanisms of bone pain in osteoporosis Until recently, the role of the nervous system in bone homeostasis was poorly understood. Emerging evidence suggests that the nervous system has a pivotal role in modulating bone tissue biology, including the regulation of local blood flow and bone remodelling [15, 16]. The skeleton is densely innervated by the peripheral nervous system (PNS). Predominantly expressed in the bone are the A-delta tropomyosin receptor kinase A (TrkA+) and the peptide-rich calcitonin gene-related peptide (CGRP)-positive fibres. A-beta or unmyelinated peptide-poor C-fibres are less expressed [12, 17]. These neurones are not only well expressed in the skeleton, but their number is more or less stable through life, leading to a higher innervation of these structures as the bone mass decreases with aging [12]. The complex neural texture present in the bone directly contributes to bone homeostasis and remodelling, participating in both catabolic and anabolic bone metabolism. In healthy bone, the crucial balance between osteoblastic and osteoclastic activity is under the control of many local and general factors, but in osteoporosis, osteoclastic activity is prominent [18–22]. Osteoclasts degrade bone mineral by secreting protons through the vacuolar H+-ATPase, creating an acidic microenvironment. An acid microenvironment activates transient potential vanilloid receptor type 1 (TRPV1)

channels that are widely expressed in peripheral sensory neurones [23, 24]. TRPV1 receptors activate peripheral bone nociceptors inducing pain and neural sensitization. On the other hand, neural TRPV1 activation induces peripheral neuropeptide release, such as CGRP or substance P, that promotes bone degradation [25–28]. These observations suggest that PNS is not only a generator of bone pain but directly modifies bone homeostasis when catabolic metabolism is prevalent. Metastatic bone disease, osteoporosis, osteogenesis imperfecta (OI) and Paget’s disease of bone (PDB) are all pathologies characterized by increased osteoclast activity. In these disorders, the increased osteoclast activity is mainly related to an alteration of the balance of receptor activator of nuclear factor K ligand (RANK-L) and osteoprotegerin (OPG) pathway, resulting in an increased RANK-L. Increased levels of RANK-L could be caused by immune system production or aberrant production by altered cells, like neoplastic clones. Neoplastic cells may also directly inactivate OPG with a consequent enhanced osteoclastic activity and bone pain [29–31]. Thus, tumours characterized by low expression of OPG, such as multiple myeloma, are commonly associated with bone pain. Conversely, diseases with normal or enhanced levels of OPG, such as Hodgkin’s and non-Hodgkin’s lymphoma, are associated with minimal bone pain [32, 33]. Table 2 summarizes the mechanisms behind the genesis and maintenance of pain in osteoporosis.

Development of chronic bone pain Our knowledge about the role of central sensitization in chronic skeletal pain is limited. Central sensitization results from persistent nociceptor input, which can trigger a prolonged increase in the excitability and the functional status of dorsal horn neurones and central nociceptive pathways. This involves the spinal release of substance P,

Table 2

Underlying mechanisms of pain in osteoporosis

Bone mass declines with age, whereas the density of sensory nerve fibres does not: as a result the ‘density’ of bone innervation relatively increases Peripheral and central sensitization processes play a significant role in the development of chronic bone pain Bone nociceptors are modified and sensitized by lowering pH, by cytokines, substance P, CGRP, VIP and NP-Y, and other mediators Neuropeptides influence bone microstructure and the regulation of local bone turnover By their involvement in nociception, inflammation, angiogenesis and cellular proliferation neuropeptides contribute to the progress of painful osteoporosis

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the activation of N-methyl-D-aspartate (NMDA) receptors, and prostaglandin production in both neurones and microglial cells of the CNS. Particularly when the nociceptive fibres conduct a repetitive and high-frequency impulse, the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors causes a strong depolarization of the plasma membrane and NMDA, leading to a prolongation and amplification of neuronal responses. The activation of NMDA receptors initiates translational changes of the second-order neurones, which may contribute to the development of chronicity of pain [34]. After the onset of activation of this functional cascade, a morphological remodelling of neuronal architecture gives rise to the transition from acute pain to a chronic pain state. A peripheral bone lesion such as an osteoporotic fracture generates centripetal persistent and strong input of pain impulses to the neurones of the spinal dorsal horn. Together with the blockade of inhibitory interneurones that are responsible for modulating spinal synaptic transmission leads to an enhanced nociceptive input towards the brain. Interestingly, osteoporotic fractures of the radius bone are frequently complicated by complex regional pain syndrome (CPRS), which is a disease characterized by central sensitization and consequent neuropathic pain [35]. Moreover, pathologic conditions characterized by central sensitization and widespread pain, like fibromylagia, seem to be a risk factor for consequent central sensitization and neuropathic pain after bone fracture, as demonstrated by a higher incidence of CPRS in these patients [36]. In this process, also activated glial cells further contribute to the development of neuropathic pain [37]. Spinal glial cell activation has been shown to have a substantial role in the development and maintenance of central sensitization by their release of proinflammatory mediators, which cause excessive stimulation of the spinal cord grey matter and produce sensory disturbances typical of neuropathic pain. In the development of chronic pain, two major nociceptive neuronal mechanisms are involved: modulation and modification. Modulation refers to a reversible change in excitability of nociceptive peripheral and central neurones mediated by post-translational modifications of various receptors and ion channels by the activation of intracellular signal-transduction cascades. Modification represents long lasting changes in gene expression of transmitters, receptors and ion channels or in the structure, connectivity and survival of neurones, altering normal stimulus-response characteristics [38]. A better understanding of changes that generate and maintain central sensitization would expand our ability to develop targeted therapies for the treatment of chronic pain resulting from many types of originally acute skeletal pain. This is of particular importance, as injury to the skeleton seems to be a stronger generator of central sensitization than damage of skin or muscles [39].

Psychological factors influencing chronic bone pain In the previous paragraph, we confronted the mechanism of transition from acute pain to chronic pain, but this progression also involves, unquestionably, psychological factors. Scientific evidence demonstrates how psychological factors were prominent in the transition from acute to chronic pain. Fear and anxiety-related experiences, such as catastrophizing, were especially significant in exacerbating pain perceptions [40]. A correct assessment and treatment of chronic bone pain require an understanding of psychological factors related to and/or precipitating the pain experience. Chronic pain patients with spine disease often live a complex psychological experience characterized by anxiety, depression, central fatigue, cognitive dysfunction, decline in social functioning and addiction risks. Perception of chronic pain, over time, could cause modification of brain structure, including loss of grey matter [41]. Treatment planning could start including management of psychological problems. A precise psychological assessment of osteoporotic patients with bone fractures is also important because many of these patients could be suitable for invasive interventions, including vertebral augmentation and implantation of devices for pharmacologic neuromodulation. The comprehension of the psychological state of the patient with a pain disorder could help us understand the factors which might adversely influence the efficacy of these invasive therapies, as well as identify risk factors which may impede outcomes. Many studies have documented that psychological factors and psychiatric disease could thwart invasive pain therapies. Moreover, an eventual failure of the invasive pain treatment could increase disability, progression of disease, negative emotions and litigation.

Medical treatment of chronic osteoporotic pain According to the World Health Organization (WHO), analgesic choices should be determined not only by the pain intensity [42] but also by the type of pain. In this context, analgesic treatment of osteoporotic fractures should provide sufficient pain relief with drugs administered at scheduled intervals throughout the day, according to their half-lives and duration of action of the different formulations. Moreover, the analgesics should be easy to administer, preferably by mouth, customizable to the needs of the individual patient. As osteoporosis is predominantly a condition of elderly women, characterized by their multiple comorbidities, a multifaceted approach [43] and concomitant pharmacological treatments for these conditions have to be considered. Table 3 describes the ten key points for good medical management of osteoporotic pain.

Osteoporos Int Table 3

Medical treatment of chronic osteoporotic pain: ten key points

Osteoporosis affects elderly with cardiovascular disease and age-related decline in renal function, also taking multiple medications The analgesic treatment should prevent the onset of pain with drugs administered at scheduled intervals throughout the day The analgesics should be easy to administer, preferably by mouth, customizable to the needs of patient The treatment of mild to moderate musculoskeletal pain is achieved by either paracetamol/acetaminophen or its combination with codeine or tramadol (WHO step II) NSAIDs including selective COX-2 inhibitors are effective in bone pain but have limitations in their dosage and duration of treatment due to adverse events Opioids are a mainstay in the treatment of OP patients with moderate to severe pain (WHO step III) Opioids are suitable for those elderly with gastrointestinal and cardiovascular comorbidities, when NSAIDs and selective COX-2 inhibitors are to be avoided All osteoporosis drugs can contribute to pain control All osteoporosis drugs act as analgesic compounds by preventing vertebral fractures There is no single ideal drug to treat pain in osteoporosis, but it is necessary to develop a multimodal clinical strategy to adequately reduce both pain and suffering

Do anti-osteoporosis drugs reduce bone pain? All drugs registered for the treatment of osteoporosis influence bone metabolism with a possible benefit for the patient’s bone pain. The anti-osteoporosis drugs can act on pain related to bone resorption and restoration of normal bone structure (Table 1). Consequently, pain represented one of the main clinical endpoints in registration trials for anti-osteoporosis drugs [44].

Calcitonin Many reports have been published on the role of calcitonin in bone pain, but the drug is no longer available in all European countries for this indication. Calcitonin was used in the past to treat acute and chronic pain in various metabolic bone diseases, such as osteoporosis and consequent fragility fractures, PDB and skeletal metastases from malignancies. In a systematic review and meta-analysis, Knopp-Sihota et al. evaluated randomized, placebo-controlled trials (RCTs) on the analgesic efficacy of calcitonin for pain due to osteoporotic vertebral compression fractures [45]. The authors did not find any convincing evidence to support the use of calcitonin for chronic pain associated with older vertebral fragility fractures [45], although calcitonin has proven efficacy in the management of acute back pain associated with a recent vertebral fragility fracture. Despite these inconclusive results, the potential role of calcitonin, as a hormone, in the control of bone pain remains an interesting question for a number of reasons. Firstly, side

effects of calcitonin are mild, with gastro-intestinal tract complains and flushing reported most frequently and considered minor and self-limiting. Secondly, calcitonin acts as an antiresorptive and thus could be a useful model to be compared with other antiresorptives (i.e. bisphosphonates) known to control bone pain. Thirdly, both in animal models and in humans, similarities have been reported between calcitonin and morphine-induced analgesia, with elevation of plasma beta-endorphin levels, proposing a potential peripheral involvement of the endogenous opiate system [46]. Moreover, two additional hypotheses for the analgesic mechanism of action of calcitonin describe a peripheral mechanism via prostaglandin and thromboxane and a central action mediated by calcitonin receptors in the brain [47–49]. Although currently not used in the therapy for osteoporosis, further studies on the various analgesic mechanisms of calcitonin could help to uncover the more general mechanisms of bone pain and its control.

Bisphosphonates Aminobisphosphonates, such as alendronate, risedronate, ibandronate and zoledronate, all registered for the therapy of osteoporosis, have been extensively used to treat bone pain in patients with fragility vertebral fractures, PDB, bone pain related to malignant metastases, polyostotic fibrous dysplasia, osteogenesis imperfecta and complex regional pain syndrome (CRPS) I. One observational study [4] and two RCT [3, 5] studies report an analgesic effect of aminobisphosphonates in postmenopausal women with osteoporosis. The mechanism by which these compounds influence bone pain appears to be associated with a decrease of bone metabolic turnover, suggesting that bone resorption due to high-turnover osteoporosis may cause bone pain.

Denosumab Denosumab is an IgG2 monoclonal antibody with high affinity for human RANK-L and acts as an antiresorptive drug able to prevent fractures in postmenopausal women with osteoporosis [50]. Denosumab modified bone pain in different clinical settings. Firstly, denosumab prevented both vertebral and appendicular fragility fractures due to its potent antiresorptive effects that could also be the basis for the control of pain related to bone resorption. Secondly, significant improvement of bone pain has been shown in studies with cancer patients treated with denosumab [51–53], with a higher potency compared to zoledronic acid [53]. Thirdly, pain has been shown to disappear in fibrous dysplasia patients treated with denosumab [54]. Unfortunately, the role of denosumab to manage osteoporotic pain has not been adequately evaluated in controlled clinical trials. Two observational studies showed

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promising results: a retrospective, single-centre study in 80 patients (10 males, 70 females) with recent osteoporotic vertebral fractures showed a more complete and faster pain relief in the denosumab-treated group compared to the alendronate treatment [6]. In a prospective, observational second study, denosumab significantly reduced bone pain in patients with and without glucocorticoid-related osteoporosis (average percentage of pain reduction 53.6 and 56.2%, respectively). The analgesic effect of the drug was notable in patients with or without prior bone fracture due to osteoporosis [7].

Selective oestrogen receptor modulators Commonly used therapeutic agents for osteoporosis are the selective oestrogen receptor modulators (SERMs), such as raloxifene and bazedoxifene [55, 56]. An observational study reported that raloxifene alleviate pain in patients with osteoporosis, decrease analgesic consumption and improve quality of sleep [8]. Raloxifene also appeared to be effective on bone and joint pain in postmenopausal women with osteoporosis and/or osteoarthritis [9].

Teriparatide Teriparatide is an anabolic drug for osteoporosis that was shown in the Fracture Prevention Trial (RCTs) to reduce the risk of new vertebral fractures and to reduce moderate or severe back pain [10, 57]. Since pain reduction was associated with fewer new vertebral fractures, this was suggested to be the mechanism for the analgesic effect of teriparatide. In separate meta-analytic [58] and open label [59]studies patients randomized to teriparatide had a reduced risk of new or worsening back pain compared to patients randomized to placebo, hormone replacement therapy or alendronate. The fact that teriparatide increases both bone formation and bone resorption rises the question of the supposed mechanism of action of antifracture agents on bone pain. It is also noteworthy that—while teriparatide has been shown to reduce the overall risk of back pain—large RCT of antiresorptive drugs have generally not reported results on back pain [60–62]. Even though the analgesic effect of teriparatide on back pain may be explained via the prevention of vertebral fractures, the acceleration of fracture healing seen with teriparatide can offer alternative explanations for an effect of anabolic agents on pain, namely the healing and stabilization of pre-existing vertebral fractures [58].

Acetaminophen, NSAIDs and selective COX-2 inhibitors in osteoporotic patients Data from a meta-analytic study suggest that acetaminophen is a suitable first-line therapy for the treatment of mild to

moderate musculoskeletal pain [63]. However, the actual role of acetaminophen in the treatment of chronic musculoskeletal pain is often limited due to its weak analgesic and antiinflammatory potency. Superior long-term safety of acetaminophen, however, is much less controversial, because of major concerns on significant cardiovascular harm with all NSAIDs [64]. Observed synergy between acetaminophen and NSAIDs suggests different analgesic mechanisms [64]. Analgesia derives mainly from its spinal and supraspinal, and to much lesser extent from peripheral mechanisms of action [64]. In addition to weak effects on COX-2, the endogenous opioid, cannabinoid and serotonergic systems seem to be involved [64], because specific inhibitors of these neurotransmitters attenuated the antinociceptive effect of acetaminophen. The active acetaminophen metabolite AM404 is another potential supraspinal analgesic mechanism, as this brain-specific lipoaminoacid inhibits prostaglandin production and allodynia in rats, acting through TRPV1-dependent Cav 3.2 current inhibition [64]. With these pharmacological characteristics, any nociceptive mild-to-moderate bone pain without signs of acute inflammation is an indication for oral acetaminophen. For such indications, acetaminophen is licensed for a maximum daily dose of 3000 or 4000 mg, depending on the respective country [64]. NSAIDs including selective COX-2 inhibitors are suitable for short-term treatment of patients with bone pain, but these non-opioid drugs often poorly control the neuropathic pain component that has a pivotal role in chronic bone pain [63]. Moreover, the safety of NSAIDs, including selective COX-2 inhibitors, has been regularly reviewed by European authorities over the past years. These reviews confirmed that NSAIDs as a class are associated with increased risk of thromboembolic events in patients with heart or circulatory diseases or certain cerebrovascular risk factors, particularly if used at high doses. The risk is similar for NSAIDs including selective COX-2 inhibitors, estimated for diclofenac at around three additional major vascular events per 1000 participants and year [64, 65]. The selective COX-2 inhibitors significantly increased the risk of major vascular events by about one third, inducing a 75% rise in the risk for major coronary vascular events [65]. All NSAIDs doubled the risk of heart failure, requiring hospital admission and increased the risk of upper gastrointestinal complications by around two to four times [65]. In the UK, the numbers of NSAID-related deaths are higher than those for asthma or cervical cancer. These facts suggest caution in the use of NSAIDs and force us to re-evaluate our practice with these molecules by limiting the dosage and duration of treatment [66]. A boxed warning of this risk is already in place, and the product

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information for all NSAIDs and selective COX-2 inhibitors recommends these analgesics to be used at the lowest effective dose and for the shortest period of time necessary to control symptoms [66]. Not many reports are found in the literature about acetaminophen in this respect, and there is no robust clinical evidence for any relevant potential cardiovascular or cerebrovascular harm associated with acetaminophen [64]. Finally, some evidence from animal models suggests that ibuprofen or selective COX-2 inhibitors may slow down the bone healing process after a fracture [67], although convincing confirmatory human data on the effects of NSAIDs and selective COX-2 inhibitors on bone healing processes are still missing. As a consequence, other analgesic options, like weak or strong opioids or antidepressants, will become suitable alternatives in the treatment of patients with moderate to severe bone pain, especially for elderly patients with major gastrointestinal and cardiovascular risks that often exclude at least the long-term use of NSAIDs and selective COX-2 inhibitors [64, 66].

Gabapentinoids and serotonin–norepinephrine reuptake inhibitors in osteoporotic patients Gabapentinoids and serotonin–norepinephrine reuptake inhibitors (SNRIs) belong to two different neuro-active classes of drugs with a demonstrated efficacy in chronic pain conditions. Gabapentinoids are a class of drugs that are derivatives of the GABA neurotransmitter, which block α2δ subunit-containing voltage-dependent calcium channels, exerting a neural membrane stabilizer effect. The most important molecules of this class are Gabapentin and Pregabalin, which are widely used to treat chronic neuropathic pain. There is no current evidence on the efficacy of gabapentinoids in the treatment of osteoporotic pain, but there are interesting data on other types of bone pain. A recent meta-analytic study demonstrated that gabapentinoids reduce post-operative pain following spinal surgery, also exerting an opioid-sparing effect [68]. Nevertheless, a recent study in animal models suggested that therapy with gabapentinoids may significantly reduce total bone mass [69]. Duloxetine and Milnacipran are two of the main SNRIs used to treat chronic disease characterized by widespread pain with neuropathic components, like fibromyalgia. Despite the efficacy of SNRIs in these chronic pain conditions, there are no data about their use in the treatment of osteoporotic pain. Moreover, evidence from longitudinal, cross-sectional, and prospective cohort studies suggests that the use of SNRIs at therapeutic doses is associated with decreased bone mineral density and increased fall and fracture risk [70].

WHO analgesic ladder step II and step III opioids WHO step II The combination of the weak opioids tramadol or codeine with non-opioids like NSAIDs or acetaminophen is considered the next step for the pharmacological management of moderate to severe osteoporosis-associated pain [64]. For adults, codeine and codeine combination analgesics are available in many countries. The analgesic effect mainly results from hepatic metabolism to morphine and morphine-6-glucuronide [64]. Normally, 5 to 10% of codeine are converted to morphine, and a dose of 30 mg codeine phosphate is considered equivalent to 3 mg morphine. The capacity to metabolize codeine to its active metabolites, however, varies genetically between individuals, with up to 10% of Caucasians, 2% of Asians and 1% of Arabs being ‘poor metabolizers’ [64]. In these individuals, codeine is an ineffective analgesic. A few individuals are ‘extensive metabolizers’ and are able to convert more of the codeine to morphine, putting them at increased risk of toxicity from standard doses [64]. The synthetic WHO step II analgesic drug tramadol has a mild inhibitory effect on neuronal serotonin and noradrenaline re-uptake and is metabolized to a weak μ-receptor agonist [71]. Tramadol is particularly suitable for mild-to-moderate pain in elderly patients, including those with musculoskeletal and neuropathic pain. Meta-analytic studies suggested that tramadol is generally safer and better tolerated than other opioids and is therefore often the agent of choice for patients with moderate bone pain, including pain related to fragility fractures [72]. Consequently, tramadol alone or its combination with acetaminophen has gradually replaced codeine as a WHO step II analgesics. The acetaminophen plus tramadol combination has clearly shown superior and longer lasting analgesic effects compared to the same dose of tramadol or acetaminophen alone [72].

WHO step III Only when pain worsens, patients may need to be switched to a WHO step III analgesic [73]. In chronic pain, the oral route is still the preferred route of analgesic administration as long as a patient is able to take oral medication [74, 75]. Longacting, oral or transdermal slow release (SR) formulations of opioids with 24 h around-the-clock dosing provide more consistent pain control, low risk of addiction or abuse and improved adherence [76].

Oral morphine Oral morphine is still considered the ‘standard’ step III opioid [76] and has been placed by WHO on its Essential Drug List.

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It has, however, a poor oral bioavailability of 20 to 30% and is metabolized in the liver generating three pharmacologically active metabolites: (1) morphine-6-glucuronide (M6G), a potent analgesic, (2) morphine-3-glucuronide (M3G), which is not analgesic but has neuroexcitatory properties and potentially causes hyperalgesia or allodynia, and (3) nor-morphine, which is also analgesic. The real difficulty in the use of oral morphine is due to the hepatic first-pass metabolism, which could cause rather unpredictable analgesic or even toxic effects in the long-term. Moreover, duration of analgesia or risk of adverse events increases with age, and morphine plasma levels are 15% higher in those older than 65 years [74].

Oral oxycodone The oral semisynthetic opioid oxycodone is clinically about 1.5 to 2 times more potent than morphine [13]. Compared to morphine, oxycodone has a high oral bioavailability of between 60 and 87%. SR and immediate-release (IR) formulations are available, the latter also combined with acetaminophen. The oxycodone-naloxone combination (OXN) combines prolonged-release (PR) oxycodone and PR naloxone at a ratio of 2:1, with the intention to counteract opioid-induced constipation. Several RCTs with OXN demonstrated the same analgesic efficacy as with oxycodone alone, but significantly less constipation [13].

Oral hydromorphone Hydromorphone is a semisynthetic opioid with an average oral bioavailability of 50%. The analgesic potency of oral hydromorphone is about five to seven times that of morphine [13]. In contrast to morphine, hydromorphone has no free 6hydroxyl group and therefore does not produce an active 6glucoronide metabolite that could accumulate in patients with renal insufficiency.

Oral methadone Methadone is a synthetic opioid, used primarily as a substitution treatment for heroin addicts. Methadone is characterized by a large inter-individual variation in pharmacokinetics and by a rapid and extensive distribution phases (half-life of 2–3 h) followed by a rather slow elimination phase. This particular pharmacokinetic profile may cause severe accumulation problems. Methadone represents a difficult to handle alternative to other opioids. Much caution is needed in its administration, and therefore its use should be reserved for experienced pain specialists.

Oral tapentadol Tapentadol is an oral innovative, centrally acting analgesic that combines two distinct mechanisms of action within one molecule, μ-opioid receptor agonism (MOR) and noradrenaline re-uptake inhibition (NRI) [77]. Data from RCTs and observational studies demonstrated that the synergistic interaction of the two combined effects (MOR-NRI) offers particular and significant advantages in terms of efficacy and tolerability in a broad range of musculoskeletal chronic pain conditions, like osteoarthritis and low back pain [78–80]. The analgesic properties of tapentadol reside in a single enantiomer and do not require metabolic activation [77]. The good safety profile is ascribed to low plasma protein binding of the drug and no relevant interactions with enzymes of the cytochrome P450 system [81]. Compared to morphine CR [82] or oxycodone CR [78], tapentadol showed a better tolerability profile with less treatment discontinuations due to fewer opioid-induced side effects thanks to the contribution of the NRI component to its analgesic effects [77–80]. The noradrenergic mechanism of tapentadol has an opioid-sparing effect, which significantly reduces gastrointestinal adverse effects compared to traditional opioids (e.g. constipation, nausea and vomiting). RCTs and observational studies have consistently demonstrated good efficacy and tolerability of tapentadol prolonged release (PR) tablets (100–250 mg bid) in the management of moderate-to-severe chronic osteoarthritis and low back pain [83, 84]. Moreover, a Cochrane review suggested a sustained efficacy of tapentadol PR in managing cancer-related pain comparable to oxycodone PR or morphine SR [85]. More important in the context of pain management for osteoporosis is the fact that tapentadol is characterized by only minor effects on the endocrine system and on sex hormones in particular. It should therefore be an ideal central analgesic drug for long-term pain control of osteoporosis patients with fragility fractures.

Transdermal buprenorphine Buprenorphine is a highly lipophilic, low molecular weight, semi-synthetic opioid derived from thebaine. Data suggest an action on the ORL-1 receptor, responsible for the ceiling effect and for the bell-shaped dose-response curve [86]. The activation of the ORL-1 receptor is known to reduce the rewarding a c t i o n s o f m o r p h i n e , c u r b i n g d r u g d e p e n d e n c y. Buprenorphine could be effectively and safely combined with full μ-agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses [87]. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction [87]. In addition, the risk of respiratory depression is lower with buprenorphine than with other opioids [88]. Unlike morphine and fentanyl, buprenorphine shows no immunosuppressive

Osteoporos Int

activity at therapeutic analgesic doses. Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous analgesic effects for up to 96 h in patients that are unable to swallow, to tolerate oral opioids or are at-risk patients, such as diabetics, elderly or renally impaired individuals.

Transdermal fentanyl Fentanyl is 100 times as potent as morphine and is a highly lipophilic, short-acting opioid derivative of meperidine. The hepatic metabolism does not produce active metabolites, and the inactive metabolites are mainly excreted in the urine. A transdermal therapeutic system (so-called fentanyl patch) provides 72 h systemic drug delivery through the skin. Concomitant use of CYP3A4 inhibitors may result in higher plasma fentanyl concentrations and increased adverse drug effects [13].

Risks of opioid treatment in patients with osteoporosis Animal models have shown the presence of opioid receptors on osteoblasts and human osteoblast-like cells MG-63 [89]. Opioids significantly reduce osteocalcin synthesis (OS), which is a marker of osteoblast activity [90]. Decreased serum osteocalcin levels were also detected in heroin and cocaine abusing pregnant women [91]. Obviously, some opioids increase the risk of fractures by their direct and indirect effects on bone metabolism: (a) through direct interaction with opioid receptors on osteoblasts and (b) by the interference with the complex mechanisms that physiologically regulate bone turnover [90]. Moreover, osteoporosis is a typical consequence of hypogonadism [92], which has been shown to arise from chronic opioid treatment [93]. Chronic opioid treatment can lead to osteoporosis, infertility and increased cardiovascular risk, and may contribute to depressed mood and diminished libido by acting on the hypothalamic-pituitary-gonadal (HPG) axis [94]. The hormonal consequences of chronic opioid therapy include sexual dysfunction, menstrual anomalies, infertility, decreased muscle mass, osteoporosis and symptoms like fatigue, weakness, depression, hot flashes and night sweats. This syndrome is called opioid-induced androgen deficiency (OPIAD) [95], and its prevalence in patients taking chronic opioid therapy is around 90%. Chronic opioid treatment can also affect the hypothalamicpituitary-adrenal axis (HPA), but these opioid effects are not as well investigated as those on the HPG axis. Main contributor to hypoadrenalism is a reduced level of corticotropinreleasing hormone (CRH), which is strongly inhibited by opioids [96], and as a consequence, the ACTH secretion from the

pituitary gland is reduced. Opioids affect, in a dose-related manner, the capacity of the pituitary gland to respond to CRH and thus interfere with the adrenal production of cortisol and dehydroepiandrosterone (DHEA), even independently from any CNS downregulation [96]. The effects of opioids on HPG and HPA axis are schematized in Fig. 1. The true risk of bone fracture remains unclear in the population of patients affected by opioid-induced endocrinopathy. Interestingly, there are significant differences in the relative fracture risk associated with different opioids. Fentanyl has a high risk with an odds ratio of 2.23, the risk with tramadol or morphine is slightly lower, but buprenorphine has the lowest relative fracture risk showing an odds ratio below 1. In this context, the new opioid drug tapentadol could represent a favourable choice [97]: Whereas single-dose morphine IR (30 mg) markedly reduced the testosteron and lutenizing hormone levels in healthy males, equianalgesic doses of tapentadol IR (50 and 100 mg) did not differ from placebo. These promising results in volunteers have been confirmed by serum testosterone measurements in male patients that were randomly treated either with oxycodone CR 20 mg or with an equianalgesic doses of 100 mg tapentadol PR. In addition, all centrally active drugs can provoke fallrelated injuries in osteoporotic elderly patients. Falls may be evoked by intrinsic or extrinsic risk factors. Intrinsic risks are functional impairment or balance disorders, which are common in frail elderly osteoporotic patients. The extrinsic risks are often linked to adverse drug reactions during treatment. Studies have documented a clear relation between the incidence of falling and the number of drugs used. Drugs with CNS side effects, such as benzodiazepines, antidepressants, neuroleptics, anticonvulsants and opioids, are well known to increase the risk of fall-related injuries and fractures. Typically, CNS effects of opioids occur when starting an opioid therapy or during and immediately after substantial dose escalation. Although tolerance development relieves most CNS symptoms, they can persist over long time in people with comorbidities, such as dementia, or in those who receive other sedating medications.

Stepwise approach for analgesic therapy of patients with osteoporosis and fragility fractures Medical management of chronic pain in osteoporosis patients with fragility fractures could be challenging. Long-term treatment with acetaminophen at scheduled doses is effective in patients with only mild pain. In such clinical setting, a shortterm combination with NSAIDs, particularly with selective COX-2 inhibitors, may represent a valuable therapeutic choice. Nevertheless, patients with fragility fractures and moderate pain should be good candidates for WHO step II

Osteoporos Int

Hypothalamus – Anterior Pituitary

HyphothalamicPituitary-Adrenal Axis Corticotropin-releasing Hormone (CRH)

HyphothalamicPituitary-Gonadal Axis Gonadotropic-releasing Hormone (GnRH)

Metabolic Effects

Reproduction Opioids (-)

Follicle-stimulating Hormone and Luteininzing Hormone

Sex Hormones

Opioids (-)

Adrenocorticotrophic Hormone

Cortisol

Fig. 1 Schematic inhibitory effects of chronic opioid treatments on the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axis

analgesics. Long-term therapies with weak opioids, particularly tramadol in combination with acetaminophen, should constitute the standard treatment. Patients with fragility fractures and moderate-to-severe symptoms often need long-term therapy with strong WHO III opioids. As the negative effects on gonadal function differ between various opioids, the choice of the opioid drug can be crucial in the treatment of patients with chronic osteoporosis pain. Men and women are differently affected by the hormonal disturbance caused by opioids. Whereas OPIAD is thought to affect 230,000 to 5 million men who are taking long-term opioid therapy for chronic non-cancer pain in the USA, OPIAD is less frequent in women than in men [94]. A few hours after administration of a single dose of morphine castration levels of testosterone were reached [93]. In contrast, buprenorphine did not reduce the testosterone levels compared to saline injection in animal experiments [93]. These results were confirmed in a clinical trial with transdermal buprenorphine patches. All measured hormones showed only slight changes under buprenorphine during the 6-month observation period in female patients [93], and in both sexes, the hypothalamic-pituitary-adrenal axis was not inhibited [93]. Also for the most recent synthetic, centrally acting analgesic tapentadol with its dual mode of action (MOR-NRI), three randomized, double-blind studies have shown only minor effects on sex hormone concentrations [97]. Buprenorphine and tapentadol turned

out to be efficacious, benign, centrally acting analgesics for moderate to severe osteoporosis pain due to fragility fractures, showing good tolerability and safety profiles with lowest endocrinological effects. In patients still symptomatic for bone pain, or that are unable to take long-standing opioid therapy, vertebral augmentation represents an additional treatment option [98]. Vertebral augmentation may be a useful therapy, especially in elderly osteoporotic patients with many comorbidities and with an increased risk of falling, to avoid further falls with consequent new bone fractures.

Conclusions and clinical implications State-of-the-art treatment of acute and chronic pain in osteoporosis needs a multimodal approach using pharmacological and non-pharmacological (e.g. physiotherapy, mobilization and rehabilitation) therapies in combination with anti-fracture and noninvasive analgesic treatments. According to the WHO analgesic ladder, a stepwise approach includes acetaminophen, NSAIDs or selective COX-2 inhibitors on WHO step I, weak or strong opioids on WHO steps II and III. If conservative treatment of osteoporotic vertebral fractures fails or is strictly contraindicated, vertebral augmentation therapy may represent a further therapeutic option.

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Despite published guidelines and the WHO analgesic ladder, the treatment of acute and chronic pain from osteoporosis remains a true challenge even for the specialist, particularly in the case of vertebral fractures. Although non-pharmacological interventions, such as psychological therapies (e.g. cognitive behavioural therapy) or physiatric approaches, can be useful in the treatment of chronic pain, opioids combined with non-opioid analgesics represent first-line drugs for managing moderate-to-severe pain in patients with osteoporosis-associated fractures. In clinical practice, there is no single ideal analgesic drug to treat every elderly patient with chronic pain caused by osteoporosis. Many opioids potentially induce hormonal changes and reduce bone density; therefore, opioid drugs that are characterized by minor or no effects on the endocrine system, particularly on sex hormones, should be preferred for long-term analgesia in patients with osteoporosis and fractures. For the future, more research is needed on the role of opioid drugs in this context, on strategies to better prevent the unwanted effects of opioid analgesics, and on new central analgesics without potential adverse effects on osteoporosis. Acknowledgments We acknowledge Fondazione F.I.R.M.O. for the support given in the preparation of the manuscript.

Compliance with ethical standards Conflicts of interest Renato Vellucci, Riccardo Terenzi, Rocco Domenico Mediati, Jean-Yves Reginster, René Rizzoli and Maria Luisa Brandi declare that they have no conflict of interest. John A. Kanis reports grants from Amgen, grants from Lilly, grants from Radius Health, other from Meda, grants and other from UCB, outside the submitted work; and John A. Kanis is a member of the National Osteoporosis Guideline Group (NOGG) and the principal architect of FRAX but derives no financial benefit. Hans G. Kress received speaker’s and/or consultancy honoraria from the following pharmaceutical companies: Abbott, Astellas, beneArzneimittel, Berlin-Chemie/Menarini, Bionorica SE, Boehringer Ingelheim, Boston Scientific, CSC Pharmaceuticals, Grünenthal GmbH, IBSA, Linde Group, Medtronic, Mundipharma International, Nevro, Pfizer, Teva ratiopharm and Trigal Pharma.

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