Drug-Induced Osteoporosis: A Review of Medications That Affect Bone Mineral Density

Release Date: October 1, 2012

Expiration Date: October 31, 2014


Suzanne Albrecht, PharmD, MSLIS
Clinical Writer, Woodstock, Illinois


Dr. Albrecht has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.


To educate pharmacists about the process of bone remodeling and which drugs can disrupt that process as well as the mechanisms involved and any protective measures to be taken.


After completing this activity, the participant should be able to:

  1. Describe the process of bone remodeling.
  2. List the drugs that can adversely affect bone.
  3. Explain the mechanisms behind druginduced osteopenia or osteoporosis.
  4. Discuss therapeutic interventions used for prevention or treatment of druginduced osteopenia or osteoporosis.

Drug-induced osteoporosis is common and may result in significant morbidity and mortality for patients. The World Health Organization (WHO) has defined osteoporosis as bone density less than 2.5 standard deviations (SD) of the mean gender-matched, young healthy population (T-score at or below -2.5). Osteopenia is defined as loss of bone with T-score between -1 and -2.5.1

Many drugs have the potential to decrease bone mineral density (BMD). TABLE 1 lists the agents discussed in this lesson. Most of the disease states that are treated with these drugs also predispose the patient to low BMD, so the medication may be adversely affecting an already compromised bone structure.2 The most significant consequence of low BMD is a fracture.3

Bones provide support for movement, protect vital organs, and are the largest repository for calcium and other minerals.3 Ninety percent of the body's calcium is in the skeleton.4 Bone is constantly being remodeled, with old bone being resorbed and new bone forming.4,5 The rate of annual calcium turnover is 100% in infants and 18% in adults. The cycle of bone resorption and consequent formation is approximately 100 days.4

Process of Bone Remodeling

Bone remodeling is a complex, highly orchestrated process involving the balance of many factors. The cycle of bone remodeling occurs in stages, beginning with the formation of osteoclasts, bone resorption (by osteoclasts), a reversal period, bone matrix formation (by osteoblasts), and, finally, mineralization of the matrix.5

The osteoclast, a derivative of a monocyte/macrophage precursor, is a polykaryon (multinucleated cell) that degrades bone. Osteoblasts are responsible for bone formation, and the two interact to regulate the proliferation and activity of one another.6 A simplified explanation follows.

Osteoblasts affect the proliferation of osteoclasts in several ways. Receptor activator of NF-kB ligand (also called RANKL) is produced by osteoblasts (and precursors) and initiates osteoclastogenesis (the process of producing osteoclasts).5 RANKL is the most integral factor in osteo-clastogenesis. RANKL activates RANK (expressed by osteoclasts).7,8 The RANKL-RANK interaction is essential for osteoclast formation and thus bone resorption.5,7

Osteoblasts produce another factor required for osteoclast formation called colony-stimulating factor-1 (CSF-1). CSF-1 promotes proliferation of precursor osteoclasts as well as the expression of RANK on the osteoclast membrane surface.5

Osteocytes are cells that are incorporated into the bony matrix. Some osteoblasts differentiate into lining cells. Lining cells play a role in the migration of osteocyte precursors. They also promote osteocyte formation and attachment to the surface of the bone. Lining cells are thought to digest a thin layer of nonmineralized matrix (osteoid), which allows the exposure of mineralized matrix for resorption by osteoclasts. The lining cells separate from the underlying osteocytes and form a canopy over the area of the bone to be remodeled.5

Under this canopy, osteoclasts attach firmly to the bone with adhesion structures called podosomes. Beneath this tight seal, osteoclasts secrete protons and proteases that demineralize and degrade the bone. The resulting bone constituents are then resorbed into the osteoclasts and released into the interstitial fluid.4,8

At the end of the bone remodeling cycle, osteoblasts differentiate into either osteocytes (within the bone matrix) or lining cells of the bone surface.5 Other hormonal and chemical agents affect the bone remodeling process, including calcitonin, osteocalcin, alkaline phosphatase, tumor necrosis factor-alpha, interleukin-1, estrogen, testosterone, and 1,25-dihydroxy vitamin D (the most active metabolite of vitamin D).3,4,8-10 These factors are involved in some of the mechanisms by which medications reduce BMD.

Glucocorticoids (GCs)

Glucocorticoid-induced osteoporosis (GIO) is the most common drug-induced osteoporosis.2,11 Although fractures can occur early in treatment, the risk of fracture is time and dose dependent.11 An increased risk of fracture is seen with prednisolone (predinsone) doses as low as 2.5 to 7.5 mg (or equivalent); daily dosing may be associated with a higher risk than cumulative doses.12 Approximately 30% to 50% of patients undergoing long-term GC therapy experience a fracture, many of which are asymptomatic. Cancellous bone is most affected by GC use; therefore, fractures tend to occur in sites rich in cancellous bone, such as the vertebrae and femoral neck.2,11

GIO is due to both increased bone resorption and decreased bone formation. There is a rapid loss of bone early after GC initiation. BMD declines within the first 3 months, and bone loss peaks at 6 months (most likely due to bone resorption). This is followed by a slower, steady loss with continued use (due to impaired bone formation).11-13 Vertebral fractures occur during the early rapid reduction of BMD.11 The risk of fracture declines after discontinuation of GCs; however, the rate at which this occurs is variable.2,11

Impaired bone formation is due to the direct effect GCs have on osteoblasts and osteocytes.11,13 Osteoblast number and function are decreased following GC exposure. GCs inhibit osteoblast differentiation. The osteoblasts that do reach maturity do not function properly. Their ability to synthesize type 1 collagen (the major component of bone matrix) becomes impaired, leading to a decrease of bone matrix available for mineralization. GCs also promote apoptosis of osteoblasts and osteocytes.11

Increased bone resorption is due to the effect GCs have on osteoclast differentiation and longevity. GCs increase the expression of CSF-1 and RANKL while decreasing OPG, thus promoting osteoclastogenesis. GCs also inhibit apoptosis of mature osteoclasts. These actions result in an increase in the number and life span of osteoclasts.11 Secondary processes that adversely affect bone integrity include decreased calcium absorption, increased calcium excretion, hypogonadism, and muscle weakness (predisposing the patient to a fall).11,13

Because GIO fractures can occur at BMD higher than that of postmenopausal women, the guidelines for treatment of postmenopausal osteoporosis are not applicable. This may be due to the adverse effects GCs have on osteoblasts and osteocytes. The architecture of cancellous bone is maintained by osteoblast and osteocyte activity. GC use impairs this activity, and the integrity of the bone is compromised. The risk of fracture may increase without any loss of BMD. Patients should be treated at BMD T-scores of -1.0 to -1.5 or below.2,11

Although there are several available agents to reduce the risk of GIO fracture, many patients do not receive therapy to prevent or treat osteoporosis, nor do they have their BMD assessed regularly. Bisphosphonates can prevent initial bone loss and reduce the risk of fracture, but their use in men and premenopausal women is low.12 Teriparatide is an anabolic agent that has demonstrated greater increases of BMD than alendronate (a bisphosphonate) with GC use.2,13

American College of Rheumatology (ACR) Guidelines: In 2010, the ACR published evidence-based guidelines for the prevention and treatment of GIO.12 The ACR recommends calcium and vitamin D supplementation (800-1,000 IU/day of vitamin D, 1,200-1,500 mg/day of calcium) for all patients taking GCs. There are several reasons the ACR makes no recommendations for the use of osteoporosis medications in premenopausal women and men aged <50 years, including: 1) a lack of evidence examining the effects of osteoporosis therapy in this population; 2) the WHO Fracture Risk Assessment Tool (FRAX, www.shef.ac.uk/FRAX) does not apply to premenopausal women and men under aged <40 years; and 3) the potential risk to a fetus after long-term osteoporosis medication therapy is unknown. In addition, the ACR refrained from making recommendations concerning the use of certain drugs used to treat osteoporosis (ibandronate, etidronate, calcitonin, estrogen, testosterone, and raloxifene) due to a lack of sufficient evidence. TABLES 2 and 3 summarize the ACR guidelines for medication use.12


Long-term unfractionated heparin (UH) use is associated with an increased risk of osteoporosis.14 The loss of bone while using UH is time and dose dependent.9 Up to one-third of patients on long-term UH therapy have a subclinical reduction of BMD, and approximately 2% to 3% experience a symptomatic fracture.14,15

Vertebral fractures are most common with heparin-induced osteoporosis.9 Because heparin remains on the bone, reduced BMD may not be readily reversible.15

Bone loss associated with UH is due to both decreased bone formation and increased bone resorption. A dose-dependent loss of osteoblast surface and osteoid surface and thickness has been observed with UH.14 In addition, a dose-dependent increase in osteoclast activity and number has been observed with UH.9,14

The mechanisms by which UH affects BMD are not entirely known. The reduction in bone formation may be associated with a decrease of osteocalcin and alkaline phosphatase (necessary for osteoblast formation).9 During maturation, osteoblasts express osteocalcin.16 Osteocalcin is a carboxylated protein and is the most abundant carboxylated protein in the bony matrix.17,18 Osteocalcin is important in incorporating calcium into bone and regulating the differentiation and maturation of osteoblasts.9,16,18

The mechanism by which UH increases bone resorption may be related to OPG. In an in vitro study, OPG-specific binding of heparin was observed on the osteoblast membrane. Inhibition of OPG activity enhances osteoclastic bone resorption by disrupting the OPG-RANK inhibition of osteoclast differentiation.7

Low-molecular-weight heparin (LMWH) is often prescribed for thromboprophylaxis in pregnant women. LMWH has a more predictable clinical response, greater bioavailability, and possibly lower incidence of adverse effects when compared to UH. BMD loss may occur in pregnant women without adequate calcium and vitamin D intake.19 LMWH may also be associated with a lower risk of osteoporosis, but the evidence is conflicting. Long-term LMWHs are most often used in pregnant women, making clinical study difficult due to ethical issues. Bone loss similar to that of UH was observed in rats being given nadroparin.20 Some studies demonstrate a lower risk of bone loss with the use of LMWHs when compared to UH.21-23 Other studies find subclinical loss of BMD with the use of LMWHs.24 Additional studies demonstrated no difference between UH and LMWHs.19

In theory, warfarin use may be associated with BMD loss. Warfarin is a vitamin K antagonist, and vitamin K is essential for the carboxylation of bone matrix proteins, including osteocalcin. Uncarboxylated or undercarboxylated osteocalcin is not incorporated into the bone.17,18,25 Vitamin K deficiency has been associated with low BMD; however, the evidence linking warfarin to loss of BMD is conflicting.18

Some studies have shown that long-term anticoagulation with warfarin is associated with low BMD.18,26 A study by Barnes et al on children treated with warfarin for an average of 8.2 years demonstrated a reduced BMD compared to controls.17 The authors concluded that, although the altered BMD is probably multifactorial, warfarin played a role. Other factors likely contributed to the lower BMD including lack of weight-bearing exercise and dietary factors (lower calcium and vitamin D intake). They recommend BMD screening for children on long-term warfarin.17

A study by Wawrzynska et al compared acenocoumarol (a warfarin derivative) to an LMWH (nadroparin or enoxaparin).24 The researchers observed a decrease of BMD in all groups; however, it was more pronounced in the LMWH group. Other studies do not support these findings. A study of elderly men found no association between lower BMD and warfarin use.25

Factor Xa inhibitors (e.g., fondaparinux) may be used in some patients. Fondaparinux was found to have no effect on osteoblast proliferation in vitro. Handschin et al concluded that the risk of osteoporosis was greatly reduced and possibly absent with the use of fondaparinux when compared to an LMWH (dalteparin).9

Depot Medroxyprogesterone Acetate (DMPA)

DMPA is an intramuscular (IM) injection administered every 11 to 13 weeks as a contraceptive.27 Circumstances warranting DMPA use include risk for thromboembolism, currently breastfeeding, initiating contraception earlier than 3 weeks postpartum, concurrent use of medications that decrease efficacy of hormonal combination contraceptives, and presence of hypertension or coronary disease.28 Bone loss is site specific, with greatest loss at the spine and hip.29 Most bone loss occurs within the first year of DMPA use.30

DMPA inhibits the hypothalamic-pituitary-ovarian axis and suppresses estrogen production by the ovaries.27Estrogen is one of the most critical hormones involved in the increase of BMD. Estrogen deficiency results in decreased calcium absorption in the intestine and reabsorption in the renal tubules.31

Studies have confirmed that young users of DMPA lose a significant amount of BMD at the hip and spine.27 The immature skeleton of adolescents is more susceptible to the effects of DMPA.29 A decrease of an average of 3.1% BMD was observed in a 2-year study of 12- to 21-year-olds. Over 2 years, the participants in the control group gained 9.5% BMD.30 Another study of first-time DMPA users aged 18 to 35 years demonstrated a mean BMD loss of 7.7% at the hip and 6.4% at the spine after 48 months. Seventy-five percent of lost hip BMD and 90% of lost spine BMD occurred in the first 2 years of medication usage.32

DMPA may be a good choice for adolescents who may not adhere to daily administration of an oral contraceptive; however, there is concern that BMD may be greatly affected and resistant to recovery during this time of accelerated BMD increase. Approximately 90% of bone is accrued by early adulthood.27 One study determined that the characteristics associated with the greatest bone loss in adolescents using DMPA include high alcohol consumption, lower calcium intake, lower body mass index (BMI) at baseline, and weight loss while using DMPA. Those who gained weight during DMPA use experienced increases in BMD (or smaller decreases).31

Once peak bone mass has been reached, initiation of DMPA does not appear to have the same profound effects as in women still accruing bone mass. A study of women aged ≥34 years demonstrated an increased rate of bone turnover. This did not translate to an increase in bone loss. BMD loss was not observed at ≥3 years after initiation of DMPA.33

Concerns exist regarding bone recovery and an increased risk of fracture, especially in adolescents. During adolescence, when BMD is rapidly accruing, the stunting of this process may be associated with adverse effects on bone integrity (e.g., fracture) later in life.34 It is unclear whether DMPA use (and subsequent bone loss) during adolescence and early adulthood is associated with an increased risk of fracture later in life.30

One study found no increase in the risk of fracture with short-term use of DMPA in females aged 13 to 20 years.27 A slight increase in the risk of fracture in participants aged 20 to 44 years was observed in another study. There appears to be a greater risk of fracture in current users; however, the risk falls as duration from the last dose increases. The researchers observed the greatest risk of fracture in women currently using DMPA for 2 to 3 years.35

Upon DMPA cessation, BMD increases, but may not reach pretreatment levels. Partial or full recovery at the spine occurs, but only partial recovery may be observed at the hip in adolescents and young women.27,30 Factors that determine the extent of recovery include age, duration of use, and extent of bone loss.27

Recovery at the spine occurred more quickly than at the hip in a study of 18- to 35-year-old females; however, the values did not return to baseline by 18 months from the last injection. Women who used DMPA for 24 to 36 months displayed a 3.1% decrease from baseline BMD of the spine, and the hip BMD remained at 4.7% below pretreatment levels.32

In 2004, the FDA issued a black box warning cautioning long-term DMPA use and bone loss. The FDA suggests DMPA should be discontinued after 2 years of treatment. The American College of Obstetricians and Gynecologists (ACOG) recommends weighing the risks versus the benefits of therapy, but does not advise against long-term use since most bone loss occurs during the first 2 years of therapy.30

Aromatase Inhibitors (AIs)

AIs are routinely used in postmenopausal estrogen receptor-positive breast cancer patients, either immediately following surgery or after a few years of tamoxifen therapy.36 Unlike tamoxifen, which has estrogen-like protective effects on the bone, AIs induce bone loss.2 AIs inhibit the aromatization of androgens, thereby suppressing peripheral estrogen production to below postmenopausal levels, resulting in a rapid loss of BMD.2,37 The average annual bone loss is 2% in the spine and 1.5% in the hip. Most loss of BMD occurs in the first 12 months.36,38 Baseline BMD and estradiol concentrations correlate to the extent of adverse skeletal effects. Initiation of therapy early after menopause is associated with an increased bone loss.2

Factors that increase the risk of fracture in women with breast cancer who are using AIs include T-score <-1.5, age >65 years, low BMI (<20 kg/m2), family history of hip fracture, personal history of fragility fracture after age 50 years, oral corticosteroid use >6 months, and smoking.37

The relative risk of vertebral and nonvertebral fractures can be increased by as much as 40% when compared to that of tamoxifen; however, the risk of fracture eventually returns to baseline upon discontinuation of the drug.2,36 Though the risk of fracture appears to return to baseline, recovery of BMD is only partial after discontinuing AIs. In one study, an increase in BMD of 1.53% at the lumbar spine was observed 24 months from drug discontinuation. Recovery at the hip was not as impressive.36

There is solid evidence that bone loss may be prevented and BMD can be increased by initiating zoledronic acid (4 mg IV every 6 months) concurrently with the AI.38 The decision to initiate antiresorptive therapy should not be made on the BMD measurements alone.

All women starting AI therapy should be assessed for fracture risk. With a T-score ≥-2.0 and no other risk factors, reassess BMD after 1 to 2 years. All women should supplement with calcium and vitamin D. Antiresorptive therapy should be started if there is evidence of a decrease of BMD ≥10% within a year (or 4%-5% if osteopenic at baseline).37

Thiazolidinediones (TZDs)

The use of TZDs has been shown to have deleterious effects on BMD. TZDs should be avoided in patients with established osteoporosis or at high risk for fracture.2 Risk factors for fracture include female gender, advanced age (>65 years), and longer duration of treatment. BMD is compromised through an increase in bone resorption and a decrease in bone formation.39

TZDs increase insulin sensitivity by acting as agonists of peroxisome proliferator-activated receptor (PPAR) gamma.13 PPAR gamma is expressed in stromal cells of the bone marrow, osteoblasts, and osteoclasts and plays an important role in the differentiation of precursor cells into osteoblasts.40 By impairing the differentiation of osteoblast precursors, bone formation is compromised. Additional ways that TZDs may act on bone are by increasing adiposity of bone marrow, decreasing aromatase activity, and promoting osteoclast differentiation, all of which increase bone resorption.41

A study on postmenopausal women using rosiglitazone demonstrated an annual reduction of BMD at the trochanter and lumbar spine of 2.56% and 2.18%, respectively. No significant difference was seen between the active group and control group at the femur neck and total hip. There were no fractures of the hip, spine, or distal forearm in either group in this study.40

A meta-analysis exploring long-term use and risk of fractures found that fracture risk was increased in women (but not men) while using rosiglitazone or pioglitazone.41

Proton Pump Inhibitors (PPIs)

PPIs appear to increase the risk of hip fracture, but not in those without preexisting fracture risk.42 Large epidemiologic studies have found an increased risk of fracture with long-term PPI use (≥1 year).43 The effects do not appear to be dose dependent.13 A large meta-analysis found that PPI (but not H2-receptor antagonist) use was associated with an increased risk of fracture.44

A second meta-analysis confirmed these results, which showed there was a modest increase in hip and vertebral fractures. Because these meta-analyses were based on observational studies (rather than randomized, controlled trials), the results should be interpreted with caution.45

Data from the Women's Health Initiative did not demonstrate an increased risk of hip fracture with PPI use.42 There was a 47% increased risk for clinical spine fracture and a 26% increased risk for forearm or wrist fracture associated with PPI use. No association was found between H2-blocker use and greater risk of fractures of the hip, spine, or forearm. Increased risk was not associated with longer use; however, few women exceeded 3 years of PPI use. No loss of bone was observed in study participants.42

Another study also failed to find an association between PPI use and a reduction of BMD in a Manitoba population consisting primarily of women aged >65 years.46

The risk of fracture appears to reverse 1 year after discontinuing the drug.2 A decrease in calcium absorption is thought to be the mechanism contributing to the increased fracture risk. Calcium carbonate needs an acidic environment for maximum absorption, and potent acid suppression can compromise calcium absorption.13,42 Supplementing with calcium citrate can improve calcium absorption when compared to calcium carbonate.

Because of the lack of evidence demonstrating a loss of BMD with PPI use, randomized controlled trials are needed to definitively prove a causal effect between PPI use and increased risk of fracture.45

Loop Diuretics (LDs)

There is evidence that LDs are associated with a loss of BMD. Loop diuretics increase the renal excretion of calcium, which can result in a hypocalcemic state.2,47 Compensatory processes are thought to be responsible for the loss of bone. One study showed a significant increase in parathyroid hormone a few hours after a dose of bumetanide, which promotes bone resorption.47 BMD loss appears to be dose-dependent.48

A study of men aged ≥65 years using LDs demonstrated BMD loss, which also appeared to be dose dependent. The loss was not as great as has been observed with postmenopausal women. Bone loss was larger in continuous users than in intermittent users or nonusers.49

In a randomized, controlled trial of postmenopausal women supplementing with calcium and vitamin D, BMD loss was observed after 1 year in the active group (bumetanide 2 mg/day). The decrease of BMD at the hip, forearm, and lumbar spine was 1.6%, 2.0%, and 1.0%, respectively. After bumetanide was discontinued, BMD appeared to recover. Six months posttreatment, there was no significant difference between the treatment group and the control group.47

Whether or not BMD loss from LDs increases the risk of fracture is uncertain. Some experts believe there is an increase in nonvertebral fractures, but the evidence is conflicting.2,50 Several studies have found no association with an increase in falls or fractures (nonvertebral or hip).50,51

Cyclosporine (CsA)

CsA has been shown to increase bone resorption in vivo.2 Since CsA is often taken with GCs, it is difficult to discern the extent to which CsA contributes to adverse skeletal effects.2,52 CsA use is associated with an increase in osteocalcin levels. Since GCs lower osteocalcin, this is suggestive of a secondary process of increased bone turnover resulting from CsA use. Bone loss appears to be dose and time dependent.52

Transplant patients often have preexisting osteopenia or osteoporosis prior to surgery.52 Risk factors that are associated with a decrease of BMD in renal transplant patients include male gender, time after transplantation, older age, and time on dialysis prior to transplantation. A study in renal patients compared CsA monotherapy to prednisolone plus azathioprine combination therapy. No significant difference in BMD loss was evident between the two groups. A loss of BMD was observed at the forearm, femoral neck, and lumbar spine, with the forearm being most evident.53

The mechanism by which CsA decreases BMD is unclear. CsA inhibits interleukin-2 production and secretion and T-lymphocyte activation. The immune system is thought to affect bone remodeling.52 CsA is thought to activate osteoclasts, suppress osteoblasts, and suppress bone formation.53 CsA may also increase the metabolism of vitamin D.2

CsA use may not contribute to an increased risk of fracture. A study of female rheumatoid arthritis patients did not find a significant difference in fracture or BMD at the lumbar spine or femoral neck between CsA (<24 months) users and nonusers. A significant difference in BMD did become evident with CsA use exceeding 24 months. The authors concluded that long-term CsA use may be associated with a decrease of BMD.54

Tacrolimus is associated with less toxicity than CsA and appears to be less detrimental to bone.55 A small study of male liver transplant patients evaluated the effects on BMD after substituting CsA with tacrolimus. Although BMD at the femoral neck did not undergo significant improvement, there was an overall improvement of BMD at the lumbar spine after 1 year.56

Since bone loss occurs early in immunosuppressive therapy, preventive and treatment measures should be initiated early.2 Some studies have shown that supplementation with calcium and vitamin D has a protective effect against bone loss in transplant patients; however, improvement in BMD was not evident when supplementation was initiated 12 months following transplant.55,57 Antiresorptive therapy is appropriate in CsA patients.2

Antiretroviral Therapy (ART)

HIV-infected patients are more prone to suffer loss of BMD. The chronic inflammation and possibly the virus itself affect bone resorption and osteoclast activity. A meta-analysis found the prevalence of osteoporosis in HIV-infected patients to be 15%, three times more than HIV-uninfected persons.58 ART is thought to contribute to BMD loss. BMD decreases 2% to 6% in the first 2 years following initiation of ART.59

ART-treated patients are twice as likely to have osteoporosis than ART-naïve patients.58 In a longitudinal cohort study, 15.5% of HIV-infected patients developed osteoporosis after an average of 2.5 years on ART. By 5 years, approximately one-third of patients had developed osteoporosis.60

HIV-infected patients are often treated with a combination of drugs, making it difficult to identify the effects individual agents have on bone. Regimens including tenofovir (TDF) induce a greater reduction of BMD than those without TDF.59,60 Protease inhibitors (PIs) have been implicated in bone loss, but it does not seem to be a class effect. Different PIs are associated with varying degrees of bone loss.60

The processes of bone loss are diverse and vary by agent. TDF damages the proximal tubules of the kidney, resulting in phosphate wasting.59 This impedes bone mineralization.58 Zidovudine promotes osteoclastogenesis, thereby increasing resorption.58,60 PIs increase osteoclast differentiation, decrease osteoblast differentiation, and alter vitamin D metabolism.60 Efavirenz (EFV) is also associated with decreased vitamin D levels.59,60

A study was completed comparing the effects on BMD of four common ART regimens.59 The regimens were abacavir (ABC) plus lamivudine (3TC) plus EFV; 3TC plus ABC plus atazanavir/ritonavir (ATV/r); TDF plus EFV plus emtricitabine(FTC); and TDF plus FTC plus ATV/r. There was no statistically significant decrease of BMD at the spine with ABC-3TC-EFV at week 96. Researchers observed a greater decrease in spine and hip BMD with TDF-FTC than with 3TC-ABC. The addition of ATV/r (a PI) induced a greater decrease of BMD at the spine than did the addition of EFV.59

Other risk factors for low BMD in HIV-infected patients include higher baseline HIV-1 RNA load, lower baseline CD4 cell count, advanced age, male gender, hepatitis C co-infection, time on a PI, and time on ART.60

Some HIV-infected persons have an increased risk of fracture.60 A large population-based study of 8,525 HIV-infected patients demonstrated a significant increase in fractures (spine, hip, or wrist) when compared to HIV-negative controls. The risk increased with age.61

Risk factors for fracture in HIV-infected individuals were identified in a cohort study of patients treated with combination ART. Risk factors included positive hepatitis status and excessive alcohol use.62 Another study of younger patients (median age 38 years) who were not prone to falls showed no increased risk of fracture.59

The Role of the Pharmacist

Management of bone health includes a reduction in risk factors, supplementation with calcium and vitamin D, and physical exercise.2 The pharmacist is an integral part of the health care delivery team and is often the first person the patient contacts for assistance. Pharmacists are able to play an important role in maintaining excellent skeletal health for their patients. All patients should have an osteoporosis/fracture risk assessment performed by their physician using nondrug factors and the WHO FRAX tool, keeping in mind that the FRAX tool is not specifically designed to account for drug-induced osteoporosis.12 The patient should be routinely reassessed to determine BMD status.13

Other factors predisposing a patient to low BMD include genetic predisposition, female gender, advanced age, low physical activity, excessive caffeine and alcohol intake, and smoking.10 The pharmacist should counsel the patient on modifiable risk factors and offer assistance with smoking cessation if necessary. Other counseling points include calcium (calcium citrate if the patient is on a PPI) and vitamin D supplementation and the importance of medication adherence.13

A drug utilization review should be performed on high-risk patients, and the pharmacist and physician should explore the option of switching patients to a safer medication alternative if available. If no safe alternatives are appropriate, initiating preventive measures should be considered.13


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  12. Grossman J, Gordon R, Ranganath V, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res. 2010;62:1515-1526.
  13. Pitts, C, Kearns A. Update on medications with adverse skeletal effects. Mayo Clin Proc. 2011;86:338-343.
  14. Muir J, Andrew M, Hirsh J, et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood. 1996;88:1314-1320.
  15. Rajgopal R, Bear M, Butcher M, Shaughnessy S. The effects of heparin and low molecular weight heparins on bone. Thrombosis Research. 2008;122:293-298.
  16. Handschin A, Egermann M, Trentz O, et al. Cbfa-1 (Runx-2) and osteocalcin expression by human osteoblasts in heparin osteoporosis in vitro. Clin Appl Thromb Hemost. 2006;12:465-472.
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