Bone density

Calcium, vitamin D failed to halt BMD loss in breast cancer.

Posted by

0


Calcium plus vitamin D supplements are often suggested for patients at risk for osteoporosis and in women undergoing breast cancer treatment, but a recent analysis published in Critical Reviews in Oncology/Hematologyhighlights the insignificant data behind this methodology.

“We evaluated clinical trial evidence for calcium and vitamin D supplementation in maintaining skeletal health of women with breast cancer,” Gary G. Schwartz, PhD, a cancer epidemiologist at Wake Forest Baptist Medical Center in Winston-Salem, N.C., said in a press release. “At the doses recommended, the data show that these supplements are inadequate to prevent loss of [bone mineral density].”

Of 16 trials, researchers found that none of them evaluated calcium plus vitamin D supplements vs. no supplements in preventing BMD loss in women with breast cancer. Additionally, researchers reported inadequacies in the prevention of BMD loss when doses of 500 mg to 1,500 mg calcium and 200 IU to 1,000 IU vitamin D per day were administered among pre- and postmenopausal women with breast cancer.

However, exercise or pharmacologic interventions could prevent BMD loss in this patient population when such supplementation is not effective, researchers wrote. The researchers added that controversial literature exists regarding the risk for cardiovascular disease with the use ofcalcium supplements.

“The take-home message is that this very common practice of supplementation doesn’t really seem to be working,” Schwartz said. “Future trials are needed to evaluate the safety and efficacy of calcium and vitamin D supplementation in women undergoing breast cancer therapy.”

Source: Endocrine Today.

 

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.

Posted by

0


Background
Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis.
Methods
We did a multicentre trial in two phases. We enrolled patients aged 5—30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3—6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551.
Findings
We screened 540 patients and enrolled 171 (mean age 13•8 years, SD 5•9, range 5—30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16•3% in the alendronate group (n=65) versus 3•1% in the placebo group (n=63; p=0•0010). 19 of 57 young people (33•3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events.
Interpretation
Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density.
Source: Lancet

Combined Teriparatide and Denosumab Is More Effective Than Either Drug Alone.

Posted by

0


Bone-mineral density was increased significantly by combination therapy in postmenopausal women with high fracture risk.

 

Bisphosphonate therapy, the first-line treatment for patients with osteoporosis, usually doesn’t restore normal bone-mineral density (BMD) and sometimes is not well-tolerated. Teriparatide (Forteo; a parathyroid hormone analog that stimulates bone formation when injected daily) and denosumab (Prolia; a long-acting injectable agent that inhibits bone resorption) are approved for treating patients with osteoporosis and high fracture risk. Combinations of bisphosphonates with teriparatide have proven to be no more effective than either agent alone, but the combination of teriparatide and denosumab has not been studied.

In a partially industry-funded study, investigators randomized 100 postmenopausal women at high risk for fracture to receive teriparatide (20 µg subcutaneously daily), denosumab (60 mg subcutaneously every 6 months), or both for 1 year. At 12 months, BMD increased significantly more in the combination group than in the monotherapy groups at the lumbar spine (9.1% vs. 6.2% and 5.2%, respectively) and at the hip. Serious adverse events in all three groups were deemed to be unrelated to study treatments.

Comment: Although only indirect comparisons can be made, combination teriparatide and denosumab seems to increase BMD more than other approved therapies do. However, this combination would need to substantially improve clinical outcomes — not just surrogate markers — to justify its very high cost (about US$9000 annually, compared with $100 annually for alendronate). Although BMD is a reliable predictor of fractures, in future studies, researchers will need to assess directly the effects of combination teriparatide and denosumab on fractures and its long-term safety.

 

Source: Journal Watch General Medicine

 

 

Calcium, vitamin D supplements failed to prevent BMD loss.

Posted by

0


Calcium and vitamin D supplementation during androgen deprivation therapy did not prevent loss of bone mineral density among men with prostate cancer, according to study results.

Bone mineral density (BMD) loss is an adverse effect of ADT for men with prostate cancer. Doctors routinely recommend 500 mg to 1,000 mg calcium and 200 IU to 500 IU vitamin D per day as a supplement, according to background information in the study.

“Calcium and/or vitamin D supplementation to prevent loss of bone mineral density in these men seems so logical that no one had questioned whether it works,” Mridul Datta, PhD, a postdoctoral fellow at Wake Forest Baptist Medical Center, said in a press release.

Datta and colleagues reviewed guidelines for calcium and vitamin D supplementation.

They also analyzed the results of 12 clinical trials that evaluated a combined 2,399 men with prostate cancer who were undergoing ADT. Those trials compared the effects of calcium supplements, vitamin D supplements and other drugs on BMD.

Only one of the 12 trials showed an increase in BMD in the lumbar spine (0.99% in 12 months). The largest decrease in BMD in the lumbar spine was –4.9% in 12 months.

The trial results indicated that calcium supplementation of about 500 mg to 1,000 mg and vitamin D supplementation of 200 IU to 500 IU did not prevent BMD loss.

“It wouldn’t be so bad if there were simply no obvious benefit,” researcher Gary G. Schwartz, PhD, MPH, associate professor in the departments of cancer biology, urology, and epidemiology and prevention at Wake Forest Baptist Medical Center, said in the release. “The problem is that there is evidence that calcium supplements increase the risk of cardiovascular disease and aggressive prostate cancer, the very disease that we are trying to treat.”

Further studies are needed to evaluate the safety and efficacy of calcium and vitamin D supplementation in this patient population, the researchers wrote.

“Clinical trials to determine the risk-benefit ratio of calcium and vitamin D supplementation in men undergoing ADT for prostate cancer are urgently needed,” they concluded.

Source: Endocrine Today.

Bone is a plastic tissue .

Posted by

0


Decades ago, medical school final exams took the form of essays rather than the current multiple choice questions. For the histology finals, I selected the topic “Bone is a plastic tissue.” I knew absolutely nothing about the skeleton other than it was brittle and broken. It turns out that not only was I wrong but I knew as little about it as the professors: for the one and only time in medical school, I topped the class.

Bone is clearly a plastic tissue subject to modeling during growth and development and remodeling shortly after epiphyseal closure. The most common skeletal disease resulting from altered remodeling is osteoporosis in which resorption outstrips formation. Monitoring resorption and formation — measures of total skeletal metabolism — is overlooked in favor of monitoring bone mineral density — measures of regional, not total, skeletal status.

Why bring this up now?

A PubMed search for the last 10 years returned 35,121 citations (275 meta-analyses) for “bone density” and 13,162 citations (28 meta-analyses) for “bone turnover markers”. There is clearly no shortage of peer-reviewed literature regarding bone turnover markers, but there is so much variability in those 13,162 citations that meaningful consensus data is lacking.

You don’t need reminding that adherence to oral medications for osteoporosis is low, and not that great for injectable (subcutaneous or IV) therapies. Several studies have examined the use of markers to improve medication adherence but, to my knowledge, none of them have found markers to be useful in maintaining compliance with therapy.

Bone turnover markers have no role in determining which patient is a candidate for osteoporosis therapy and have not had much effect on patient adherence to therapy. My own practice is to measure markers as I recommend the patient start therapy and re-check markers after 6 months of therapy to both monitor that the therapy is effective and that the patient is adherent to therapy. My success rate in the latter is no better than reported in the literature.

I repeat measurement of markers when serial measurement of BMD indicates that BMD is no longer increasing. Ongoing use of osteoporosis therapies is safe for the vast majority of patients in whom BMD has plateaued, but there is increasing awareness of atypical femoral shaft fractures in a small minority of patients on long-term antiresorptive therapy. With that in mind, I interrupt therapy in patients with stable BMD, where bone turnover markers are in the bottom quartile of the reference interval. I re-check them at 6 monthly intervals until the values get to the top half of the reference interval, at which time therapy is re-started. That happens infrequently. When allowed by insurance coverage, I repeat BMD measurement after 1 year off therapy but have yet to see a patient in whom BMD has declined during that year. I cannot recall a patient in whom an uptick in remodeling has not occurred within 2 years without antiresorptive therapy and use that as an indication to re-start treatment.

Which markers to use? My preference is or serum CTX (resorption) and P1NP (formation) because patients are never in a hurry to provide a 24-hour urine collection or even a fasting urine sample.

Much has been written about the diurnal variation of biochemical markers of bone remodeling and the intra- and interassay variability. These are specious arguments against serial measurements of bone turnover markers. Firstly, when remodeling is suppressed as a result of therapy, even 50% variability in markers (it is not that variable) does not move many patients from one quartile to another. Secondly, there are many laboratory tests in which the variability is the same or even worse than for bone turnover markers. That has not stopped any clinician I know from continuing to order and rely on those results.

The bottom line — patient adherence to therapy tests our skills as clinicians every day. Asking a patient to wait 2 years to see if the therapy we prescribe is effective or not makes little sense to me.

Michael Kleerekoper, MD, MACE, has joined the faculty at the University of Toledo Medical School where he is Professor in the Department of Internal Medicine and section chief of the Endocrinology Division. The author of numerous journal studies, Dr. Kleerekoper serves on the editorial boards for Endocrine Today, Endocrine Practice, Journal of Clinical Densitometry, Journal of Women’s Health, Osteoporosis International and Calcified Tissue International. Dr. Kleerekoper is also a founding board member of the newly formed Academy of Women’s Health.

Source: Endocrine Today.

 

Expansile, lytic and hypermetabolic bone lesions not always metastatic cancer .

Posted by

0

A 44-year-old man was referred for evaluation of hypercalcemia. He had atraumatic rib and clavicle fractures in the setting of marked hypercalcemia and symptomatic nephrolithiasis.

His medical history included chronic kidney disease due to obstructive bilateral hydronephrosis and coronary artery disease requiring multiple percutaneous coronary interventions. His symptoms, consistent with hypercalcemia, included polyuria, nocturia, malaise, muscle weakness, depression and early morning nausea. He had no family history of endocrine disease. Physical examination was remarkable for widespread nonspecific bony tenderness on deep palpation. Proximal muscle weakness was prominent, including an inability to rise from a crouched position or walking up a step without aid. Thyroid and neck examination were unremarkable.

His serum calcium levels ranged from 10.9 mg/dL to 13.3 mg/dL during the previous year, with corresponding intact parathyroid (PTH) between 3,111 pg/mL and 4,023 pg/mL. His 25-hydroxyvitamin D level was 23 ng/mL. Serum phosphorus level was suppressed to 2 mg/dL, and serum creatinine trended up from 1.5 mg/dL to 2.2 mg/dL.

His markers of bone turnover were very elevated, with an alkaline phosphatase of 1,344 units/L (reference: 25-100 units/L), spot urinary N-telopeptide of 311 nmol/mmol (reference: 9-60 nmol/mmol) and serum osteocalcin .300 ng/mL (reference: 9-38 ng/mL).

Extensive imaging studies were performed for the presumed diagnosis of pathological fractures. An 18F-fluorodeoxyglucose (FDG) PET/CT scan revealed hypermetabolic lesions corresponding to expansile and lytic regions in multiple ribs, vertebral bodies, iliac bones, pubic rami, acetabulum and right clavicle (Figures 1 and 2). Axial DXA bone mineral density scan showed osteopenia at both the lumbar spine (T-score –2.2) and femoral neck (T-score –2.2), and the distal radius showed marked bone loss (T-score –6.9) demonstrating preferential cortical bone loss from hyperparathyroidism (HPT). A bone biopsy of one of the larger lesions was performed with pathology consistent with osteitis fibrosa cystica (OFC).

A diagnosis of primary HPT was established with elevated PTH and calcium levels with nephrolithiasis, chronic kidney disease, osteoporosis and OFC with pathological multisite fractures.

Initial 99-technetium sestamibi PTH scan at an outside hospital was non-localizing, but when repeated with mediastinal views, abnormal uptake in the anterior mediastinum was seen, consistent with a 5-cm mediastinal PTH adenoma or carcinoma.

OFC was once the dominant clinical manifestation of primary HPT. With modern improvement in laboratory testing and early diagnosis, OFC has become exceedingly rare but is still seen in the developing world. Friedrich Daniel Von Recklinghausen is credited with describing the first case of OFC in 1891; however, the association with parathyroid disease was noted by Askanazy in 1904. OFC is also known as Recklinghausen’s disease of bone. The more severe cystic changes seen in OFC have been termed “brown tumors.” Histologically, these “tumors” are highly vascular and are composed of clusters of giant cells in a background of mononuclear or spindle cells with hemosiderin. OFC is characterized by PTH-mediated increase in osteoclast activity, peritrabecular fibrosis and “tunneling” resorption of trabeculae, which leads to the cystic changes and expansile, lytic features noted on imaging.

Cortical, rather than trabecular, bone loss is more prominent due to the anabolic effect of PTH on trabecular bone. However, in severe long-standing cases, trabecular bone is not spared and osteoporosis at axial skeletal sites is common. In severe forms of the disease, marked skeletal deformity, minimal trauma fractures and bony pain may result in severe disability. Primary HPT with osteoporosis or OFC would warrant surgical resection of the parathyroid adenoma, given the risk for progressive bone remodeling, fractures and potential skeletal deformity.

A case series of 51 patients in India with primary HPT and OFC were followed after parathyroidectomy with an intention to measure bone recovery postoperatively. BMD recovery was impressive and occurred early (within 1 week) and was more prominent in trabecular bone than cortical bone sites. Bone pain improved in 71% of patients. Despite improvements in BMD after surgery, re-mineralization was not universal at all bone sites and many patients never regained normal BMD after 4 years of follow-up. Brown tumors and skeletal deformity improved overall; however, radiological deformity persists and may require corrective surgery.

OFC is an increasingly uncommon presentation of primary hyperparathyroidism. The diagnosis should be suspected in patients with pathological fractures and hypercalcemia. Appropriate surgical removal of the causative parathyroid tumor has early and positive benefits on bone health, but the most severe form of HPT osteodystrophy, brown tumors or OFC, may not structurally return to normal and continue to be at an increased risk for fracture.

References:
  • Agarwal G. Surgery. 2002;132:1075-1083.
  • Kearns AE. Mayo Clin Proc. 2002;77:87-91.
  • Pai M. Clin Nucl Med.1997;22:691-694.

 

Source: the Oncologist.