Therapies for osteoporosis have been traditionally based on our understanding of bone cell activities. Bone tissue is constantly being removed and replaced (bone turnover) by osteoclasts which resorb bone and osteoblasts which lay down new bone. Bone turnover is essential for the maintenance of a healthy skeleton by removing or repairing the microscopic damage that results from everyday physical activity.
Therapies for osteoporosis have been traditionally based on our understanding of bone cell activities. Bone tissue is constantly being removed and replaced (bone turnover) by osteoclasts, which resorb bone, and osteoblasts, which lay down new bone. Bone turnover is essential for the maintenance of a healthy skeleton by removing or repairing the microscopic damage that results from everyday physical activity. These processes of resorption and formation are linked or ‘coupled’ so that bone turnover proceeds in an orderly fashion.
When these processes become imbalanced or uncoupled, resorption can exceed formation and bone loss then occurs leading to an increased risk of fractures [1–4]. Traditionally, drugs which reduce osteoclastic activity have been the mainstay of treatment. Thus, agents such as estrogens and bisphosphonates have been widely used with considerable success. Agents that act directly on osteoblasts to increase bone formation are few, with parathyroid hormone (PTH) and PTH-related peptide (PTHrP) analogues being the main ones. However, more recent understanding of bone biology has led to the recognition of cell signalling systems that regulate both osteoclasts and osteoblasts. New therapies are being developed which target these cell signals. Receptor activator of nuclear factor kappa-B ligand (RANKL) plays a key role in the differentiation, activation and survival of osteoclasts. RANKL, which is produced by preosteoblasts and osteoblasts, is a member of the tumour necrosis factor super-family and plays a pivotal role in osteoclastogenesis. Another member of this system is osteoprotegerin (OPG), a soluble receptor for RANKL produced by osteoblasts, which acts in the opposite way by inhibiting RANKL-induced bone resorption.
Antibodies to RANKL have been developed and act as powerful inhibitors of bone resorption [1–4]. A major signalling pathway to the osteoblasts is the Wnt low-density lipoprotein receptor-related proteins (LRP) pathway, which stimulates differentiation of preosteoblasts into mature bone-forming osteoblasts. This signalling pathway has two natural inhibitors, sclerostin and Dickkopf-1 (Dkk-1), and these have become targets for the development of antibodies blocking their actions and hence enhancing the stimulatory signals of Wnt-LRP. Finally, an understanding of the mechanisms by which osteoclasts resorb bone has led to the development of inhibitors of proteases secreted by osteoclasts, thereby inhibiting their resorptive actions without influencing their cell activity or numbers. This potentially avoids a concomitant reduction of osteoblastic activity via the coupling mechanisms, which is normally seen with agents that reduce osteoclastic cell activity .
Osteoporosis is a term used to describe a condition of bone microarchitecture deterioration and subsequent predisposition to fractures. It constitutes a major health problem, affecting millions of people worldwide and is associated with increased morbidity and mortality. The hallmark of osteoporosis diagnosis is low bone mineral density (BMD), usually assessed by dual-energy X-ray absorptiometry (DXA). Although women with the lowest BMD have the highest risk of fracture, the majority of fractures occur in women with osteopenia rather than osteoporosis, highlighting the importance of assessing fracture risk on an individual basis. The decision for treatment should thus be based both on BMD measurement and individual fracture risk profile. Medical history and clinical examination (in order to exclude causes of secondary osteoporosis and estimate fracture risk), taking into account the patient’s age, lifestyle habits (exercise, smoking, alcohol) and specific medications associated with bone loss, should always precede DXA assessment [1,2].
Anti-fall strategies and nutritional measures, including a balanced diet with adequate calcium and vitamin D, should precede any major therapeutic intervention. Interventions which aim at modifying several risk factors associated with falls, such as decreased visual acuity, medications affecting balance, and home environment obstacles such as slippery floors, insufficient lighting and the installation of handrails, are recommended. Furthermore, avoidance of smoking, excessive alcohol and caffeine intake are also helpful in maintaining bone mass.
To gain the best available benefit with anti-osteoporosis medications, optimal calcium and vitamin D intake must be assured. Assessing 25-hydroxy-vitamin D [25(OH)D] levels prior to commencing any major anti-osteoporosis treatment may be prudent if there is suspected deficiency because optimizing vitamin D status may significantly increase the anti-fracture efficacy of osteoporosis treatment . In general, doses >800 IU/day are more effective than lower doses. In patients with severe vitamin D deficiency (<25 nmol/l or <10 ng/ml) high loading doses, i.e. 300 000 IU, may be considered, which correspond to weekly doses of 50 000 IU for 6 weeks, followed by maintenance doses of 800–2000 IU/day. Specific considerations are recommended for special patient groups, such as pregnant or lactating women, obese women, those with malabsorption disorders or receiving corticosteroid or anti-convulsant medication. Regarding obesity, there is an inverse association between 25(OH)D concentrations and BMI or waist circumference, although the exact mechanisms have not been fully elucidated. The decreased bioavailability of vitamin D metabolites in adipose tissue and the reduced sun exposure due to a sedentary lifestyle are the most plausible explanations.
In general, the evidence for anti-fracture efficacy of vitamin D supplementation is weak . However, this seems to be the case when vitamin D is co-administered with calcium. Indeed, calcium, either as monotherapy (dietary or supplement) or in combination with vitamin D, seems to modestly reduce hip and non-vertebral fracture risk, especially in older individuals. Compliance is always a key factor determining anti-fracture efficacy .
Major Pharmacological Interventions
The findings from the Women’s Health Initiative (WHI) trial, which was designed to assess the prevention of common chronic diseases in women, such as cardiovascular disease, cancer and osteoporosis, showed a beneficial effect of estrogen on bones. In particular both estrogen [conjugated equine estrogen (CEE), at a daily dose of 0.625 mg] plus progestin (medroxyprogesterone acetate 2.5 mg/day) and CEE alone were efficient in reducing the risk of vertebral and hip fractures by 35 per cent and 33 per cent, respectively, in comparison with placebo. Mean BMD in lumbar spine and total hip and femoral neck increased by a mean of 7.6 per cent and 4.5 per cent, respectively, after 3 years of treatment, compared with 1.5 per cent and −0.3 per cent in the placebo group.
However, there was a small increased risk of venous thromboembolism (VTE) [1,4]. An increased risk of stroke in those initiating therapy at older ages was not seen in those initiating therapy below age 60 years. Breast cancer incidence was significantly reduced with cumulative follow-up of the estrogen-alone users. Moreover, breast cancer incidence was not significantly increased with combination therapy after adjustment for confounding variables, a finding confirmed in a more recent smaller but longer-duration randomized MHT trial. For those initiating estrogen-alone MHT below the age of 60, a reduction in coronary heart disease became evident during long-term follow-up. Although not currently recommended by regulatory authorities, we believe that the use of MHT for the sole treatment of osteoporosis should be considered as first-line therapy in postmenopausal women. The risks of VTE and stroke may be minimized or even prevented by the use of appropriately low doses of estrogen on initiating therapy or by the use of non-oral administration.
MHT is an effective, safe and cheap therapy for osteoporosis prevention [1,4]. The bone-preserving effect of estrogen is dose dependent and lower-than-standard doses are effective in older women. Higher doses may be necessary in young women who have premature ovarian insufficiency or have undergone a menopause induced by surgery, radiation or chemotherapy. However, rapid bone loss at pretreatment rates usually occurs after MHT discontinuation, although a recent study showed preservation of benefit at the level of bone microarchitecture.
Tibolone is a synthetic steroid, with a mixed estrogenic, progestogenic and androgenic profile, used as an alternative to estrogen for relief of menopausal symptoms [1,4]. Clinical trials have shown that tibolone 2.5 mg/day can prevent bone loss in both spine and proximal femur. In comparative studies, tibolone seems to be as effective as MHT regimens regarding its effect on BMD. Data show a significant reduction in vertebral and non-vertebral fracture risk by 45 per cent and 26 per cent, respectively. No adequate data exist with respect to its effect on hip fracture prevention. Tibolone has some adverse metabolic effects on lipid metabolism and insulin resistance. It may also increase the risk of stroke and its effect on breast cancer risk is unclear.
Selective estrogen receptor modulators (SERMs) [1,4] exert estrogenic and anti-estrogenic properties, depending on the target tissue(see Chapter 24). In terms of bone, SERMs inhibit osteoclast-mediated bone resorption. Two members of this family are currently available for the treatment of postmenopausal osteoporosis, these being raloxifene and bazedoxifene. Raloxifene has estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on uterine and breast tissue. Raloxifene administered at 60 mg daily has been associated with a significant reduction in the incidence of new vertebral fractures by 61 per cent in women without prevalent vertebral fractures and by 37 per cent in those with prevalent vertebral fractures. However, it has not shown any significant effect with respect to the risk of non-vertebral fractures. Raloxifene has also been approved for the prevention of invasive breast cancer. The most common side effects include increased risk of deep vein thrombosis (DVT), hot flashes, leg cramps and endometrial hyperplasia.
The other representative [1,4] of this drug category, bazedoxifene, is effective in reducing vertebral fracture risk in postmenopausal women with osteoporosis (by 42 per cent, compared with placebo) and that of non-vertebral fractures in high-risk populations (50 per cent and 44 per cent compared with placebo and raloxifene, respectively). Its effect on the endometrium is neutral. Other SERMs which have not been approved for osteoporosis treatment are tamoxifen and toremifene (used for prevention and treatment of breast cancer), ospemifene (approved for treatment of dyspareunia from menopausal vaginal atrophy) and lasofoxifene. A new promising formulation is the tissue-selective estrogen complex (TSEC), a pairing of CEE with bazedoxifene, which allows both relief of vasomotor symptoms and prevention of bone loss without any stimulatory effect on the breast or the endometrium.
Bisphosphonates [1,4] are synthetic analogues of pyrophosphate, in which the oxygen atom has been substituted by a carbon atom. Their different action is dependent on the variable R2 side chain, bound to the carbon atom and in particular the nitrogen compound. The main representatives of this category used for the treatment of osteoporosis are alendronate, ibandronate (with their nitrogen found in the straight alkyl chain), risedronate and zoledronate (with their nitrogen being part of a cyclized aromatic ring). Their main action is inhibition of bone resorption, by inhibition of farnesyl pyrophosphate synthase, a key enzyme in the mevalonic acid pathway, which blocks specific signalling molecules (GTPases) involved in major osteoclastic functions, such as maintenance of the cytoskeleton and formation of ruffled borders. Because of the coupling of bone resorption to bone formation, the inhibition of resorption by these agents is associated with a reduction in bone formation, but the former effect is initially greater than the latter, leading to a refilling of the remodelling space and a subsequent increase in mineralization density. Consequently, they are associated with a reduction in fracture risk due both to a decrease in bone remodelling and to an increase in bone mass.
Both oral (weekly administered alendronate and risedonate or monthly ibandronate) and intravenous (i.v.) bisphosphonates (ibandronate administered every 3 months and zoledronate administered annually) have been associated with significant reductions in vertebral fractures (40–70 per cent) and non-vertebral fractures (30–40 per cent) [1,4]. Hip fracture efficacy has been shown for alendronate, risedronate and zoledronate (40–50 per cent). Greater antifracture efficacy has been seen with the latter in terms of vertebral, non-vertebral and hip fractures, although direct head-to-head comparisons between bisphosphonates do not exist with regard to fracture risk. It is of note that the anti-resorptive effect of zoledronate may persist for at least 5 years after a single injection, as demonstrated by a sustained reduction in bone turnover markers and increase in BMD. Extension trials show maintained benefit with 5 years of oral bisphosphonates (alendronate) and 6 years with zoledronate in patients at high fracture risk, such as those with femoral neck T-score less than −2.5 or with prevalent vertebral fractures. In cases at low fracture risk, a ‘drug holiday’ may be considered, in particular after 5 years with alendronate and 3 years with zoledronate or risedronate therapy. In these cases, BMD seems to be generally preserved above pretreatment values. Continuous monitoring at regular intervals, depending mainly on acquisition of BMD at the time of bisphosphonate withdrawal, and re-initiation of therapy if fracture risk increases, is recommended.
The overall benefits of bisphosphonate therapy generally outweigh its risks . Some concerns with oral bisphosphonates are symptoms from the upper gastrointestinal tract, such as esophagitis, esophageal ulcer and bleeding, although these have been minimized with less frequent dosing. There is conflicting evidence concerning an association with increased risk of esophageal cancer. An acute phase reaction (characterized by fever, headache, myalgia, arthralgia, malaise) may occur in 18 per cent of patients with in 24–36 hours after zoledronate infusion, lasting up to 3 days. This reaction can be significantly reduced with acetaminophen and with subsequent infusions. In the HORIZON trial, the pivotal trial of zoledronate, there was an increased risk of serious atrial fibrillation (1.3 per cent vs 0.5 per cent with placebo), but the overall incidence of atrial fibrillation did not differ between the two groups. This risk has also been observed in some studies of oral bisphosphonates.
The two major concerns with bisphosphonate use are the risk of atypical subtrochanteric and diaphyseal femur fractures (AFF), and osteonecrosis of the jaw (ONJ) . The absolute risk for AFF is very low (around 5 cases per 10 000 person-years), taking also into account that these fractures constitute <1 per cent of all hip and femoral fractures. It is increased in cases of prolonged bisphosphonate use (>5 years) and use of other concomitant drugs, such as glucocorticoids. With regard to ONJ, this is mostly seen in patients with underlying malignancies treated with high doses of i.v. bisphosphonates (4 mg zoledronic acid/3–4 weeks), with a reported risk of 1–10 per cent. ONJ is associated with prolonged suppression of bone turnover and its risk is mainly increased in patients undergoing tooth extractions, and in those with other comorbidities. The absolute risk of ONJ when bisphosphonates are administered for osteoporosis is extremely low (1 case per 100 000 person-years). The prevalence of ONJ with oral bisphosphonates was found to be one case in 250 000, in a German registry of osteoporotic patients treated with oralbisphosphonates. However, higher prevalence has been reported in studies by oral and maxillofacial surgeons, varying from 1 in 1000 to 1 in 100 000. It has been speculated that a ‘drug holiday’ may reduce the risk of ONJ and AFF, although evidence for the effectiveness of this policy is still lacking. Only one prospective study has shown a 71 per cent reduction in AFF risk per year since bisphosphonate discontinuation.
Finally, it should be remembered that bisphosphonates have a prolonged skeletal retention time, perhaps around 12–15 years for alendronate and probably considerably longer for the more potent bisphosphonates [1,4]. The very long-term consequences of this skeletal retention are not known, and hence caution should be taken when considering their use in younger patients. In 80-year-old osteoporotics, unknown clinical consequences some 20 years later are unlikely to be considered important, but this may not be true for those aged around 60 years. A very recent study also showed anti-fracture efficacy with zoledronate after four infusions (at 18 months apart) in older patients with osteopenia.