Drugs that affect bone metabolism

INTRODUCTION — 

Many drugs can affect bone metabolism. As examples, heparin, warfarin, cyclosporine, glucocorticoids, medroxyprogesterone acetate, cancer drugs, and thyroid hormone can cause bone loss, whereas thiazide diuretics can minimize bone loss [1,2]. This topic will review the skeletal effects of some of these drugs. The effects of glucocorticoids, aromatase inhibitors, and thyroid hormone are discussed separately.

●(See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

●(See "Evaluation and management of aromatase inhibitor-induced bone loss".)

●(See "Bone disease with hyperthyroidism and thyroid hormone therapy".)

DRUGS WITH ADVERSE EFFECTS

Heparin — Heparin can cause bone loss. The underlying mechanisms may include decreased bone formation [3], increased bone resorption, or both [4]. Other anticoagulants appear to have less or no effect on bone metabolism. (See 'Anticoagulants' below.)

Nonetheless, since heparin is usually given for brief periods of time, its adverse effects on the skeleton are usually trivial.

Long-term use

●Use during pregnancy – Heparin may be given for a prolonged period during pregnancy since warfarin is relatively contraindicated in the first trimester due to its teratogenic effects [5]. During pregnancy, chronic heparin therapy reduces bone mineral density (BMD) [6-8] and may increase fracture risk [2]. Bone density increases postpartum after heparin is discontinued [6-8]. It is unclear, however, if BMD recovery is complete or whether recovery is due in part to heparin discontinuation or solely to the cessation of pregnancy.

•Changes in BMD – In one study of pregnant women treated with heparin (n = 14) or not treated with heparin (n = 14), mean hip BMD fell by approximately 5 percent in the group receiving heparin; in contrast, BMD did not change in the untreated group [6]. Hip BMD decreased by >10 percent in 5 of the 14 women in the heparin group (36 percent) versus in no women in the untreated group. Similar results were reported in another that examined the effect of heparin on forearm BMD [7].

•Fracture risk – Many case reports and series describe pregnant women with osteoporotic fractures during and after prolonged heparin therapy [9]. One of the largest studies followed 184 pregnant women who were given heparin; four (2.2 percent) had osteoporotic vertebral fractures [9]. Although the incidence of fractures was low, they occurred in young women in whom osteoporotic fractures are extremely rare. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing".)

●Use in patients undergoing dialysis – Long-term use of unfractionated heparin is also common among patients undergoing chronic hemodialysis. However, collective data do not clearly demonstrate an association between heparin use and either BMD loss or worsening of chronic kidney disease-mineral and bone disorder [10,11].

Low molecular weight heparin — Low molecular weight heparins may have less of an adverse effect on bone than unfractionated heparin [10,12-14]. However, trials have been small, and a larger, prospective observational study found no difference between the two heparin preparations [15].

Other anticoagulants appear to have lesser effects on bone and are discussed below. (See 'Anticoagulants' below.)

Medroxyprogesterone acetate (monotherapy) — The higher doses of medroxyprogesterone acetate that have been used as monotherapy to treat gynecologic disorders have been associated with bone loss, presumably at least in part due to the induction of estradiol deficiency. This topic is reviewed in detail elsewhere. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Reduction in bone mineral density'.)

In contrast, the low doses (5 to 10 mg/day) of medroxyprogesterone acetate that are typically used in combination with estrogens as part of a regimen of menopausal hormone therapy have no effect on the protective skeletal effects of estrogens. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, 875 women were randomly assigned to placebo or one of four treatment arms consisting of conjugated estrogens (0.625 mg/day) alone or with one of three progestogen regimens [16]. Over three years, BMD increased similarly in all treatment groups and decreased in the placebo group. (See "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)

Chemotherapeutic drugs — Most cases of skeletal fragility in patients treated for cancer are due to either the hypogonadism that results from chemotherapy and/or radiation therapy or to glucocorticoid therapy [17]. (See "Evaluation and management of aromatase inhibitor-induced bone loss" and "Overview of side effects of chemotherapy for early-stage breast cancer", section on 'Risk factors'.)

However, direct adverse skeletal effects also have been described for certain chemotherapeutic drugs:

Methotrexate — High-dose methotrexate regimens (such as those used for osteosarcoma or acute lymphoblastic leukemia) are associated with an increase in bone resorption and an inhibition of bone formation, contributing to both osteoporosis and fractures [17,18]. However, these adverse effects have only rarely been observed with methotrexate in the dose range used for rheumatic disease [19,20]. (See "Major adverse effects of low-dose methotrexate", section on 'Others'.)

Ifosfamide — Ifosfamide can damage the proximal tubules in the kidney, causing metabolic acidosis, phosphate loss, hypercalciuria, and, in severe cases, hypophosphatemic osteomalacia. (See "Ifosfamide nephrotoxicity".)

Imatinib — Imatinib mesylate, a drug used to treat chronic myeloid leukemia, gastrointestinal stromal tumors, and other malignancies, may be associated with changes in bone turnover [21,22]. In one preliminary report, patients receiving imatinib had increases in markers of bone formation (serum osteocalcin and N-terminal propeptide of type I procollagen [PINP]) but no change in a marker of bone resorption (beta isomer of C-terminal telopeptide of type I collagen) within three months of initiating therapy [22]. In some instances, changes in bone turnover were associated with low-normal serum calcium, secondary hyperparathyroidism, renal phosphate wasting, and hypophosphatemia [21,22]. The mechanism and clinical consequences of these findings are unclear. (See "Hypophosphatemia: Causes of hypophosphatemia".)

Antiseizure medications — Enzyme-inducing antiseizure medications (ASMs) such as phenobarbital, phenytoin, carbamazepine, and primidone increase the activity of P450 enzymes. In ambulatory patients, long-term antiseizure therapy has been associated with low BMD and increased fracture rate. The increase in fracture rate is due to both seizure-related injuries and the adverse effects of ASMs on bone strength. This topic is reviewed in detail separately. (See "Antiseizure medications and bone disease".)

Opioids — Chronic opioid use is associated with bone loss and increased fracture risk, which may reflect both direct and indirect effects of opioids on bone. Given these associated risks, the Society of Obstetricians and Gynaecologists of Canada recommends that women taking higher-dose opioids (daily dose of morphine >100 mg or equivalent) undergo screening for osteoporosis at age 50 years [23]. Similarly, the Endocrine Society recommends BMD measurement in patients with long-term opioid use, particularly if hypogonadism is present [24]. Very limited data support the potential skeletal benefits of sex hormone replacement in patients with hypogonadism due to chronic opioid use; this is reviewed in detail separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Neuroendocrine effects'.)

●Indirect effects

•Hypogonadism – In adults, chronic opioid use has been associated with high rates of hypogonadotropic hypogonadism, which can lead to accelerated bone loss. For example, among patients on methadone maintenance therapy for opioid substance use disorder, the prevalence of hypogonadism is approximately 35 to 40 percent [25]. Some cross-sectional studies have found an independent association between opioid use and low BMD, whereas in other studies, the association is lost after adjusting for hypogonadism [25].

•Increased fall risk – Opioid use contributes to fall risk due to central nervous system side effects, and risk of fall and fracture may be even higher among patients with underlying cognitive impairment [26]. Fall risk appears highest sooner after initiation of opioid treatment and declines thereafter [24].

●Possible direct effects on bone – Preclinical data indicate that opioids also exert direct effects on bone, and chronic opioid exposure reduces bone formation. Osteoblasts express opioid receptors, and opioids have been shown to inhibit osteoblast activity and the differentiation of mesenchymal stem cells into osteoblasts [24]. Animal data further suggest that opioids impair bone healing after trauma.

DRUGS WITH POSSIBLE ADVERSE EFFECTS

Anticoagulants

Warfarin — Warfarin may adversely affect skeletal health, but this potential risk is supported only by indirect evidence. If a causal association exists between warfarin and fracture risk, the effect is small. Therefore, when anticoagulation is indicated, fracture risk is generally not a factor in agent selection.

●Hypothesized effect on bone – Warfarin inhibits the vitamin K-dependent gamma-carboxylation of clotting factors II, VII, IX, and X [5]. Noncarboxylated clotting factors do not bind to calcium and, therefore, cannot participate in the coagulation cascade. (See "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla".)

Warfarin also inhibits the gamma-carboxylation of osteocalcin, a major protein involved in bone formation; noncarboxylated osteocalcin cannot effectively bind to calcium [27], suggesting that warfarin may adversely affect skeletal health by inhibiting bone mineralization. This hypothesis is supported by limited observational evidence [28,29]. For example, mean serum vitamin K concentrations in patients who have fractures may be lower than in individuals without fracture history [30,31]. Another study found that risk of hip fracture was greater in women with high serum concentrations of noncarboxylated osteocalcin compared with those with low concentrations (relative risk [RR] 5.9) [32].

●Clinical relevance – Nonetheless, the clinical importance of these observations is uncertain. Some cross-sectional studies found that mean bone mineral density (BMD) in warfarin-treated patients was lower than in control patients [33-35], and a retrospective cohort study found that long-term exposure to warfarin was associated with an increased risk of vertebral and rib fractures [36]. Low BMD was also reported in a small case-control study comparing children on long-term warfarin versus control children [37]. In a retrospective cohort study of hospitalized patients with atrial fibrillation, men, but not women, who had taken warfarin for more than one year were at increased risk for osteoporotic fracture (odds ratio [OR] 1.63, 95% CI 1.26-2.10) [38]. However, these are observational studies with potential confounding variables and cannot demonstrate causality.

In other studies, warfarin had no adverse effect on BMD [39,40] or fracture rates [41-43]. In a prospective observational study of women aged ≥65 years, for example, those taking warfarin (n = 149) and those not taking warfarin (n = 6052) had similar rates of bone loss at the hip (1.1 and 0.8 percent, respectively) over two years and similar fracture rates over 3.5 years of follow-up [41].

Direct oral anticoagulants — Other oral anticoagulants do not affect the vitamin K pathway and would not be expected to have an adverse effect on BMD. Some [44-47], but not all [48], observational studies suggest that direct oral anticoagulants (DOACs) are associated with lower risk of fractures than warfarin. The reason for this difference in fracture risk, if real, is unknown. Nor is it clear whether it represents an increase in risk with warfarin or a decrease in risk with DOACs.

Calcineurin inhibitors — Bone loss is common in many of the conditions treated with calcineurin inhibitors, but the causal role of cyclosporine or tacrolimus alone in bone loss has not been determined. UpToDate authors do not recommend any specific bone-targeted treatment in patients taking these agents. Nonetheless, such patients should adhere to general measures for preventing bone loss. (See "Prevention and treatment of bone disease after kidney transplantation", section on 'General measures for all transplant recipients'.)

Cyclosporine — Abundant animal data suggest that cyclosporine adversely affects bone. Administration of cyclosporine to rats, for example, causes an increase in both bone resorption and bone loss, or "high-turnover" osteoporosis [49-51]. Some evidence supports similar effects of cyclosporine on bone turnover in humans [52,53].

However, the effect of cyclosporine on bone metabolism in humans is less clear and confounded by the presence of other illnesses or drugs that affect bone, particularly glucocorticoids [52]. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation" and "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

Notably, in a study in patients with primary biliary cholangitis that compared cyclosporine with placebo, participants who received cyclosporine had biochemical evidence of increased bone turnover and did not exhibit bone loss, whereas bone loss occurred in the placebo group [53]. (See "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)".)

Tacrolimus — Animal data similarly support adverse effects of tacrolimus on bone, although the mechanisms of bone loss may differ from those of cyclosporine. For example, in one study in rats that directly compared treatment with cyclosporine and tacrolimus, tacrolimus increased bone resorption but did not impact bone formation, in contrast with cyclosporine-induced increases in both bone formation and bone resorption [54]. Similar to the data for cyclosporine, clinical data regarding the skeletal effects of tacrolimus are limited and confounded by glucocorticoid treatment, comorbid conditions, and other clinical risk factors for bone loss among transplant recipients. Nonetheless, in one small study of kidney transplant recipients, tacrolimus treatment was associated with higher serum concentrations of the bone resorption marker tartrate-resistant acid phosphatase-5b (TRAP-5b) compared with sirolimus treatment, and tacrolimus promoted greater osteoclast proliferation in vitro [55]. In another study of 72 kidney transplant recipients receiving tacrolimus treatment, the frequency of bone loss was greater among those with tacrolimus blood levels ≥6 ng/mL than among those with blood levels <6 ng/mL (45.5 versus 20 percent, respectively) [56].

Vitamin A and synthetic retinoids — Vitamin A is required for normal growth, vision, reproduction, cell proliferation, and cell differentiation. However, excess intake appears to increase the risk of hip fracture in women. The mechanism by which this may occur has been studied in animals, in which vitamin A inhibits osteoblast activity, stimulates osteoclast formation [57], and counteracts the ability of vitamin D to maintain normal serum calcium concentrations [58], thereby leading to accelerated bone resorption and fractures. Data in humans have been conflicting, and a U-shaped relationship between vitamin A intake and fracture risk may exist, as both excessively low and high circulating retinol levels have been associated with increased risk of hip fracture [59]. Very high vitamin A intake leading to toxicity can cause hypercalcemia mediated by increased bone absorption. (See "Overview of vitamin A", section on 'Excess'.)

Based on available BMD and fracture data, individuals in Western countries should be cautioned against excessive retinol intake. Common food sources of vitamin A include liver, milk, egg yolk, butter, and some fruits and vegetables; those with diets high in these foods should avoid supplements containing vitamin A. In contrast to high intake of preformed vitamin A (retinol or retinyl esters), high consumption of foods containing provitamin A carotenoids (eg, beta-carotene) may not confer adverse effects on bone. Vitamin A deficiency is still fairly common in African and Asian countries, and inadequate vitamin A intake may also increase fracture risk [60]. For populations in which vitamin A deficiency is endemic, supplementation is recommended. (See "Overview of vitamin A", section on 'Requirements' and "Overview of vitamin A", section on 'Deficiency'.)

Loop diuretics — Loop diuretics increase calcium loss by impairing reabsorption in the loop of Henle. The ensuing negative calcium balance has been associated with a decrease in BMD and an increased risk of hip fracture in some [61-63], but not all [64], studies. (See "Diuretics and calcium balance", section on 'Loop of Henle and loop diuretics'.)

For example, in a trial of 87 healthy, postmenopausal women randomly assigned to receive the loop diuretic bumetanide or placebo for one year, urinary calcium and serum parathyroid hormone increased (17 and 9 percent, respectively), and BMD decreased at the hip (-2 percent) and whole body (-1.4 percent) in the bumetanide group compared with placebo [61]. This detrimental effect on bone occurred despite supplementation with calcium and vitamin D. In a subsequent cohort study in 3269 men, the use of loop diuretics was also associated with a greater decline in total hip BMD compared with nonuse (annual rate of decline -0.78 versus -0.33 percent, respectively) [62].

The effect of loop diuretics is in contrast to that of thiazide diuretics, which reduce calcium excretion and may increase BMD. (See 'Thiazide diuretics' below.)

Gastric acid inhibitors — Insoluble calcium (eg, calcium carbonate) requires an acidic environment for optimal absorption. As a result, drugs that reduce stomach acid secretion (proton pump inhibitors [PPIs] and histamine-2 [H2] blockers) may reduce calcium absorption. Because calcium absorption decreases with aging, a further reduction in calcium absorption due to such drugs may have a particularly adverse impact on skeletal health in older individuals.

Despite inconsistent clinical data, we advise that postmenopausal women taking long-term PPI or H2 blocker therapy increase dietary calcium and, if needed, use calcium supplements that do not require acid for absorption, such as calcium citrate. If calcium carbonate is used instead, it should be consumed with food for adequate absorption. The treatment of postmenopausal women with or at risk for osteoporotic fracture is reviewed separately. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Supplements' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Low bone mass'.)

●Fracture risk – PPIs but not H2 blockers have been consistently associated with increased fracture risk. However, the underlying peptic ulcer disease itself may be independently associated with an increased risk of hip fracture [65].

In meta-analyses of case-control and cohort studies, the risks of hip, spine, and any-site fractures were modestly but significantly increased in patients taking PPIs (RRs 1.30, 1.56, and 1.16, respectively) [66-69]. In some [68,70], but not all [71], studies, fracture risk was highest in long-term users of high-dose PPI therapy. In one analysis, the risk was confined to patients with at least one other risk factor for hip fracture [72], and in another, to current or former smokers [68]. H2 blockers were associated with an increased risk of hip fracture in some reports (adjusted odds ratio [AOR] 1.23, 95% CI 1.14-1.39) [70,72,73] but with decreased [71] or unchanged [69,74] risk in others.

The largest prospective cohort study (from the Women's Health Initiative) did not find an association between PPI use and hip fracture (hazard ratio [HR] 1.00, 95% CI 0.71-1.40) [74]. However, PPI use was associated with an increased risk of clinical vertebral (HR 1.47, 95% CI 1.18-1.82), wrist, and total fractures. The lack of association with hip fracture risk was confounded by the low number of hip fracture events and the disproportionate use of hormone therapy among PPI users.

●Impact on osteoporosis pharmacotherapy – In an analysis of a national prescription database, concurrent use of PPIs and alendronate compared with alendronate alone was associated with loss of protection against hip fracture (fracture risk reduction with alendronate 39 versus 19 percent in non-PPI versus PPI users, respectively) [75]. In contrast, concurrent treatment with H2 blockers did not modify the treatment response to alendronate.

●BMD – In a prospective cohort study, chronic PPI use was associated with lower baseline BMD at the femoral neck and total hip, but use over 10 years was not associated with accelerated BMD decline [76]. In addition, other studies have not found a decrease in BMD in PPI users compared with nonusers [77,78], although one study found an increased risk of falls and fractures in PPI users [77]. Thus, factors independent of BMD (eg, frailty) may contribute to fracture risk, and PPI use may be a marker of frailty since PPI users are, as a group, sicker than controls [76].

●Potential mechanisms of skeletal effects

•Reduced calcium absorption – Some [79], but not all [80,81], studies show that PPIs reduce fractional absorption of calcium in postmenopausal women. Discordant results among studies may partly reflect differences in study design, including selection of isotope-labeled calcium (calcium carbonate capsules versus calcium chloride solution), method of measurement (fasting serum isotope-labeled calcium levels versus dual isotope measurements with a meal), duration (eg, 7 versus 30 days) and type of PPI treatment (omeprazole versus a different PPI), and patient characteristics (eg, mean age 76 versus 58 years). In healthy individuals treated with omeprazole, dietary calcium (milk and cheese) absorption was not reduced [82,83], suggesting that a meal induces a sufficient amount of acid secretion for calcium absorption despite PPI therapy.

•Other mechanisms – PPIs also could have adverse skeletal effects due to impaired absorption of other vitamins and minerals essential for bone health, including vitamin B12 and magnesium [84]. Further, the combined effects of reduced calcium absorption and hypergastrinemia could potentially lead to increased parathyroid hormone secretion; however, direct evidence supporting this phenomenon is scant [85]. Notably, some data support potentially protective skeletal effects of PPIs, which have been shown to inhibit osteoclast vacuolar-type H⁺-ATPases and therefore could suppress bone resorption [86].

Antidepressants — Both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of fragility fracture in observational studies [87-89]. However, prospective trials are needed to definitively determine the relationship between antidepressants and fracture. The decision to prescribe SSRIs versus TCAs should not be driven by fracture data, since only observational data support increased fracture risk with either class of agent.

For all patients initiating treatment with a TCA or SSRI, we recommend counseling regarding fall prevention, adequate calcium and vitamin D supplementation, and smoking cessation. BMD measurement should be considered in patients receiving SSRIs, especially if other risk factors for fracture are present (eg, advanced age, prior fragility fracture). (See "Osteoporotic fracture risk assessment" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Lifestyle measures to reduce bone loss'.)

●Fracture risk – In meta-analyses of case-control and cohort studies, an increased risk of fracture (predominantly hip and nonvertebral fracture) was evident in patients who had taken an SSRI (RR 1.72, 95% CI 1.51-1.95) [90,91]. Similarly, in a separate meta-analysis of case-control and cohort studies examining the association between TCAs and risk of fracture, an increased risk of fracture was found in users of TCAs compared with nonusers (adjusted RR 1.36, 95% CI 1.24-1.50) [92]. In both meta-analyses, the increased risk persisted after confining the analysis to studies that adjusted for important fracture risk factors (age, comorbidities, medications known to increase fracture risk, BMD). Nonetheless, these observational data do not prove causality, and other potential confounders may explain the reported association.

●Potential mechanisms of increased fracture risk – One plausible explanation for the possible association between antidepressants and fracture is an increased risk of falls due to drug-related side effects, including sedation and postural hypotension. Medication-related declines in BMD are also possible. In some large cross-sectional and prospective cohort studies, use of SSRIs (but not TCAs) has been associated with reduced BMD in older men [93] and increased rates of bone loss at the hip in older women [94]. Thus, SSRIs may exert direct effects on bone metabolism, although this possibility is not supported by clinical trial data [95,96].

Thiazolidinediones — Some evidence suggests that thiazolidinediones adversely impact skeletal health, including an increased risk of fractures in women (humerus, hand, foot). This is reviewed in detail separately. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Safety'.)

Antiretroviral therapy — Individuals with human immunodeficiency virus (HIV) have an increased risk of low BMD. Low BMD among patients with HIV infection is usually multifactorial. This topic is reviewed elsewhere. (See "Bone and calcium disorders in patients with HIV".)

DRUGS WITH POSSIBLE BENEFICIAL EFFECTS

Thiazide diuretics — Thiazide diuretics stimulate renal calcium reabsorption in the distal tubule, leading to a decrease in urinary calcium excretion. This effect is used clinically to reduce the frequency of stone formation in patients with recurrent nephrolithiasis and hypercalciuria. As a result, long-term thiazide therapy may increase bone mineral density (BMD) and decrease fracture risk. This is in contrast to loop diuretics, which increase calcium excretion and may reduce BMD. (See "Diuretics and calcium balance" and "Kidney stones in adults: Prevention of recurrent kidney stones" and 'Loop diuretics' above.)

Although trial data are lacking, available evidence suggests that thiazide therapy attenuates bone loss and may reduce fracture risk, but the effect is modest. We do not routinely recommend the administration of thiazides to prevent or treat osteoporosis, but a thiazide diuretic is a reasonable choice if a patient with osteoporosis has hypertension, nephrolithiasis, or renal calcium leak.

●BMD – In cross-sectional studies, patients taking a thiazide had higher BMD than control patients [97,98]. Clinical trial data further demonstrate a beneficial effect of thiazide diuretics on BMD [99,100]. For example, a three-year trial of 320 healthy adults aged 60 to 79 years examined the effect of hydrochlorothiazide (12.5 or 25 mg/day) versus placebo. In women, hip and spine BMD were 1.4 and 1.3 percent higher, respectively, in the 25 mg group compared with the placebo group [100]; the effect of the 12.5 mg dose was smaller. Hydrochlorothiazide also prevented bone loss in men, although the effect was less than in women.

●Fracture risk – Most [97,101-108], but not all [63,109], observational studies have shown a beneficial effect of thiazides on fracture risk. A meta-analysis of 21 observational studies involving almost 400,000 individuals noted a significant reduction in risk of hip fracture with long-term thiazide therapy (relative risk [RR] 0.76, 95% CI 0.64-0.89) [105].

Statins — Beneficial skeletal effects may result from treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), which are used for the treatment of hypercholesterolemia, but data are conflicting. In some studies, statin therapy was associated with a decrease in fractures or an increase in BMD [110-115], but in others, no decrease in fracture risk was evident [116-118]. Notably, study design including the specific statin varied, and many of the studies predominantly included men. Most were case-control or retrospective studies.

In a meta-analysis of eight observational studies that reported statin use and documented fracture outcomes in postmenopausal women, statin use was associated with a lower risk of hip fracture (odds ratio [OR] 0.43, 95% CI 0.25-0.75 for users versus nonusers) [119]. However, post hoc analyses of two statin cardiovascular outcome trials did not support a protective effect [116,118]. Further, in one clinical trial designed to evaluate skeletal endpoints, 82 postmenopausal women were randomly assigned to simvastatin (40 mg/day) or placebo for one year. No effects of simvastatin were apparent on biochemical bone markers or on BMD at the hip or spine, although an increase in forearm BMD was seen.

Nitrates — In animal studies, nitric oxide slows bone remodeling and bone loss in animals [120]. In observational studies in humans, nitrate administration, which increases nitric oxide levels, is associated with an increase in BMD and a reduction in fracture risk [121]. However, trial data have not shown benefit. In a three-year trial of nitroglycerin ointment (22.5 mg/day) versus placebo in 186 postmenopausal women without osteoporosis (BMD T-scores between 0 and -2.5 and no prior vertebral or hip fracture), women in both groups had similar reductions in lumbar spine and total hip BMD after 36 months (-2.06 versus -2.48 percent and -4.38 versus -4.03 percent for lumbar spine and total hip, respectively) [122]. The trial was not powered to assess fracture outcomes.

Beta blockers — In animal models, beta blockers stimulate bone formation and inhibit bone resorption [123]. Data in humans are inconsistent, with some studies showing a lower risk of fracture with current use of beta blockers [124,125] and another showing no effect [126]. A meta-analysis of 16 observational studies showed a significant reduction in fracture risk in patients receiving beta blockers, a finding primarily driven by a reduction in risk of hip fracture [127]. The meta-analysis was limited by significant heterogeneity in the results. Given the limitations of the observational data and the absence of clinical trial data, beta blockers have no current role in osteoporosis management.

SUMMARY

●Drugs with adverse skeletal effects – Chronic use of drugs including heparin, chemotherapeutics, antiseizure medications (ASMs), and opioids have been associated with bone loss and/or increased fracture risk. For some agents, these risks are predominantly due to medication-induced hypogonadism, whereas others also exert direct effects on bone. When long-term use of such medications cannot be avoided, bone mineral density (BMD) measurement and general measures to prevent falls and bone loss are often warranted. If no contraindications are present, treating medication-induced hypogonadism also may help attenuate bone loss and fracture risk. (See 'Drugs with adverse effects' above.)

The management of patients with low BMD and/or increased fracture risk is reviewed elsewhere. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men" and "Evaluation and treatment of premenopausal osteoporosis".)

●Drugs that may have adverse effects on bone – In observational studies, commonly used medications, such as proton pump inhibitors (PPIs), antidepressants, anticoagulants, and loop diuretics have been associated with an increased risk of fracture. (See 'Drugs with possible adverse effects' above.)

Adverse skeletal effects are not a concern with short-term use of such agents. However, because long-term therapy may have detrimental skeletal effects, older patients should be evaluated for other risk factors for osteoporosis and fracture. BMD measurement should be considered in some patients, especially when other risk factors for fracture are present, such as advanced age or prior history of fragility fracture. Older patients should receive counseling regarding fall prevention, adequate calcium and vitamin D supplementation, and smoking cessation. (See "Osteoporotic fracture risk assessment" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men".)

●Drugs that may have beneficial effects on bone – Long-term thiazide therapy may increase bone density and decrease fracture risk. Data are inconsistent for the effects of statins, nitrates, and beta blockers on BMD and fracture risk. None of these medications are recommended specifically for skeletal protection. (See 'Drugs with possible beneficial effects' above.)