Iatrogenic bone loss and increased fracture risk caused by therapies for nonskeletal diseases is a growing and important cause of osteoporosis. The skeletal effects of glucocorticoids, progestins, excess thyroid hormone, chemotherapy, and calcineurin inhibitors are described in other sections of the primer.
Medications that will be covered in this chapter include aromatase inhibitors (AIs), androgen deprivation therapy, gonadotropin-releasing hormone (GnRH) agonist/antagonists, thiazolidinediones (TZDs), canagliflozin, proton pump inhibitors (PPIs), opiods and heparin, and medications that have been associated with adverse effects on bone and fracture risk ( Table 42.1 ). A study from Denmark shows the use of these drugs increased substantially between 1999 and 2016 . We will also address the small list of medications that have beneficial effects on bone ( Table 42.2 ).
|Thyroxine in supraphysiologic doses|
|Medications that reduce sex steroids|
|Androgen deprivation therapy (GnRH agonist/antagonists, antiandrogenic agents)|
|GnRH agonist/antagonists for other uses|
|Proton pump inhibitors|
|Antiepilepsy drugs (often used off-label for other conditions)|
|Selective serotonin reuptake inhibitors|
|Thiazide and other proximally acting diuretics|
|Beta-adrenergic receptor blockers|
Magnitude of fracture risk is hard to discern. Dose and duration of drug use is not certain. Should one look at only current users or include past users? How long does use have to be to show a negative effect? What about intermittent use? Many studies provide relative risks and 95% confidence intervals (or hazard ratios, or odds ratios) for hip fractures, all fractures, nonvertebral fractures, etc. Occurrence of vertebral fractures is difficult to ascertain. Figures of relative risk have limited generalizability (is risk the same for men vs women, old vs young, dose of drug, duration of treatment, patients with prior fracture, etc.) and the confidence intervals are often broad. When there is more than one study with different estimates of risk, which to use—the latest? The one with the largest number of subjects? The one with the most events? The one with the narrowest confidence intervals? Rather than clutter this chapter with relative risks and confidence intervals of uncertain relevance, the author has elected to give this information only in a few instances. Readers interested in the magnitude of fracture risk increase should directly review the relevant references, including those published after this chapter was prepared.
Where mechanisms causing bone loss or skeletal fragility are known, information is provided here, although other factors may also be involved. When such information is available, it is likely that there is a causal association between drug use and skeletal risk. When such information is not available, caution should be exercised before deciding that there is a causal relationship between medication use and fracture risk and/or bone loss—there may simply be a chance association.
For long-term users of drugs such as PPIs and selective serotonin receptor uptake inhibitors (SSRIs), even though mechanism(s) for increased fracture risk is not known, fracture risk assessment, including bone mineral density (BMD) testing if appropriate, should be considered for all postmenopausal women and men 50 and older, and use of these medications considered in deciding to treat with pharmacologic agents to reduce fracture risk (i.e., if the decision to treat is uncertain, use of PPI, SSRI, etc. might tip the scale to “treat”).
Medications that reduce sex steroids
Androgen deprivation therapy, gonadotropin-releasing hormone analogs
Reducing levels of testosterone is beneficial in many cases of prostate cancer. Androgen deprivation therapy (ADT) can be accomplished with surgery or medications, including GnRH analogs, and antiandrogenic agents, including cyproterone acetate, flutamide, and bicalutamide. ADT is associated with increased bone loss and fractures .
Men receiving long-term ADT should undergo baseline assessment of fracture risk using BMD measurement and clinical risk factors, with repeat BMD measurement at 1–2 years as clinically indicated. Bone-protective therapy should be started in men with a history of hip or vertebral fracture and/or a T -score ≤−2.5. In addition, fracture-reducing therapy has been recommended in men with low T -scores (−1.0 to −2.5) and a 10-year risk of ≥3% for hip fracture or ≥20% for major osteoporotic fracture as assessed by FRAX .
A number of interventions have been shown to have beneficial effects on BMD in men treated with ADT: raloxifene, toremifene, risedronate, pamidronate, zoledronic acid, and denosumab . Reduction in vertebral fracture risk has been shown for toremifene and denosumab . Data for these interventions have recently been reviewed and summarized and guidelines presented .
Other uses of gonadotropin-releasing hormone analogs
The development of orally active, nonpeptide GnRH antagonists such as elagolix, centrorelix, TAK-385, ASP-1707, and SKI-2670 has opened potential uses for long-term treatment of polycystic ovary syndrome , uterine fibroids, and endometriosis . GnRH suppression with these agents is dose-dependent (i.e., partial suppression is possible). Bone loss does occur with long-term use of higher doses that may be partially reversible when treatment is stopped and could be at least reduced and possibly prevented with hormonal add-back therapy.
AIs block peripheral conversion of androgens to estrogen, reducing endogenous estrogen by 80%–90%. They have largely replaced the selective estrogen receptor modulator, tamoxifen, as the preferred treatment to reduce the risk of recurrence in women with early-stage estrogen receptor–positive breast cancer. The most commonly used AIs are exemestane, anastrazole, and letrozole .
In contrast to tamoxifen, which may be bone-protective in postmenopausal women (but has the opposite effect in premenopausal women), AIs increase rates of bone loss and fracture risk (but do not increase the risk of falls ). Interpretation of studies of the effects of AIs on bone is complicated by the use of tamoxifen as a comparator in many studies and also, in some, use of tamoxifen before AI therapy. In addition, there are no comparative data on the effects of different AIs on BMD and fracture rates. Nevertheless, the existing biomarker data indicate that all AIs increase bone turnover. There may be at least partial recovery of BMD when AIs are stopped , but the increased fracture risk from AIs cannot be fully explained by changes in BMD .
Although tamoxifen appears to be protective against bone loss, recent studies show, although fractures are less likely in tamoxifen users than in AI users, fracture rates with tamoxifen are not different from breast cancer nonusers .
Prevention of bone loss associated with AI therapy has been demonstrated with intravenous zoledronic acid , oral risedronate , and denosumab , although fracture reduction has only been shown for denosumab .
Guidelines for management of bone health in AI users have been published . Fracture risk assessment and advised exercise and calcium/vitamin D supplementation are recommended for all patients. Bone-directed therapy should be given to all patients with a T -score <−2.0 or with a T -score of <−1.5 SD with one additional risk, or with two risk factors (without BMD) for the duration of AI treatment. Patients with T -score>−1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12–24 months. Because of the decreased incidence of bone recurrence and breast cancer–specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.
It has been well-known that long-term opioid use can cause hypogonadism . There is recent evidence that long-term use of opioids is associated with reduced BMD and, in nursing home residents, increased risk of fractures . Opioid users are probably more likely to fall.
Canagliflozin is one of numerous inhibitors of sodium glucose cotransporter 2 (SGLT2), lowering blood glucose levels by promoting urinary glucose excretion. Prospective studies showed bone small but statistically significant BMD loss in the total hip (but not at other sites) and an increase in fractures, primarily at peripheral sites . The incidence of fractures was small and limited to a subgroup, but the increase was seen as early as 6 weeks after the start of canagliflozin treatment, too soon to be explained by changes in BMD, suggesting that nonskeletal factors, such as falling, may be responsible. More research is needed on canagliflozin and other SGLT2 inhibitors to determine the significance of these findings and whether this is a class effect or possibly due to chance alone . A recent observational study failed to find an increased fracture risk .
TZDs are ligands for peroxisome proliferator-activated receptor γ (PPARγ) used to treat type 2 diabetes. Activation of PPARγ increases marrow adiposity and insulin sensitivity and suppresses bone formation . The mechanisms by which suppression of bone formation occurs have not been fully established but may include inhibition of the Wnt/ß-catenin signaling pathway, inhibition of osteoblast differentiation genes, including Runx2 and osterix, and suppression of insulin-like growth factor production .
The effects of TZDs in humans are particularly relevant in view of the increased risk of fracture associated with type 2 diabetes. In observational studies and clinical trials, TZDs have been shown to increase rates of bone loss and fracture risk . No studies have been done to see if any of the current bone-active agents will protect against the negative skeletal effects of TZDs; therefore it seems prudent to avoid TZD use in patients at high risk of fractures.
Increased risk of fracture has been reported in individuals treated with acid-suppressive medications, including H2-receptor blockers but primarily with PPIs . Overall, current data support an association between acid-suppressive medication and hip fracture, magnitude 1.20–1.26 (95% CIs 1.14, 1.35) , although not found in all studies ; also, the limitations of observational studies, particularly the effects of potential but unmeasured confounding factors, have to be recognized.
Inhibition of the osteoclastic proton pump would be expected to have beneficial skeletal actions. The mechanism(s) by which PPIs increase fracture risk is not clear. It does not appear to be due to changes in calcium absorption or increased rates of bone turnover or bone loss , although trabecular bone score has been found to be lower in PPI users . Recent data suggest that PPIs cause an increased risk for falling , which could be due in part the underlying disorders for which PPIs are prescribed.
Given the lack of understanding of why PPIs cause increased fracture risk and therefore lack of effective countermeasures, it is reasonable to try to avoid their use in patients at high risk of fracture, understanding that this may not always be possible. It is unknown whether current treatments for osteoporosis will reduce fracture risk due to PPI use.
An association between antiepileptic drugs (AEDs), increased rates of bone loss, and fracture risk has been reported . However, the underlying pathogenesis is unclear; vitamin D deficiency, trauma during seizures, increased risk of falling, and comedications, including glucocorticoids, may all contribute. Older AEDs increase the clearance of vitamin D , which could lead to rickets or osteomalacia. Some AEDs have been shown to be associated with lower BMD or increased bone turnover . Newer AEDs do not appear to be associated with lower BMD . Currently, there are insufficient data to distinguish between the skeletal effects of specific AED regimens.
Management guidelines to prevent and treat bone disease in AED users have been proposed, although at present, these lack a robust evidence base. Routine prophylaxis of vitamin D deficiency should be considered in high-risk individuals (e.g., elderly or institutionalized); higher than normal doses of vitamin D may be required in patients taking some AEDs, and in such cases, calcium supplements should also be considered. Routine bone densitometry in all AED users cannot be justified at present, although BMD should be measured in those who present with fracture or have other clinical risk factors. Treatment of established osteoporosis in this population has not been specifically evaluated.
Selective serotonin receptor uptake inhibitors
SSRIs are widely prescribed as antidepressants as well as used for other indications. Depression itself has been implicated as a risk factor for fracture , but SSRIs appear to increase fracture risk further; A recent estimate for all fracture risk was 1.67 (95% CI 1.56, 1.79) , similar to an earlier study, which also estimated hip fracture risk to be 1.64 (95% CI 1.42, 1.89) . SSRIs have also been shown to be associated with an increased fracture risk in postmenopausal women who are not depressed . SSRI use has been associated with low bone density and increased rates of bone loss in older women and low bone mass in adolescents and in men . While SSRIs have been implicated in bone loss and fracture risk, there is little information about selective norepinephrine reuptake inhibitors .
High serotonin levels have been associated with increased hip fracture risk in Swedish men . Lower bone turnover markers have been found in younger men using SSRIs . The negative skeletal effects of SSRIs appear due at least in part to actions in the wnt signaling pathway . As with PPIs, there do not appear to be any effective countermeasures against the increased fracture risk of SSRIs; therefore it is reasonable to try to avoid their use in patients at high risk of fracture, understanding that this may not always be possible.
Heparin and oral anticoagulants
Long-term heparin therapy, which is used as prophylaxis against thromboembolism in high-risk women during pregnancy, is associated with an increased risk of reduced BMD, rates of bone loss, and fracture risk , although the mechanisms responsible for bone loss have not been established. The use of low-molecular-weight heparin and of newer antithrombotic agents such as fondaparinux may be associated with fewer adverse skeletal effects but osteoporosis and fractures have been reported with enoxaparin . Calcium and vitamin D supplements are often advocated but, in common with other antiresorptive regimens, have not been formally evaluated in this situation.
Warfarin, a vitamin K antagonist oral anticoagulant, has been widely used for decades. Because vitamin K is essential for the posttranslation carboxylation of osteocalcin, warfarin has been postulated to increase fracture risk; however, evidence for this is weak . It is not clear that newer oral anticoagulants that do not interfere with vitamin K are safer than warfarin in this regard, but at least suggestive evidence that they may be .
Drugs that may protect against osteoporosis
Beta-adrenergic receptor blocking agents
A protective effect of beta-adrenergic blocker therapy on fracture risk has been reported . This is a side benefit worth noting; however, using beta-adrenergic blocker therapy to reduce fracture risk is not advisable.
Dipeptidyl peptidase-4 inhibitors
Used to treat diabetes, these drugs increase incretin levels (GLP-1 and GIP), inhibiting glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels. Dipeptidyl peptidase-4 inhibitors were shown in a large observational database to be associated with reduced fracture risk .
Users of thiazide diuretics appear to have a reduced risk of hip fractures . Prospective studies have shown improvement in BMD and reduction in fracture risk . Increased renal calcium reabsorption is thought to play a role . Thiazide diuretics may play be useful in management of osteoporosis in patients with hypercalciuria .
Statins inhibit the enzyme 3-hydroxy-3-methyl-glutarylcoenzyme A reductase in the mevalonate pathway, thus not only reducing cholesterol biosynthesis but also preventing the prenylation of GTP-binding proteins, thus inhibiting osteoclast activity. Beneficial skeletal effects of statins in animals have been shown in vitro and in vivo , but studies in humans have produced conflicting results. A metaanalysis of the effect of statins on fracture showed no benefit . A metaanalysis of the effect of statins on BMD showed a small but statistically significant benefit , but a double-blind randomized placebo-controlled trial using clinically relevant doses of atorvastatin showed no effect on BMD or biochemical indices of bone metabolism . A recent study showed a reduced risk of fracture but limited to high-potency statins (atorvastatin and rosuvastatin) .
Long-term lithium use has been associated with a reduced risk of fractures . The mechanism for this is not known.