What are the treatment goals?
It should be noted that the essential goal of osteoporosis treatment is to reduce the risk for clinical fractures, namely of the hip and vertebrae. Change in BMD during drug treatment is clinically less important than the treatment effect on subsequent fracture risk. It is should be stressed that the reduction of fracture risk with drug treatment is not explained by its effect on BMD (39 – 41). Even if BMD declines during pharmacotherapy, whether the patient would have had a much greater BMD decline without treatment cannot be ascertained.
It is for the clinicians to emphasize to patients that the goal of treatment is to prevent disabling fractures. Since drug treatment does not always achieve this goal, a single fracture during treatment may not necessarily constitute evidence of treatment failure. However, it could indicate a higher risk for future fractures. It is recommended that patients who suffer fractures while on drug treatment are assessed for compliance, underlying medical conditions (e.g., secondary causes), and fall tendency with consideration of preventive measures. For patients who have had multiple fractures or fractures with severe clinical consequences during treatment, clinicians may consider starting an alternate therapy or referring to a subspecialist.
It is also recommended that medication lists are reviewed to identify those with adverse effects on bone metabolism and whether their use can be minimized or discontinued altogether. Medications with established associations with osteoporosis and higher fracture risk include long-term heparin, antiepileptic drugs, cyclosporine, tacrolimus, such chemotherapeutic agents as aromatase inhibitors, glucocorticoids, gonadotropinreleasing hormone agonists, thiazolidinediones, excessive doses of L-thyroxine, proton-pump inhibitors, selective serotonin reuptake inhibitors, parenteral nutrition, depo-medroxyprogesterone contraception, methotrexate, and aluminum antacids (42).
Identifying patients who should take calcium and vitamin D supplement
Clinicians are referred to the recommendations of the Institute of Medicine 2011 regarding calcium and vitamin D intake (33). It is advisable that patients are encouraged to obtain these nutrients through dietary sources and only in patients who do not meet intake levels that supplementation should be recommended. Calcium supplements include calcium carbonate and calcium citrate. The necessary dose to meet daily requirements should be based on the elemental calcium content (34). Vitamin D3 supplements are available in several doses, and many multivitamins contain 400 IU of vitamin D3. It is important to educate the patients on the fact that excessive calcium intake can do more harm than good, for instance nephrolithiasis, and that they should not exceed recommended doses (33).
Although a systematic review of trials of combined calcium and vitamin D supplementation (43) has reported a reduction in fracture risk with supplementation, it is interesting to note that the effects were smaller and not significant among community-dwelling older adults than among institutionalized elderly persons. Thus, combined calcium and vitamin D supplementation at prescribed doses should be recommended in older institutionalized patients and community-dwelling older adults who have inadequate dietary intake.
How to sort patients requiring drug treatment
Among postmenopausal women with osteoporosis (that is defined as a BMD T-score ≤2.5 or existing radiographic vertebral fractures), treatment with alendronate, risedronate, zoledronic acid, or denosumab reduces risk for clinical fractures, including those of the hip and vertebrae. Several drug treatments lower risk for new radiographic vertebral fractures. Among men and women aged 50 years or older with recent low trauma hip fracture, treatment with zoledronic acid reduces the risk for clinical fractures. Although alendronate, risedronate, or zoledronic acid decrease risk for new radiographic vertebral fracture in men with osteoporosis, the efficacy of drug treatment in preventing clinical or nonvertebral fractures in men remains to be established.
Some guidelines from the US (3, 8, 13) endorse the use of specific FRAX intervention thresholds (10-year absolute probability of hip fracture ≥3% or 10-year absolute probability of major osteoporotic fracture ≥20%) to aid clinicians in deciding whether to recommend drug treatment in adults aged 50 years or older with osteopenia. These guidelines recommend initiation of drug treatment in adults with osteopenia who have a 10-year fracture probability at or above either FRAX intervention thresholds. In addition, the National Bone Health Alliance (NBHA) (44) has proposed changes in the diagnostic criteria for osteoporosis and recommends that adults aged 50 years or older be diagnosed with osteoporosis regardless of BMD if they have a FRAX score at or above either of the National Osteoporosis Foundation (NOF) FRAX intervention thresholds. Adoption of NOF or NBHA guidelines greatly expands the proportion of older adults identified as having an indication for drug treatment (26, 45)
Although basing a treatment decision on a patient's absolute risk for fracture sounds reasonable, whether pharmacotherapy reduces risk for clinical fractures among adults without osteoporosis remains unsubstantiated. Systematic reviews of bisphosphonate trials in postmenopausal women have not reported significantly reduced risk for nonvertebral fractures among women without osteoporosis (defined as BMD T-score ≤2.5) or existing vertebral fractures (46, 47). Pivotal trials of alendronate, risedronate, and denosumab found that treatment did not reduce risk for clinical fractures in postmenopausal women who did not meet these criteria (48 –50). Thus, adoption of the guidelines may result in a substantial proportion of older adults with a problem that might not benefit from pharmacologic therapy. It also increases demands on the health care system to identify and treat the excess patients meeting the expanded criteria (51).
The American College of Physicians (ACP) (52) recommends that multitude parameters are applied in decision making on whether to initiate drug treatment in osteopenic women aged 65 years or older who are at high risk for fracture (weak recommendation, low-quality evidence). ACP recognises that clinicians can use their judgment for assessing fracture risk by an evaluation of risk factor status or application of an assessment tool. Randomized trials are needed to determine whether drug treatment is efficacious in preventing clinical fractures among middle-aged and older adults with osteopenia who have a higher estimated fracture risk. These data would inform treatment guidelines for this patient population.
Choosing the appropriate pharmacologic agent for patients meeting the criteria for drug therapy
Bisphosphonates are the first-line agents for treatment of osteoporosis, and are now all available in generic form. Ibandronate is rarely prescribed as there is no clinical evidence from randomized trials that it reduces risk for nonvertebral fractures. Bisphosphonates are not recommended for patients with severe renal impairment. Thus, assessment of renal function is appropriate before treatment is initiated, and creatinine clearance (CrCl) in patients prescribed bisphosphonates should exceed 35 mL/min/1.73 m2 . Oral bisphosphonates should be taken with a glass of water on an empty stomach to maximize absorption. These drugs are contraindicated in cases of esophageal stricture, achalasia, or Barrett esophagus, but are often tolerated in patients with a remote history of peptic ulcer disease or those with gastroesophageal reflux controlled with medications. Common adverse effects of oral bisphosphonates include upper gastrointestinal tract irritation and musculoskeletal problems. Risk for gastrointestinal irritation is minimized by adherence to dosing instructions. Common adverse effects of zoledronic acid include flu-like symptoms or bone pain—typically with the initial dose—and musculoskeletal symptoms. Rare but serious adverse effects of oral and intravenous bisphosphonates include osteonecrosis of the jaw (exposed bone in the maxillofacial region that does not heal within 8 weeks) and atypical femoral fractures (low-trauma subtrochanteric or femoral shaft fractures).
Patients with contraindications or intolerance to oral or intravenous bisphosphonates or those with severe renal impairment can be prescribed denosumab. It is important that hypocalcemia is treated before denosumab is started, and serum calcium level should be checked first. In patients predisposed to hypocalcemia and disturbances of mineral metabolism, it is recommended that serum calcium, phosphorus, and magnesium levels are checked within 2 weeks of denosumab injection.
Raloxifene, is a selective estrogen receptor modulator which diminishes the risk of vertebral fractures in postmenopausal women with osteoporosis but with no effect on risk for nonvertebral fractures. Unsurprisingly it is not a first-line agent for postmenopausal osteoporosis. It is known that chronic use of raloxifene decreases risk for breast cancer among women at higher risk but increases the risk for venous thromboembolic events. It should be stressed that use of estrogen therapy or combined hormone therapy (estrogen plus progestin) is not recommended or approved by the Food and Drug Administration (FDA) for treatment of postmenopausal osteoporosis. Although use of estrogen plus progestin or estrogen alone is moderately beneficial in reducing the risk for fractures, the benefits are not sufficient to outweigh the potential harm in most postmenopausal women (53-59).
Teriparatide is an anabolic agent which reduces risk of vertebral and nonvertebral fractures among women with postmenopausal osteoporosis. However, to date there is no evidence that it can reduce the risk for hip fracture. It is administered by daily subcutaneous injection. As its efficacy and safety have not been explored beyond 2 years of treatment, the FDA recommends limiting the treatment period to a maximum of 2 years during a lifetime. Common adverse effects of teriparatide include nausea, arthralgia, leg cramps, hypercalcemia, and hypercalcuria. Rare adverse effects include hyperuricemia and hypotension. Long-term studies of teriparatide in rodents indicate a black box warning of osteosarcoma risk. Candidates for teriparatide treatment include patients with contraindications to oral and intravenous bisphosphonates, those who have had a major osteoporotic fracture while receiving oral bisphosphonates, and treatment-naive persons with very low BMD T-scores (≤3.5). Abaloparatide, a human parathyroid hormone peptide analogue that is administered by daily subcutaneous injection, was recently approved by the FDA for treatment of postmenopausal women with osteoporosis who are at high risk for fracture. The efficacy and safety profiles and treatment period of abaloparatide are similar to those of teriparatide (61-63).
It should be noted that combination pharmacotherapy for osteoporosis is not recommended. The antifracture efficacy of combination medication regimens has not been adequately evaluated in controlled clinical trials, and safety has not been evaluated. ACP (52) recommends treatment with alendronate, risedronate, zoledronic acid, or denosumab in women with osteoporosis to reduce the risk for hip and vertebral fractures. It recommends against use of estrogen therapy, combined hormone therapy, or raloxifene in this group. Among men with osteoporosis, ACP recommends treatment with bisphosphonates to reduce the risk for vertebral fractures. Additionally, it is known that increasing duration of bisphosphonate use is associated with increasing incidence of atypical femoral fractures. In an analysis of 188 814 patients receiving bisphosphonates, the age-adjusted incidence rates increased from 1.8 per 100 000 persons per year with a 2-year exposure to a whopping 113 per 100 000 persons per year with an 8- to 10-year exposure (64).
The American Society for Bone and Mineral Research (60) has recommended that a drug holiday be considered in postmenopausal women after five or more years of oral bisphosphonate therapy (or ≥3 years of intravenous bisphosphonate therapy) if the patients satisfy the following three criteria: 1) they have had no hip, spine, or multiple other osteoporotic fractures before or during the initial treatment period; 2) hip BMD T-score is >2.5 after the initial treatment period; and 3) they are not at high fracture risk. It is also advised that a drug holiday is reassessed every 2–3 years.
There are no guidelines which specifically address the role of a drug holiday for patients treated with medications other than bisphosphonates. Treatment with denosumab, raloxifene, or teriparatide results in BMD gains that rapidly wear off following discontinuation of treatment. An antiresorptive agent is recommended after discontinuation of teriparatide due to the ensuing rapid bone loss. Although the risk for atypical femoral fractures may increase with longer duration of denosumab treatment, stopping usage can lead to accelerated bone loss. In addition, “rebound fractures” after discontinuation have recently been reported (65-69, 70).
Based on the treatment duration of up to 5 years in randomized trials, ACP (52) recommends that women with osteoporosis be treated with pharmacologic therapy (i.e., alendronate, risedronate, zoledronic acid, or denosumab) for five years. ACP also acknowledges that continuing treatment after five years may benefit some patients. Prescribing oral bisphosphonates for five years (or intravenous bisphosphonates for three years) should be effective in preventing fractures and minimizing potential harms of long-term exposure. It is advised that clinicians counsel patients with osteoporosis on taking these medications for five years, because the reduction in risk for disabling fractures outweighs the risk for short-term potential harms of treatment, and the potential risks for long-term harms of treatment are avoided with this strategy.
Deciding when to refer
Referral to an osteoporosis specialist should be considered if there is uncertainty regarding whether a patient will benefit from pharmacotherapy for fracture prevention, when to resume medication after a drug holiday, or which medication should be used after a drug holiday. Consultation may also be warranted in patients with intolerance to standard drug treatments or those in whom treatment failure is suspected. Consultation with orthopedic or physical medicine and rehabilitation specialists is often required for management of patients presenting with an acute fracture.
Evaluation of quality of care
The Healthcare Effectiveness Data and Information Set includes two measures on osteoporosis in women aged 65–85 years: osteoporosis testing and osteoporosis management in women who have had a fracture. A recent survey (58) of postmenopausal women with osteoporotic fractures reported that 93% had contact with their primary care physician during the six months after fracture; 73% indicated that their primary care physician knew about the fracture, but 63% and 55% reported that management of osteoporosis and fracture prevention, respectively, were not discussed at these visits. Management of patients after fracture is problematic and must be addressed by a concerted effort of health care systems, primary care physicians, specialists, and patients.
This article is intended for medical professionals.
Dr Reshma Ramracheya
Diabetes UK RD Lawrence Research Fellow
Senior Research Fellow at Wolfson College
Investigator at Oxford Centre for Diabetes, Endocrinology & Metabolism
University of Oxford, UK
Reshma.ramracheya@ocdem.ox.ac.uk
Tel: 59111128
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