International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

Calcium and bone health--goodbye, calcium supplements?

This review assesses (1) the potential role of calcium supplements in the prevention and treatment of osteoporosis and osteoporotic fractures, and (2) the safety of calcium supplements with respect to cardiovascular health as well. With regard to (1), a total calcium intake of < 800 mg/day is associated with increased loss of bone mineral density in peri- and postmenopausal women with an increase in fracture risk. Hereby, the effect of calcium supplements on fracture prevention is dependent primary on baseline calcium intake. The strongest protective effect has been reported in individuals with a calcium intake < 700 mg/day and in high-risk groups. A calcium intake of about 1000-1200 mg/day seems to be sufficient for general fracture prevention. With regard to (2), an analysis of the data based on the Hill criteria does not demonstrate convincing evidence that calcium supplements increase cardiovascular risk. In the long term, total calcium intake of 2500 mg/day (from food and supplements) continues to be classified as safe. This value should not be exceeded for an extended period of time.

Successful treatment of 1-34 parathyroid hormone (PTH) after failure of bisphosphonate therapy in a complex case of pregnancy associated osteoporosis and multiple fractures.

INTRODUCTION: Pregnancy associated osteoporosis (PAO) was first reported almost half a century ago. The most common symptom is acute lower back pain due to vertebral fractures in the last trimester or immediately after birth. PATIENT: We present a case involving a female patient born in 1971 (gravida II, para I) with a history of PAO. In April 2000 at the age of 28 years, she delivered a son and breastfed him for 4 months. A first magnetic resonance tomography (MRT) screening in June 2000 showed osteoporotic fractures at lumbar vertebra 1-4. Therefore, the patient received oral alendronate therapy. In May 2001, a second MRT exhibited burst fracture of thoracic 8, end-plate fracture of thoracic 11, 12, lumbar 2-5 and compression fracture of lumbar 1. The oral therapy was switched to ibandronate (3 mg) intravenously every 3 months. An X-ray in December 2002 showed 3 new additional end-plate fractures at thoracic 4, 6 and 7. Ibandronate was discontinued in September 2004 and the patient received daily subcutaneous (s. c.) injections of 1-34 PTH in September 2005. RESULTS: After starting 1-34 PTH treatment for 18 months, a further increase in bone mineral density (BMD) was achieved without any further fracture. CONCLUSION: We presented for the first time a case of severe PAO with 11 spine fractures. We observed an unsatisfactory effect of oral and i. v. bisphosphonates in combination with adequate calcium and vitamin D supplementation. The treatment with 1-34 PTH showed an increase in BMD with no further fractures.

Effects of zoledronic acid on bone mineral density in premenopausal women receiving neoadjuvant or adjuvant therapies for HR+ breast cancer: the ProBONE II study.

UNLABELLED: The effects of bisphosphonates on altered bone turnover marker (BTM) levels associated with adjuvant endocrine or chemotherapy in early breast cancer have not been systematically investigated. In ProBONE II, zoledronic acid decreased these elevated BTM levels and increased bone mineral density (BMD) during adjuvant therapy, consistent with its antiresorptive effects. INTRODUCTION: Adjuvant chemotherapy or endocrine therapy for early hormone receptor-positive breast cancer (HR(+) BC) is associated with rapid BMD loss and altered BTM levels. Adjuvant bisphosphonate studies demonstrated BMD increases, but did not investigate BTM effects. The randomized, double-blind, ProBONE II study investigated the effect of adjuvant zoledronic acid (ZOL) on BMD and BTM in premenopausal women with early HR(+) BC. METHODS: Seventy premenopausal women with early HR(+) BC received adjuvant chemotherapy and/or endocrine therapy plus ZOL (4 mg IV every 3 months) or placebo for 24 months. Primary endpoint was change in lumbar spine BMD at 24 months versus baseline. Secondary endpoints included femoral neck and total femoral BMD changes, changes in BTM, and safety. RESULTS: Lumbar spine BMD increased 3.14% from baseline to 24 months in ZOL-treated participants versus a 6.43% decrease in placebo-treated participants (P < 0.0001). Mean changes in T- and Z-scores, and femoral neck and total femoral BMD, showed similar results. Bone resorption marker levels decreased ∼ 55% in ZOL-treated participants versus increases up to 65% in placebo-treated participants (P < 0.0001 for between-group differences). Bone formation marker (procollagen I N-terminal propeptide) levels decreased ∼ 57% in ZOL-treated participants versus increases up to 45% in placebo-treated participants (P < 0.0001 for between-group differences). Adverse events were consistent with the established ZOL safety profile and included one case of osteonecrosis of the jaw after a tooth extraction. CONCLUSIONS: Adding ZOL to adjuvant therapy improved BMD, reduced BTM levels, and was well tolerated in premenopausal women with early HR(+) BC receiving adjuvant chemotherapy and/or endocrine therapy.

Cancer treatment-induced bone loss in premenopausal women: a need for therapeutic intervention?

Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <-2.0 or Z-score ≤-1.0 and/or a 5-10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements.

Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German substudy.

AIM: The aim of this study was to compare the effects of exemestane and tamoxifen on hormone levels in postmenopausal patients with hormone receptor-positive breast cancer within a Germany substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. METHODS: Within the TEAM trial, patients were randomized to receive adjuvant treatment with exemestane for 5 years or tamoxifen for 2.5-3 years followed by exemestane for 2-2.5 years. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)-intact were measured at screening and after 3, 6 and 12 months of treatment. RESULTS: Data on hormone levels were available from 63 patients in the tamoxifen arm and 68 patients in the exemestane arm. Treatment with exemestane resulted in decreases from baseline in SHBG and PTH-intact levels, and increases from baseline in testosterone, DHEAS and FSH levels. Tamoxifen treatment resulted in increases from baseline in SHBG and PTH-intact, whereas levels of testosterone and FSH decreased and DHEAS levels did not change. At all time points assessed, the absolute change from baseline was significantly different between tamoxifen and exemestane for testosterone, SHBG, FSH and PTH-intact (all p < 0.0001). CONCLUSIONS: Exemestane and tamoxifen had statistically significantly different effects on hormone levels, including testosterone, SHBG, FSH and PTH-intact.

Aromatase inhibitor-associated bone loss and its management with bisphosphonates in patients with breast cancer.

Postmenopausal women have an increased risk of osteopenia and osteoporosis due to loss of the bone-protective effects of estrogen. Disease-related processes may also contribute to the risk of bone loss in postmenopausal women with breast cancer. One of the most common and severe safety issues associated with cancer therapy for patients with breast cancer is bone loss and the associated increase in risk of fractures. This paper reviews the recent literature pertaining to aromatase inhibitor (AI)-associated bone loss, and discusses suggested management and preventative approaches that may help patients remain on therapy to derive maximum clinical benefit. A case study is presented to illustrate the discussion. We observed that AIs are in widespread use for women with hormone receptor-positive breast cancer and are now recommended as adjuvant therapy, either as primary therapy or sequential to tamoxifen, for postmenopausal women. AIs target the estrogen biosynthetic pathway and deprive tumor cells of the growth-promoting effects of estrogen, and AI therapies provide benefits to patients in terms of improved disease-free survival. However, there is a concern regarding the increased risk of bone loss with prolonged AI therapy, which can be managed in many cases with the use of bisphosphonates and other interventions (eg, calcium, vitamin D supplementation, exercise).

Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment.

BACKGROUND: Bone mineral density (BMD)-based guidelines for bone-directed therapy in women with early breast cancer (EBC) appear inadequate for averting fractures, particularly during aromatase inhibitor (AI) therapy. Therefore, an algorithm was developed to better assess risk and direct treatment (Hadji P, Body JJ, Aapro MS et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol 2008; 19: 1407-1416). Here, we provide updated guidance on pharmacologic interventions to prevent/treat aromatase inhibitor-associated bone loss (AIBL). DESIGN: Systematic literature review identified recent advances in preventing/treating AIBL. Individual agents were assessed based on trial size, design, follow-up, and safety. RESULTS: Fracture risk factors in patients with EBC remain unchanged (Hadji P, Body JJ, Aapro MS et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol 2008; 19: 1407-1416). The World Health Organization Fracture Risk Assessment Tool algorithm includes fracture risk factors plus BMD but does not adequately address AIBL effects. Several antiresorptives can prevent/treat AIBL. However, concerns regarding compliance and long-term efficacy/safety remain. Overall, evidence is strongest for twice-yearly zoledronic acid (ZOL), and recent advances support additional anticancer benefits from ZOL. CONCLUSIONS: All patients initiating AIs need advice regarding exercise, calcium/vitamin D supplements, baseline BMD monitoring (when available), and bone-directed therapy if T-score <-2.0 or at least two fracture risk factors were observed. Patients with T-score > -2.0 and no risk factors should be managed based on BMD loss during years 1-2. Unsatisfactory compliance/decreasing BMD after 12-24 months on oral bisphosphonates should trigger a switch to i.v. bisphosphonate.

Managing bone health with zoledronic acid: a review of randomized clinical study results.

AIM: To systematically review randomized, controlled clinical trials for managing osteoporosis, cancer treatment-induced bone loss, and bone metastases from breast cancer using zoledronic acid (ZOL). METHOD: A systematic review of published literature and meeting abstracts was conducted to examine the efficacy of ZOL dosing strategies in clinical trials of osteoporosis, adjuvant therapy for breast cancer, and bone metastases from breast cancer. Bone resorption rates, tumor burden, skeletal health goals, and clinical data were considered when assessing ZOL in each setting. RESULTS: Dosing schedules vary between approved indications for osteoporosis and bone metastases and the investigational use in women receiving endocrine therapy for BC, taking into consideration the different levels of bone loss and tumor burden in each setting. Gradual bone loss in healthy postmenopausal women with osteopenia or osteoporosis can be prevented or treated with the approved biennial or annual ZOL (5 mg), respectively. Rapid bone loss in patients receiving adjuvant chemotherapy and/or endocrine therapy for early-stage BC and low tumor burden is managed in the clinical setting with ZOL 4 mg every 6 months. In patients with bone metastases, very high tumor burden, high bone resorption levels, and decreases in bone integrity are managed by the approved ZOL schedule (4 mg every 3-4 weeks) to prevent skeleton-related events. CONCLUSIONS: Dosing schedules are based on clinical evidence and vary depending on goals of therapy, rate of bone loss, and tumor burden. ZOL 5 mg every 12 months and every 24 months are approved for osteoporosis and osteopenia, respectively, whereas ZOL 4 mg every 6 months has been used during adjuvant endocrine therapy and ZOL 4 mg every 3-4 weeks is approved for managing bone metastases.

The effect of exemestane or tamoxifen on markers of bone turnover: results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Adjuvant treatment of breast cancer with aromatase inhibitors has been associated with increased bone loss. In this study, postmenopausal patients with oestrogen receptor positive breast cancer were randomised to exemestane for 5 years or tamoxifen for 2-2.5 years, followed by exemestane for 2-2.5 years. Levels of bone formation markers (bone specific alkaline phosphatase, amino terminal propeptide of type I procollagen, osteocalcin), and the bone resorption marker (carboxyterminal crosslinked telopeptide of type I collagen), were assessed at baseline and after 3, 6 and 12 months of treatment. Exemestane (n=78) resulted in increases from baseline in all bone turnover marker levels at all timepoints. In contrast, levels of all bone marker turnovers decreased with tamoxifen (n=83). Differences between tamoxifen and exemestane were statistically significant for all bone turnover markers at all timepoints. In conclusion, exemestane results in increases in markers of bone formation and resorption, while decreases are observed with tamoxifen.

Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy.

BACKGROUND: Adjuvant treatment of hormone receptor-positive breast cancer in postmenopausal women with aromatase inhibitors may be associated with increased bone loss. PATIENTS AND METHODS: Two hundred patients were randomised to receive exemestane or tamoxifen as adjuvant treatment of hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6 and 12 months treatment. RESULTS: One hundred and sixty-one patients were assessable. Tamoxifen treatment resulted in a 0.5% increase from baseline in BMD at the spine, which was maintained at 12 months. Exemestane-treated patients experienced a 2.6% decrease from baseline in BMD at the spine at 6 months and a further 0.2% decrease at 12 months. There were significant differences in the changes in BMD between tamoxifen and exemestane at 6 and 12 months (P = 0.0026 and P = 0.0008, respectively). The mean changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen at 6 and 12 months (P = 0.0009 and P = 0.04, respectively). There was no difference between tamoxifen and exemestane in mean changes in BMD from baseline at the femoral neck. CONCLUSIONS: Exemestane treatment resulted in an increase in bone loss at 6 months; bone loss stabilised after 6- to 12-month treatment.

Practical guidance for the management of aromatase inhibitor-associated bone loss.

BACKGROUND: Recent studies indicate that women with breast cancer are at increased risk of fracture compared with their age-matched peers. Current treatment guidelines are inadequate for averting fractures in osteopenic women, especially those receiving aromatase inhibitor (AI) therapy. Therefore, we sought to identify clinically relevant risk factors for fracture that can be used to assess overall fracture risk and to provide practical guidance for preventing and treating bone loss in women with breast cancer receiving AI therapy. METHODS: Systematic review of pertinent information from published literature and meeting abstracts through December 2007 was carried out to identify factors contributing to fracture risk in women with breast cancer. An evidence-based medicine approach was used to select risk factors that can be used to determine when to initiate bisphosphonate treatment of aromatase inhibitor-associated bone loss (AIBL). RESULTS: Fracture risk factors were chosen from large, well-designed, controlled, population-based trials in postmenopausal women. Evidence from multiple prospective clinical trials in women with breast cancer was used to validate AI therapy as a fracture risk factor. Overall, eight fracture risk factors were validated in women with breast cancer: AI therapy, T-score <-1.5, age >65 years, low body mass index (BMI <20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking. Treatment recommendations were derived from randomized clinical trials. CONCLUSIONS: The authors recommend the following for preventing and treating AIBL in women with breast cancer. All patients initiating AI therapy should receive calcium and vitamin D supplements. Any patient initiating or receiving AI therapy with a T-score >/=-2.0 and no additional risk factors should be monitored every 1-2 years for change in risk status and bone mineral density (BMD). Any patient initiating or receiving AI therapy with a T-score <-2.0 should receive bisphosphonate therapy. Any patient initiating or receiving AI therapy with any two of the following risk factors-T-score <-1.5, age >65 years, low BMI (<20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking-should receive bisphosphonate therapy. BMD should be monitored every 2 years, and treatment should continue for at least 2 years and possibly for as long as AI therapy is continued. To date, the overwhelming majority of clinical evidence supports zoledronic acid 4 mg every 6 months to prevent bone loss in women at high risk. Although there is a trend towards fewer fractures with zoledronic acid, studies completed to date have not been designed to capture significant differences in fracture rate, and longer follow-up is needed.

Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel.

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

Reducing the risk of bone loss associated with breast cancer treatment.

Women with breast cancer experience more fractures than their healthy peers. Fracture risk factors that are frequently observed in healthy postmenopausal women may already be present when breast cancer is diagnosed. Although low bone mineral density (BMD) significantly increases fracture risk, additional clinical risk factors that are independent of BMD, including age, previous fragility fracture, premature menopause, family history of hip fracture, use of corticosteroids, and low body mass index, also increase fracture risk. Additionally, cancer therapies can further increase fracture risk. Most notably, gonadotropin-releasing hormone analogues and aromatase inhibitor (AI) therapy increase bone loss and fracture incidence. Therefore, patients receiving AIs require a comprehensive fracture risk assessment including all risk factors and BMD when available. Zoledronic acid is an effective therapy for the prevention of AI-associated bone loss and, when combined with AI therapy, may provide the greatest clinical benefit without increasing fracture risk.

The use of i. v. bisphosphonate in pregnancy-associated osteoporosis--case study.

OBJECTIVE: Diagnosis of pregnancy-associated osteoporosis is often delayed and therapeutic interventions insufficient. STUDY DESIGN: A 28-year-old patient (BMI=18.6) with no additional risks for osteoporosis experienced acute lumbosacral pain two months postpartum, while lactating. After conservative therapy, thoracic and lumbar spine were X-rayed: severe pregnancy-associated osteoporosis with vertebral fractures was diagnosed. 2-year treatment with i. v. bisphosphonate ibandronate was initiated (2 mg every 3 months) and calcium and vitamin D supplementation. RESULTS: Rapid improvement was observed. Conclusion: In cases with multiple fractures i. v. bisphosphonate leads to substantial decrease of symptoms and further fractures and significant increase of bone mass density (BMD). CONCLUSION: In severe cases of pregnancy-associated osteoporosis with multiple fractures i. v. biphosphonate therapy leads to a decrease of symptoms and fracture risk and an increase of bone mass density (BMD).