|Year : 2019 | Volume
| Issue : 5 | Page : 44-51
Drug-induced bone disorders: A systematic review
Anshita Aggarwal1, Meha Sharma2, Indira Maisnam3, Soumitra Ghosh4, Sameer Aggarwal5, Saptarshi Bhattacharya6, Deep Dutta7
1 Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Dr. Ram Manohar Lohia Hospital, New Delhi, India
2 Department of Rheumatology, Center for Endocrinology, Diabetes, Arthritis, and Rheumatism Superspeciality Clinics, New Delhi, India
3 Department of Endocrinology, RG Kar Medical College, Kolkata, West Bengal, India
4 Department of Medicine, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
5 Department of Endocrinology, Apex Hospitals, Rohtak, Haryana, India
6 Department of Endocrinology, Max Superspeciality Hospitals, New Delhi, India
7 Department of Endocrinology, Center for Endocrinology, Diabetes, Arthritis, and Rheumatism Superspeciality Clinics, New Delhi, India
|Date of Web Publication||2-Dec-2019|
Dr. Deep Dutta
Department of Endocrinology, Center for Endocrinology, Diabetes, Arthritis, and Rheumatism Superspeciality Clinics, 33 DDA MIG, Pocket-1, Netaji Subhash Sector 13, Dwarka, New Delhi - 110 078
Source of Support: None, Conflict of Interest: None
Drug-induced bone disorders are a group of disorders characterized by osteomalacia or osteoporosis, with the common denominator being the iatrogenic nature of the disease. Drug-induced bone disorders are either due to the drug directly effecting the bone microarchitecture (osteoblastic or osteoclastic activity) or indirectly by interfering with Vitamin D metabolism, Vitamin D/calcium absorption, and excess calcium loss or due to altered hormone states which promote bone loss (hypogonadism, hyperthyroidism, somatostatin excess states, insulin deficiency, increased systemic inflammation, and oxidative stress). References for this review were identified through searches of PubMed, Medline, and Embase for articles published until July 2019 using the terms “drug induced bone disorders” (MeSH Terms) AND “osteoporosis” (All Fields) OR “osteomalacia” (All Fields). Anti-epileptics, proton pump inhibitors, glucocorticoids, immunosuppressants (calcineurin inhibitors), anticoagulants, glitazones, SGLT2 inhibitors, somatostatin analogs, anticancer medications, and protein kinase inhibitors are some of the commonly used medications associated with bone mineral loss. An increased awareness, minimizing the use of these medications in patients at increased risk of fractures, keeping dosage and duration of therapy to the lowest, ensuring Vitamin D and calcium adequacy either through diet or supplements, and prophylactic use of bisphosphonates (where indicated) can play a major role in preventing morbidity associated with drug-induced bone disorders.
Keywords: Drug-induced osteoporosis, drug-induced osteomalacia, metabolic bone disease, Vitamin D
|How to cite this article:|
Aggarwal A, Sharma M, Maisnam I, Ghosh S, Aggarwal S, Bhattacharya S, Dutta D. Drug-induced bone disorders: A systematic review. Indian J Rheumatol 2019;14, Suppl S1:44-51
|How to cite this URL:|
Aggarwal A, Sharma M, Maisnam I, Ghosh S, Aggarwal S, Bhattacharya S, Dutta D. Drug-induced bone disorders: A systematic review. Indian J Rheumatol [serial online] 2019 [cited 2019 Dec 9];14, Suppl S1:44-51. Available from: http://www.indianjrheumatol.com/text.asp?2019/14/5/44/272152
| Introduction|| |
Drug-induced bone disorders are a group of disorders characterized by osteomalacia or osteoporosis, with the common denominator being the iatrogenic nature of the disease. Many of the drugs used in treating various systemic disorders can have a myriad of adverse effects on bone health, by interfering with Vitamin D metabolism, interfering with Vitamin D/calcium absorption, promoting calcium loss through urine, or by directly affecting osteoblastic or osteoclastic activity. In addition, conscious efforts have been made to find drugs which cause altered hormone states which, in turn, promote bone loss (hypogonadism, hyperthyroidism, somatostatin excess states, insulin deficiency, increased systemic inflammation, and oxidative stress). As many such drugs find a routine use in clinical practice, it is prudent for the clinician to be cognizant with the mechanisms and prevention/treatment strategies of these drug-induced bone disorders. This review has attempted to consolidate the available data on this subject and present it lucidly. The various drugs have been classified based on the organ systems for which they are used in different medical conditions.
| Search Strategy and Selection Criteria|| |
References for this review were identified through searches of PubMed, Medline, and Embase for articles published until July 2019 using the terms “drug induced bone disorders” (MeSH Terms) AND “osteoporosis” (All Fields) OR “osteomalacia” (All Fields). The reference lists of the articles thus identified were also searched. The search was not restricted to English-language literature.
| Drugs Used in Neurological Disorders|| |
Epilepsy is one of the most common neurological disorders, which usually requires very long-term treatment. Anti-epileptic drugs (AEDs) are used widely not only for epilepsy but also for certain psychiatric conditions and chronic pain disorders. The relationship between AED use and increased fracture risk and metabolic bone disease (MBD) has been known since long. Various theories for the plausible mechanisms have been proposed. The most accepted theory is that AEDs such as phenytoin and phenobarbital, which are inducers of cytochrome p450 enzymes, expedite Vitamin D metabolism, leading to Vitamin D deficiency-related bone disorders such as osteomalacia. However, several studies have challenged this hypothesis by demonstrating the presence of bone disease even in the absence of Vitamin D deficiency and even with nonenzyme-inducing AEDs such as valproate.
Other postulated mechanisms for AED effects on bone health include the direct inhibition of intestinal calcium absorption due to phenytoin or phenobarbital use, which has been shown in rat models.
Poor bone mineral density (BMD) as a consequence of hypogonadism due to alterations in the sex steroids by a varied mechanism such as the anti-androgenic activity of valproate and increase in sex hormone-binding globulin by carbamazepine has also been implicated.
Apart from these, other factors relating to the disease perse may also come into play, such as reduced physical activity, poor dietary consumption of calcium, and less sun exposure. In addition, a fall during the seizure may increase the fracture risk.
Various studies have shown reduced BMD with the use of AEDs. In a Japanese study by Sato et al., BMD at the second metacarpal was compared in forty individuals receiving phenytoin or valproate monotherapy against forty healthy controls. There were 14% and 13% reduction in BMD in the valproate and phenytoin groups, respectively. The phenytoin group also had Vitamin D deficiency with secondary hyperparathyroidism and high bone turnover. Similar findings were seen in the studies by Gough et al. in 1986, Feldkamp et al., and Välimäki et al.
Boluk et al. in their study illustrated a lower BMD at the proximal femur and lumbar spine in fifty adults on valproate monotherapy for a mean duration of 7.7 years, as compared to healthy controls. BMD was repeated at 6 months, and there was a further reduction in BMD by 4.6% at the lumbar spine and 4.9% at the femur in valproate users.
In a study by Pack et al., among individuals taking monotherapy with varied AEDs, calcium levels were lower in the carbamazepine, phenytoin, and valproate groups when compared to lamotrigine, with comparable daily calcium intake. However, BMD Z scores did not significantly differ between groups. This was probably due to the cross-sectional nature of the study. More longitudinal studies are needed to know the true impact of AEDs on bone health.
Although there are no consensus guidelines on the treatment of AED-related bone disorders, it is generally recommended that a baseline serum calcium and phosphorous and BMD should be assessed at the initiation of therapy, and if that is abnormal, then Vitamin D and parathyroid hormone (PTH) levels should be assessed. The National Institute for Clinical Excellence recommends the test of bone metabolism every 2-5 years for adults taking liver enzyme-inducing AEDs. Patients who are on such AEDs such as barbiturates and carbamazepine should be routinely given calcium and Vitamin D supplementation. Certain newer AEDs such as lamotrigine, which do not affect bone accrual, may be preferred over older AEDs.
| Drugs Used in Gastrointestinal Disorders|| |
Proton pump inhibitors (PPIs) find a widespread and often over-the-counter use for various gastrointestinal disorders. The association between long-term PPI use and increased risk of fractures has been time and again proven in various studies. However, there is still a lack of conclusive evidence of causality.
A Swedish prospective study included 6414 postmenopausal women (The WHILA project) in 1995-2000. During the follow-up period, the risk of fracture was doubled in women using PPIs (odds ratio [OR]: 2.53 [95% confidence interval (CI): 1.28-4.99]). A modestly increased risk for hip fractures (OR: 1.09 [95% CI: 1.01-1.17]) among patients on PPIs was found in a UK primary practice nested case-control study consisting of 10,958 patients with incident hip fractures and 20,000 nonfracture control patients.
Various hypotheses have been proposed for the mechanism of PPI-induced bone loss, the most popular of these is the reduced intestinal absorption of calcium and magnesium which is seen with prolonged PPI use because of interference with the acidic gastric environment. PPI use may also lead to Vitamin B12 deficiency, which could lead to neuropathy and hence increased risk of falls and fractures. However, various confounding factors may come into play, such as age-related bone decline and comorbid illnesses, which is noteworthy as the maximum consumption of PPIs is seen in the aging population.
Regardless of the possible impact of these confounding factors and lack of proven causality, the current evidence is strong enough to warrant a judicious and vigilant prescription of PPIs, with the use being limited to the lowest possible dose and for the shortest possible duration. Over-the-counter use of PPIs should be strongly discouraged. Those individuals who are on long-term PPI treatment must be offered calcium and Vitamin D supplementation under supervision.
| Drugs Used in Rheumatology and Immunology|| |
Autoimmune disorders are in general associated with systemic and tissue-specific inflammation. Increased systemic inflammation (increased circulating cytokines) is associated with osteoclast activation and inhibition of osteoblasts, explaining the bone mineral loss in rheumatologic disorders. In patients with rheumatoid arthritis (RA), increased disease activity is a strong predictor of bone mineral loss. Increased RA severity is associated with lean muscle mass loss, which also contributes to impaired bone health. Glucocorticoids (GCs) also find wide use in the management of rheumatological disorders but are associated with a myriad of adverse effects on bone health, which have been discussed later.
The advent of the use of biologics has revolutionized the treatment of rheumatological disorders. These diseases are associated with bone loss perse because of the inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which activate osteoclastic bone resorption. The use of biologics such as TNF-α inhibitors has rather been associated with an improvement in BMD  and a reduction in fracture risk, except in the bones of the hand, where no protective action has been observed, possibly because of the lack of local anti-inflammatory effect. However, better results have been seen with IL-6 antagonists in terms of localized bone loss. Very few studies have reported inhibition of bone loss after rituximab and abatacept treatment. Anti-receptor activator of nuclear factor kappa-B ligand (RANKL) therapy has shown beneficial effects in the preservation of bone mass in RA, especially in juxta-articular osteoporosis, although this treatment cannot alter the inflammatory process.
Cyclosporine is commonly used as a GC sparing agent in autoimmune disorders. Use of cyclosporine is associated with bone mineral loss. Tacrolimus is a common part of different immunosuppressive regimens used in organ transplant patients. Chronic use of tacrolimus is also associated with osteoporosis. Calcineurin inhibitors (cyclosporine and tacrolimus) cause Vitamin D resistance through their blockade effect on Vitamin D receptors, resulting in renal calcium wasting, leading to bone mineral loss.
| Drugs Used in Cardiology|| |
Research has shown that Vitamin K plays a role in bone metabolism and is potentially protective against osteoporosis. Vitamin K is required for the gamma-carboxylation of osteocalcin, which is a bone protein. A similar process of gamma-carboxylation also occurs in the liver for several coagulation factors; hence, there is a concern involving adverse effects on bone of agents such as coumarin-based anticoagulants which interfere with this process.
Over the last few years, revelations have been made about the role of other Vitamin K-dependent proteins concerning bone metabolism, other than that involved in gamma-carboxylation. These proteins include osteocalcin, matrix Gla protein, and protein S. They have a pivotal role in vascular repair, prevention of vascular calcification, cell-cell adhesion, cell cycle regulation, and signal transduction. Osteocalcin, in turn, is required for bone mineralization, maturation, and remodeling.
Various short-term and long-term clinical trials have consistently reported positive effects of Vitamin K supplementation on osteocalcin, BMD, indices of bone strength, or fracture risk. Few studies have shown an adverse effect of long-term warfarin on BMD and fracture risk.
The adverse effects of warfarin on bone health are directly related to the duration of treatment, with a significant deterioration seen only with a therapy lasting for >1 year. In addition, the maximum brunt is seen to be borne by the trabecular-rich vertebral sites. However, most of the studies were fraught with limitations such as inability to control for important factors such as calcium and Vitamin D intake, Vitamin K status, body mass index, exercise, or BMD. Furthermore, these studies do not show causality conclusively.
In light of the available evidence, it makes sense to carefully weigh the risk-benefit ratio while prescribing long-term warfarin therapy, particularly in the aging population. Moreover, now, anticoagulants such as ximelagatran are available that do not interfere with Vitamin K metabolism. BMD of patients who are on long-term anticoagulant therapy should be regularly monitored and their Vitamin D and calcium status should be optimized vis-a-vis diet and supplementations, if required.
Heparin is yet another commonly used anticoagulant. Although its short-term use is not associated with reductions in BMD or increased fractures, its long-term use may lead to these complications. Mechanistically, unfractionated heparin inhibits osteoblast differentiation and function, leading to decrease in bone formation. In addition, heparin increases bone resorption by leading to reductions in osteoprotegerin (OPG), favoring RANKL-induced osteoclast differentiation.
Newer anticoagulants such as fondaparinux are bone neutral and may be preferred in high-risk cases when long-term anticoagulation is desired.
| Drugs Used in Diabetes|| |
The increasing diabetes pandemic is perhaps the most important contributor to impaired bone health in the general population. India currently has a 9% prevalence of diabetes, and an additional 14%-18% prevalence of prediabetes., Diabetes perse is associated with an increased risk of fractures. Studies in Type 1 diabetes mellitus (T1DM) have shown a six- to nine-fold increase in the relative risk (RR) for hip fractures; the RR for any other nonvertebral fracture is 1.3-3. Studies in Type 2 diabetes mellitus (T2DM) have shown an increased risk in hip, vertebral, and other nonvertebral fractures, in both men (RR: 2.8; 95% CI: 1.2-6.6) and women (RR: 2.1; 95% CI: 1.6-2.7). Impaired bone mineral mass in T1DM due to loss of trophic effect of insulin and impaired bone mineral quality in T2DM are primarily responsible for increased fractures in patients with diabetes.,
With the exponential rise in the incidence of diabetes, the use of antidiabetic medications is also on the rise. T2DM is primarily a disease of the aging population, wherein osteoporosis is a commonly occurring comorbidity. The impact of diabetes as well as oral antidiabetic drugs (OADs) on BMD and fractures has been reported in a few studies over the last couple of decades.
Among all the classes of OADs, thiazolidinediones are the most notorious for their adverse effects on BMD. Pioglitazone, a thiazolidinedione antidiabetic agent, promotes adipocyte differentiation into smaller and insulin-sensitive adipocytes as a trade-off for osteoblast formation. This suppressed osteoblast formation has a detrimental effect on bone health and increases fracture risk. In a recent meta-analysis involving 22 randomized controlled trials (RCTs) (n = 29,544), a statistically significantly increased incidence of fracture was found in women on thiazolidinediones (OR: 1.94; 95% CI: 1.60-2.35; P < 0.001). It is for this reason that these drugs should be prescribed with caution, particularly in elderly women, who are as such predisposed for osteoporosis.
With sulphonylureas, the risk of hypoglycemia-mediated falls leading to fractures is a concern. As such, existing data support the impression that sulfonylureas have a minimal effect and are at least neutral concerning BMD, and their effects regarding fractures are confounded by the hypoglycemia-induced fall risk in elderly patients.
SGLT-2 (sodium-glucose linked transporter) inhibitors are the newest class of drugs in the antidiabetic armamentarium. Bone mineral loss due to SGLT2i is a class effect. The greater the potency of the drug, the more is the likely bone mineral loss., Hence, bone mineral loss has maximally been linked with canagliflozin, followed by empagliflozin and dapagliflozin., One plausible explanation is the increased risk of hypoglycemia-mediated falls. The risk of fall may also be increased by the mild volume depletion caused by these drugs. SGLT-2 inhibitors could also lead to poorer bone mechanical quality. It is well established that they induce weight loss, which may predispose patients to a reduction in BMD. These drugs also lead to increased tubular reabsorption of phosphate, and increased serum phosphate levels are capable of stimulating PTH secretion, which ultimately enhances bone resorption and the risk of fractures.
In fact, in a recent meta-analysis of 38 RCTs with 496 fracture events among 30,384 patients with T2DM followed up for 24-160 weeks, none of the three SGLT-2 inhibitors were shown to augment fracture risk. The authors suggested that the increased fracture rate associated with canagliflozin in one study might be attributable to chance or possibly other risk factors, even in subgroups of patients with an increased risk of fracture. However, it must be realized that this meta-analysis was based on RCTs having a median follow-up of 2-4 years. Bone mineral changes are accrued over decades. Hence, we need longer follow-up studies of >10 years' duration, before we can really say that adverse bone mineral outcomes and increased fractures do not occur with the long-term use of SGLT2i.
Insulin has an anabolic effect on bone metabolism; thus, theoretically, the hyperinsulinemia seen in T2DM should lead to an increase in BMD. However, insulin therapy perse can augment the risk of fractures due to hypoglycemia-mediated falls. The lack of RCTs regarding that effect makes it difficult to draw absolute conclusions. Among the other agents, metformin, GLP-1 analogs, and DPP-4 inhibitors have a neutral effect on bone health. It is important to consider that lack of physical activity-related loss of lean muscle mass, which is also an important predictor of bone mineral loss in diabetes.
| Glucocorticoids (Use in Different Clinical Scenarios Across Different Organ Systems)|| |
GCs have an important role in the treatment of various auto-immune and inflammatory conditions. However, their use is associated with many side effects, including bone loss and increased fracture risk. As many as 30%-40% of patients on long-term GC therapy have radiographic evidence of vertebral fractures.
The highest rate of bone loss is observed within the first 3-6 months of GC treatment, although a slower decline continues with persistent use. The maximum impact is seen on the metabolically active trabecular bone such that most of the fractures involve the vertebrae. This fracture risk is a function of both the daily dose and the cumulative dose of GCs.
However, GC treatment is a potentially reversible risk factor for glucocorticoid-induced osteoporosis (GIOP); if GC treatment is terminated, BMD increases and fracture risk declines.
The mechanism behind GIOP is multifactorial. This includes direct suppression of osteoblasts, enhanced RANKL activity leading to augmented osteoclastic resorption, reduced intestinal calcium absorption, and hypercalciuria leading to secondary hyperparathyroidism. The ACR guidelines recommend that all adult patients on GCs should be evaluated for bone health using the FRAX tool (https://www.shef.ac.uk/FRAX/tool.jsp) as soon as possible, or at least within 6 months of initiating GCs. For those patients who are only on calcium and Vitamin D supplements, a reassessment with a repeat BMD is recommended at 1-3 years, whereas for those on specific anti-osteoporotic treatment, it is recommended at 2-3 years. These criteria are applicable for high-risk patients. These include those on an initial dose of prednisone >30 mg/day or a cumulative dose of 5 g in the preceding 1 year.
For patients at a lower risk, a lesser frequency of reassessment would suffice. All patients on GCs should be advised to optimize calcium intake (1,000-1,200 mg/day) and Vitamin D intake (600-800 IU/day; serum level >20 ng/ml). Those adults who are at moderate and high risk (10-year major osteoporotic fracture risk of 10%-19% and >20%, respectively) should be treated with oral bisphosphonates (bisPs). If oral bisPs are deemed inappropriate, then intravenous (IV) bisPs should be given. If IV bisP cannot be given, teriparatide or denosumab are the other treatment options.
It is important to consider that GC replacement, even at the so-called physiologic replacement doses used in various endocrinology disorders (Addison's disease, panhypopituitarism), has been reported to be associated with impaired bone health and avascular necrosis of the bone.,
| Drugs Used in Nephrology|| |
MBD is a characteristic feature of chronic kidney disease, which includes secondary/tertiary hyperparathyroidism, osteomalacia, and adynamic bone disease (ABD). Hyperphosphatemia is a forerunner of MBD. It is a potent stimulus for secondary hyperparathyroidism, thus leading to increased bone resorption and osteitis fibrosa. Sevelamer, which is a noncalcium phosphate binder, decreases the hyperphosphatemic stimulus for parathyroid gland hyperplasia and therefore diminishes the risk of overt hyperparathyroidism and osteitis fibrosa.
ABD, which is most often iatrogenic, is characterized by overtly suppressed bone turnover and can be reliably diagnosed only by a bone biopsy. Oversuppression of PTH is an additional hallmark of ABD. Overenthusiastic use of Vitamin D analogs and/or calcimimetics is the main culprit, and treatment involves stepping down on these agents. The use of calcium-containing phosphate binders can also lead to the oversuppression of PTH. This can be managed by switching over to noncalcium-containing binders such as sevelamer. Teriparatide (PTH 1-34), which has been Food and Drug Administration approved to treat postmenopausal osteoporosis, may have a growing role in the treatment of ABD.
| Drugs Used in Endocrinology|| |
Antidiabetic medication-related bone mineral loss has already been discussed previously (vide supra). In addition, GC-related bone mineral loss has been discussed. Thyroxine, which is commonly used for the treatment of hypothyroidism, when used in more-than-required doses leading to iatrogenic hyperthyroidism, is associated with weight loss, bone mineral loss, and increased risk of atrial fibrillation. Symptoms and manifestations of iatrogenic hyperthyroidism are akin to endogenous hyperthyroidism (Grave's disease and thyroiditis). Long-term use of GnRH analogs (leuprolide, triptorelin, and goserelin) have been linked with increased bone mineral loss. Bone mineral loss is due to the hypogonadism caused by these medications. Sex steroids, especially estrogen, have a potent trophic impact on bone health. GnRH analogs are used in the management of menorrhagia, dysfunctional uterine bleeding, and precocious puberty. Cinacalcet is used in the management of renal osteodystrophy-related tertiary hyperparathyroidism, medical management of primary hyperparathyroidism, and hypophosphatemic osteomalacia; the overdose of this medication can lead to too much suppression of PTH levels, which can lead to ABD., Somatostatin receptor analogs such as depot octreotide and sandostatin-LAR, which are used in the management of neuroendocrine tumors, have also been linked with impaired Vitamin D metabolism, calcium malabsorption, and bone mineral loss.,
bisPs are recommended agents for the prevention of osteoporosis in patients with high risk of osteoporosis such as those on prolonged GCs use (vide supra). However, it must be remembered that prolonged continuous use of bisPs leads to chronic persistent loss of osteoclasts, leading to a secondary loss of osteoblasts, resulting in a bone metabolic state akin to ABD. Here, although the BMD may appear higher, it is falsely reassuring, as the bone quality is impaired, and the patient has a risk of fractures at atypical sites even after trivial injury (e.g. atypical femoral fractures). This is the cause of loss of bone matrix, and the bone becomes akin to a chalk stick. Intermittent use of bisPs, giving a drug holiday of few years after 3-4 years of bisP use, is the best way to prevent atypical fractures. Osteonecrosis of jaw is another rare complication reported with bisP and denosumab use. It is predominantly seen in patients with a history of hematologic or other malignancies.
| Drugs Used in Infectious Diseases|| |
HIV-1 infection is associated with upregulation of pro-inflammatory cytokines (e.g., TNF-α), which can lead to increased osteoclastic activity and hence bone resorption. More severe disease activity, lower baseline CD4 cell count, greater loss of lean muscle mass, hypogonadism, and Vitamin D deficiency all have been documented to be independent predictors of impaired bone mineral health and fractures in people living with HIV infection.,, This risk of poor bone health is further compounded by antiretroviral therapy. Disturbed Vitamin D metabolism, i.e., an increased vitamin degradation due to induction of CYP3A4, appears to play a major role. In a study of 1077 HIV-infected patients, the risk of severe Vitamin D deficiency was significantly increased by the intake of the nonnucleoside reverse transcriptase inhibitor efavirenz. In light of the available evidence, Vitamin D administration in individuals infected with HIV is imperative, to reduce the risk of drug-induced osteopathy.
Drugs such as rifampicin and isoniazid can lead to accelerated Vitamin D metabolism, via induction of cytochrome P-450 dependent enzymes, and can thus lead to osteomalacia. In addition, extensive sarcopenia, fat mass loss, and overall significant weight loss also contribute to impaired bone mineral health in tuberculosis. Use of antibiotics results in alternation of gut flora, resulting in an increased Firmicutes: Bacteroidetes ratio, which, in turn, results in increased gut permeability, increased systemic inflammation, and trabecular bone loss. Probiotic Lactobacillus reuteri has been demonstrated to prevent postantibiotic bone loss by reducing intestinal dysbiosis and preventing barrier disruption.
| Drugs Used in Oncology|| |
Doxorubicin, commonly used in different combination cocktails for the treatment of childhood hematologic cancers and solid tumors, is associated with impaired bone architecture, leading to bone mineral loss. Cancer chemotherapy agents (alkylating agents and taxanes among others) are commonly associated with primary gonadal failure (primary ovarian insufficiency in females and testicular failure in males). Hypogonadism in any form is associated with increased bone mineral loss and fractures due to loss of trophic effect of sex steroids on bone mineral health. Ovarian failure has been documented to develop within 1 year of methotrexate/cyclophosphamide/5-fluorouracil- or doxorubicin/5-fluorouracil/cyclophosphamide-based chemotherapy in 63% to 96% of premenopausal women. Selective estrogen receptor modulators have a negative effect on BMD in premenopausal women, and aromatase inhibitors (anastrozole, letrozole, and exemestane) are associated with significant bone loss in postmenopausal women. They also have an adverse impact on bone health primarily due to their anti-estrogen properties. Cancer chemotherapy-induced muscular degeneration and sarcopenia also contribute to bone mineral loss. Many chemotherapy regimens for hematologic malignancies as well as solid tumors have GCs also as a part of the treatment regimen, which contributes to bone mineral loss (vide supra). Platinum-based chemotherapy agents such as cisplatin cause hypomagnesemia, which can lead to the suppression of osteoblast activity and inhibition of bone formation. Ifosfamide has been linked with renal tubular dysfunction and hypophosphatemic osteomalacia. The inhibitory effect of methotrexate on bone formation is dose dependent and maximally seen at cumulative doses exceeding 40,000 mg/m2.
| Summary|| |
Bone mineral loss is a common but often missed complication with many medications across the different organ systems. Anti-epileptics, PPIs, GCs, immunosuppressants (calcineurin inhibitors), anticoagulants, glitazones, SGLT2 inhibitors, somatostatin analogs, anticancer medications, and protein kinase inhibitors are some of the medications which are associated with bone mineral loss. Drug-induced bone disorders are either due to the direct impact of the medication on the bone microarchitecture or through indirect mechanisms such as impaired Vitamin D metabolism, calcium loss, or altered hormone states, which promote bone loss (hypogonadism, hyperthyroidism, somatostatin excess states, insulin deficiency, increased systemic inflammation, and oxidative stress).
An increased awareness of the medications which are linked with impaired bone health, minimizing the use of them in patients who are at an increased risk of fractures, keeping the dosage as well as duration of therapy to as low as possible, ensuring Vitamin D and calcium adequacy either through diet or supplements, and prophylactic use of bisPs (where indicated) can play a major role in preventing morbidity associated with drug-induced bone disorders.
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| References|| |
Dussault PM, Lazzari AA. Epilepsy and osteoporosis risk. Curr Opin Endocrinol Diabetes Obes 2017;24:395-401.
Koch HU, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972;13:829-34.
Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al.
Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001;57:445-9.
Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on Vitamin D and calcium metabolism in out-patients with epilepsy. Q J Med 1986;59:569-77.
Feldkamp J, Becker A, Witte OW, Scharff D, Scherbaum WA. Long-term anticonvulsant therapy leads to low bone mineral density - Evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells. Exp Clin Endocrinol Diabetes 2000;108:37-43.
Välimäki MJ, Tiihonen M, Laitinen K, Tähtelä R, Kärkkäinen M, Lamberg-Allardt C, et al.
Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res 1994;9:631-7.
Boluk A, Guzelipek M, Savli H, Temel I, Ozişik HI, Kaygusuz A, et al.
The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol Res 2004;50:93-7.
Pack AM, Morrell MJ, Marcus R, Holloway L, Flaster E, Doñe S, et al.
Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol 2005;57:252-7.
Moberg LM, Nilsson PM, Samsioe G, Borgfeldt C. Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas 2014;78:310-5.
Cea Soriano L, Ruigómez A, Johansson S, García Rodríguez LA. Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy 2014;34:570-81.
Sharma M, Dhakad U, Wakhlu A, Bhadu D, Dutta D, Das SK. Lean mass and disease activity are the best predictors of bone mineral loss in the premenopausal women with rheumatoid arthritis. Indian J Endocrinol Metab 2018;22:236-43.
Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 2009;5:667-76.
González-Alvaro I, Ortiz AM, Tomero EG, Balsa A, Orte J, Laffon A, et al.
Baseline serum RANKL levels may serve to predict remission in rheumatoid arthritis patients treated with TNF antagonists. Ann Rheum Dis 2007;66:1675-8.
Campistol JM, Holt DW, Epstein S, Gioud-Paquet M, Rutault K, Burke JT, et al.
Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus. Transpl Int 2005;18:1028-35.
Lee CT, Ng HY, Lien YH, Lai LW, Wu MS, Lin CR, et al.
Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 2011;34:87-94.
Weber P. Vitamin K and bone health. Nutrition 2001;17:880-7.
Tsaioun KI. Vitamin K-dependent proteins in the developing and aging nervous system. Nutr Rev 1999;57:231-40.
Caraballo PJ, Heit JA, Atkinson EJ, Silverstein MD, O'Fallon WM, Castro MR, et al.
Long-term use of oral anticoagulants and the risk of fracture. Arch Intern Med 1999;159:1750-6.
Rajgopal R, Bear M, Butcher MK, Shaughnessy SG. The effects of heparin and low molecular weight heparins on bone. Thromb Res 2008;122:293-8.
Dutta D, Mukhopadhyay S. Intervening at prediabetes stage is critical to controlling the diabetes epidemic among Asian Indians. Indian J Med Res 2016;143:401-4.
] [Full text]
Dutta D, Choudhuri S, Mondal SA, Maisnam I, Reza AH, Ghosh S, et al.
Tumor necrosis factor alpha -238G/A (rs 361525) gene polymorphism predicts progression to type-2 diabetes in an Eastern Indian population with prediabetes. Diabetes Res Clin Pract 2013;99:e37-41.
Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 2007;166:495-505.
Dutta D, Dharmshaktu P, Aggarwal A, Gaurav K, Bansal R, Devru N, et al.
Severity and pattern of bone mineral loss in endocrine causes of osteoporosis as compared to age-related bone mineral loss. J Postgrad Med 2016;62:162-9.
] [Full text]
Gilbert MP, Pratley RE. The impact of diabetes and diabetes medications on bone health. Endocr Rev 2015;36:194-213.
Zhu ZN, Jiang YF, Ding T. Risk of fracture with thiazolidinediones: An updated meta-analysis of randomized clinical trials. Bone 2014;68:115-23.
Dutta D, Khandelwal D. Sodium glucose transporter 2 inhibition, euglycemic ketosis and bone mineral loss: Refining clinical practices. Indian J Endocrinol Metab 2015;19:854-5.
Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 2015;3:8-10.
Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, et al.
Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016;101:157-66.
Mannucci E, Monami M. Bone fractures with sodium-glucose co-transporter-2 inhibitors: How real is the risk? Drug Saf 2017;40:115-9.
Tang HL, Li DD, Zhang JJ, Hsu YH, Wang TS, Zhai SD, et al.
Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016;18:1199-206.
Thrailkill KM, Lumpkin CK Jr., Bunn RC, Kemp SF, Fowlkes JL. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 2005;289:E735-45.
Maisnam I, Dutta D, Mukhopadhyay S, Chowdhury S. Lean mass is the strongest predictor of bone mineral content in type-2 diabetes and normal individuals: An Eastern India perspective. J Diabetes Metab Disord 2014;13:90.
Curtis JR, Westfall AO, Allison J, Bijlsma JW, Freeman A, George V, et al.
Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum 2006;55:420-6.
Laan RF, van Riel PL, van de Putte LB, van Erning LJ, van't Hof MA, Lemmens JA. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized, controlled study. Ann Intern Med 1993;119:963-8.
Dharmshaktu P, Aggarwal A, Dutta D, Kulshreshtha B. Bilateral femoral head avascular necrosis with a very low dose of oral corticosteroid used for panhypopituitarism. BMJ Case Rep 2016;2016. pii: bcr2015212803.
Katsumata K, Kusano K, Hirata M, Tsunemi K, Nagano N, Burke SK, et al.
Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats. Kidney Int 2003;64:441-50.
Biswas D, Dutta D, Maisnam I, Mukhopadhyay S, Chowdhury S. Occurrence of osteoporosis and factors determining bone mineral loss in young adults with Graves' disease. Indian J Med Res 2015;141:322-9.
] [Full text]
Kulshreshtha B, Sharma L, Sharma N, Singh Y, Aggarwal A, Dharmshaktu P, et al
. Octreotide and cinacalcet have limited role managing surgically incurable tumor induced osteomalacia. Acta Endo (Buc) 2015;11:517-23.
Meyyur Aravamudan V, Er C. Osteonecrosis of the jaw and concomitant atypical femoral fractures with bisphosphonates: A comprehensive literature review. Cureus 2019;11:e5113.
Dutta D, Garga UC, Gadpayle AK, Bansal R, Anand A, Gaurav K, et al.
Occurrence & predictors of osteoporosis and impact of body composition alterations on bone mineral health in asymptomatic pre-menopausal women with HIV infection. Indian J Med Res 2018;147:484-95.
] [Full text]
Dutta D, Sharma M, Bansal R, Sharma N, Garga UC, Anand A, et al.
Low skeletal mass is an important predictor of osteoporosis in HIV-infected men in India. Endokrynol Pol 2017;68:642-51.
Dutta D, Sharma LK, Sharma N, Gadpayle AK, Anand A, Gaurav K, et al.
Occurrence, patterns and predictors of hypogonadism in patients with HIV infection in India. Indian J Med Res 2017;145:804-14.
] [Full text]
Welz T, Childs K, Ibrahim F, Poulton M, Taylor CB, Moniz CF, et al.
Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 2010;24:1923-8.
Choi CJ, Choi WS, Kim CM, Lee SY, Kim KS. Risk of sarcopenia and osteoporosis in male tuberculosis survivors: Korea national health and nutrition examination survey. Sci Rep 2017;7:13127.
Schepper JD, Collins FL, Rios-Arce ND, Raehtz S, Schaefer L, Gardinier JD, et al.
Probiotic lactobacillus reuteri prevents postantibiotic bone loss by reducing intestinal dysbiosis and preventing barrier disruption. J Bone Miner Res 2019;34:681-98.
Mwale F, Ciobanu I, Demers CN, Antoniou J, Héon S, Servant N, et al.
Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. Calcif Tissue Int 2005;77:175-9.
Gargus E, Deans R, Anazodo A, Woodruff TK. Management of primary ovarian insufficiency symptoms in survivors of childhood and adolescent cancer. J Natl Compr Canc Netw 2018;16:1137-49.
Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996;14:1718-29.
Khachidze N, Giorgadze E, Tsagareli M. Adjuvant (hormonal) therapy as a cause of bone loss in patients with breast cancer (review of literature). Georgian Med News 2017;262:39-42.
Sturgeon KM, Mathis KM, Rogers CJ, Schmitz KH, Waning DL. Cancer- and chemotherapy-induced musculoskeletal degradation. JBMR Plus 2019;3:e10187.
Von Hoff DD, Schilsky R, Reichert CM, Reddick RL, Rozencweig M, Young RC, et al.
Toxic effects of cis-dichlorodiammineplatinum (II) in man. Cancer Treat Rep 1979;63:1527-31.
Burk CD, Restaino I, Kaplan BS, Meadows AT. Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms tumor. J Pediatr 1990;117:331-5.
Mandel K, Atkinson S, Barr RD, Pencharz P. Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol 2004;22:1215-21.